Others titles

NGC Guideline Summaries
Evidence-based Clinical Practice Guidelines
Guidline Summaries by Clinical Speciality
Guidline Summaries by Category
Guidline Summaries by Intended Users

Keywords

Clinical Guidelines
Practice Guidelines
Guideline Attributes
Inclusion Criteria
Guideline Summary
MESH Terminology

Clinical Practice Guideline Summaries

Name: Clinical Practice Guideline Summaries
Creator: John Snow Labs

This dataset contains summaries of evidence-based clinical practice guidelines. Clinical practice guidelines are statements that include recommendations intended to optimize patient care that is informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options.

Complexity

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Description

National Guideline Clearinghouse (NGC) provides structured summaries containing information from clinical practice guidelines. NGC is an initiative of the Agency for Healthcare Research and Quality (AHRQ),U.S. Department of Health and Human Services.

NGC supports AHRQ’s mission to produce evidence to make health care safer, higher quality, more accessible, equitable, and affordable by providing objective, detailed information on clinical practice guidelines, and to further their dissemination, implementation, and use in order to inform health care decisions.

NGC uses a systematic approach to decide when it is appropriate to include author, year citations in the Major Recommendations field and full citations in the References Supporting the Recommendations field. Two criteria drive the decision-making process: (1) the recommendations are explicitly stated, and (2) those explicit statements are referenced. The first criterion means that the recommendations in the guideline document are easily identified, stand-alone and action-oriented statements. Explicit recommendation statements are not interspersed among rationale in the guideline document. The rationale for the recommendations may be provided in sections before or after the actual recommendations but not within the same body of content as the recommendations. The second criterion means that the reference(s) supporting the explicit recommendation is (are) provided at the end of the statement. References cited in the rationale for the recommendation are not captured.

NGC’s master’s level indexers apply terms from selected UMLS vocabularies to each guideline summary to facilitate searching and browsing and to create relationships between similar documents. These vocabularies are:
-Healthcare Common Procedure Coding System (HCPCS)
-International Classification of Diseases – Clinical Modification (ICD-9-CM)
-Medical Subject Headings (MeSH)
-Physician Data Query (PDQ)
-Standard Product Nomenclature (SPN)
-Systemized Nomenclature of Medicine (Clinical Terms) (SNOMED CT)
-UMLS Metathesaurus (MTH)
-Universal Medical Device Nomenclature System (UMDNS)

As part of the NGC Annual Verification, many guidelines are withdrawn from the Web site at the end of every year because they no longer meet the Inclusion Criteria with respect to date. NGC’s inclusion criteria specifically require that guidelines represented in their database have been developed, reviewed, or revised within the last five years. All guidelines that no longer meet this criterion are removed from the Web site at the end of each calendar year.

About this Dataset

Data Info

Date Created	1997
Last Modified	2018-07-02
Version	2018-07-02
Update Frequency	Never
Temporal Coverage	N/A
Spatial Coverage	N/A
Source	John Snow Labs; National Guideline Clearinghouse (NGC);
Source License URL
Source License Requirements	N/A
Source Citation	N/A
Keywords	Clinical Guidelines, Practice Guidelines, Guideline Attributes, Inclusion Criteria, Guideline Summary, MESH Terminology
Other Titles	NGC Guideline Summaries, Evidence-based Clinical Practice Guidelines, Guidline Summaries by Clinical Speciality, Guidline Summaries by Category, Guidline Summaries by Intended Users

Data Fields

Name	Description	Type	Constraints
Guideline_ID	The Guideline unique identifier	integer	required : 1level : Nominal
Guideline_Title	Identifies the complete title of the guideline.	string	required : 1
Bibliographic_Sources	Identifies the complete bibliographic source(s) for the published guideline as disseminated by the guideline developer(s). The number of references cited is included for each source.	string	-
Guideline_Status	Identifies the current status of the summary including whether the guideline is an updated version of a previously issued document, whether an update is in progress, and whether the guideline meets the 2013 (revised) inclusion criteria.	string	-
Regulatory_Alert	Identifies important warnings and/or revised regulatory information released by the U.S. Food and Drug Administration (FDA) or other official regulatory body for a drug and/or device for which recommendations are provided in the original guideline document.	string	-
Scope_Disease_Conditions	Identifies the major areas of clinical medicine or health care addressed in the guideline. Values are expressed using the natural language expressions found in the text of the guideline.	string	-
Scope_Other_Disease_Conditions	Indicates the presence of multiple chronic conditions by listing co-existing or comorbid chronic diseases or conditions for which specific recommendations are provided.	string	-
Scope_Guideline_Category	Classifies the major focus of the guideline. Values are selected from the appropriate concepts in the Classification Scheme.	string	-
Scope_Clinical_Speciality	Classifies the clinical specialties that might use the guideline professionally. Values are selected from the appropriate concepts in the Classification Scheme.	string	-
Scope_Intended_Users	Classifies the groups intended to use the guideline. Values are selected from the appropriate concepts in the Classification Scheme.	string	-
Scope_Guideline_Objectives	Describes the objectives of the guideline as specified in the original guideline document.	string	-
Scope_Target_Population	Describes the target population(s) addressed in the guideline.	string	-
Scope_Interventions_and_Practices_Considered	Identifies the specific clinical interventions and practices considered in the guideline. Values are expressed using natural language expressions found in the text of the guideline.	string	-
Scope_Major_Outcomes_Considered	Describes the most important specific outcomes or performance measures considered in the guideline. Includes patient outcomes described in treatment guidelines and diagnostic test performance characteristics described in diagnosis or screening guidelines.	string	-
Methodology_Evidence	Classifies the methods used to collect and select the evidence that were evaluated. Values are selected from the appropriate concepts in the Classification Scheme.	string	-
Methodology_Description_Evidence	Describes/summarizes the specific methods used to collect and select the evidence, as identified in the text of the guideline or by the guideline developer. Can include detailed search strategies, lists of journals scanned, keywords, database sources, inclusion and exclusion criteria, etc.	string	-
Methodology_Number_of_Documents	Identifies the number of source documents that were identified by the methods described above under "Methodology_Description_Evidence".	string	-
Methodology_Quality_and_Strength_Evidence	Classifies the methods used by the guideline developer to determine what relative importance to give the evidence they obtained. Values are selected from the appropriate concepts in the Classification Scheme.	string	-
Methodology_Rating_Scheme_Evidence	Presents the rating scheme for strength of evidence, when given.	string	-
Methodology_Analysis	Classifies the methods used by the guideline developer to evaluate the data in the evidence they obtained. Values are selected from the appropriate concepts in the Classification Scheme.	string	-
Methodology_Description_Analysis	Describes the methods used to analyze the evidence. Presents additional definition for the values presented under "Methodology_Analysis" (for example, defines "systematic" or summarizes the details of the meta-analyses).	string	-
Methodology_Recommendations	Identifies the methods used to translate evidence into statements that will assist practitioners and patients in making decisions about appropriate health care for specific clinical circumstances. Values are selected from the appropriate concepts in the Classification Scheme.	string	-
Methodology_Description_Recommendations	Captures the details of the methods used to translate evidence into recommendation statements. Issues considered by the guideline developers during recommendation formulation such as cost, patient preference, and values, are also captured.	string	-
Methodology_Rating_Scheme_Recommendations	Captures the weighted scheme used by the guideline developer to determine what relative strength or importance to give to the recommendations being made.	string	-
Methodology_Cost_Analysis	Describes any formal cost analysis performed and any published cost analyses reviewed.	string	-
Methodology_Guideline_Validation	Lists the method(s) used to validate the recommendations of the guideline.	string	-
Methodology_Description_Guideline_Validation	Captures the details of the method(s) used by the guideline developer to validate the guideline.	string	-
Recommendations_Major	Identifies the major recommendations of the guideline.	string	-
Recommendations_Clinical_Algorithms	Identifies the recommendations expressed in the form of clinical algorithm(s) and where the algorithm(s) are provided	string	-
Supporting_Recommendations_References	Lists the references of evidence supporting the recommendations when applicable. This field opens in a new window and PubMed links are provided when available.	string	-
Supporting_Recommendations_Evidence_Type	Describes the type of evidence supporting the recommendations.	string	-
Implementing_Recommendations_Potential_Benefits	Describes the anticipated benefits associated with implementing the guideline's recommendations. When applicable, the field also includes information on the major subgroup(s) of patients within the target population most likely to benefit from the guideline recommendations.	string	-
Implementing_Recommendations_Potential_Harms	Description of the anticipated harms, potential risks or adverse consequences associated with the guideline's recommendations, as stated in the guideline text, to target populations or intended users.	string	-
Contraindications	Identifies the instances (e.g., co-morbidities) that might render the use of medications or procedures improper, undesirable, or inadvisable.	string	-
Qualifying_Statements	Presents qualifying statements or important caveats pertaining to the major recommendations of the guideline. Identifies areas of uncertainty and presents a brief description of how the guideline developer addressed this uncertainty in developing the recommendations.	string	-
Guidelines_Implementation_Strategy	Describes specific strategies, aims, performance measures, or plans for implementing the guideline recommendations.	string	-
Guidelines_Implementation_Tools	Identifies the types of implementation tools provided by the guideline developer to facilitate the implementation of the guideline. Values are selected from the appropriate concepts in the Classification Scheme	string	-
Guidelines_Implementation_NQMC_Measures	Identifies link(s) to related quality measures in the National Quality Measures Clearinghouse™ (NQMC).	string	-
IOM_Care_Need	Classifies the guideline into one of four Institute of Medicine (IOM) care need classifications: End of life care; Getting better; Living with illness; Staying healthy.	string	-
IOM_Domain	Classifies the guideline into one or more of the four Institute of Medicine (IOM) care domains: Effectiveness; Patient-centeredness; Safety; Timeliness.	string	-
Information_Adaptation	Identifies that the guideline has been adapted from another guideline and identifies the source document.	string	-
Information_Date_Released	Identifies the date the guideline was released to the public.	string	-
Information_Guideline_Developers	Identifies the organization(s) responsible for the development of the guideline.	string	-
Information_Guideline_Developers_Comment	If the guideline developer is a consortium or represents a group of organizations, this field identifies the individual organizations by name.	string	-
Information_Source_Funding	Identifies source(s) of financial support for guideline development, as identified in the guideline text or by the guideline developer. Lists any gran numbers associated with funding, as identified in the guideline text or by the guideline developer.	string	-
Information_Guideline_Committee	Identifies formal name, if any, of committee/subcommittee within the guideline developer organization(s) responsible for developing the guideline.	string	-
Information_Guideline_Author_Group	Describes the composition of the group/committee that authored the guideline, including professional degrees and affiliations, and lists the names of individual committee members, where given.	string	-
Information_Conflicts_of_Interest	Captures relationships between individuals of the guideline development committee/group and for-profit and not-for-profit companies or organizations that could potentially influence that individual's contribution to the guideline's development.	string	-
Information_Endorsers	Identifies organization(s) that have endorsed the guideline. Each organization is classified by the major designation or function (derived from the Organization Type attribute), such as "Medical Specialty Society" or "Professional Association."	string	-
Information_Guideline_Availability	Identifies information about the availability of the guideline. Provides links to the full-text document and ordering information for print copies.	string	-
Information_Companion_Document_Availability	Identifies the companion documents produced by the guideline developer that are considered relevant to the guideline.	string	-
Information_Patient_Resources	Identifies patient resources that are directly related (i.e., derived and/or prepared from the guideline by the guideline developer) to the guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.	string	-
Information_NGC_Status	Identifies when the guideline was completed or revised by ECRI Institute, and verified by the developing organization(s).	string	-
Information_Copyright_Statement	Provides the copyright statement of the organization that submitted the guideline.	string	-
NGC_Disclaimer	Provides disclaimer information about the relationship between NGC (including its sponsor, the Agency for Healthcare Research and Quality (AHRQ), and its contractor, ECRI Institute) and the guidelines and guideline developers represented on the Web site.	string	-

Data Preview

Guideline ID

Guideline Title

Bibliographic Sources

Guideline Status

Regulatory Alert

Scope Disease Conditions

Scope Other Disease Conditions

Scope Guideline Category

Scope Clinical Speciality

Scope Intended Users

Scope Guideline Objectives

Scope Target Population

Scope Interventions and Practices Considered

Scope Major Outcomes Considered

Methodology Evidence

Methodology Description Evidence

Methodology Number of Documents

Methodology Quality and Strength Evidence

Methodology Rating Scheme Evidence

Methodology Analysis

Methodology Description Analysis

Methodology Recommendations

Methodology Description Recommendations

Methodology Rating Scheme Recommendations

Methodology Cost Analysis

Methodology Guideline Validation

Methodology Description Guideline Validation

Recommendations Major

Recommendations Clinical Algorithms

Supporting Recommendations References

Supporting Recommendations Evidence Type

Implementing Recommendations Potential Benefits

Implementing Recommendations Potential Harms

Contraindications

Qualifying Statements

Guidelines Implementation Strategy

Guidelines Implementation Tools

Guidelines Implementation NQMC Measures

IOM Care Need

IOM Domain

Information Adaptation

Information Date Released

Information Guideline Developers

Information Guideline Developers Comment

Information Source Funding

Information Guideline Committee

Information Guideline Author Group

Information Conflicts of Interest

Information Endorsers

Information Guideline Availability

Information Companion Document Availability

Information Patient Resources

Information NGC Status

Information Copyright Statement

NGC Disclaimer

10000

Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma).

Dearden C, Johnson R, Pettengell R, Devereux S, Cwynarski K, Whittaker S, McMillan A. Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma). London (UK): British Committee for Standards in Haematology (BCSH); 2013 Aug. 99 p. [359 references]

This is the current release of the guideline. This guideline updates a previous version: Dearden C, Johnson R, Pettengell R, Devereux S, Cwynarski K, Whittaker S, McMillan A, British Committee for Standards in Haematology. Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma). Br J Haematol. 2011 May;153(4):451485.

Mature T-cell and natural killer (NK)-cell neoplasms (excluding cutaneous T-cell lymphoma)

Diagnosis;Evaluation;Management;Risk Assessment;Treatment

Dermatology;Hematology;Internal Medicine;Medical Genetics;Oncology;Pathology;Radiation Oncology;Radiology

Advanced Practice Nurses;Physician Assistants;Physicians

To provide healthcare professionals with clear guidance on the management of patients with mature T-cell and natural killer (NK)-cell neoplasms

Patients with mature T-cell and natural killer (NK)-cell neoplasms (excluding cutaneous T-cell lymphoma) Note: The guidance may not be appropriate to all patients in this disease group.

Diagnosis/Evaluation Expert examination of tissue including a detailed phenotypic assessment Blood and bone marrow examination Radiology Assessment of performance status and prognostic factors using the International Prognostic Index (IPI) or other scoring system Lumbar puncture (not routinely recommended) Magnetic resonance imaging (MRI) (not routinely recommended) Positron emission tomography (not routinely recommended) Demonstration of Epstein-Barr virus (EBV) Prevention Antimicrobial prophylaxis Central nervous system (CNS) prophylaxis Treatment Intravenous alemtuzumab Purine analogue (pentostatin) Autologous or allogeneic stem cell transplantation Oral ciclosporin Oral low-dose methotrexate Growth factors (erythropoietin, granulocyte colony stimulating factor [G-CSF]) Cyclophosphamide Anti-retroviral therapy (zidovudine, interferon-, monoclonal antibodies) Cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other multi-agent regimen + G-CSF Novel agents (e.g., arsenic trioxide) Fludarabine + cyclophosphamide (FC) Entry of patients into clinical trials when possible Immunomodulatory therapy (steroids, ciclosporin, thalidomide, lenalidomide) Radiotherapy Local excision Salvage therapy with brentuximab vedotin Etoposide- or asparaginase-based chemotherapy Autograft Nutrition considerations Note: There are insufficient data to recommend novel agents such as gemcitabine, bendamustine, pralatrexate, and romidepsin.

Effectiveness of diagnosis and staging, according to clinical, haematologic, cytogenetic, pathologic and imaging features of disease Predictive value of prognostic tests Efficacy and effectiveness of treatments (e.g., measured by response rate, duration of response, remission rate, disease progression and survival) Treatment-related toxicity

Searches of Electronic Databases

The production of the guidelines involved review of key literature in English, including MedLine, EMBASE and Internet searches up to December 2012.

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Quality of Evidence The quality of evidence is graded as high (A), moderate (B) or low (C). To put this in context it is useful to consider the uncertainty of knowledge and whether further research could change what is known or is certain. (A) High Further research is very unlikely to change confidence in the estimate of effect. Current evidence derived from randomised clinical trials without important limitations. (B) Moderate Further research may well have an important impact on confidence in the estimate of effect and may change the estimate. Current evidence derived from randomised clinical trials with important limitations (e.g., inconsistent results, imprecision wide confidence intervals or methodological flaws e.g., lack of blinding, large losses to follow up, failure to adhere to intention to treat analysis), or very strong evidence from observational studies or case series (e.g., large or very large and consistent estimates of the magnitude of a treatment effect or demonstration of a dose-response gradient). (C) Low Further research is likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate. Current evidence from observational studies, case series, or just opinion.

Review of Published Meta-Analyses;Systematic Review with Evidence Tables

Expert Consensus

Strength of Recommendations Strong (grade 1): Strong recommendations (grade 1) are made when there is confidence that the benefits do or do not outweigh harm and burden. Grade 1 recommendations can be applied uniformly to most patients. Regard as 'recommend'. Weak (grade 2): Where the magnitude of benefit or not is less certain a weaker grade 2 recommendation is made. Grade 2 recommendations require judicious application to individual patients. Regard as 'suggest'.

A formal cost analysis was not performed and published cost analyses were not reviewed.

Not stated

Not applicable

Definitions for the quality of the evidence (AC) and strength of recommendations (strong [grade 1], weak [grade 2]) are given at the end of the "Major Recommendations" field. Diagnosis and Staging Diagnosis requires expert examination of tissue including a detailed phenotypic assessment. Clonality should be assessed by polymerase chain reaction (PCR) for T-cell receptor (TCR) gene rearrangements. This is the subject of a separate British Committee for Standards in Haematology (BCSH) guideline. Staging should include blood and bone marrow examination and radiology as well as assessment of performance status and prognostic factors to allow assignment of a prognostic score and planning of therapy. Lumbar puncture/magnetic resonance imaging (MRI) of brain is not routinely required in the absence of central nervous system (CNS) symptoms or signs. Positron emissions tomography (PET) scanning is not established in the routine staging of peripheral T-cell lymphoma (PTCL). The T-cell malignancies are rare and often complex diseases. Diagnosis and management should be discussed in a network multi-disciplinary team meeting and those patients requiring treatment should generally be referred to a cancer centre or tertiary centre with specialist expertise. Prognosis The International Prognostic Index (IPI) gives useful prognostic information in PTCL and should be calculated, but it clusters many cases in the higher risk groups. Newer T-cell specific prognostic scores appear to be more discriminatory and may be valuable in prospective trials. Mature T-cell Leukaemias T-prolymphocytic Leukaemia (T-PLL) Intravenous alemtuzumab should be used as first line therapy for T-PLL (Grade 1B). Patients failing to respond should receive the combination of alemtuzumab plus pentostatin or another purine analogue (Grade 1C). All eligible patients should proceed to either autologous or allogeneic stem cell transplant in first remission (Grade 1C). Patients should be entered into clinical trials wherever possible. T-large Granular Lymphocytic Leukaemia (T-LGL) Patients do not require therapy unless symptomatic from cytopenias or other complications. The majority of cases will follow an indolent course and aggressive chemotherapy is not indicated. The decision to treat is based on: significant symptomatic anaemia (9 g/dl) and/or the need for transfusion; severe neutropenia (0.5 x109/l) associated with infection; severe thrombocytopenia (50 x 109/l); or any combination of these. Oral ciclosporin or weekly oral low dose methotrexate (10 mg/m2/week) are effective in more than 75% of cases (Grade 1B). Responses may be enhanced by the use of growth factors (erythropoietin and/or granulocyte colony stimulating factor [G-CSF] (Grade 1B). Second line treatments include purine analogues (pentostatin), cyclophosphamide and alemtuzumab (Grade 1B). Chronic Lymphoproliferative Disease of Natural Killer (NK) Cells (CLPD-NK) Management same as for T-LGL. Aggressive NK-cell Leukaemia Rare aggressive NK-cell leukaemias occurring in younger adults require a different therapeutic approach and consideration of stem cell transplantation (Grade 2C). Patients should be entered into clinical trials wherever possible. Adult T-cell Leukaemia Lymphoma (ATL) Exclude co-infection with strongyloides prior to commencing therapy. Appropriate antimicrobial prophylaxis during therapy should be instituted for seropositive patients. Smouldering and chronic: No benefit from early chemotherapy therefore watch and wait Zidovudine (ZDV) + Interferon (IFN) +/- monoclonal antibodies (MoAbs) may be considered (especially in chronic ATL) in the context of a clinical trial (Grade 1B). Lymphoma type: Induction with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or alternative multi-agent regimen plus G-CSF (Grade 1B) with concurrent ZDV + IFN (Grade 1B) ZDV + IFN maintenance +/- MoAbs OR Allogeneic transplant in 1st complete remission (CR) for eligible patients (Grade 2C) Leukaemia (acute) type: Induction with anti-retroviral therapy alone (ZDV + IFN) OR Induction with CHOP or alternative multi-agent regimen plus G-CSF (Grade 1B) + concurrent ZDV + IFN Allogeneic haemopoietic stem cell transplantation (allo-HSCT) in 1st CR for eligible patients (Grade 1B) OR ZDV + IFN maintenance +/- MoAbs (Grade 2C) OR Consolidation with novel agents (e.g., arsenic trioxide, IFN); proteasome inhibitor in clinical trials CNS prophylaxis should be considered using the same criteria as for diffuse large B-cell non-Hodgkin lymphoma (NHL) (Grade 2C). Nodal PTCL PTCL, Not Otherwise Specified (PTCL-NOS) Primary treatment of PTCL-NOS should be within the context of a clinical trial if possible as standard therapy gives disappointing results (Grade 1B). Outside trial, CHOP remains the standard therapy. Consideration should be given to consolidation with autologous haemopoietic stem cell transplantation (auto-HSCT) (Grade 2B). Relapsed or refractory disease should be treated with relapse-schedule combination chemotherapy and considered for allo-HSCT with reduced intensity conditioning (Grade 2B) or autologous stem cell transplantation (Grade 2B) or novel therapies within a trial setting. Outside a trial a number of agents show promise, particularly gemcitabine, bendamustine, pralatrexate and romidepsin but the data are insufficient to recommend routine use. CNS prophylaxis should be considered using the same criteria as for diffuse large B-cell NHL (Grade 2C). Angio-immunoblastic T-cell Lymphoma (AITL) The timing and selection of therapy depend on clinical presentation and prognostic features. Patients requiring therapy should be entered into available clinical trials where possible. Outside a clinical trial, CHOP or fludarabine + cyclophosphamide (FC) would be considered as standard therapies (Grade 1B). Immunomodulatory therapies such as steroids, ciclosporin, thalidomide and lenalidomide have some evidence of efficacy in chemo-refractory cases (Grade 2B). Consolidation with auto-HSCT should be considered for patients with chemosensitive disease in first remission or after relapse (Grade 2B). Routine CNS prophylaxis is not warranted. Anaplastic Large Cell Lymphoma (ALCL) The IPI has predictive value in ALCL but anaplastic lymphoma kinase (ALK) positivity is the most important prognostic factor. Patients with limited stage anaplastic large cell lymphoma and no adverse prognostic features by IPI should be treated with 3 to 4 cycles of CHOP chemotherapy and involved field radiotherapy. All other patients should be entered into a clinical trial or receive 6 to 8 cycles of CHOP chemotherapy (Grade 1A). ALK-neg ALCL should be treated as for PTCL-NOS. Primary cutaneous ALCL (ALK-neg) should be managed with local excision +/- radiotherapy and chemotherapy reserved for those patients with systemic disease. At relapse patients should receive platinum-based chemotherapy or an alternative salvage regimen such as brentuximab vedotin and patients with chemosensitive disease should be considered for transplant. Extranodal PTCL Extranodal NK/T-cell Lymphoma, Nasal Type Diagnosis and staging uses the same investigations and techniques as for PTCL-NOS. Demonstration of Epstein-Barr virus (EBV) in the biopsy is important diagnostically. Assigning a conventional IPI score is of limited value as most cases are localised and have a low score, yet the survival is still poor (Grade 1B). The distinction at diagnosis between localised disease and disseminated disease is important as the latter has a dismal prognosis and might be considered for experimental therapy as first line if available (Grade 1B). Assessment of EBV by PCR can be helpful in monitoring disease and may have prognostic relevance. Outcome is unsatisfactory with CHOP-like therapy and entering patients into relevant clinical trials if available is recommended. Patients with localised disease should receive radiation with 5055 Gy (Grade 1B). The value of additional chemotherapy (CHOP, etoposide-based or asparaginase-based) for local disease remains unclear but is considered conventional pending more information (Grade 1B). Asparaginase-containing regimens should be considered in disseminated first-line and in relapsed or refractory disease (Grade 1B). High dose therapy is unproven and there is no basis to recommend it outside a trial. Enteropathy-associated T-cell Lymphoma (EATL) Diagnosis and staging use the same investigations and techniques as for PTCL-NOS. In addition, it is important to liaise with an experienced gastroenterologist to assist with biopsy, staging and follow up and to manage nutritional problems (Grade 1C). Assigning a conventional IPI score is of limited value as there is no good prognostic group and most cases are stage I-IIE. If there are trials available at the time of diagnosis, entry should be strongly considered as there is no satisfactory standard therapy. CHOP-like therapy, with or without an up-front autograft remains a common approach outside a trial and adoption of a more intensive approach such as the National Cancer Research Institute/Scottish and Newcastle Lymphoma Group (NCRI/SNLG) protocol is a reasonable option in fitter patients (Grade 2B). Nutrition is a major issue in managing these patients and dietetic/gastroenterology advice is essential at all stages of treatment and follow-up (Grade 1C). Hepatosplenic T-cell Lymphoma No satisfactory recommendations can be made from the limited evidence base. Trial or experimental therapy should be considered if available. Allogeneic bone marrow transplantation could be considered but the evidence is purely anecdotal. Conventional chemotherapy approaches as for PTCL-NOS are the default and there are some survivors reported in the literature (Grade 2C). Subcutaneous Panniculitis-like T-cell Lymphoma (SPTCL) No conclusive recommendations can be made from the limited evidence base. The cases described in the literature are not uniform. This is not a universally aggressive disease and careful initial assessment and observation should be undertaken before committing to treatment (Grade 2C). CHOP-like chemotherapy appears to be effective and produces survivors (Grade 2C). Relapsed disease may respond to dose intensification in some patients (Grade 2C). Local radiotherapy has a place for good prognosis localised symptomatic skin involvement which does not resolve with topical steroids (Grade 2C). Definitions: Quality of Evidence The quality of evidence is graded as high (A), moderate (B) or low (C). To put this in context it is useful to consider the uncertainty of knowledge and whether further research could change what is known or is certain. (A) High Further research is very unlikely to change confidence in the estimate of effect. Current evidence derived from randomised clinical trials without important limitations. (B) Moderate Further research may well have an important impact on confidence in the estimate of effect and may change the estimate. Current evidence derived from randomised clinical trials with important limitations (e.g., inconsistent results, imprecision wide confidence intervals or methodological flaws e.g., lack of blinding, large losses to follow up, failure to adhere to intention to treat analysis), or very strong evidence from observational studies or case series (e.g., large or very large and consistent estimates of the magnitude of a treatment effect or demonstration of a dose-response gradient). (C) Low Further research is likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate. Current evidence from observational studies, case series or just opinion. Strength of Recommendations Strong (grade 1): Strong recommendations (grade 1) are made when there is confidence that the benefits do or do not outweigh harm and burden. Grade 1 recommendations can be applied uniformly to most patients. Regard as 'recommend'. Weak (grade 2): Where the magnitude of benefit or not is less certain a weaker grade 2 recommendation is made. Grade 2 recommendations require judicious application to individual patients. Regard as 'suggest'.

None provided

The type of supporting evidence is identified and graded for selected recommendation (see the "Major Recommendations" field).

Appropriate management of mature T-cell and natural killer (NK)-cell neoplasms (excluding cutaneous T-cell lymphoma)

Treatment-related toxicity and side-effects

An implementation strategy was not provided.

Getting Better;Living with Illness

Effectiveness;Patient-centeredness

Not applicable: The guideline was not adapted from another source.

2011 May (revised 2013 Aug)

British Committee for Standards in Haematology

British Committee for Standards in Haematology Writing Group

Writing Group Members: C Dearden, The Royal Marsden NHS Foundation Trust, London; R Johnson, St James Hospital, Leeds; R Pettengell, St George's Hospital, London; S Devereux, Kings College Hospital, London; K Cwynarski, Royal Free Hospital, London; S Whittaker, St Johns Institute of Dermatology, London; A McMillan, Nottingham University Hospital NHS Trust, Nottingham

Not stated

Electronic copies: Available from the British Committee for Standards in Haematology Web site. Print copies: Available from the British Committee for Standards in Haematology; Email: bcsh@b-s-h.org.uk.

None available

This NGC summary was completed by ECRI Institute on October 18, 2013.

This NGC summary is based on the original guideline, which is copyrighted by the British Committee for Standards in Haematology. For more information, contact the BCSH Secretary, 100 White Lion Street, London, UK, N1 9PF; Email: bcsh@b-s-h.org.uk.

10001

Management of cytomegalovirus infection in haemopoietic stem cell transplantation.

Emery V, Zuckerman M, Jackson G, Aitken C, Osman H, Pagliuca A, Potter M, Peggs K, Clark A, British Committee for Standards in Haematology, British Society of Blood and Marrow Transplantation, UK Virology Network. Management of cytomegalovirus infection in haemopoietic stem cell transplantation. Br J Haematol. 2013 Jul;162(1):25-39. [146 references] PubMed

This is the current release of the guideline.

Cytomegalovirus infection in haemopoietic stem cell transplantation Note: The guidelines also are relevant to other areas of haematological oncology where there is an increased risk of cytomegalovirus infection, such as haematological cancers where intense anti-T-cell therapy has been deployed.

Diagnosis;Management;Prevention;Treatment

Hematology;Infectious Diseases;Internal Medicine;Medical Genetics;Oncology

Advanced Practice Nurses;Physician Assistants;Physicians

To expand and adapt previous guidance on management of cytomegalovirus infection in haemopoietic stem cell transplantation

Patients with cytomegalovirus infection in haemopoietic stem cell transplantation

Assessment/Diagnosis Diagnosis according to established, internationally accepted criteria Risk-adapted patient assessment Testing for the presence of cytomegalovirus (CMV) immunoglobulin G (IgG) antibody Investigation of CMV seroconversion Optimum human leucocyte antigen (HLA) matching for donors Prevention/Management/Treatment Ganciclovir Aciclovir Valaciclovir Valganciclovir Intravenous immunoglobulin Real-time quantitative polymerase chain reaction (PCR) CMV viral load monitoring Foscarnet Sequence analysis of the UL97 and UL54 genes for drug resistance screening Reduction in immunosuppression

Signs and symptoms of cytomegalovirus (CMV) infection Risk factors of CMV infection (e.g., measured by incidence of transfusion-transmitted CMV infection, incidence of CMV reactivation, incidence of CMV-related complications, survival/mortality) Effectiveness of CMV prevention (e.g., measured by CMV infection, CMV reactivation) Sensitivity and accuracy of diagnostic tests Efficacy/effectiveness of treatments (e.g., measured by response rates, resistance rates, progression to CMV, survival) Treatment-related toxicity

Searches of Electronic Databases

The production of these guidelines involved literature review to 1 May 2012 including Medline, PubMed, and Cochrane reviews databases.

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Review of Published Meta-Analyses;Systematic Review

Expert Consensus

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review;Internal Peer Review

The production of these guidelines involved the following steps: Initial review of manuscript, performed by the UK Clinical virology Network, British Society of Blood and Marrow Transplantation executive committee, and the British Committee for Standards in Haematology (BCSH) Haem-Onc Task Force. Final review by sounding boards of the British Society for Haematology and British Society of Blood and Marrow Transplantation.

Definitions for the quality of the evidence (AC) and strength of recommendations (strong [grade 1], weak [grade 2]) are given at the end of the "Major Recommendations" field. Background Cytomegalovirus (CMV) infection and CMV disease should be diagnosed according to established, internationally accepted, standardized criteria (Grade 1C). Risk-adapted patient assessment should inform clinical management (Grade 1B). Impact of Host and Donor CMV Serostatus All potential haemopoietic stem cell transplantation (HSCT) recipients should be tested for the presence of CMV immunoglobulin G (IgG) antibody at diagnosis (Grade 1C). Once optimum human leucocyte antigen (HLA) matching has been performed, a CMV IgG-negative donor should be chosen for a CMV IgG-negative recipient and a CMV IgG-positive donor should be chosen for CMV IgG-positive recipient when possible (Grade 1A). Donors or recipients who are initially found to be CMV IgG-negative should be retested pre-transplant to exclude primary CMV infection (Grade 1C). Apparent CMV seroconversion in potential allograft recipients who have received unscreened blood products should be actively investigated to exclude passively acquired antibody (Grade 1C). Any CMV IgG-negative HSCT recipient transplanted from a CMV IgG-negative donor who develops CMV infection post-transplant must be reported to the Serious Hazards of Transfusion (SHOT) (Grade 1C). Primary and Secondary Prophylaxis for CMV Primary prophylaxis with ganciclovir is not generally recommended as toxicity outweighs efficacy in HSCT patients (Grade 1B). Primary prophylaxis with aciclovir or valaciclovir can be deployed but only in conjunction with appropriate monitoring of CMV in the blood (Grade 1B). Valaciclovir or valganciclovir are valid treatment options for secondary prophylaxis with appropriate monitoring of CMV in the blood (Grade 1C). Intravenous immunoglobulins are not recommended for prophylaxis of CMV infection (Grade 1A). Pre-emptive Therapy Real-time quantitative polymerase chain reaction (PCR) is the preferred option for monitoring CMV deoxyribonucleic acid (DNA) levels in HSCT patients (Grade 1B). All diagnostic laboratories should deploy the CMV international standard to allow CMV DNA loads to be compared between centres (Grade 1C). Monitoring of CMV DNA load should be undertaken at least weekly for the first 3 months post-HSCT (Grade 2C). CMV viral load monitoring should continue to 612 months if the patient has chronic graft-versus-host disease (GvHD) or prolonged T-cell immunodeficiency (Grade 1B). Treatment Thresholds Each transplant centre should have a risk-adapted policy detailing threshold values for treatment of CMV infection, taking into account patient factors and local PCR methodology (Grade 2C). Antiviral Agents Used in Pre-emptive Therapy Ganciclovir is recommended as first line pre-emptive therapy for CMV in HSCT patients (Grade 1A). Oral valganciclovir is a useful alternative when gastrointestinal absorption is normal or minimally impaired (Grade 1B). Foscarnet is recommended as an alternative first line agent if neutropenia is present or for ganciclovir treatment failures (Grade 1A). Pre-emptive therapy with cidofovir can be considered as third line in patients unresponsive or intolerant of a ganciclovir preparation or foscarnet (Grade 2B). Switching Pre-emptive Therapy In patients where CMV DNA loads in blood increase by 1 log10 over 2 weeks of pre-emptive therapy with a first line drug, an alternative agent and drug resistance profiling should be considered (Grade 2C). Antiviral Drug Resistance Drug resistance should be considered if the CMV DNA load in blood fails to respond after 14 days of therapy, especially in non-lymphopenic or multiply pre-treated patients (Grade 2C). Sequence analysis of the UL97 and UL54 genes is the preferred option for monitoring resistance to currently available drugs (Grade 1B). Management of CMV Disease A multidisciplinary approach to management of CMV disease is required (Grade 1C). De novo CMV disease should be treated with ganciclovir or foscarnet, plus intravenous immunoglobulin (Grade 1B). CMV disease that develops while on pre-emptive therapy or is clinically progressive requires drug resistance testing, increased drug doses and/or a change of drug (Grade 1B). Reduction in immunosuppression, especially corticosteroid dosage, is strongly recommended (Grade 1B). Definitions: Quality of Evidence The quality of evidence is graded as high (A), moderate (B) or low (C). To put this in context it is useful to consider the uncertainty of knowledge and whether further research could change what is known or is certain. (A) High Further research is very unlikely to change confidence in the estimate of effect. Current evidence derived from randomised clinical trials without important limitations. (B) Moderate Further research may well have an important impact on confidence in the estimate of effect and may change the estimate. Current evidence derived from randomised clinical trials with important limitations (e.g., inconsistent results, imprecision wide confidence intervals or methodological flaws e.g., lack of blinding, large losses to follow up, failure to adhere to intention to treat analysis), or very strong evidence from observational studies or case series (e.g., large or very large and consistent estimates of the magnitude of a treatment effect or demonstration of a dose-response gradient). (C) Low Further research is likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate. Current evidence from observational studies, case series, or just opinion. Strength of Recommendations Strong (grade 1): Strong recommendations (grade 1) are made when there is confidence that the benefits do or do not outweigh harm and burden. Grade 1 recommendations can be applied uniformly to most patients. Regard as 'recommend'. Weak (grade 2): Where the magnitude of benefit or not is less certain a weaker grade 2 recommendation is made. Grade 2 recommendations require judicious application to individual patients. Regard as 'suggest'.

None provided

The type of supporting evidence is identified and graded for each recommendation (see the "Major Recommendations" field).

Appropriate prevention and management of cytomegalovirus infection in haemopoietic stem cell transplantation

Drugs Used for Cytomegalovirus (CMV) Prevention Ganciclovir prophylaxis significantly reduced the incidence of CMV infection and disease during the period of prophylaxis. However neutropenia occurred in up to 30% of cases treated and infective complications were increased. Prolonged exposure of CMV to ganciclovir, especially in the setting of T-cell depletion, may encourage resistance, as occurs in solid organ transplantation. Routine use of aciclovir or valaciclovir for CMV prophylaxis is relatively non-toxic but will result in some patients being overtreated. Side Effects of Drugs Used to Treat CMV Infection Ganciclovir: myelosuppression Valganciclovir: haemolysis, nausea/vomiting, fever, rash, mental state changes, urinary symptoms Foscarnet: electrolyte abnormalities, renal impairment, nausea/vomiting, genitourinary, urinary symptoms Cidofovir: renal impairment, nausea/vomiting, ocular In 1 study (which compared 60 mg/kg foscarnet with ganciclovir 5 mg/kg), renal insufficiency was more common with foscarnet and myelosuppression with ganciclovir.

An implementation strategy was not provided.

Getting Better;Staying Healthy

Effectiveness;Patient-centeredness;Safety

These evidence-based guidelines expand and adapt previous guidance: Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, Wingard JR, Young JA Boeckh MJ. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biology of Blood and Marrow Transplantation. 2009;15:11431238. Andrews PA, Emery VC Newstead C. Summary of the British transplantation society guidelines for the prevention and management of CMV disease after solid organ transplantation. Transplantation. 2011;92:11811187.

2013 Jul

British Committee for Standards in Haematology

Authors: Vincent Emery, Department of Virology, University College London School of Life and Medical Sciences, London; Mark Zuckerman, Department of Virology, King's College Hospital, London; Graham Jackson, Department of Haematology, Freeman Road Hospital, Newcastle; Celia Aitken, West of Scotland specialist virology centre, Gartnavel General Hospital, Glasgow; Husam Osman, Birmingham HPA Laboratory, Birmingham Heartlands Hospital, Birmingham; Anthony Pagliuca, Department of Haematology, King's College Hospital, London; Mike Potter, Section of Haemato-oncology, The Royal Marsden NHS Foundation Trust, London; Karl Peggs, Department of Haematology, University College London Hospitals, London; Andrew Clark, Blood and Marrow Transplant Unit, Beatson Oncology Centre, Glasgow, UK

The authors report no conflicts of interest.

Electronic copies: Available from the British Journal of Haematology Web site. Print copies: Available from the British Committee for Standards in Haematology; Email: bcsh@b-s-h.org.uk.

None available

This NGC summary was completed by ECRI Institute on October 18, 2013.

10003

Bortezomib in multiple myeloma and lymphoma.

Kouroukis CT, Reece D, Baldassarre FG, Haynes AE, Imrie K, Cheung M, Hematology Disease Site Group. Bortezomib in multiple myeloma and lymphoma. Toronto (ON): Cancer Care Ontario (CCO); 2013 Mar 18. 209 p.(Evidence-based series; no. 6-18). [293 references]

This is the current release of the guideline. This guideline updates a previous version: Reece D, Kouroukis T, Haynes AE, Imrie K. Bortezomib in multiple myeloma and lymphoma. Toronto (ON): Cancer Care Ontario (CCO); 2008 Nov 24. 41 p. (CED-CCO special advice report; no. 11). The EVIDENCE-BASED SERIES report, initially the full original Guideline, over time will expand to contain new information emerging from their reviewing and updating activities. Please visit the Cancer Care Ontario Web site for details on any new evidence that has emerged and implications to the guidelines.

Multiple myeloma Lymphoma Waldenstrm's macroglobulinemia

Assessment of Therapeutic Effectiveness;Treatment

Hematology;Internal Medicine;Oncology

Advanced Practice Nurses;Health Care Providers;Nurses;Physician Assistants;Physicians

To evaluate the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (e.g., time-to-progression [TTP]), response duration, or response rate in patients with multiple myeloma, or lymphoma, including Waldenstrm's macroglobulinemia To evaluate the toxicity associated with the use of bortezomib To determine which patients are more or less likely to benefit from treatment with bortezomib

Adult patients with multiple myeloma, or lymphoma of any type, stage, histology, or performance status

Bortezomib alone or in combination with other agents

Survival Time-to-progression/progression-free survival Response duration Response rate Quality of life Toxicity

Hand-searches of Published Literature (Primary Sources);Hand-searches of Published Literature (Secondary Sources);Searches of Electronic Databases

Literature Search Strategy MEDLINE (Ovid) (October 2004 through August 2012), EMBASE (Ovid) (2004 Week 42 through August 27, 2012), and the Cochrane Library (August 2012) databases were searched. The search strategies for MEDLINE and EMBASE are shown in Appendix 2 of the original guideline. The search strategies were adapted for the Cochrane database. In addition, the Working Group members' personal files and conference proceedings of the American Society of Clinical Oncology (ASCO) (2005-2012) and the American Society of Hematology (ASH) (2005-2011) were searched for relevant trials. The following Web sites were also searched for existing evidence-based practice guidelines: Canadian Medical Association Infobase (https://www.cma.ca/en/Pages/cma_default.aspx#) National Guideline Clearinghouse (http://www.guideline.gov/) National Institute for Health and Care Excellence (http://www.nice.org.uk/) Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from these sources were searched for additional trials. Study Selection Criteria Multiple Myeloma (MM) Inclusion Criteria Articles were selected for inclusion in this systematic review of the evidence if they were published full report articles or published meeting abstracts of: Systematic reviews (only of full report articles), meta-analyses, or evidence-based clinical practice guidelines of bortezomib in adult patients with MM Randomized studies including adult patients with MM and evaluating bortezomib as a single agent or in combination with other regimens Trials could compare bortezomib to any agent, any combination of agents, or placebo Trials reporting one or more of the following outcomes: survival, quality of life, disease control (e.g., time-to-progression [TTP]), response duration, response rate, or adverse effects Exclusion Criteria Studies were excluded if they were: Letters, comments, books, notes, editorial publication types, or abstract publication of systematic reviews Articles published in a language other than English, due to the cost of translations Clinical practice guidelines without a description of a systematic literature search Lymphoma Inclusion Criteria Articles were selected for inclusion in this systematic review of the evidence if they were published full report articles or published meeting abstracts of: Systematic reviews (only full report articles), meta-analyses, or evidence-based clinical practice guidelines of bortezomib in adult patients with Waldenstrm's macroglobulinemia (WM) or lymphoma Studies including adult patients with WM or lymphoma (any histologic subtype, stage, performance status, or disease type) Randomized trials in which bortezomib could be compared with any agent, any combination of agents, or placebo Single-arm phase II trials evaluating bortezomib as a single agent or in combination with other regimens Trials reporting one or more of the following outcomes: survival, quality of life, disease control (e.g., TTP), response duration, response rate, or adverse effects Exclusion Criteria Studies were excluded if they were: Letters, comments, books, news, editorial publication types, or abstract publication of systematic reviews Single-arm phase II trials reporting fewer than 20 patients (all disease types combined) Abstract reports of single-arm phase II trials that have not been previously fully published Phase I trials Clinical practice guidelines without a description of a systematic literature search Abstracts that were reports of interim analyses, as well as abstracts of non-comparative studies, (as per Program in Evidence-based Care [PEBC] policy) and systematic reviews that were more than two years old were also not included. The methodologist screened the titles and the abstracts of the citations identified by the electronic databases and the titles of the abstracts from ASCO and ASH conference proceedings and excluded the citations that reported on studies that did not investigate the use of bortezomib or that did not meet the inclusion criteria for design (i.e., were not randomized trials or were not systematic reviews for MM or were retrospective studies for lymphoma). The full texts of the remaining articles were retrieved in the library, and two authors for myeloma and two authors for lymphoma reviewed them against the selection criteria.

Multiple Myeloma A total of 26 unique studies (6 systematic reviews, 17 unique randomized controlled trials [RCTs], and 3 guidelines) and 40 companion publications were included. Lymphoma and Waldenstrm's Macroglobulinemia A total of 28 unique studies (1 Phase III RCT, 3 randomized Phase II trials, 23 Phase II single arm studies, and 1 abstract of interim analysis) and 7 companion publications were included.

Expert Consensus

Not applicable

Review of Published Meta-Analyses;Systematic Review with Evidence Tables

Expert Consensus

Not applicable

The guideline developers reviewed published cost analyses.

External Peer Review;Internal Peer Review

Report Approval Panel Review and Approval Prior to the submission of this Evidence-based Series (EBS) draft report for External Review, the report was reviewed and approved by the Program in Evidence-based Care (PEBC) Report Approval Panel, a panel that includes oncologists and whose members have clinical and methodological expertise. External Review by Ontario Clinicians and Other Experts The PEBC external review process is two-pronged and includes a targeted peer review that is intended to obtain direct feedback on the draft report from a small number of specified content experts and a professional consultation that is intended to facilitate dissemination of the final guidance report to Ontario practitioners. Following the review and discussion of Section 1: Recommendations and Section 2: Evidentiary Base of this EBS and the review and approval of the report by the PEBC Report Approval Panel, the Hematology Disease Site Group (DSG) circulated Sections 1 and 2 to external review participants for review and feedback. Methods Targeted Peer Review During the guideline development process, eight targeted peer reviewers from Ontario considered clinical and/or methodological experts on the topic were identified by the Hematology DSG. Several weeks prior to completion of the draft report, the nominees were contacted by email and asked to serve as reviewers. Three reviewers agreed, and the draft report and a questionnaire were sent via email for their review. The questionnaire consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations, and whether the draft recommendations should be approved as a guideline. Written comments were invited. The questionnaire and draft document were sent out on June 6, 2012. Follow-up reminders were sent at two weeks (email), and at four weeks (telephone call). The Hematology DSG reviewed the results of the survey. Professional Consultation Feedback was obtained through a brief online survey of health care professionals who are the intended users of the guideline. All hematologists, medical oncologists, pharmacists, and nurses working in Ontario and listed in the PEBC database were contacted by email to inform them of the survey. Participants were asked to rate the overall quality of the guideline (see Section 1 in the original guideline) and whether they would use and/or recommend it. Written comments were invited. Participants were contacted by email and directed to the survey website where they were provided with access to the survey, the guideline recommendations (see Section 1 in the original guideline) and the evidentiary base (see Section 2 in the original guideline). The notification email was sent on June 20, 2012. The consultation period ended on July 18, 2012. The Hematology DSG reviewed the results of the survey.

Question 1. Efficacy of Bortezomib Multiple Myeloma (MM): Previously Untreated Patients Patients Who Are Ineligible for Autologous Stem Cell Transplantation (ASCT) For patients with previously untreated MM who are ineligible for ASCT, the combination of bortezomib, melphalan, and prednisone is a recommended first-line treatment option and preferred over treatment with melphalan and prednisone alone. The recommended dose and schedule of bortezomib is 1.3 mg/m2 given as a rapid intravenous bolus over 3 to 5 seconds on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. Melphalan 9 mg/m2 and prednisone 60 mg/m2 are to be given on days 1 through 4 of a six-week cycle. A total of nine cycles is given. Patients Who Are Candidates for ASCT In patients with previously untreated MM, a recommended option is the use of bortezomib in combination with dexamethasone or other immunomodulatory or alkylating agents as induction therapy prior to ASCT, and it is preferred over induction therapy without novel agents (i.e., dexamethasone alone or vincristine, doxorubicin and dexamethasone [VAD]). The recommended dose and schedule of bortezomib should be 1.3 mg/m2 given as a rapid intravenous bolus over 3 to 5 seconds days 1, 4, 8, and 11 of four 3-week cycles. Multiple Myeloma: Patients with Relapsed/Refractory Disease The combination of bortezomib and pegylated liposomal doxorubicin (PLD) is a recommended treatment option for patients with MM that has relapsed or is refractory to previous treatment who are candidates for further chemotherapy; who have no clinically significant cardiac disease; who have received less than 240 mg/m2, or the equivalent cumulative dose of doxorubicin; who have a left ventricular ejection fraction in the normal range; and who would be expected to tolerate the myelosuppression of combination therapy. The recommended dose and schedule of bortezomib is 1.3 mg/m2 given as a rapid intravenous bolus over three to five seconds on days 1, 4, 8, and 11 of an every-21-days cycle. PLD 30 mg/m2 is administered as a one-hour infusion on day 4 of each cycle. Treatment should be continued for eight cycles unless disease progression or unacceptable treatment-related toxicity occurs. Patients who are still responding and who are tolerating therapy well may continue until the criteria of progressive myeloma are met, i.e., at least a 25% increase in the serum monoclonal protein level (which must be an absolute minimum increase of 5 g/L). The treatment can be discontinued two to four cycles after the achievement of complete remission (CR) (as determined by negative electrophoresis and immunofixation). For patients with MM refractory or relapsed to previous treatment, who are candidates for further chemotherapy but are not candidates for the combination of bortezomib and PLD, bortezomib monotherapy is recommended as a preferred treatment option. The recommended dose and schedule of bortezomib is 1.3 mg/m2, given as a rapid intravenous bolus over three to five seconds on days 1, 4, 8, and 11 for eight three-week cycles, and then on days 1, 8, 15, and 22 for three five-week maintenance cycles. Lymphoma (Including Waldenstrm's Macroglobulinemia) For patients with relapsed or refractory mantle cell lymphoma, bortezomib monotherapy is a reasonable treatment option. Bortezomib should be administered at a dose of 1.3 mg/m2 given as a rapid intravenous bolus over three to five seconds on days 1, 4, 8, and 11 of a 21-day cycle. Treatment should continue until disease progression or intolerance, or until two to four cycles after maximal response has been achieved. Question 2. Toxicity A complete blood count is recommended with blood chemistries, including electrolytes and creatinine levels, all to be monitored at minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately for the development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain, or other toxicities. In lymphoma, a weekly bortezomib (alone or in combination) schedule is preferable to a bi-weekly schedule to prevent excess toxicity. Because bortezomib is fatal if administered intrathecally, the recommendation is to administer it only by the approved intravenous or subcutaneous routes. Question 3. Patient Subgroups That Are More or Less Likely to Benefit from the Use of Bortezomib In MM, treatment with bortezomib combinations (i.e., bortezomib with melphalan and prednisone for newly diagnosed patients, or either bortezomib and dexamethasone or bortezomib and pegylated liposomal doxorubicin for those with relapsed or refractory disease) is recommended for all patient subgroups (i.e., patients who are older, patients with impaired renal function, patients with a high-risk cytogenetic profile, patients exposed to multiple previous lines of therapy and ASCT, and patients with an elevated level of 2-microglobulin).

None provided

The recommendations are supported by randomized and non-randomized trials.

One randomized controlled trial (RCT) compared bortezomib plus melphalan and prednisone (n=344) to melphalan and prednisone (n=338) in patients with autologous stem cell transplantation (ASCT) ineligible, previously untreated multiple myeloma (MM). The authors reported a significantly higher median time-to-progression for the bortezomib/melphalan/prednisone arm (24.0 vs. 16.6 months; hazard ratio [HR], 0.48; p0.001). Overall survival for patients who received bortezomib plus melphalan and prednisone was also higher compared to melphalan and prednisone only (at 24 months, 84% vs. 70%; HR, 0.61; p=0.008). Three RCTs of bortezomib as an induction prior to ASCT in previously untreated MM patients have been reported: two full publications and one in abstract form. One group of researchers compared induction therapy with bortezomib plus dexamethasone to vincristine, doxorubicin, and dexamethasone (VAD) prior to ASCT and found a statistically significant, better complete response and a trend toward significance in progression-free survival in the bortezomib arm. Another group compared induction therapy with bortezomib plus dexamethasone and thalidomide to dexamethasone and thalidomide followed by a double ASCT. These authors also reported a significant and better complete remission (CR) and a better progression-free survival in the bortezomib arm. One RCT compared bortezomib plus pegylated liposomal doxorubicin (PLD) (n=324) to bortezomib alone (n=322) in patients with relapsed or refractory MM and reported that overall survival at 15 months was superior for the combination compared to bortezomib monotherapy (76% vs. 65%; p=0.03). The median time-to-progression was also significantly higher in the PLD plus bortezomib arm (9.3 months vs. 6.5 months, respectively; HR, 1.82; 95% confidence interval [CI], 1.41 to 2.35; p=0.000004). The Hematology Disease Site Group (DSG) opinion is that the treatment can be discontinued two to four cycles after the achievement of CR. One RCT compared bortezomib monotherapy (n=333) to dexamethasone (n=336) in patients with relapsed or refractory MM and reported that the median overall survival was significantly higher for patients who received bortezomib (29.8 months vs. 23.7 months; HR, 0.77; p=0.027). The median time-to-progression was also significantly higher in the bortezomib arm (HR, 0.55; p0.001). Of note, grade 3 adverse events were more common in the bortezomib arm (61% vs. 44%; p0.01). One large single-arm phase II trial was identified that investigated the use of bortezomib monotherapy in 155 patients with relapsed or refractory mantle cell lymphoma. The authors reported a median time-to-progression (TTP) of 6.7 months after a median follow-up of 26.4 months and a one-year survival of 69%. In newly diagnosed multiple myeloma patients, melphalan, prednisone, and bortezomib was superior in all patient subgroups to melphalan and prednisone alone. In refractory MM patients, bortezomib and dexamethasone has been shown to be superior to dexamethasone alone in patients 65 years or older (response rate p=0.0004; TTP p=0.002) and patients with International Staging System (ISS) stage II and III disease (response rate p0.0004; TTP p=0.0002) and patients refractory to the most recent therapy or patients who have previously received greater than one prior line of therapy (response rate p0.0001 and TTP p0.0001 for both subgroups), as well as in patients with renal impairment. Bortezomib plus pegylated liposomal doxorubicin was also more efficacious than bortezomib alone in most subgroups analyzed. An advantage of bortezomib and pegylated liposomal doxorubicin compared to bortezomib alone was observed in patients with cytogenetic abnormalities, except for deletion 13q.

Because bortezomib is fatal if administered intrathecally, the recommendation is to administer it only by the approved intravenous or subcutaneous routes. Multiple myeloma: In all patients, bortezomib drug combinations were associated with an increased incidence of peripheral neuropathy and hematologic events, as well as nausea and diarrhea, in contrast to non-bortezomib-containing regimens (see Table 7 in Section 2 of the original guideline document for details). The Disease Site Group opinion is that blood count, blood chemistries, and creatinine levels should be monitored on days 1 and 8 of each cycle. Lymphoma: Several phase II randomized controlled trials (RCTs) of a weekly versus bi-weekly bortezomib schedule have shown an increased incidence of toxicities in the bi-weekly schedule. Cases of accidental intrathecal administration of bortezomib have been reported, and Health Canada issued an alert on January 26, 2012.

An implementation strategy was not provided.

Getting Better;Living with Illness

Effectiveness

Not applicable: The guideline was not adapted from another source.

2006 Apr 3 (revised 2013 Mar 18)

The Program in Evidence-based Care (PEBC) is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care.

Hematology Disease Site Group

For a current list of past and present members, please see the Cancer Care Ontario Web site.

The authors of this report disclosed potential conflicts of interest relating to the topic of this evidence-based series. One author (DR) was the principal investigator or the local investigator and received research funding for four trials, including one of the randomized controlled trials (RCTs) in multiple myeloma (MM) reported here. That author was also a consultant for the manufacturer of bortezomib, was an advisory board participant for a future trial, and received honoraria. One other author (TK) received honoraria while acting as a consultant for the manufacturer of bortezomib and was an advisory board participant.

Electronic copies: Available in Portable Document Format (PDF) from the Cancer Care Ontario Web site.

The following is available: Program in evidence-based care handbook. Toronto (ON): Cancer Care Ontario (CCO); 2012. 14 p. Electronic copies: Available in Portable Document Format (PDF) from the CCO Web site.

None available

This NGC summary was completed by ECRI on June 29, 2006. The updated information was verified by the guideline developer on July 7, 2006. This NGC summary was updated by ECRI Institute on September 24, 2009. This summary was updated by ECRI Institute on February 26, 2010 following the U.S. Food and Drug Administration advisory on Velcade (bortezomib). This summary was updated by ECRI Institute on October 29, 2013.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions. Please refer to the Copyright and Disclaimer Statements posted at the Program in Evidence-based Care section of the Cancer Care Ontario Web site.

10004

Routine HPV testing in head and neck squamous cell carcinoma.

Lacchetti C, Waldron J, Perez-Ordonez B, Kamel-Reid S, Cripps C, Gilbert R, Head and Neck Cancer DSG. Routine HPV testing in head and neck squamous cell carcinoma. Toronto (ON): Cancer Care Ontario (CCO); 2013 May 13. 58 p.(Evidence-based series; no. 5-9). [103 references]

This is the current release of the guideline. The EVIDENCE-BASED SERIES report, initially the full original Guideline, over time will expand to contain new information emerging from their reviewing and updating activities. Please visit the Cancer Care Ontario Web site for details on any new evidence that has emerged and implications to the guidelines.

Head and neck squamous cell carcinoma

Diagnosis;Evaluation;Screening

Internal Medicine;Oncology;Otolaryngology;Pathology

Advanced Practice Nurses;Clinical Laboratory Personnel;Health Care Providers;Nurses;Physician Assistants;Physicians

To evaluate the appropriateness of, and make recommendations on, routine testing for human papillomavirus (HPV) status in adult patients with primary, or neck nodal metastatic, squamous cell carcinoma (SCC) of the head and neck

Adult patients with squamous cell carcinomas (SCCs) arising in oropharynx, larynx, hypopharynx, nasopharynx, sinonasal tract, or oral cavity subsites or an unknown primary head and neck site

Testing of oropharyngeal squamous cell carcinoma (SCC) tumours for human papillomavirus (HPV) status Testing of neck nodal tissue of patients with metastatic SCC from an unknown head and neck primary for HPV status Use of immunohistochemical (IHC) staining for p16 to determine HPV status, with confirmation by validated polymerase chain reaction (PCR) or in situ hybridization (ISH) technique for high-risk HPV subtypes in select cases

Overall survival Progression-free survival Disease-specific survival Prevalence of human papillomavirus (HPV)-associated squamous cell carcinoma (SCC) Sensitivity, specificity, and concordance/correlation of diagnostic testing methods

Hand-searches of Published Literature (Primary Sources);Hand-searches of Published Literature (Secondary Sources);Searches of Electronic Databases

Literature Search The literature was searched using MEDLINE (OVID: 1996 through March Week 4, 2013), Ovid MEDLINE(R) In-Process Other Non-Indexed Citations (April 09, 2013), EMBASE (OVID: 1996 through 2013, Week 14), and the Cochrane Library (OVID: 1st Quarter 2013). In addition, the proceedings of the meetings of the American Society of Clinical Oncology (ASCO), the American Society of Therapeutic Radiology and Oncology (ASTRO), and the European Society for Radiotherapy and Oncology (ESTRO) were all searched for relevant abstracts from 2007 to 2010. Reference lists of studies deemed eligible for inclusion were scanned for additional citations. The literature search of the electronic databases combined disease-specific terms (squamous cell carcinoma, cancer, malignancy, neoplasm, tumour) along with site-specific terms (oropharynx, larynx, hypopharynx, oral cavity) and testing-specific terms (HPV, p16, immunohistochemistry, polymerase chain reaction, in situ hybridization) for all study designs (see Appendix 1 in the original guideline document). After this initial literature search was completed, the Working Group recognized the need to include an additional question on HPV and cancers of unknown primaries (CUPs). That systematic search was conducted in June 2012 and updated in April 2013 in MEDLINE and EMBASE for all study designs (see Appendix 2 in the original guideline document). A priori decision rules were established that specified only comprehensive systematic reviews with relevance to at least one of the three original questions posed would receive formal quality assessments. Identified systematic reviews that required further consideration based on the criteria above were assessed using the'assessment of multiple systematic reviews' (AMSTAR) tool. The results of the AMSTAR assessment were used to determine whether or not an existing review could be incorporated as part of the evidentiary base. Any identified reviews that did not meet the criteria above, whose AMSTAR assessment indicated important deficiencies in quality, or that were otherwise not incorporated as part of the evidence base would be reported in the reference list, but not further described or discussed. Further to the searches of the electronic databases, an internet search of Canadian and international health organizations and the National Guideline Clearinghouse was conducted for existing guidelines and systematic reviews relevant to the research questions. Guidelines were included if they were published since 2008 in English. This environmental scan yielded one practice guideline. The Working Group decided that proceeding with a new systematic review that includes the latest research was warranted given the lack of reporting of the literature included in this practice guideline. Study Selection Criteria and Protocol Inclusion Criteria Articles were eligible for inclusion in this systematic review of the evidence if they met the following criteria: Human Papillomavirus (HPV) Positivity Full reports or abstracts of phase III randomized controlled trials that evaluated tumour HPV status and clinical outcome Studies that included adult patients with squamous cell carcinomas arising in the oropharynx, larynx, hypopharynx, nasopharynx, sinonasal tract, or oral cavity Results were reported for one or more of the following outcomes: overall survival, disease-free survival, disease-specific survival or progression-free survival. Prevalence Studies that included a minimum of 50 cases of head and neck squamous cell carcinoma (HNSCC) Testing that included a clearly described detection method of interest Prevalence of HPV-associated tumours for any of the following subsites is reported: oropharynx, larynx, hypopharynx, nasopharynx, sinonasal tract or oral cavity Unknown Primaries Studies that included a minimum of 20 cases of nodal metastatic squamous cell carcinoma from an unknown head and neck primary Testing that included a clearly described detection method of interest Results were reported for one or more of the following outcomes: prevalence of HPV-associated metastatic squamous cell carcinoma, correlation between HPV positivity and later detection of the primary tumour, or the sensitivity and specificity of a test for a diagnosis of an oropharyngeal tumour Testing Comparative studies that evaluated the following HPV detection methods: p16 immunohistochemistry (IHC), polymerase chain reaction (PCR), or in situ hybridization (ISH) Concordance between detection methods or sensitivity and specificity of the detection method are reported or enough information is provided to allow for the calculation of these outcomes, using PCR for high-risk HPV as the gold standard comparator Exclusion Criteria Articles published in languages other than English were excluded because of limited translation resources. A review of the titles and abstracts that resulted from the search was done by one reviewer. For those items that warranted full-text review, one reviewer reviewed each item with collaboration from a second reviewer if uncertainty existed.

Thirty-six studies met the inclusion criteria and were included in the systematic review.

Expert Consensus

Not applicable

Meta-Analysis;Review of Published Meta-Analyses;Systematic Review with Evidence Tables

Expert Consensus

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review;Internal Peer Review

Internal Review Almost all Program in Evidence-based Care (PEBC) documents undergo internal review. This review is conducted by the Expert Panel and the Report Approval Panel (RAP). The Working Group was responsible for incorporating the feedback and required changes of both of these panels, and both panels had to approve the document before it could be sent to External Review. Expert Panel Review and Approval The Head and Neck Disease Site Group (DSG) acted as the Expert Panel for this document. The document must be approved by a formal vote. In order to be approved, 75% of the Head and Neck DSG membership must cast a vote or abstain, and of those that vote, 75% must approve the document. At the time of the voting, the Head and Neck DSG members could suggest changes to the document, and possibly make their approval conditional on those changes. In those cases, the Working Group was responsible for considering the changes, and if those changes could be made without substantially altering the recommendations, the altered draft would not need to be resubmitted for approval. The Head and Neck DSG reviewed the document during the fall of 2012. During this review, the Head and Neck DSG unanimously approved the document and no changes were requested nor made. On January 6, 2013, by email, the Head and Neck DSG formally approved the document by vote. Of the 14 members of the Head and Neck DSG (who were not part of the working group), 11 members cast votes, for a total of 79% response. Of those who cast votes, all 11 approved the document (100%). RAP Review and Approval The purpose of the RAP review is to ensure the methodological rigour and quality of PEBC documents. The RAP consists of nine clinicians with broad experience in clinical research and guideline development, and the Director of the PEBC. For each document, three RAP members review the document: the Director and two others. RAP members must not have had any involvement in the development of the guideline prior to Internal Review. All three RAP members must approve the document, although they may do so conditionally. If there is a conditional approval, the Working Group is responsible for ensuring the necessary changes are made, with the Assistant Director of Quality and Methods, PEBC, making a final determination that the RAP's concerns have been addressed. In December 2012, the RAP reviewed and approved this document. External Review by Ontario Clinicians and Other Experts The PEBC external review process is two-pronged and includes a targeted peer review that is intended to obtain direct feedback on the draft report from a small number of specified content experts and a professional consultation that is intended to facilitate dissemination of the final guidance report to Ontario practitioners. Following approval of the document at Internal Review, the Head and Neck DSG circulated the draft document with recommendations to external review participants for review and feedback. Methods Targeted Peer Review During the guideline development process, five targeted peer reviewers from Ontario, Canada and across the United States considered to be clinical and/or methodological experts on the topic were identified by the working group. Several weeks prior to completion of the draft report, the nominees were contacted by email and asked to serve as reviewers. Five reviewers agreed and the draft report and a questionnaire were sent via email for their review. The questionnaire consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a guideline. Written comments were invited. The questionnaire and draft document were sent out on February 5, 2013. Follow-up reminders were sent at two weeks (email) and at four weeks (telephone call). The Working Group reviewed the results of the survey. Professional Consultation Feedback was obtained through a brief online survey of health care professionals who are the intended users of the guideline. All clinicians in Ontario in the PEBC database whose discipline was categorized as pathology and laboratory medicine or head and neck were contacted by email to inform them of the survey. Participants were asked to rate the overall quality of the guideline (see Section 1 in the original guideline document) and whether they would use and/or recommend it. Written comments were invited. Participants were contacted by email and directed to the survey website where they were provided with access to the survey, the guideline recommendations (see Section 1 in the original guideline document) and the evidentiary base (see Section 2 in the original guideline document). The notification email was sent on February 5, 2013. The consultation period ended on March 19, 2013. The Working Group reviewed the results of the survey. During the professional consultation phase, the PEBC was contacted by the College of American Pathologists (CAP) for an opportunity to also review the draft report. The draft report was provided to four CAP chairs, three of which provided written feedback. Conclusion This Evidence-Based Series (EBS) report reflects the integration of feedback obtained through the external review process with final approval given by the Head and Neck DSG and the Report Approval Panel of the PEBC. Updates of the report will be conducted in accordance with the PEBC Document Assessment and Review Protocol.

Recommendation 1 The tumours of all adult patients presenting with oropharyngeal squamous cell carcinomas (SCCs) should be routinely tested for human papillomavirus (HPV) status. Recommendation 2 It is recommended that the neck nodal tissue of patients with metastatic SCC to neck nodes from an unknown head and neck primary be routinely tested for HPV status. Recommendation 3 It is recommended that HPV status in oropharyngeal SCC be initially determined using immunohistochemical (IHC) staining for p16. IHC staining for p16 can be considered positive when the following three criteria are met: Cytoplasmic and nuclear staining Staining is moderate to strong and diffuse Staining is present in at least 50% of tumour cells Refer to the algorithm on page 5 in the original guideline document for a validated polymerase chain reaction (PCR) or in situ hybridization (ISH) technique for high-risk HPV subtypes that may be necessary to confirm p16 results in selected cases. Technical Considerations for Recommendation 3 While it is not possible to make evidence-based recommendations regarding the minimum set of criteria requiring adherence in a pathology laboratory with respect to HPV testing at this time, the following guidance is offered based on expert opinion and a consensus process by members of the Head and Neck Disease Site Group (DSG): Analysis should be performed on sections from paraffin blocks or unstained slides cut at 4 microns In cases of metastatic disease, where a core biopsy may not be a possibility, all efforts should be made to obtain enough tissue with fine needle aspiration (FNA) to prepare cell blocks.

An algorithm on validated polymerase chain reaction (PCR) or in situ hybridization (ISH) technique for high-risk human papillomavirus (HPV) subtypes is provided in the original guideline document.

The recommendations are supported by randomized and non-randomized trials.

There is evidence from a meta-analysis of randomized trials that human papillomavirus (HPV)-positivity is a strong predictor of prognosis in patients with oropharyngeal squamous cell carcinoma. In addition, it is likely that HPV status will influence management decisions in the near future and is now regarded as a mandatory stratification factor for clinical trials. Therefore, even though at this time no recommendation can be made to base clinical management decisions on HPV status, the valuable prognostic benefits of HPV testing are sufficient to warrant routine testing. The evidence indicates that there is relationship between HPV positivity and whether the initial cancer arises in the oropharynx or not. As detection of the primary tumour offers a reduction in morbidity due to the benefits of localized treatment, the additional diagnostic information provided by HPV status is sufficient to warrant routine testing of these tissues. The current evidence suggests that polymerase chain reaction (PCR), deoxyribonucleic acid in situ hybridization (DNA ISH), and immunohistochemical (IHC) staining are all comparable. With no unequivocal evidence exclusively supporting any particular scheme, the Head Neck Disease Site Group (DSG) believes this scheme is practical and simple, and it minimizes the impact of testing on available pathology resources and is appropriate until such time as further evidence becomes available. The Head Neck DSG acknowledges that the algorithm in the original guideline documentmay be considered controversial by some, but it is believed to address the proficiencies that are most readily available in laboratories across the province.

Not stated

An implementation strategy was not provided.

Clinical Algorithm

Living with Illness

Effectiveness

Not applicable: The guideline was not adapted from another source.

2013 May 13

The Program in Evidence-Based Care (PEBC) is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care.

Head and Neck Cancer Disease Site Group

For a current list of past and present members, please see the Cancer Care Ontario Web site.

In accordance with the Program in Evidence-based Care (PEBC) Conflict of Interest (COI) Policy, the guideline authors, Head and Neck Disease Site Group (DSG) members, and internal and external reviewers were asked to disclose potential conflicts of interest. The authors, members, and reviewers reported that they had no conflicts of interest.

Electronic copies: Available in Portable Document Format (PDF) from the Cancer Care Ontario Web site.

None available

This NGC summary was completed by ECRI Institute on October 29, 2013.

10006

Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update.

Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013 Sep;94(3):317-23. [40 references] PubMed

This is the current release of the guideline. This guideline updates a previous version: Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA, Roden DM, Klein TE, Shuldiner AR; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther. 2011 Aug;90:32832.

Diseases and conditions requiring antiplatelet therapy, particularly among patients with acute coronary syndromes undergoing percutaneous coronary intervention

Prevention;Risk Assessment;Treatment

Cardiology;Family Practice;Internal Medicine;Medical Genetics;Pharmacology;Preventive Medicine

Advanced Practice Nurses;Pharmacists;Physician Assistants;Physicians

To update the 2011 Clinical Pharmacogenetics Implementation Consortium guideline on the clinical use of cytochrome P450 (CYP)2C19 genotype test results for patients requiring antiplatelet therapy To help clinicians understand how available CYP2C19 genetic test results can be used to optimize clopidogrel drug therapy

Patients requiring antiplatelet therapy, particularly patients with acute coronary syndromes undergoing percutaneous coronary intervention

Use of antiplatelet therapy (clopidogrel, prasugrel, ticagrelor) based on cytochrome P450 (CYP)2C19 genotype

Risk for serious adverse cardiovascular events, such as cardiovascular death, myocardial infarction, stroke, or stent thrombosis in relation to cytochrome P450 (CYP)2C19 genotypes Adverse effects of antiplatelet agents in relation to CYP2C19 genotypes

Searches of Electronic Databases

The PubMed database (National Center for Biotechnology Information [NCBI]) was searched using the keywords (CYP2C19 OR cytochrome P450-2C19) AND (clopidogrel) from 1966 to January 2013. To construct a cytochrome P450 (CYP)2C19 minor allele frequency table based on ethnicity, the PubMed database (1966 to January 2011) and Ovid MEDLINE (1950 to January 2011) were searched using the following criteria: ((CYP2C19 or 2C19) AND (genotype OR allele OR frequency OR minor allele OR variant OR ethnic OR race OR racial OR ethnicity)) with filter limits set to retrieve "full-text" and "English" literature. Studies were considered for inclusion if: (1) the ethnicity of the population was clearly indicated; (2) either allele frequencies or alleles for CYP2C19 genotypes were reported; (3) the method by which CYP2C19 was genotyped appeared reliable; (4) the sample population consisted of at least 50 individuals; and (5) the study represented publication of novel data (no reviews or meta-analyses). In instances where genotype data from large cohorts of ethnically-diverse individuals were reported, without respect to ethnicity, studies were only considered if one ethnicity was 95% of the majority. The combined analysis grouped subpopulations based on the Human Genome Diversity Project-Centre Etude Polymorphism Humain (HGDP-CEPH) and included 7,970 Africans, 7,920 Americans, 36,030 East Asians, 121,808 Europeans, 2,140 Middle Easterns, 13,742 Oceanians, and 7,248 South/Central Asians.

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Levels of Evidence Linking Genotype to Phenotype High: Evidence includes consistent results from well-designed, well-conducted studies. Moderate: Evidence is sufficient to determine effects, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; generalizability to routine practice; or indirect nature of the evidence. Weak: Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information.

Review of Published Meta-Analyses;Systematic Review with Evidence Tables

Expert Consensus

Strength of Therapeutic Recommendations Strong: The evidence is high quality and the desirable effects clearly outweigh the undesirable effects. Moderate: There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects. Optional: The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.

A formal cost analysis was not performed and published cost analyses were not reviewed.

Peer Review

Not stated

The strength of therapeutic recommendations (Strong, Moderate, Optional) is defined at the end of the "Major Recommendations" field. Genetic Test Interpretation Clinical genotyping tests are available that interrogate variant cytochrome P450 (CYP)2C19 alleles and predict an individual's CYP2C19 metabolizer phenotype. Each named star (*) allele is defined by the genotype at one or more specific single-nucleotide polymorphisms (see Supplementary Table S1 online [see the "Availability of Companion Documents" field]) and is associated with a level of enzyme activity (see Supplementary Table S2 online [see the "Availability of Companion Documents" field]). Table 1 below and Supplementary Table S5 online (see the "Availability of Companion Documents" field) summarize the assignment of the likely CYP2C19 phenotype based on common star allele diplotypes, and these assignments are used to link genotypes with personalized antiplatelet therapy. Table 1. Assignment of Likely CYP2C19 Phenotypes Based on Genotypes Likely Phenotype Genotypes Examples of Diplotypes Ultrarapid metabolizer: normal or increased activity (~530% of patients) An individual carrying two increased activity alleles (*17) or one functional allele (*1) plus one increased-activity allele (*17) *1/*17, *17/*17 Extensive metabolizer: homozygous wild-type or normal activity (~3550% of patients) An individual carrying two functional (*1) alleles *1/*1 Intermediate metabolizer: heterozygote or intermediate activity (~1845% of patients) An individual carrying one functional allele (*1) plus one loss-of-function allele (*2*8) or one loss-of-function allele (*2*8) plus one increased-activity allele (*17) *1/*2, *1/*3, *2/*17 Poor metabolizer: homozygous variant, mutant, low, or deficient activity (~215% of patients) An individual carrying two loss-of-function alleles (*2*8) *2/*2, *2/*3, *3/*3 Some rare genotype combinations have unclear predicted metabolic phenotypes; see Supplementary Table S5 online (see the "Availability of Companion Documents" field). Therapeutic Recommendations Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are designed to help clinicians understand how available genetic test results can be used to optimize drug therapy rather than to recommend in whom pharmacogenetic testing should be conducted. With the growing ease and availability of genetic testing and other sequencing programs, an increasing number of patients in the near future may already know their CYP2C19 genotype status at the time of treatment, and this document provides guidance on clinical management for those in whom genotype is available or for whom the clinician chooses to order a CYP2C19 genotyping test. With respect to other professional statements, the 2012 American College of Cardiology Foundation/American Heart Association acute coronary syndrome (ACS) guidelines noted that genetic testing for CYP2C19 loss-of-function alleles may be considered on a case-by-case basis, especially for patients who experience recurrent ACS events despite ongoing therapy with clopidogrel. In addition, the committee recommended that genotyping might be considered if results of testing may alter management, which they suggest until better clinical evidence exists to provide a more scientifically derived recommendation. Optimal individualized antiplatelet treatment should maximize benefit by reducing risk of recurrent cardiovascular (CV) events while minimizing adverse effects such as bleeding. Prasugrel is an approved antiplatelet agent that was superior to clopidogrel in a large-scale randomized trial of ACS patients with planned percutaneous coronary intervention (PCI), with a hazards ratio (HR) for CV death, myocardial infarction, or stroke for prasugrel vs. clopidogrel of 0.81 (95% confidence interval [CI] = 0.730.90, P 0.001), as well as a 42% reduction in stent thrombosis. However, it may not represent a substitute for clopidogrel in all patients due to an increased risk of non-coronary artery bypass grafting thrombolysis in myocardial infarction (TIMI) major bleeding (HR = 1.32, 95% CI =1.031.68; P = 0.03), including fatal bleeding (prasugrel = 0.4% vs. clopidogrel = 0.1%; P = 0.002); its contraindication in some patients (e.g., history of transient ischemic attack, stroke, or intracranial bleeding); and the lower expense of generic clopidogrel following the recent expiration of its patent. Of note, the benefit of prasugrel over clopidogrel was found to be greater in patients with a CYP2C19 loss-of-function allele, with no significant difference estimated in composite outcome risk between the two antiplatelet agents among CYP2C19 extensive metabolizers (i.e., *1/*1 patients). In addition to prasugrel, ticagrelor is a recently approved antiplatelet agent that also was superior to clopidogrel in a large-scale randomized trial of ACS patients with an HR for CV death, myocardial infarction, or stroke for ticagrelor vs. clopidogrel of 0.84 (95% CI = 0.770.92; P 0.001), including a 26% reduction in stent thrombosis and 18% reduction in all-cause mortality. In the genetic substudy, as compared with clopidogrel, ticagrelor reduced the primary end point by 23% among patients carrying any CYP2C19 loss-of-function allele (8.6 vs. 11.2%; HR = 0.77, 95% CI = 0.600.99; P = 0.0380) and 14% among patients without any CYP2C19 loss-of-function allele (8.8 vs. 10.0%; HR = 0.86, 95% CI = 0.741.01), although this reduction did not reach statistical significance (P = 0.0608). However, formal interaction testing that evaluated if the effect of ticagrelor vs. clopidogrel varied by genotype was also not significant. Of note, the benefit of ticagrelor as compared with clopidogrel was subsequently shown to appear to be most pronounced among the subset of patients with CYP2C19 loss-of-function alleles who were undergoing PCI (carriers: 7.7 vs. 10.6%, HR = 0.71; noncarriers: 7.4 vs. 8.2%, HR = 0.90). In addition, it is not known to what extent twice-daily dosing may affect the efficacy of ticagrelor relative to clopidogrel in a real-world setting. Despite the improvements in overall efficacy reported for prasugrel and ticagrelor as compared with clopidogrel, it is anticipated that clopidogrel will continue to be a widely prescribed medication for ACS/PCI patients. Genotype-directed therapy could identify patients who benefit most from alternative antiplatelet therapy. For clinicians considering treatment with clopidogrel, Table 2 below and Figure 1 in the original guideline document summarize the therapeutic recommendations for antiplatelet therapy based on CYP2C19 status. Standard dosing of clopidogrel, as recommended in the product insert, is warranted among ACS/PCI patients with a predicted CYP2C19 extensive metabolizer or ultrarapid metabolizer phenotype (i.e., *1/*1, *1/*17, and *17/*17). If genotyping from a Clinical Laboratory Improvement Amendmentscertified laboratory identifies a patient as a CYP2C19 poor metabolizer (PM) (i.e., *2/*2), current literature supports the use of an alternative antiplatelet agent (e.g., prasugrel or ticagrelor) when not contraindicated clinically. The most challenging patient population to address is the CYP2C19 intermediate metabolizer (IM) phenotype (e.g., *1/*2, *1/*3, and *2/*17). IMs have higher on-treatment residual platelet activity on average as compared with extensive metabolizers, and ACS/PCI CYP2C19*2 heterozygotes treated with clopidogrel have increased risks for serious adverse CV outcomes, including stent thrombosis (see Supplementary Materials and Methods online [see the "Availability of Companion Documents" field]). Consequently, these data support switching to an alternative antiplatelet agent for IMs when not contraindicated. However, given the wide interindividual variability in residual platelet activity observed among clopidogrel-treated IMs, clinical judgment also taking into account other factors that may place an IM at increased risk of a CV event (or adverse bleeding event) must be considered to most effectively individualize therapy. In addition, although these guidelines have been focused on CYP2C19*2 and *3, many clinical genotyping platforms include other variant alleles (e.g., *4*8 and *17) that can alter a patient's predicted metabolizer phenotype interpretation (see Supplementary Table S5 online [see the "Availability of Companion Documents" field]). As mentioned above, the *4*8 alleles have strong in vitro evidence for complete loss of function of the CYP2C19 enzyme. Consequently, when these alleles are identified among ACS/PCI patients treated with clopidogrel, they should be considered as influencing clopidogrel metabolism and clinical outcomes consistent with the *2 loss-of-function allele. Table 2. Antiplatelet Therapy Recommendations Based on CYP2C19 Status When Considering Clopidogrel for ACS/PCI Patients Phenotype (Genotype) Implications for Clopidogrel Therapeutic Recommendations Classification of Recommendations Ultrarapid metabolizer (UM) (*1/*17, *17/*17) and extensive metabolizer (EM) (*1/*1) Normal (EM) or increased (UM) platelet inhibition; normal (EM) or decreased (UM) residual platelet aggregationa Clopidogrel: label-recommended dosage and administration Strong Intermediate metabolizer (*1/*2, *1/*3, *2/*17) Reduced platelet inhibition; increased residual platelet aggregation; increased risk for adverse cardiovascular events Alternative antiplatelet therapy (if no contraindication), e.g., prasugrel, ticagrelor Moderate Poor metabolizer (*2/*2, *2/*3, *3/*3) Significantly reduced platelet inhibition; increased residual platelet aggregation; increased risk for adverse cardiovascular events Alternative antiplatelet therapy (if no contraindication), e.g., prasugrel, ticagrelor Strong aThe CYP2C19*17 allele may be associated with increased bleeding risks. Definitions: Strength of Therapeutic Recommendations Strong: The evidence is high quality and the desirable effects clearly outweigh the undesirable effects. Moderate: There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects. Optional: The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.

An algorithm titled "Algorithm for suggested clinical actions based on CYP2C19 genotype when considering treatment with clopidogrel for ACS patients undergoing PCI (ACS/PCI)" is provided in the original guideline document.

Every effort was made to present evidence from high-quality studies and to take into consideration all available peer-reviewed published literature, which provided the framework for the strength of therapeutic recommendations (see the "Major Recommendations" field).

Optimal individualized antiplatelet treatment should maximize benefit by reducing risk of recurrent cardiovascular (CV) events while minimizing adverse effects such as bleeding. Genotype-directed therapy could identify patients who benefit most from alternative antiplatelet therapy. The potential benefits of cytochrome P450 (CYP)2C19 testing are that when considering treatment with clopidogrel in acute coronary syndrome (ACS)/percutaneous coronary intervention (PCI) patients, genotypes that confer a higher risk of a CV event on clopidogrel can be identified, and an alternative antiplatelet strategy can be instituted.

Cytochrome P450 (CYP)2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Some studies indicate that the common CYP2C19*17 allele results in enhanced platelet inhibition and clopidogrel response and perhaps an increased risk of bleeding complications. Large meta-analyses have shown that clopidogrel-treated ACS patients undergoing PCI who are CYP2C19*2 heterozygotes or homozygotes have an increased risk for major adverse CV events as compared with *1 homozygotes (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.112.17 for heterozygotes; HR = 1.76, 95% CI = 1.242.50 for homozygotes) and increased risks of stent thrombosis (HR = 2.67, 95% CI = 1.694.22 for heterozygotes; HR = 3.97, 95% CI = 1.759.02 for homozygotes). A lack of effect of CYP2C19 loss-of-function alleles on adverse CV outcomes has been reported among clopidogrel-treated patients with lower clinical risks and/or other indications (e.g., atrial fibrillation, stroke). Although CYP2C19 genotyping is straightforward and reliable when performed in qualified laboratories, as with any laboratory test, an additional possible risk to the patient is an error in genotyping. Because genotypes are lifelong test results, any such error could have adverse health implications for the life of the patient. See "Implications for Clopidogrel" in Table 2 of the original guideline document for more information.

Prasugrel is contraindicated in some patients (e.g., history of transient ischemic attack, stroke, or intracranial bleeding).

An implementation strategy was not provided.

Clinical Algorithm;Resources

Getting Better;Staying Healthy

Effectiveness;Patient-centeredness

Not applicable: The guideline was not adapted from another source.

2011 Aug (revised 2013 Sep)

The authors acknowledge the critical input of the Clinical Pharmacogenetics Implementation Consortium (CPIC) of the Pharmacogenomics Research Network and PharmGKB, funded by the National Institutes of Health (NIH). This work was supported in part by NIH grants KL2TR000069 (S.A.S), R24GM61374 (K.S. and T.E.K.), U01HL65962 (C.M.S.), U19HL065962-10 (D.M.R.), U01GM074492 (J.A.J.), U01HL105198 (A.R.S.), and U01GM92666 (CPIC). A.R.S. also acknowledges support from the Baltimore Veterans Administration Medical Center.

Not stated

Authors: SA Scott, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; K Sangkuhl, Department of Genetics, Stanford University, Stanford, California, USA; CM Stein, Division of Clinical Pharmacology, Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; J-S Hulot, Department of Pharmacology, Universit Pierre et Marie Curie-Paris 6, INSERM UMR S 956, Piti-Salptrire University Hospital, Paris, France, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA; JL Mega, Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; DM Roden, Department of Medicine and Pharmacology, Office of Personalized Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; TE Klein, Department of Genetics, Stanford University, Stanford, California, USA; MS Sabatine, Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; JA Johnson, Department of Pharmacotherapy and Translational Research, Colleges of Pharmacy and Medicine, Gainesville, Florida, USA, Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA, Department of Medicine (Cardiology), Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida, USA; AR Shuldiner, Department of Medicine and Program for Genomic and Personalized Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA, Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA

S.A.S. receives support from the National Institutes of Health (NIH) for antiplatelet pharmacogenomics research, is a consultant to USDS Inc., and is an associate director of a clinical laboratory that performs CYP2C19 testing. J.-S.H. has received research grant support from Biotronik and Medco Research Institute and consulting fees from Biotronik and Medco Health Solutions. J.L.M. receives research grant support through Brigham and Women's Hospital from Bayer Healthcare, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Johnson Johnson, Sanofi-Aventis, Accumetrics, and Nanosphere, and is a consultant to Boehringer Ingelheim, Janssen, and American Genomics. D.M.R. receives support from the NIH for pharmacogenomics research and is a consultant to Merck, Novartis, Dai-Ichi, Sanofi, and Astellas. M.S.S. receives research grant support through Brigham and Women's Hospital from AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, Bristol-Myers Squibb/Sanofi-Aventis Joint Venture, Daiichi-Sankyo, Eisai, Merck, Sanofi-Aventis, Abbott Laboratories, Accumetrics, Nanosphere, and Roche Diagnostics, and is a consultant to AstraZeneca/Bristol-Myers Squibb Alliance, Merck, and Sanofi-Aventis. J.A.J receives support from NIH for cardiovascular pharmacogenomics research, including clopidogrel. A.R.S receives support from the NIH for antiplatelet pharmacogenomics research and is a consultant to USDS Inc. The other authors declared no conflict of interest.

Electronic copies: Available from Pharmacogenomics Knowledgebase Web site.

The following are available: Supplementary material, including tables and methodological information, is available from the Pharmacogenomics Knowledgebase Web site. An interactive dosing table is available at the Pharmacogenomics Knowledgebase Web site. A clopidogrel metabolism pathway is also available from the Pharmacogenomics Knowledgebase Web site.

None available

This NGC summary was completed by ECRI Institute on October 31, 2013. The information was verified by the guideline developer on December 6, 2013.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions. CPIC is a registered service mark of the U.S. Department of Health Human Services (HHS).

10008

Screening for peripheral artery disease and cardiovascular disease risk assessment with the anklebrachial index in adults: U.S. Preventive Services Task Force recommendation statement.

U.S. Preventive Services Task Force. Screening for peripheral artery disease and cardiovascular disease risk assessment with the ankle-brachial index in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 Sep 3;159(5):342-8. [17 references] PubMed

This is the current release of the guideline. This guideline updates a previous version: U.S. Preventive Services Task Force. Screening for peripheral arterial disease: recommendation statement. Am Fam Physician. 2006 Feb 1;73(3):497-500.

Peripheral artery disease (PAD)

Prevention;Screening

Cardiology;Family Practice;Geriatrics;Internal Medicine;Preventive Medicine

Advanced Practice Nurses;Allied Health Personnel;Health Care Providers;Health Plans;Managed Care Organizations;Nurses;Physician Assistants;Physicians

To review the evidence on the use of resting ankle-brachial index (ABI) as a screening test for peripheral artery disease (PAD) or as a risk predictor for cardiovascular disease (CVD) To update the 2005 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for PAD

Asymptomatic adults who do not have a known diagnosis of peripheral artery disease (PAD), cardiovascular disease (CVD), severe chronic kidney disease, or diabetes

Resting anklebrachial index (ABI) as a screening test for peripheral artery disease (PAD) or as a risk predictor for cardiovascular disease (CVD)

Key Question 1: Is screening generally asymptomatic adults for peripheral arterial disease (PAD) using ankle-brachial index (ABI) effective in reducing cardiovascular disease (CVD) morbidity (e.g., myocardial infarction [MI], cardiovascular accident [CVA]), morbidity from PAD (e.g., amputation, impaired ambulation, impaired function), or mortality (e.g., CVD specific, overall)? Does the effectiveness of screening for PAD vary by subgroup (i.e., age [especially for age 65 years and older], sex, race, risk factors)? Key Question 2: In generally asymptomatic adults, what is the diagnostic accuracy (e.g., sensitivity, specificity, positive and negative predictive value) of ABI as a screening test for PAD? Does the diagnostic accuracy of ABI screening vary by subgroup (i.e., age [especially for age 65 years and older], sex, race, risk factors)? Key Question 3: What are the harms of screening (e.g., diagnostic inaccuracy [overdiagnosis], harms of additional testing)? Do the harms of screening vary by subgroup (i.e., age [especially for age 65 years and older], sex, race, risk factors)? Key Question 4: Does ABI in generally asymptomatic adults accurately predict CVD morbidity (e.g., MI, CVA) and mortality independent of traditional risk factors? What is the prevalence of a normal and abnormal ABI among low-, intermediate-, and high-risk adults? At what frequency does the use of ABI significantly change the risk of CVD morbidity or mortality based on traditional risk factors alone (e.g., from intermediate risk to low or high risk)? What is the accuracy of risk reclassification of CVD morbidity or mortality (in addition to traditional risk factors)? Key Question 5: Does treatment of asymptomatic or minimally symptomatic adults with PAD lead to improvement in patient outcomes beyond the benefits of treatment in symptomatic adults, or beyond the benefits of treatment of adults with known CVD risk factors (i.e., smoking, hypertension, hyperlipidemia)? Does the effectiveness of treatment vary by subgroup (i.e., age [especially for age 65 years and older], sex, race, risk factors)? Key Question 6: What are the harms of treatment of screen-detected PAD? Do the harms of treatment vary by subgroup (i.e., age [especially for age 65 years and older], sex, race, risk factors)?

Hand-searches of Published Literature (Primary Sources);Hand-searches of Published Literature (Secondary Sources);Searches of Electronic Databases

Note from the National Guideline Clearinghouse (NGC): An evidence synthesis was prepared by the Kaiser Permanente Research Affiliates Evidence-based Practice Center (EPC) for the U.S. Preventive Services Task Force (USPSTF) (see the "Availability of Companion Documents" field). Data Sources and Searches The EPC staff searched MEDLINE and the Cochrane Central Registry of Controlled Trials from 1996 through September 2012 to locate relevant English-language studies for all Key Questions. The staff supplemented searches with suggestions from experts and reference lists from 62 recent relevant existing systematic reviews. The staff also searched ClinicalTrials.gov on September 12, 2012 for relevant ongoing trials. Study Selection Two investigators independently reviewed 4,434 abstracts and 418 full-text articles (see Appendix D of the comparative effectiveness review) against the specified inclusion criteria (see Appendix E of the comparative effectiveness review). We resolved discrepancies by consultation with a third investigator. We list the studies we excluded at the full-text phase (i.e., based on exclusion criteria or for poor quality) in Appendix Fof the comparative effectiveness review. The review focuses on the clinical utility of resting ankle-brachial index (ABI) as the primary screening modality because it is the most commonly used and is able to detect asymptomatic persons. Therefore, this review excluded other methods of screening (e.g., questionnaires, exercise ABI, toe pressure measurement, pulse oximetry, duplex ultrasound, magnetic resonance angiography [MRA]). This review also focuses on generally asymptomatic adults, which may include populations with atypical symptoms or minor symptoms not recognized as peripheral arterial disease (PAD). The EPC staff excluded studies whose subjects primarily had known intermittent claudication. The staff also excluded studies conducted exclusively in persons with known cardiovascular disease (CVD), diabetes, or severe chronic kidney disease (stage 4 and 5). The staff excluded studies conducted in hospital or specialty settings (i.e., vascular clinics or laboratories), as these settings typically represented populations selected for known or highly suspected PAD. Because the focus is on largely asymptomatic persons, primary outcomes of interest are CVD events and risk factor reduction, rather than lower-extremity symptoms. If studies that met the inclusion criteria also reported PAD-specific outcomes (e.g., limb function, ambulation, amputation), however, the EPC staff considered these outcomes. Likewise, included treatments focused on pharmacologic or lifestyle interventions primarily aimed at CVD risk reduction (e.g., smoking cessation, cholesterol lowering, blood pressure control, and antiplatelet therapy). Therefore, the staff excluded interventions aimed primarily at management of lower-extremity symptoms or functioning (e.g., cilostazol, supervised exercise training or physical therapy, revascularization). For Key Question (KQ) 1, the EPC staff considered any trial (randomized, controlled trial [RCT] or controlled clinical trial [CCT]) or systematic review that compared ABI screening to no screening reporting any outcome of interest (i.e., CVD or PAD-specific morbidity or mortality). For KQ 2, the staff considered prospectively conducted diagnostic accuracy studies or well-conducted systematic reviews of diagnostic accuracy. The staff excluded case-control studies in which cases were selected based on having known PAD. Distorted selection of subjects in recruitment or case-control designs has repeatedly been shown to overestimate sensitivity. A distorted selection of subjects directly affects the applicability of the study findings and threatens its validity (i.e., spectrum bias). Spectrum bias refers to the phenomenon that the diagnostic test performance may change between clinical settings due to changes in patient case-mix. For KQ 2, diagnostic accuracy studies had to compare ABI with a reference standard. Because the gold standard, digital subtraction angiography (DSA), is an invasive test that presents known risks, it is not ethical to administer this test in asymptomatic persons. Therefore, the staff considered any diagnostic test that could image the degree of atherosclerosis (e.g., MRA, computed tomography angiography [CTA]) or degree of impaired blood flow (e.g., duplex ultrasound) to be a reasonable diagnostic reference standard. The staff accepted all measures of diagnostic accuracy (e.g., sensitivity, specificity, positive or negative predictive values, positive or negative likelihood ratios). For KQ 4, the staff considered prospective longitudinal cohort studies or systematic reviews of risk prediction. Included risk prediction studies had to assess ABI in addition to existing Framingham Risk Score (FRS) factors, as defined in ATP III (i.e., age, sex, smoking status, systolic blood pressure, total cholesterol, and high-density lipoprotein [HDL] cholesterol). While studies could adjust for additional known risk factors, the staff excluded studies that did not consider all existing FRS factors as a minimum. For KQ 5, the staff included any trial (RCT or CCT) or systematic review with at least 12 weeks of follow-up that compared treatment of PAD with no treatment, with placebo treatment, or with delayed treatment. Again, the EPC staff considered any outcome of interest (i.e., CVD or PAD-specific morbidity or mortality). While the staff included reviews, trials, cohort studies, and case-control studies for KQs 3 and 6, case series or case reports were excluded.

Key Question 1: 0 articles Key Question 2: 2 articles Key Question 3: 1 article Key Question 4: 16 articles Key Question 5: 3 articles Key Question 6: 3 articles

Expert Consensus

Not applicable

Review of Published Meta-Analyses;Systematic Review with Evidence Tables

Balance Sheets;Expert Consensus

What the U.S. Preventive Services Task Force (USPSTF) Grades Mean and Suggestions for Practice Grade Grade Definitions Suggestions for Practice A The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service. B The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service. C The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small. Offer or provide this service only if other considerations support offering or providing the service in an individual patient. D The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Discourage the use of this service. I Statement The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be measured. Read "Clinical Considerations" section of USPSTF Recommendation Statement (see the "Major Recommendations" field). If the service is offered, patients should understand the uncertainty about the balance of benefits and harms. USPSTF Levels of Certainty Regarding Net Benefit Definition: The USPSTF defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service. Level of Certainty Description High The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. Moderate The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by factors such as: The number, size, or quality of individual studies Inconsistency of findings across individual studies Limited generalizability of findings to routine primary care practice; and Lack of coherence in the chain of evidence As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. Low The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: The limited number or size of studies Important flaws in study design or methods Inconsistency of findings across individual studies Gaps in the chain of evidence Findings not generalizable to routine primary care practice; and A lack of information on important health outcomes More information may allow an estimation of effects on health outcomes.

A formal cost analysis was not performed and published cost analyses were not reviewed.

Comparison with Guidelines from Other Groups;External Peer Review;Internal Peer Review

Peer Review. Before the U.S. Preventive Services Task Force (USPSTF) makes its final determinations about recommendations on a given preventive service, the Evidence-based Practice Center and the Agency for Healthcare Research and Quality send a draft evidence review to 4 to 6 external experts and to Federal agencies and professional and disease-based health organizations with interests in the topic. The experts are asked to examine the review critically for accuracy and completeness and to respond to a series of specific questions about the document. After assembling these external review comments and documenting the proposed response to key comments, the topic team presents this information to the USPSTF in memo form. In this way, the USPSTF can consider these external comments before it votes on its recommendations about the service. Draft recommendation statements are then circulated for comment among reviewers representing professional societies, voluntary organizations, and Federal agencies, as well as posted on the Task Force Web site for public comment. These comments are discussed before the final recommendations are confirmed. Response to Public Comment. A draft version of this recommendation statement was posted for public comment on the USPSTF Web site from 19 March to 15 April 2013. The USPSTF received few comments, several of which agreed with the recommendation. Some comments provided additional studies and different interpretations of the evidence reviewed by the USPSTF. The USPSTF reviewed all of these studies and determined that they did not provide the necessary evidence to change its conclusions because the recommendation focuses on asymptomatic adults who do not have a known diagnosis of peripheral artery disease (PAD), cardiovascular disease (CVD), severe chronic kidney disease, or diabetes and are treated in a primary care setting. Comparison with Guidelines from Other Groups. Recommendations for screening from the following groups were discussed: American College of Cardiology Foundation and the American Heart Association (AHA).

The U.S. Preventive Services Task Force (USPSTF) grades its recommendations (A, B, C, D, or I) and identifies the levels of certainty regarding net benefit (High, Moderate, and Low). The definitions of these grades can be found at the end of the "Major Recommendations" field. Summary of Recommendations and Evidence The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for peripheral artery disease (PAD) and cardiovascular disease (CVD) risk assessment with the anklebrachial index (ABI) in adults. (I statement) Clinical Considerations Patient Population Under Consideration This recommendation applies to asymptomatic adults who do not have a known diagnosis of PAD, CVD, severe chronic kidney disease, or diabetes. Assessment of Risk In addition to older age, major risk factors for PAD include diabetes, smoking, hypertension, high cholesterol level, obesity, and physical inactivity, with smoking and diabetes showing the strongest association. PAD is more common in men than in women and occurs at an earlier age in men, possibly in part because of the higher prevalence of smoking in men. Among healthy U.S. men aged 40 to 75 years without a history of CVD, the risk for PAD over 25 years in the absence of 4 conventional cardiovascular risk factors (smoking, hypertension, hypercholesterolemia, or type 2 diabetes) is rare (9 cases per 100,000 person-years). These 4 risk factors account for 75% of all cases of PAD, and at least 1 of them is present at the time of PAD diagnosis in 96% of men. Therefore, if screening is determined to be beneficial, it would probably be most beneficial to persons who are at increased risk for PAD and are not already receiving cardiovascular risk reduction interventions. PAD is a manifestation of systemic atherosclerosis and is typically considered a predictor for other types of CVD (CAD or cerebrovascular disease) and CVD events, such as myocardial infarction (MI), cerebrovascular accident, and death. Patients with PAD are at increased risk for CVD events because of concomitant coronary and cerebrovascular disease. Screening Tests Resting ABI is the most commonly used test in screening for and detection of PAD in clinical settings, although variation in measurement protocols may lead to differences in the ABI values obtained. The ABI is calculated as the systolic blood pressure obtained at the ankle divided by the systolic blood pressure obtained at the brachial artery while the patient is lying down. A ratio of less than 1 (typically defined as 0.9) is considered abnormal and is commonly used to define PAD. Physical examination has low sensitivity for detecting mild PAD in asymptomatic persons. Although femoral bruit, pulse abnormalities, or ischemic skin changes significantly increase the likelihood ratio for low ABI (0.9), these signs indicate moderate to severe obstruction or clinical signs of disease. Although often done, the clinical benefits and harms of screening for PAD with a physical examination have not been well-evaluated and are beyond the scope of this review. In addition to its ability to detect PAD, an abnormal ABI may be a useful predictor of CVD morbidity and mortality. ABI measurement may increase the discrimination or calibration of existing CVD risk assessments apart from whether it accurately detects PAD. However, the number of patients with an abnormal ABI who also have other diseases or findings that would indicate treatment and whether there is value to these patients knowing they have an abnormal ABI is not clear. Screening Intervals No studies provided evidence about the intervals for screening for PAD with the ABI. Treatment Evidence shows that low-dose aspirin treatment in asymptomatic patients with a low ABI does not improve health outcomes and may increase bleeding. No trials provided evidence on other interventions to reduce CVD events or interventions that might delay the onset of lower extremity symptoms. Suggestions for Practice Regarding the I Statement In deciding whether to screen for PAD with the ABI in asymptomatic adults, clinicians should consider the following factors. Potential Preventable Burden The true prevalence of PAD in the general population is not known. Recent data from the National Health and Nutrition Examination Survey show that 5.9% of the U.S. population aged 40 years or older (7.1 million persons) has a low ABI (0.9). More than half of these persons do not have typical symptoms of PAD. The proportion of these patients who will go on to develop symptoms is not known; however, PAD is an indicator of CVD. Studies estimate that in persons with stable claudication but not critical ischemia, approximately 70% to 80% will remain stable over 5 years, whereas 10% to 20% will have worsening claudication and 1% to 2% will develop critical ischemia. Similar data are not available for asymptomatic patients with a low ABI. Potential Harms Although minimal harms are associated with the ABI test itself, downstream harms are possible. False-positive results, anxiety, labeling, and exposure to gadolinium or contrast dye if either magnetic resonance angiography (MRA) or computed tomography angiography (CTA) is used to confirm diagnosis may occur. Using the ABI in conjunction with Framingham Risk Score (FRS) results may reclassify a patient's risk. Given the uncertainty of the appropriateness of such reclassifications, patients could either be reclassified to a higher risk category and receive additional treatments with resulting adverse effects or be reclassified to a lower risk category and discontinue treatments that may be beneficial. Cost The cost of the ABI test is primarily in time and staff resources; performing the test in the office setting takes approximately 15 minutes. In addition, new equipment that performs pulse volume recordings or Doppler wave form tracings may need to be purchased. Providing this test to asymptomatic patients may divert time from other prevention activities that may be more beneficial to the patient. Current Practice In a survey of primary care practices across the United States, nearly 70% of providers reported never using the ABI in their practice settings, 6% to 8% reported using it once a year, and only 12% to 13% reported using it once a week or month. Definitions: What the U.S. Preventive Services Task Force (USPSTF) Grades Mean and Suggestions for Practice Grade Grade Definitions Suggestions for Practice A The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service. B The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service. C The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small. Offer or provide this service only if other considerations support offering or providing the service in an individual patient. D The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Discourage the use of this service. I Statement The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be measured. Read "Clinical Considerations" section of USPSTF Recommendation Statement (see the "Major Recommendations" field). If the service is offered, patients should understand the uncertainty about the balance of benefits and harms. USPSTF Levels of Certainty Regarding Net Benefit Definition: The USPSTF defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service. Level of Certainty Description High The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. Moderate The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by factors such as: The number, size, or quality of individual studies Inconsistency of findings across individual studies Limited generalizability of findings to routine primary care practice; and Lack of coherence in the chain of evidence As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. Low The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: The limited number or size of studies Important flaws in study design or methods Inconsistency of findings across individual studies Gaps in the chain of evidence Findings not generalizable to routine primary care practice; and A lack of information on important health outcomes More information may allow an estimation of effects on health outcomes.

None available

The type of supporting evidence is not specifically stated for each recommendation.

Benefits of Detection and Early Treatment The U.S. Preventive Services Task Force (USPSTF) found no evidence that screening for and treatment of peripheral arterial disease (PAD) in asymptomatic patients leads to clinically important benefits. It also reviewed the potential benefits of adding the ankle-brachial index (ABI) to the Framingham Risk Score (FRS) and found evidence that this results in some patient risk reclassification; however, how often the reclassification is appropriate or whether it results in improved clinical outcomes is not known. Determining the overall benefit of ABI testing requires not only evidence on appropriate risk reclassification but also evidence that this reclassification leads to treatments shown to improve clinical outcomes. One randomized trial found that aspirin did not reduce CVD events in patients with a low ABI. No studies assessed the effect of lipid-lowering therapy or other cardiovascular risk reduction interventions in patients with asymptomatic PAD and no known diagnosis of CVD or diabetes. The USPSTF found inadequate evidence that early treatment of screen-detected PAD leads to improvement in clinical outcomes.

Harms of Detection and Early Treatment The U.S. Preventive Services Task Force (USPSTF) found no studies addressing the magnitude of harms of screening for peripheral arterial disease (PAD) with the ankle-brachial index (ABI); however, the direct harms to the patient of screening itself, beyond the time needed for the test, are probably minimal. Other harms resulting from testing may include false-positive results, exposure to gadolinium or contrast dye if magnetic resonance angiography (MRA) or computed tomography angiography (CTA) is used to confirm diagnosis, anxiety, labeling, and opportunity costs. The USPSTF found inadequate evidence on the harms of early treatment of screen-detected PAD. One study showed that low-dose aspirin treatment in asymptomatic patients with a low ABI may increase bleeding. Additional harms associated with treatment include use of unnecessary medications (or higher doses) and their resulting adverse effects and discontinuation of medications known to be effective in patients with established coronary artery disease (CAD) if the patient is reclassified to a lower risk category on the basis of a normal ABI.

The experiences of the first and second U.S. Preventive Services Task Force (USPSTF), as well as that of other evidence-based guideline efforts, have highlighted the importance of identifying effective ways to implement clinical recommendations. Practice guidelines are relatively weak tools for changing clinical practice when used in isolation. To effect change, guidelines must be coupled with strategies to improve their acceptance and feasibility. Such strategies include enlisting the support of local opinion leaders, using reminder systems for clinicians and patients, adopting standing orders, and audit and feedback of information to clinicians about their compliance with recommended practice. In the case of preventive services guidelines, implementation needs to go beyond traditional dissemination and promotion efforts to recognize the added patient and clinician barriers that affect preventive care. These include clinicians' ambivalence about whether preventive medicine is part of their job, the psychological and practical challenges that patients face in changing behaviors, lack of access to health care or of insurance coverage for preventive services for some patients, competing pressures within the context of shorter office visits, and the lack of organized systems in most practices to ensure the delivery of recommended preventive care. Dissemination strategies have changed dramatically in this age of electronic information. While recognizing the continuing value of journals and other print formats for dissemination, the USPSTF Task Force will make all its products available through its Web site. The combination of electronic access and extensive material in the public domain should make it easier for a broad audience of users to access USPSTF materials and adapt them for their local needs. Online access to USPSTF products also opens up new possibilities for the appearance of the annual, pocket-size Guide to Clinical Preventive Services. To be successful, approaches for implementing prevention have to be tailored to the local level and deal with the specific barriers at a given site, typically requiring the redesign of systems of care. Such a systems approach to prevention has had notable success in established staff-model health maintenance organizations, by addressing organization of care, emphasizing a philosophy of prevention, and altering the training and incentives for clinicians. Staff-model plans also benefit from integrated information systems that can track the use of needed services and generate automatic reminders aimed at patients and clinicians, some of the most consistently successful interventions. Information systems remain a major challenge for individual clinicians' offices, however, as well as for looser affiliations of practices in network-model managed care and independent practice associations, where data on patient visits, referrals, and test results are not always centralized.

Foreign Language Translations;Mobile Device Resources;Patient Resources;Pocket Guide/Reference Cards

Staying Healthy

Effectiveness;Patient-centeredness

Not applicable: The guideline was not adapted from another source.

2006 Feb (revised 2013 Sep 3)

The U.S. Preventive Services Task Force (USPSTF) is an independent, voluntary body. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF.

U.S. Preventive Services Task Force (USPSTF)

Task Force Members*: Virginia A. Moyer, MD, MPH (Chair) (American Board of Pediatrics, Chapel Hill, North Carolina); Michael L. LeFevre, MD, MSPH (Co-Vice Chair) (University of Missouri School of Medicine, Columbia, Missouri); Albert L. Siu, MD, MSPH (Co-Vice Chair) (Mount Sinai School of Medicine, New York, and James J. Peters Veterans Affairs Medical Center, Bronx, New York); Linda Ciofu Baumann, PhD, RN (University of Wisconsin, Madison, Wisconsin); Kirsten Bibbins-Domingo, PhD, MD (University of California, San Francisco, San Francisco, California); Susan J. Curry, PhD (University of Iowa College of Public Health, Iowa City, Iowa); Mark Ebell, MD, MS (University of Georgia, Athens, Georgia); Glenn Flores, MD (University of Texas Southwestern, Dallas, Texas); Francisco A.R. Garca, MD, MPH (Pima County Department of Health, Tucson, Arizona); Adelita Gonzales Cantu, RN, PhD (University of Texas Health Science Center, San Antonio, Texas); David C. Grossman, MD, MPH (Group Health Cooperative, Seattle, Washington); Jessica Herzstein, MD, MPH (Air Products, Allentown, Pennsylvania); Wanda K. Nicholson, MD, MPH, MBA (University of North Carolina School of Medicine, Chapel Hill, North Carolina); Douglas K. Owens, MD, MS (Veterans Affairs Palo Alto Health Care System, Palo Alto, and Stanford University, Stanford, California); William R. Phillips, MD, MPH (University of Washington, Seattle, Washington); and Michael P. Pignone, MD, MPH (University of North Carolina, Chapel Hill, North Carolina)Former USPSTF member who contributed to the development of this recommendation: Timothy Wilt, MD, MPH*Members of the USPSTF at the time this recommendation was finalized. For a list of current Task Force members, go to http://www.uspreventiveservicestaskforce.org/Page/Name/our-members.

The U.S. Preventive Services Task Force (USPSTF) has an explicit policy concerning conflict of interest. All members disclose at each meeting if they have a significant financial, professional/business, or intellectual conflict for each topic being discussed. USPSTF members with conflicts may be recused from discussing or voting on recommendations about the topic in question. Potential Conflicts of Interest: Dr. Moyer: Support for travel to meetings for the study and other purposes: Agency for Healthcare Research and Quality. Disclosure forms from USPSTF members can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1670.

Electronic copies: Available from the Annals of Internal Medicine Web site.

The following are available:Evidence Reviews: Lin JS, Olson CM, Johnson ES, Senger CA, Soh CB, Whitlock EP. The anklebrachial index for peripheral artery disease screening and cardiovascular disease prediction among asymptomatic adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159:333-341. Lin JS, Olson CM, Johnson ES, Senger CA, Soh CB, Whitlock EP. The ankle brachial index for peripheral artery disease screening and cardiovascular disease prediction in asymptomatic adults: a systematic evidence review for the U.S. Preventive Services Task Force. Evidence synthesis No. 100. AHRQ Publication No. 12-05162-EF-1. Rockville (MD): Agency for Healthcare Research and Quality; 2013 Sep. 112 p. Electronic copies: Available from the U.S. Preventive Services Task Force (USPSTF) Web site.Background Articles: Barton MB et al. How to read the new recommendation statement: methods update from the U.S. Preventive Services Task Force. Ann Intern Med 2007;147:123-127. Guirguis-Blake J et al. Current processes of the U.S. Preventive Services Task Force: refining evidence-based recommendation development. Ann Intern Med 2007;147:117-122. Sawaya GF et al. Update on the methods of the U.S. Preventive Services Task Force: estimating certainty and magnitude of net benefit. Ann Intern Med 2007;147:871-875. Petitti DB et al. Update on the methods of the U.S. Preventive Services Task Force: insufficient evidence. Ann Intern Med. 2009;150:199-205. Electronic copies: Available from the USPSTF Web site.The following are also available: Screening for peripheral artery disease and cardiovascular disease risk assessment with the anklebrachial index in adults. Clinical summary of U.S. Preventive Services Task Force Recommendations. Rockville (MD): Agency for Healthcare Research and Quality; 2013 Sep. Electronic copies: Available from the USPSTF Web site. The guide to clinical preventive services, 2012. Recommendations of the U.S. Preventive Services Task Force. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); 2012. 128 p. Electronic copies available from the AHRQ Web site. See the related QualityTool summary on the Health Care Innovations Exchange Web site. The Electronic Preventive Services Selector (ePSS) is an application designed to provide primary care clinicians and health care teams timely decision support regarding appropriate screening, counseling, and preventive services for their patients. It is based on the current, evidence-based recommendations of the USPSTF and can be searched by specific patient characteristics, such as age, sex, and selected behavioral risk factors.

The following are available: Understanding task force recommendations: screening for peripheral artery disease and cardiovascular disease risk assessment with the ankle-brachial index in adults. Rockville (MD): Agency for Healthcare Research and Quality; 2013 Sep. 3 p. Electronic copies: Available from the U.S. Preventive Services Task Force (USPSTF) Web site. Screening for peripheral artery disease and cardiovascular disease risk assessment with the ankle-brachial index in adults. U.S. Preventive Services Task Force recommendation statement. Summary for patients. Ann Intern Med. 2013 Sep 3;159(5):I-28. Electronic copies: Available from the Annals of Internal Medicine Web site. Women: stay healthy at any age. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ). AHRQ Pub. No. 10-IP002-A. 2010 Aug. 2 p. Electronic copies: Available in Portable Document Format (PDF) in English and Spanish from the AHRQ Web site. See the related QualityTool summary on the Health Care Innovations Exchange Web site. Men: stay healthy at any age. Rockville (MD): Agency for Healthcare Research and Quality. AHRQ Pub. No. 10-IP004-A. 2010 Aug. 2 p. Electronic copies: Available in PDF in English and Spanish from the AHRQ Web site. See the related QualityTool summary on the Health Care Innovations Exchange Web site. Print copies: Available in English and Spanish from the AHRQ Publications Clearinghouse. For more information, go to http://www.ahrq.gov/research/publications/index.html or call 1-800-358-9295 (U.S. only).Myhealthfinder is a new tool that provides personalized recommendations for clinical preventive services specific to the user's age, gender, and pregnancy status. It features evidence-based recommendations from the USPSTF and is available at www.healthfinder.gov.Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

This NGC summary was completed by ECRI on June 10, 2005. The information was verified by the guideline developer on June 17, 2005. This NGC summary was updated by ECRI Institute on October 25, 2013. The updated information was verified by the guideline developer on November 11, 2013.

Requests regarding copyright should be sent to: Lisa S. Nicolella, Senior Editor, Office of Communications and Knowledge Transfer, Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850. E-mail: lisa.nicolella@ahrq.hhs.gov.

10009

Acute kidney injury. Prevention, detection and management of acute kidney injury up to the point of renal replacement therapy.

National Clinical Guideline Centre. Acute kidney injury. Prevention, detection and management of acute kidney injury up to the point of renal replacement therapy. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 39 p.(Clinical guideline; no. 169).

This is the current release of the guideline.

Acute kidney injury

Counseling;Diagnosis;Evaluation;Management;Prevention;Risk Assessment;Treatment

Emergency Medicine;Family Practice;Geriatrics;Internal Medicine;Nephrology;Pediatrics;Pharmacology;Preventive Medicine;Urology

Advanced Practice Nurses;Allied Health Personnel;Health Care Providers;Hospitals;Nurses;Patients;Physician Assistants;Physicians

To provide best practice advice on prevention, detection, and management of acute kidney injury up to the point of renal replacement therapy To emphasise early intervention and stress the importance of risk assessment and prevention, early recognition and treatment

Adults, children (older than 1 month) and young people (up to 18 years) Note: Particular consideration will be given to the needs of older patients (65 years and older) and people at high risk of developing acute kidney injury (AKI), such as people with chronic kidney disease and urological disorders. The guideline does not cover neonates (less than 1 month), pregnant women and AKI in renal transplant patients. It goes not cover aspects of renal replacement therapy beyond the decision to initiate it such as type, modality and length.

Investigation for acute kidney injury (AKI) by measuring serum creatinine and comparing with baseline Identification of AKI in patients with no obvious illness Assessment of risk factors in adults having iodinated contrast agents Measuring estimated glomerular filtration rate (eGFR) Discussion of risks and benefits of the imaging procedure Assessment of risk factors in adults having surgery Ongoing assessment of condition of patients in hospital Use of early warning scores Monitoring for oliguria Preventing AKI in adults having iodinated contrast agents Intravenous volume expansion Temporarily stopping angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARBs) Discussion of care with a nephrology team Monitoring and preventing deterioration in patients with or at high risk of AKI Use of electronic clinical decision support systems (CDSS) Consultation with pharmacist Temporarily stopping ACE inhibitors and ARBs Detecting AKI Use of specific laboratory criteria Monitor serum creatinine regularly in all adults, children and young people at risk Identification of causes of AKI Urinalysis Ultrasound Managing AKI Relieving urological obstruction (nephrostomy, stenting) Pharmacological management (loop diuretics, not recommended routinely) Referral for renal replacement therapy Information and support for patients and carers Note: Low-dose dopamine was considered but not recommended.

Sensitivity, specificity, positive predictive value, negative predictive value and likelihood ratio of diagnostic tests Incidence of acute kidney injury Cardiovascular events All-cause mortality Number of patients needing renal replacement therapy Length of hospital stay Cost-effectiveness

Hand-searches of Published Literature (Primary Sources);Hand-searches of Published Literature (Secondary Sources);Searches of Electronic Databases

The number of studies identified for each clinical question is provided in Appendix E in the full version of the original guideline document (see the "Availability of Companion Documents" field).

Weighting According to a Rating Scheme (Scheme Given)

Overall Quality of Outcome Evidence in Grading of Recommendations Assessment, Development and Evaluation (GRADE) Level Description High Further research is very unlikely to change confidence in the estimate of effect. Moderate Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate. Low Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate. Very Low Any estimate of effect is very uncertain.

Meta-Analysis;Review of Published Meta-Analyses;Systematic Review with Evidence Tables

Expert Consensus;Informal Consensus

Strength of Recommendations Some recommendations can be made with more certainty than others. The Guideline Development Group (GDG) makes a recommendation based on the trade-off between the benefits and harms of an intervention, taking into account the quality of the underpinning evidence. For some interventions, the GDG is confident that, given the information it has looked at, most patients would choose the intervention. The wording used in the recommendations in this guideline denotes the certainty with which the recommendation is made (the strength of the recommendation). Interventions That Must (or Must Not) Be Used The GDG usually uses 'must' or 'must not' only if there is a legal duty to apply the recommendation. Occasionally 'must' (or 'must not') is used if the consequences of not following the recommendation could be extremely serious or potentially life threatening. Interventions That Should (or Should Not) Be Used a 'Strong' Recommendation The GDG uses 'offer' (and similar words such as 'refer' or 'advise') when confident that, for the vast majority of patients, an intervention will do more good than harm, and be cost effective. Similar forms of words (for example, 'Do not offer') are used when the GDG is confident that an intervention will not be of benefit for most patients. Interventions That Could Be Used The GDG uses 'consider' when confident that an intervention will do more good than harm for most patients, and be cost effective, but other options may be similarly cost effective. The choice of intervention, and whether or not to have the intervention at all, is more likely to depend on the patient's values and preferences than for a strong recommendation, and so the healthcare professional should spend more time considering and discussing the options with the patient.

Undertaking New Health Economic Analysis As well as reviewing the published economic literature for each review question, as described above, new economic analysis was undertaken by the health economist in selected areas. Priority areas for new health economic analysis were agreed by the Guideline Development Group (GDG) after formation of the review questions and consideration of the available health economic evidence. The GDG identified Contrast Induced Acute Kidney Injury as the highest priority area for original economic modelling. Please see Chapter 6.2 of the full version of the original guideline document (see the "Availability of Companion Documents" field) for a full discussion of the rationale behind this decision. The following general principles were adhered to in developing the cost-effectiveness analysis: Methods were consistent with the NICE reference case. The GDG was involved in the design of the model, selection of inputs, and interpretation of the results. Model inputs were based on the systematic review of the clinical literature supplemented with other published data sources where possible. When published data was not available GDG expert opinion was used to populate the model. Model inputs and assumptions were reported fully and transparently. The results were subject to sensitivity analysis and limitations were discussed. The model was peer-reviewed by another health economist at the National Clinical Guidelines Centre. Full methods for the cost-effectiveness analysis for contrast induced acute kidney injury question are described in Appendix K of the original guideline document (see the "Availability of Companion Documents" field). Cost-effectiveness Criteria In general, an intervention was considered to be cost-effective if either of the following criteria applied (given that the estimate was considered plausible): The intervention dominated other relevant strategies (that is, it was both less costly in terms of resource use and more clinically effective compared with all the other relevant alternative strategies), or The intervention cost less than 20,000 per quality-adjusted life-year (QALY) gained compared with the next best strategy. If the GDG recommended an intervention that was estimated to cost more than 20,000 per QALY gained, or did not recommend one that was estimated to cost less than 20,000 per QALY gained, the reasons for this decision are discussed explicitly in the 'from evidence to recommendations' section of the relevant chapter with reference to issues regarding the plausibility of the estimate or to the factors set out in the National Institute for Health and Care Excellence (NICE) report 'Social value judgements: principles for the development of NICE guidance'. If a study reported the cost per life year gained but not QALYs, the cost per QALY gained was estimated by multiplying by an appropriate utility estimate to aid interpretation. The estimated cost per QALY gained is reported in the economic evidence profile with a footnote detailing the life-years gained and the utility value used. When QALYs or life years gained are not used in the analysis, results are difficult to interpret unless one strategy dominates the others with respect to every relevant health outcome and cost. See the individual chapters in the full version of the original guideline document (see the "Availability of Companion Documents" field) for discussions of the cost-effectiveness of specific recommendations. In the Absence of Economic Evidence When no relevant published studies were found, and a new analysis was not prioritised, the GDG made a qualitative judgement about cost effectiveness by considering expected differences in resource use between options and relevant UK National Health Service unit costs alongside the results of the clinical review of effectiveness evidence. The UK National Health Service costs reported in the guideline were those presented to the GDG and they were correct at the time recommendations were drafted; they may have been revised subsequently by the time of publication. However, the GDG has no reason to believe they have been changed substantially.

External Peer Review;Internal Peer Review

The guidance is subject to a six week public consultation and feedback as part of the quality assurance and peer review the document. All comments received from registered stakeholders are responded to in turn and posted on the National Institute for Health and Care Excellence (NICE) Web site when the pre-publication check of the full guideline occurs. The final draft was submitted to the Guideline Review Panel for review prior to publication.

Note from the National Guideline Clearinghouse (NGC): This guideline was developed by the National Clinical Guideline Centre (NCGC) on behalf of the National Institute for Health and Care Excellence (NICE). See the "Availability of Companion Documents" field for the full version of this guidance. The wording used in the recommendations in this guideline (for example words such as 'offer' and 'consider') denotes the certainty with which the recommendation is made (the strength of the recommendation) and is defined at the end of the "Major Recommendations" field. Assessing Risk of Acute Kidney Injury (AKI) Identifying AKI in Patients with Acute Illness Investigate for AKI, by measuring serum creatinine and comparing with baseline, in adults with acute illness if any of the following are likely or present: Chronic kidney disease (adults with an estimated glomerular filtration rate [eGFR] less than 60 ml/min/1.73 m2 are at particular risk) Heart failure Liver disease Diabetes History of AKI Oliguria (urine output less than 0.5 ml/kg/hour) Neurological or cognitive impairment or disability, which may mean limited access to fluids because of reliance on a carer Hypovolaemia Use of drugs with nephrotoxic potential (such as non-steroidal anti-inflammatory drugs [NSAIDs], aminoglycosides, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists [ARBs], and diuretics) within the past week, especially if hypovolaemic Use of iodinated contrast agents within the past week Symptoms or history of urological obstruction, or conditions that may lead to obstruction Sepsis Deteriorating early warning scores Age 65 years or over Investigate for AKI, by measuring serum creatinine and comparing with baseline, in children and young people with acute illness if any of the following are likely or present: Chronic kidney disease Heart failure Liver disease History of AKI Oliguria (urine output less than 0.5 ml/kg/hour) Young age, neurological or cognitive impairment, or disability, which may mean limited access to fluids because of reliance on a parent or carer Hypovolaemia Use of drugs with nephrotoxic potential (such as NSAIDs, aminoglycosides, ACE inhibitors, ARBs and diuretics) within the past week, especially if hypovolaemic Symptoms or history of urological obstruction, or conditions that may lead to obstruction Sepsis A deteriorating paediatric early warning score Severe diarrhoea (children and young people with bloody diarrhoea are at particular risk) Symptoms or signs of nephritis (such as oedema or haematuria) Haematological malignancy Hypotension Identifying AKI in Patients with No Obvious Acute Illness Be aware that in adults, children and young people with chronic kidney disease and no obvious acute illness, a rise in serum creatinine may indicate AKI rather than a worsening of their chronic disease. Ensure that AKI is considered when an adult, child or young person presents with an illness with no clear acute component and has any of the following: Chronic kidney disease, especially stage 3B, 4, or 5, or urological disease New onset or significant worsening of urological symptoms Symptoms suggesting complications of AKI Symptoms or signs of a multi-system disease affecting the kidneys and other organ systems (for example, signs or symptoms of AKI, plus a purpuric rash) Assessing Risk Factors in Adults Having Iodinated Contrast Agents Before offering iodinated contrast agents to adults for non-emergency imaging, investigate for chronic kidney disease by measuring eGFR or by checking an eGFR result obtained within the past 3 months. Before offering iodinated contrast agents to adults for emergency or non-emergency imaging, assess their risk of AKI. Be aware that increased risk is associated with: Chronic kidney disease (adults with an eGFR less than 40 ml/min/1.73 m2 are at particular risk) Diabetes but only with chronic kidney disease (adults with an eGFR less than 40 ml/min/1.73 m2 are at particular risk) Heart failure Renal transplant Age 75 years or over Hypovolaemia Increasing volume of contrast agent Intra-arterial administration of contrast agent Ensure that risk assessment does not delay emergency imaging. Include the risks of developing AKI in the routine discussion of risks and benefits of the imaging procedure. Follow the recommendations on shared decision-making in Patient experience in adult NHS services (NICE clinical guidance 138). Assessing Risk Factors in Adults Having Surgery Assess the risk of AKI in adults before surgery. Be aware that increased risk is associated with: Emergency surgery, especially when the patient has sepsis or hypovolaemia Intraperitoneal surgery Chronic kidney disease (adults with an eGFR less than 60 ml/min/1.73 m2 are at particular risk) Diabetes Heart failure Age 65 years or over Liver disease Use of drugs with nephrotoxic potential in the perioperative period (in particular, NSAIDs after surgery) Use the risk assessment to inform a clinical management plan. Include the risks of developing AKI in the routine discussion of risks and benefits of surgery. Follow the recommendations on shared decision-making in Patient experience in adult NHS services (NICE clinical guidance 138). Preventing AKI Ongoing Assessment of the Condition of Patients in Hospital Follow the recommendations in Recognition of and response to acute illness in adults in hospital (NICE clinical guideline 50) on the use of track and trigger systems (early warning scores) to identify adults who are at risk of AKI because their clinical condition is deteriorating or is at risk of deteriorating. When adults are at risk of AKI, ensure that systems are in place to recognise and respond to oliguria (urine output less than 0.5 ml/kg/hour) if the track and trigger system (early warning score) does not monitor urine output. Consider using a paediatric early warning score to identify children and young people admitted to hospital who are at risk of AKI because their clinical condition is deteriorating or is at risk of deteriorating. Record physiological observations at admission and then according to local protocols for given paediatric early warning scores. Increase the frequency of observations if abnormal physiology is detected. If using a paediatric early warning score, use one with multiple-parameter or aggregate weighted scoring systems that allow a graded response and: Define the parameters to be measured and the frequency of observations. Include a clear and explicit statement of the parameters, cut-off points, or scores that should trigger a response. If using a paediatric early warning score, use one with multiple-parameter or aggregate weighted scoring systems that measure: Heart rate Respiratory rate Systolic blood pressure Level of consciousness Oxygen saturation Temperature Capillary refill time When children and young people are at risk of AKI because of risk factors listed under "Identifying AKI in Patients with Acute Illness" above: Measure urine output Record weight twice daily to determine fluid balance Measure urea, creatinine, and electrolytes Think about measuring lactate, blood glucose, and blood gases Preventing AKI in Adults Having Iodinated Contrast Agents Offer intravenous volume expansion to adults having iodinated contrast agents if: They are at increased risk of contrast-induced AKI because of risk factors listed under "Assessing Risk Factors in Adults Having Iodinated Contrast Agents," above or They have an acute illness Offer either isotonic sodium bicarbonate or 0.9% sodium chloride. Consider temporarily stopping ACE inhibitors and ARBs in adults having iodinated contrast agents if they have chronic kidney disease with an eGFR less than 40 ml/min/1.73 m2. Discuss care with a nephrology team before offering iodinated contrast agent to adults with contraindications to intravenous fluids if: They are at increased risk of contrast-induced AKI, or They have an acute illness, or They are on renal replacement therapy Monitoring and Preventing Deterioration in Patients with or at High Risk of AKI Consider electronic clinical decision support systems (CDSS) to support clinical decision-making and prescribing, but ensure they do not replace clinical judgement. When acquiring any new CDSS or systems for electronic prescribing, ensure that any systems considered: Can interact with laboratory systems Can recommend drug dosing and frequency Can store and update data on patient history and characteristics, including age, weight, and renal replacement therapy Can include alerts that are mandatory for the healthcare professional to acknowledge and review Seek advice from a pharmacist about optimising medicines and drug dosing in adults, children, and young people with or at risk of AKI. Consider temporarily stopping ACE inhibitors and ARBs in adults, children, and young people with diarrhoea, vomiting or sepsis until their clinical condition has improved and stabilised. Detecting AKI Detect AKI, in line with the (p)RIFLE1, AKIN2 or KDIGO3 definitions, by using any of the following criteria: A rise in serum creatinine of 26 mol/litre or greater within 48 hours A 50% or greater rise in serum creatinine known or presumed to have occurred within the past 7 days A fall in urine output to less than 0.5 ml/kg/hour for more than 6 hours in adults and more than 8 hours in children and young people A 25% or greater fall in eGFR in children and young people within the past 7 days Monitor serum creatinine regularly4 in all adults, children, and young people with or at risk of AKI. 1Risk, Injury, Failure, Loss, End stage renal disease, (p) refers to the paediatric classification. 2Acute Kidney Injury Network 3Kidney Disease: Improving Global Outcomes 4The GDG did not wish to define 'regularly' because this would vary according to clinical need but recognised that daily measurement was typical while in hospital. Identifying the Cause(s) of AKI Identify the cause(s) of AKI and record the details in the patient's notes. Urinalysis Perform urine dipstick testing for blood, protein, leucocytes, nitrites, and glucose in all patients as soon as AKI is suspected or detected. Document the results and ensure that appropriate action is taken when results are abnormal. Think about a diagnosis of acute nephritis and referral to the nephrology team when an adult, child, or young person with no obvious cause of AKI has urine dipstick results showing haematuria and proteinuria, without urinary tract infection or trauma due to catheterisation. Ultrasound Do not routinely offer ultrasound of the urinary tract when the cause of the AKI has been identified. When pyonephrosis (infected and obstructed kidney[s]) is suspected in adults, children and young people with AKI, offer immediate ultrasound of the urinary tract (to be performed within 6 hours of assessment). When adults, children and young people have no identified cause of their AKI or are at risk of urinary tract obstruction, offer urgent ultrasound of the urinary tract (to be performed within 24 hours of assessment). Managing AKI Relieving Urological Obstruction Refer all adults, children, and young people with upper tract urological obstruction to a urologist. Refer immediately when one or more of the following is present: Pyonephrosis An obstructed solitary kidney Bilateral upper urinary tract obstruction Complications of AKI caused by urological obstruction When nephrostomy or stenting is used to treat upper tract urological obstruction in adults, children, and young people with AKI, undertake as soon as possible and within 12 hours of diagnosis. Pharmacological Management Do not routinely offer loop diuretics to treat AKI. Consider loop diuretics for treating fluid overload or oedema while: An adult, child or young person is awaiting renal replacement therapy, or Renal function is recovering in an adult, child, or young person not receiving renal replacement therapy Do not offer low-dose dopamine to treat AKI. Referring for Renal Replacement Therapy Discuss any potential indications for renal replacement therapy with a nephrologist, paediatric nephrologist, and/or critical care specialist immediately to ensure that the therapy is started as soon as needed. When an adult, child, or young person has significant comorbidities, discuss with them and/or their parent or carer and within the multidisciplinary team whether renal replacement therapy would offer benefit. Follow the recommendations on shared decision-making in Patient experience in adult NHS services (NICE clinical guidance 138). Refer adults, children, and young people immediately for renal replacement therapy if any of the following are not responding to medical management: Hyperkalaemia Metabolic acidosis Symptoms or complications of uraemia (for example, pericarditis or encephalopathy) Fluid overload Pulmonary oedema Base the decision to start renal replacement therapy on the condition of the adult, child, or young person as a whole and not on an isolated urea, creatinine, or potassium value. When there are indications for renal replacement therapy, the nephrologist and/or critical care specialist should discuss the treatment with the adult, child, or young person and/or their parent or carer as soon as possible and before starting treatment. Follow the recommendations on shared decision-making in Patient experience in adult NHS services (NICE clinical guidance 138). Referring to Nephrology Refer adults, children and young people with AKI to a nephrologist, paediatric nephrologist, and/or critical care specialist immediately if they meet criteria for renal replacement therapy listed under "Referring for Renal Replacement Therapy," above. Do not refer adults, children or young people to a nephrologist or paediatric nephrologist when there is a clear cause for AKI and the condition is responding promptly to medical management, unless they have a renal transplant. Consider discussing management with a nephrologist or paediatric nephrologist when an adult, child, or young person with severe illness might benefit from treatment, but there is uncertainty as to whether they are nearing the end of their life. Refer adults, children and young people in intensive care to a nephrology team when there is uncertainty about the cause of AKI or when specialist management of kidney injury might be needed. Discuss the management of AKI with a nephrologist or paediatric nephrologist as soon as possible and within 24 hours of detection when one or more of the following is present: A possible diagnosis that may need specialist treatment (for example, vasculitis, glomerulonephritis, tubulointerstitial nephritis, or myeloma) AKI with no clear cause Inadequate response to treatment Complications associated with AKI Stage 3 AKI (according to [p]RIFLE, AKIN, or KDIGO criteria) A renal transplant Chronic kidney disease stage 4 or 5 Monitor5 serum creatinine after an episode of AKI. Consider referral to a nephrologist or paediatric nephrologist when eGFR is 30 ml/min/1.73 m2 or less in adults, children, and young people who have recovered from an AKI. Consider referral to a paediatric nephrologist for children and young people who have recovered from an episode of AKI but have hypertension, impaired renal function or 1+ or greater proteinuria on dipstick testing of an early morning urine sample. 5The frequency of monitoring should be based on the stability and degree of renal function at the time of discharge. Information and Support for Patients and Carers Discuss immediate treatment options, monitoring, prognosis, and support options as soon as possible with people with AKI and/or, if appropriate, their parent or carer. Follow the recommendations on patient views and preferences and shared decision-making in Patient experience in adult NHS services (NICE clinical guidance 138). Give information about long-term treatment options, monitoring, self-management, and support to people who have had AKI (and/or their parent or carer, if appropriate) in collaboration with a multidisciplinary team appropriate to the person's individual needs. Give information about future care to people needing renal replacement therapy after discharge following AKI. This should include information about the frequency and length of dialysis sessions and the preparation needed (such as having a fistula or peritoneal catheter). Discuss the risk of developing AKI, particularly the risk associated with conditions leading to dehydration (for example, diarrhoea, and vomiting) and drugs with nephrotoxic potential (including over-the-counter NSAIDs), with people who are at risk of AKI, particularly those who have: Chronic kidney disease with an eGFR less than 60 ml/min/1.73 m2 Neurological or cognitive impairment or disability, which may mean limited access to fluids because of reliance on a carer Involve parents and carers in the discussion if appropriate Definitions: Strength of Recommendations Some recommendations can be made with more certainty than others. The Guideline Development Group (GDG) makes a recommendation based on the trade-off between the benefits and harms of an intervention, taking into account the quality of the underpinning evidence. For some interventions, the GDG is confident that, given the information it has looked at, most patients would choose the intervention. The wording used in the recommendations in this guideline denotes the certainty with which the recommendation is made (the strength of the recommendation). Interventions That Must (or Must Not) Be Used The GDG usually uses 'must' or 'must not' only if there is a legal duty to apply the recommendation. Occasionally 'must' (or 'must not') is used if the consequences of not following the recommendation could be extremely serious or potentially life threatening. Interventions That Should (or Should Not) Be Used a 'Strong' Recommendation The GDG uses 'offer' (and similar words such as 'refer' or 'advise') when confident that, for the vast majority of patients, an intervention will do more good than harm, and be cost effective. Similar forms of words (for example, 'Do not offer') are used when the GDG is confident that an intervention will not be of benefit for most patients. Interventions That Could Be Used The GDG uses 'consider' when confident that an intervention will do more good than harm for most patients, and be cost effective, but other options may be similarly cost effective. The choice of intervention, and whether or not to have the intervention at all, is more likely to depend on the patient's values and preferences than for a strong recommendation, and so the healthcare professional should spend more time considering and discussing the options with the patient.

A National Institute for Health and Care Excellence (NICE) care pathway titled "Acute Kidney Injury Overview" is available from the NICE Web site.

The type of evidence supporting the recommendations is not specifically stated.

Appropriate prevention, detection, and management of acute kidney injury up to the point of renal replacement therapy See the "Trade off between clinical benefits and harms" sections in the full version of the original guideline document for additional details about benefits of specific interventions.

Assessing Risk of Acute Kidney Injury (AKI) Although there is minimal physical harm if patients with a falsely elevated risk of AKI undergo more intensive and more frequent monitoring, it is certainly not desirable from the patient's perspective in the presence of an already established illness or indeed from the perspective of the effective use of National Health Service (NHS) resources. If a false negative risk assessment results in a change to an inferior therapy, patients may come to harm in both the short and longer term. Risk assessment tools might potentially influence clinical decision making in a deleterious way. For example they may deter clinicians from deploying investigations and treatments which they consider potentially nephrotoxic but may otherwise benefit the patient. As such, risk assessment tools and the clinical behaviours they drive, need to be carefully considered. Another potential harm of the completion of risk-assessment tools is the impact on workload and time which may divert from other aspects of care although this is considered minimal in light of the potential benefit that can be derived if properly applied. Preventing AKI The regular physiological assessment of children can cause anxiety to the child and their parents/carers, especially as such assessments are disruptive and cause disturbed sleep. There appeared to be a greater need for renal replacement therapy in the group given intravenous sodium bicarbonate versus no intravenous hydration for prevention of contrast induced AKI. However the uncertainty of these effects were too large to make clear conclusions about clinical harm. Detecting AKI It would be most important not to miss or delay diagnosis with a false negative result as this could lead to deterioration of the patient's clinical condition and increased complications (such as need for renal replacement therapy). False positive diagnosis could lead to unnecessary monitoring, blood tests, or other investigations, such as ultrasound scan, inappropriate administration of drugs, or withholding of drugs which would be given if the patient did not have AKI. This could lead to anxiety to patients and their families, and incorrect use of resources, with a likely increase in hospital stay. In a few cases, the false positive diagnosis might lead to unnecessary exposure to more invasive tests, exposure to radiation (e.g., if a computed tomography [CT] scan were performed). The Guideline Development Group (GDG) is aware that an acute creatinine increase of 26 mol/L in people with a raised baseline creatinine (i.e., those with chronic kidney disease) may lead to a false positive diagnosis as noted by the Acute Kidney Injury Network (AKIN). This is because increments at the lower end of the spectrum may not exceed any expected change attributable to the combined pre-analytical, biological, and analytical variability between measurements. However, clinicians need to recognise the serious risks that AKI poses for a patient with chronic kidney disease. Until further evidence is available, the current definitions may serve to heighten awareness and increase vigilance. Identifying the Cause of AKI The main potential harms with urine dipstick testing would arise in the case of false negative or false positive results. The implications of false negative results (under investigation of a potential glomerulonephritis as a cause of AKI) are minimised when a full evaluation and confirmation of urinalysis results using the correct procedure, as per the instructions of the dipstick manufacturer is undertaken. False positive haematuria on dipstick testing can lead to significant over investigation. In a patient with AKI, glomerular disease must be considered, which might require a series of relatively expensive biochemical and immunological tests (such as immunoglobulin, complement, autoimmune screen, antineutrophil cytoplasmic antibody [ANCA], anti-GBM). If doubt remains then renal biopsy might be required. This would represent a major additional cost, inconvenience and risk to the patient if it were undertaken on the basis of a false positive dipstick test. The clinical consequences of a failure to diagnose obstruction with ultrasound are potentially large. This must be balanced against the resource implications of routine ultrasound for all AKI, which is present in about 15% of hospital admissions. The potential risk of guidance which restricts access to ultrasound is that patients have undiagnosed obstruction with its attendant risks of worsening of AKI, severe sepsis (with an infected and obstructed urinary tract), development of AKI complications, exposure to the risks of renal replacement therapy, and potentially irreversible renal damage. It is acknowledged that ultrasound is not without 'harm' when unnecessarily undertaken in an unwell patient by adding further inconvenience and anxiety. Targeted ultrasound should mitigate against this potential harm. Managing AKI Possible harms of early relief of upper tract urological obstruction by nephrostomy or stenting include complications of the procedure including bleeding, infection/sepsis and injury to the obstructed kidney leading to worsening of chronic kidney disease or end stage renal disease, or injury to nearby organs. Evidence fromthe review suggests that loop diuretics resulted in possibly more deaths and an increased requirement for renal replacement therapy compared to placebo or usual care. There was also a suggestion that loop diuretics could cause hearing loss, although it is uncertain whether this difference is clinically important because the event rate was low and hearing loss was not consistently reported. Referring for Renal Replacement Therapy Early initiation of renal replacement therapy may result in patients who may have otherwise recovered renal function with conservative management alone to be exposed to the side effects of renal replacement therapy, in particular complications related to line insertion, risk of line infection, and bleeding complications as a result of anticoagulation. Renal replacement therapy in children is only available in paediatric intensive care units and in 11 paediatric nephrology centres in England and Wales, consequently often necessitating transfer over considerable distance with implications for the family and carers. Short term renal replacement therapy is offered at some adult centres for larger children and may be beneficial to stabilise critically ill children locally before transfer to a specialist centre to avoid unnecessary harm. Unlike in adults, the placement of dialysis access catheters in children almost always requires a general anaesthetic. The placement of these catheters is usually undertaken by consultant surgeons or anaesthetists whereas many adult access lines are placed by doctors in training. The early initiation of renal replacement therapy in children therefore requires careful consideration in light of the significant disruption for the child and family and the health care resource required for this to be successful. Delayed initiation of renal replacement therapy may cause harm to both adults and children by increasing the risk of uraemic emergencies and by making fluid and electrolyte management more challenging. This may worsen patient outcomes. Of particular concern to the GDG was the issue regarding the initiation of renal replacement therapy in patients who had significant comorbidities in whom the decision to commence renal replacement therapy may be inappropriate and adversely affect quality of life. For example, individuals with significant comorbidities may be more appropriately managed by an end of life care pathway/conservative management strategy as renal replacement therapy would be intrusive and potentially cause psychological harm to the patient or the patient's carers or family. The above trade-offs apply to both adults and children. Information and Support for Patients and Carers As with any potentially serious medical condition, there will be some patients who might react negatively to the provision of information about their condition. It might cause anxiety or depression, even if the details are presented in a sensitive manner. See the "Trade-off between clinical benefits and harms" sections of the full version of the original guideline document for additional details about harms of specific interventions.

For patients in whom intravenous fluids may be contraindicated, for example those with heart failure or chronic kidney disease with fluid overload, and at high risk of contrast-induced acute kidney injury, the Guideline Development Group recommended (by consensus) that their care should be discussed with a member of the nephrology team.

Audit Criteria/Indicators;Clinical Algorithm;Foreign Language Translations;Mobile Device Resources;Patient Resources;Resources

Getting Better;Staying Healthy

Effectiveness;Patient-centeredness

Not applicable: The guideline was not adapted from another source.

2013 Aug

National Institute for Health and Care Excellence (NICE)

Guideline Development Group (GDG)

Guideline Development Group Members: Mark Thomas (Chair), Consultant Physician and Nephrologist, Heart of England NHS Foundation Trust, Birmingham; Annette Davies, Lecturer Practitioner, The Renal Unit King's College Hospital, London and the Florence Nightingale School of Nursing and Midwifery, King's College London; Anne Dawnay, Consultant Clinical Scientist, Department of Clinical Biochemistry, University College London Hospitals; Mark Devonald, Consultant Nephrologist, Nottingham University Hospitals NHS Trust; Mark Downes (expert adviser), Consultant Radiologist, Kent and Canterbury Hospital; Coral Hulse, Nurse Consultant, Critical Care Outreach Service at Mid Cheshire Hospitals NHS Foundation Trust; Lyda Jadresic (expert adviser), Consultant Paediatrician, Gloucestershire Royal Hospital; Chris Laing, Consultant Nephrologist, University College London Centre for Nephrology Royal Free Hospital; John Lemberger, Consultant Urological Surgeon, City Hospital Nottingham; Andrew Lewington, Consultant Renal Physician/Clinical Sub Dean, Leeds Teaching Hospitals; Fiona Loud, Patient member, Director of Kidney Alliance; David Millford, Consultant Paediatric Renal Physician, Birmingham Children's Hospital; Shelagh O'Riordan (expert adviser), Consultant in Geriatric and General Medicine, Kent and Canterbury Hospital; Marlies Ostermann, Consultant in Nephrology and Critical Care, Guy's St Thomas' Hospital, London; Rajib Pal (expert adviser), GP Principal, Hall Green Health, West Midlands; Nicholas Palmer, Patient member, Head of Advocacy at the National Kidney Federation; Mark Rigby (expert adviser), Renal Clinical Nurse, Nottingham University Hospitals NHS Trust; Sue Shaw, Pharmacist, Renal Services, Royal Derby Hospital

At the start of the guideline development process all Guideline Development Group (GDG) members declared interests including consultancies, fee-paid work, share-holdings, fellowships, and support from the healthcare industry. At all subsequent GDG meetings, members declared arising conflicts of interest. Members were either required to withdraw completely or for part of the discussion if their declared interest made it appropriate. The details of declared interests and the actions taken are shown in Appendix B in the full version of the original guideline document (see the "Availability of Companion Documents" field).

Electronic copies: Available from the National Institute for Health and Care Excellence (NICE) Web site. Also available for download as a Kindle or EPUB ebook from the NICE Web site.

The following are available: Acute kidney injury. Prevention, detection and management up to the point of renal replacement therapy. Full guideline. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 283 p. (Clinical guideline; no 169). Electronic copies: Available in Portable Document Format (PDF) from the NICE Web site. Acute kidney injury. Prevention, detection and management up to the point of renal replacement therapy. Appendices. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 445 p. (Clinical guideline; no 169). Electronic copies: Available in PDF from the NICE Web site. Acute kidney injury. Prevention, detection and management up to the point of renal replacement therapy. Baseline assessment tool. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. (Clinical guideline; no 169). Electronic copies: Available from the NICE Web site. Acute kidney injury. Prevention, detection and management up to the point of renal replacement therapy. Clinical audit tools. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. (Clinical guideline; no 169). Electronic copies: Available from the NICE Web site. Acute kidney injury. Prevention, detection and management up to the point of renal replacement therapy. Costing statement. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 7 p. (Clinical guideline; no 169). Electronic copies: Available in PDF from the NICE Web site. Acute kidney injury overview. NICE pathway. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. Electronic copies: Available from the NICE Web site. The guidelines manual 2009. London (UK): National Institute for Health and Care Excellence (NICE); 2009 Jan. Electronic copies: Available in PDF from the NICE Archive Web site.

The following is available: Acute kidney injury. Information for the public. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. Electronic copies: Available from the National Institute for Health and Care Excellence (NICE) Web site. Also available for download as a Kindle or EPUB ebook from the NICE Web site. Also available in Welsh from the NICE Web site. Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

This summary was completed by ECRI Institute on November 27, 2013. The National Institute for Health and Care Excellence (NICE) has granted the National Guideline Clearinghouse (NGC) permission to include summaries of their clinical guidelines with the intention of disseminating and facilitating the implementation of that guidance. NICE has not yet verified this content to confirm that it accurately reflects that original NICE guidance and therefore no guarantees are given by NICE in this regard. All NICE clinical guidelines are prepared in relation to the National Health Service in England and Wales. NICE has not been involved in the development or adaptation of NICE guidance for use in any other country. The full versions of all NICE guidance can be found at www.nice.org.uk.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

10010

Autism. The management and support of children and young people on the autism spectrum.

National Collaborating Centre for Mental Health. Autism. The management and support of children and young people on the autism spectrum. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 36 p.(Clinical guideline; no. 170).

This is the current release of the guideline. This guideline meets NGC's 2013 (revised) inclusion criteria.

The autism spectrum

Anxiety Depression Sleep problems

Counseling;Evaluation;Management;Prevention;Risk Assessment;Treatment

Family Practice;Neurology;Nutrition;Pediatrics;Physical Medicine and Rehabilitation;Preventive Medicine;Psychiatry;Psychology;Speech-Language Pathology

Advanced Practice Nurses;Allied Health Personnel;Dietitians;Health Care Providers;Nurses;Occupational Therapists;Other;Patients;Physician Assistants;Physicians;Psychologists/Non-physician Behavioral Health Clinicians;Public Health Departments;Social Workers;Speech-Language Pathologists

To provide best practice advice on the management and support of children and young people on the autism spectrum

Children and young people (from birth until their 19th birthday) with autism (across the full range of intellectual ability) and their families and carers Note: These guidelines do not apply to adults (19 years and older).

Patient access to health and social care services, including mental health services Local autism team approach and specialist care with appropriate training Adjustments to social and physical environment Visual supports Personal space Sensory sensitivities to light, noise, colour of walls and furnishings Adjustment to health and social care processes, including timing and location of appointments Patient, family and carer involvement in decision-making Psychosocial interventions Play-based strategies Therapist modelling and video-interaction feedback Anticipation and prevention of challenging behavior Assessment of factors (e.g., coexisting physical disorders or mental problems, exploitation or abuse by others) Development of a care plan to address risk factors Assessment of and intervention for challenging behavior Reassessment of factors in the care plan Treatment of coexisting physical disorders or mental problems Consultation and multidisciplinary review Psychosocial interventions Pharmacological therapy (antipsychotic medication) Interventions for coexisting problems Cognitive behavioural therapy (CBT) Identification and treatment of sleep problems Transition to adult services Information and support for families and carers Note: The following were considered but not recommended: pharmacological therapy for the core features of autism; neurofeedback and auditory integration training to manage speech and language problems; omega-3 fatty acids to manage sleep problems; secretin, chelation, and hyperbaric oxygen therapy in any context.

Quality of life Adverse effects of treatment drugs Experience of care, including experience of services and transition Cost-effectiveness (e.g., quality-adjusted life year)

Hand-searches of Published Literature (Primary Sources);Hand-searches of Published Literature (Secondary Sources);Searches of Electronic Databases;Searches of Unpublished Data

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Overall Quality of Outcome Evidence in Grading of Recommendations Assessment, Development and Evaluation (GRADE) Level Description High Further research is very unlikely to change confidence in the estimate of effect Moderate Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate Low Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate Very Low Any estimate of effect is very uncertain

Meta-Analysis;Review of Published Meta-Analyses;Systematic Review with Evidence Tables

Expert Consensus;Informal Consensus

Presentation of Economic Evidence The economic evidence considered in the guideline is provided in the respective evidence chapters, following presentation of the relevant clinical evidence. The references to included studies and the respective evidence tables with the study characteristics and results are provided in Appendix 16 of the full version of the original guideline document. Methods and results of economic modelling undertaken alongside the guideline development process are presented in the relevant evidence chapters. Characteristics and results of all economic studies considered during the guideline development process (including modelling studies conducted for this guideline) are summarised in economic evidence profiles accompanying respective Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence profiles in Appendix 17 of the full version of the original guideline document. The completed methodology checklists for all economic evaluations considered in the guideline are provided in Appendix 15 in the full version of the original guideline document.

External Peer Review;Internal Peer Review

Validation of the Guideline Registered stakeholders had an opportunity to comment on the draft guideline, which was posted on the National Institute for Health and Care Excellence (NICE) website during the consultation period. Following the consultation, all comments from stakeholders and experts (see Appendix 3 in the full version of the original guideline document [see the "Availability of Companion Documents" field]) were responded to, and the guideline revised as appropriate. NICE also reviewed the guideline and checked that stakeholders' comments had been addressed. Following the consultation period, the Guideline Development Group finalised the recommendations and the National Collaborating Centre for Mental Health (NCCMH) produced the final documents. These were then submitted to NICE for a quality assurance check. Any errors were corrected by the NCCMH, then the guideline was formally approved by NICE and issued as guidance to theNational Health Service in England and Wales.

Note from the National Guideline Clearinghouse (NGC): This guideline was developed by the National Collaborating Centre for Mental Health (NCCMH) on behalf of the National Institute for Health and Care Excellence (NICE) (see the "Availability of Companion Documents" field for the full version of this guidance). The wording used in the recommendations in this guideline (for example, words such as 'offer' and 'consider') denotes the certainty with which the recommendation is made (the strength of the recommendation) and is defined at the end of the "Major Recommendations" field. General Principles of Care Access to Health and Social Care Services Ensure that all children and young people with autism have full access to health and social care services, including mental health services, regardless of their intellectual ability or any coexisting diagnosis. Organisation and Delivery of Services The overall configuration and development of local services (including health, mental health, learning disability, education, and social care services) for children and young people with autism, should be coordinated by a local autism multi-agency strategy group (for people with autism of all ages) in line with the NGC summaries of NICE guidelines Autism: recognition, referral and diagnosis of children and young people on the autism spectrum (NICE clinical guideline 128) (covering identification and diagnosis) and Autism: recognition, referral, diagnosis and management of adults on the autism spectrum (NICE clinical guideline 142). The assessment, management and coordination of care for children and young people with autism should be provided through local specialist community-based multidisciplinary teams ('local autism teams') which should include professionals from health, mental health, learning disability, education and social care services in line with the NGC summaries of the NICE guidelines Autism: recognition, referral and diagnosis of children and young people on the autism spectrum (NICE clinical guideline 128) (covering identification and diagnosis) and Autism: recognition, referral, diagnosis and management of adults on the autism spectrum (NICE guideline 142). Local autism teams should ensure that every child or young person diagnosed with autism has a case manager or key worker to manage and coordinate treatment, care, support and transition to adult care in line with the NGC summary of the NICE guideline Autism: recognition, referral and diagnosis of children and young people on the autism spectrum (NICE clinical guideline 128) (covering identification and diagnosis). Local autism teams should provide (or organise) the interventions and care recommended in this guideline for children and young people with autism who have particular needs, including: Looked-after children and young people Those from immigrant groups Those with regression in skills Those with coexisting conditions such as: Severe visual and hearing impairments Other medical problems including epilepsy or sleep and elimination problems Motor disorders including cerebral palsy Intellectual disability Severe communication impairment, including lack of spoken language, or complex language disorders Mental health problems Local autism teams should have a key role in the delivery and coordination of: Specialist care and interventions for children and young people with autism, including those living in specialist residential accommodation Advice, training and support for other health and social care professionals and staff (including in residential and community settings) who may be involved in the care of children and young people with autism Advice and interventions to promote functional adaptive skills including communication and daily living skills Assessing and managing behaviour that challenges Assessing and managing coexisting conditions Reassessing needs throughout childhood and adolescence, taking particular account of transition to adult services Supporting access to leisure and enjoyable activities Supporting access to and maintaining contact with educational, housing, and employment services Providing support for families (including siblings) and carers, including offering short breaks and other respite care Producing local protocols for: Information sharing, communication, and collaborative working among healthcare, education and social care services, including arrangements for transition to adult services Shared care arrangements with primary care providers and ensuring that clear lines of communication between primary and secondary care are maintained Refer children and young people with autism to a regional or national autism service if there is a lack of: Local skills and competencies needed to provide interventions and care for a child or young person with a complex coexisting condition, such as a severe sensory or motor impairment or mental health problem, or Response to the therapeutic interventions provided by the local autism team Knowledge and Competence of Health and Social Care Professionals Health and social care professionals working with children and young people with autism in any setting should receive training in autism awareness and skills in managing autism, which should include: The nature and course of autism The nature and course of behaviour that challenges in children and young people with autism Recognition of common coexisting conditions, including: Mental health problems such as anxiety and depression Physical health problems such as epilepsy Sleep problems Other neurodevelopmental conditions such as attention deficit hyperactivity disorder (ADHD) The importance of key transition points, such as changing schools or health or social care services The child or young person's experience of autism and its impact on them The impact of autism on the family (including siblings) or carers The impact of the social and physical environment on the child or young person How to assess risk (including self-harm, harm to others, self-neglect, breakdown of family or residential support, exploitation or abuse by others) and develop a risk management plan The changing needs that arise with puberty (including the child or young person's understanding of intimate relationships and related problems that may occur, for example, misunderstanding the behaviour of others) How to provide individualised care and support and ensure a consistent approach is used across all settings Skills for communicating with a child or young person with autism Making Adjustments to the Social and Physical Environment and Processes of Care Take into account the physical environment in which children and young people with autism are supported and cared for. Minimise any negative impact by: Providing visual supports, for example, words, pictures, or symbols that are meaningful for the child or young person Making reasonable adjustments or adaptations to the amount of personal space given Considering individual sensory sensitivities to lighting, noise levels, and the colour of walls and furnishings Make adjustments or adaptations to the processes of health or social care, for example, arranging appointments at the beginning or end of the day to minimise waiting time, or providing single rooms for children and young people who may need a general anaesthetic in hospital (for example, for dental treatment). Information and Involvement in Decision-making Provide children and young people with autism, and their families and carers, with information about autism and its management and the support available on an ongoing basis, suitable for the child or young person's needs and developmental level. This may include: Contact details for local and national organisations that can provide: Support and an opportunity to meet other people, including families or carers, with experience of autism Information on courses about autism Advice on welfare benefits, rights and entitlements Information about educational and social support and leisure activities Information about services and treatments available Information to help prepare for the future, for example, transition to adult services Make arrangements to support children and young people with autism and their family and carers during times of increased need, including major life changes such as puberty, starting or changing schools, or the birth of a sibling. Explore with children and young people with autism, and their families and carers, whether they want to be involved in shared decision-making and continue to explore these issues at regular intervals. If children and young people express interest, offer a collaborative approach to treatment and care that takes their preferences into account. Families and Carers Offer all families (including siblings) and carers verbal and written information about their right to: Short breaks and other respite care A formal carer's assessment of their own physical and mental health needs, and how to access these Offer families (including siblings) and carers an assessment of their own needs, including whether they have: Personal, social and emotional support Practical support in their caring role, including short breaks and emergency plans A plan for future care for the child or young person, including transition to adult services When the needs of families and carers have been identified, discuss help available locally and, taking into account their preferences, offer information, advice, training and support, especially if they: Need help with the personal, social or emotional care of the child or young person, including age-related needs such as self-care, relationships, or sexuality. Are involved in the delivery of an intervention for the child or young person in collaboration with health and social care professionals. Specific Interventions for the Core Features of Autism Psychosocial Interventions Consider a specific social-communication intervention for the core features of autism in children and young people that includes play-based strategies with parents, carers and teachers to increase joint attention, engagement and reciprocal communication in the child or young person. Strategies should: Be adjusted to the child or young person's developmental level Aim to increase the parents', carers', teachers', or peers' understanding of, and sensitivity and responsiveness to, the child or young person's patterns of communication and interaction Include techniques of therapist modelling and video-interaction feedback Include techniques to expand the child or young person's communication, interactive play, and social routines The intervention should be delivered by a trained professional. For pre-school children consider parent, carer, or teacher mediation. For school-aged children consider peer mediation. Pharmacological and Dietary Interventions Do not use the following interventions for the management of core features of autism in children and young people: Antipsychotics Antidepressants Anticonvulsants Exclusion diets (such as gluten- or casein-free diets) Interventions for Behaviour That Challenges Anticipating and Preventing Behaviour That Challenges Assess factors that may increase the risk of behaviour that challenges in routine assessment and care planning in children and young people with autism, including: Impairments in communication that may result in difficulty understanding situations or in expressing needs and wishes Coexisting physical disorders, such as pain or gastrointestinal disorders Coexisting mental health problems such as anxiety or depression and other neurodevelopmental conditions such as ADHD The physical environment, such as lighting and noise levels The social environment, including home, school and leisure activities Changes to routines or personal circumstances Developmental change, including puberty Exploitation or abuse by others Inadvertent reinforcement of behaviour that challenges The absence of predictability and structure Develop a care plan with the child or young person and their families or carers that outlines the steps needed to address the factors that may provoke behaviour that challenges, including: Treatment, for example, for coexisting physical, mental health, and behavioural problems Support, for example, for families or carers Necessary adjustments, for example, by increasing structure and minimising unpredictability Assessment and Initial Intervention for Behaviour That Challenges If a child or young person's behaviour becomes challenging, reassess factors identified in the care plan and assess for any new factors that could provoke the behaviour. Offer the following to address factors that may trigger or maintain behaviour that challenges: Treatment for physical disorders, or coexisting mental health and behavioural problems Interventions aimed at changing the environment, such as: Providing advice to families and carers Making adjustments or adaptations to the physical surroundings (see "Making Adjustments to the Social and Physical Environment and Processes of Care," above) If behaviour remains challenging despite attempts to address the underlying possible causes, consult senior colleagues and undertake a multidisciplinary review. At the multidisciplinary review, take into account the following when choosing an intervention for behaviour that challenges: The nature, severity and impact of the behaviour The child or young person's physical and communication needs and capabilities The environment The support and training that families, carers or staff may need to implement the intervention effectively The preferences of the child or young person and the family or carers The child or young person's experience of, and response to, previous interventions Psychosocial Interventions for Behaviour That Challenges If no coexisting mental health or behavioural problem, physical disorder, or environmental problem has been identified as triggering or maintaining the behaviour that challenges, offer the child or young person a psychosocial intervention (informed by a functional assessment of behaviour) as a first-line treatment. The functional assessment should identify: Factors that appear to trigger the behaviour Patterns of behaviour The needs that the child or young person is attempting to meet by performing the behaviour The consequences of the behaviour (that is, the reinforcement received as a result of the behaviour) Psychosocial interventions for behaviour that challenges should include: Clearly identified target behaviour A focus on outcomes that are linked to quality of life Assessment and modification of environmental factors that may contribute to initiating or maintaining the behaviour A clearly defined intervention strategy that takes into account the developmental level and coexisting problems of the child or young person A specified timescale to meet intervention goals (to promote modification of intervention strategies that do not lead to change within a specified time) A systematic measure of the target behaviour taken before and after the intervention to ascertain whether the agreed outcomes are being met Consistent application in all areas of the child or young person's environment (for example, at home and at school) Agreement among parents, carers and professionals in all settings about how to implement the intervention Pharmacological Interventions for Behaviour That Challenges Consider antipsychotic medication1 for managing behaviour that challenges in children and young people with autism when psychosocial or other interventions are insufficient or could not be delivered because of the severity of the behaviour. Antipsychotic medication should be initially prescribed and monitored by a paediatrician or psychiatrist who should: Identify the target behaviour. Decide on an appropriate measure to monitor effectiveness, including frequency and severity of the behaviour and a measure of global impact. Review the effectiveness and any side effects of the medication after 3 to 4 weeks. Stop treatment if there is no indication of a clinically important response at 6 weeks. If antipsychotic medication is prescribed: Start with a low dose. Use the minimum effective dose needed. Regularly review the benefits of the antipsychotic medication and any adverse events. When choosing antipsychotic medication, take into account side effects, acquisition costs, the child or young person's preference (or that of their parent or carer where appropriate), and response to previous treatment with an antipsychotic. When prescribing is transferred to primary or community care, the specialist should give clear guidance to the practitioner who will be responsible for continued prescribing about: The selection of target behaviours Monitoring of beneficial and side effects The potential for minimally effective dosing The proposed duration of treatment Plans for stopping treatment 1At the time of publication (August 2013), no antipsychotic medication had a UK marketing authorisation for use in children for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Interventions for Life Skills Offer children and young people with autism support in developing coping strategies and accessing community services, including developing skills to access public transport, employment, and leisure facilities. Interventions for Autism That Should Not Be Used Do not use neurofeedback to manage speech and language problems in children and young people with autism. Do not use auditory integration training to manage speech and language problems in children and young people with autism. Do not use omega-3 fatty acids to manage sleep problems in children and young people with autism. Do not use the following interventions to manage autism in any context in children and young people: Secretin Chelation Hyperbaric oxygen therapy Interventions for Coexisting Problems Offer psychosocial and pharmacological interventions for the management of coexisting mental health or medical problems in children and young people with autism in line with NICE guidance for children and young people, including: The NGC summary of the NICE guideline Attention deficit hyperactivity disorder: diagnosis and management (NICE clinical guideline 72) The NGC summary of the NICE guideline Antisocial behaviour and conduct disorders in children and young people: recognition, intervention and management (NICE clinical guideline 158) The NICE guideline Constipation in children and young people. Diagnosis and management of idiopathic childhood constipation in primary and secondary care (NICE clinical guideline 99) Depression in children and young people: identification and management in primary, community and secondary care (NICE clinical guideline 28) The NGC summary of The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (NICE clinical guideline 137) Core interventions in the treatment of obsessive-compulsive disorder and body dysmorphic disorder (NICE clinical guideline 31) Post-traumatic stress disorder: The management of PTSD in adults and children in primary and secondary care (NICE clinical guideline 26) Consider the following for children and young people with autism and anxiety who have the verbal and cognitive ability to engage in a cognitive behavioural therapy (CBT) intervention: Group CBT adjusted to the needs of children and young people with autism Individual CBT for children and young people who find group-based activities difficult Consider adapting the method of delivery of CBT for children and young people with autism and anxiety to include: Emotion recognition training Greater use of written and visual information and structured worksheets A more cognitively concrete and structured approach Simplified cognitive activities, for example, multiple-choice worksheets Involving a parent or carer to support the implementation of the intervention, for example, involving them in therapy sessions Maintaining attention by offering regular breaks Incorporating the child or young person's special interests into therapy if possible Interventions for Sleep Problems If a child or young person with autism develops a sleep problem offer an assessment that identifies: What the sleep problem is (for example, delay in falling asleep, frequent waking, unusual behaviours, breathing problems or sleepiness during the day) Day and night sleep patterns, and any change to those patterns Whether bedtime is regular What the sleep environment is like, for example: The level of background noise Use of a blackout blind A television or computer in the bedroom Whether the child shares the room with someone Presence of comorbidities especially those that feature hyperactivity or other behavioural problems Levels of activity and exercise during the day Possible physical illness or discomfort (for example, reflux, ear or toothache, constipation, or eczema) Effects of any medication Any other individual factors thought to enhance or disturb sleep, such as emotional relationships or problems at school The impact of sleep and behavioural problems on parents or carers and other family members If the child or young person with autism snores loudly, chokes, or appears to stop breathing while sleeping, refer to a specialist to check for obstructive sleep apnoea. Develop a sleep plan (this will often be a specific sleep behavioural intervention) with the parents or carers to help address the identified sleep problems and to establish a regular night-time sleep pattern. Ask the parents or carers to record the child or young person's sleep and wakefulness throughout the day and night over a 2-week period. Use this information to modify the sleep plan if necessary and review the plan regularly until a regular sleep pattern is established. Do not use a pharmacological intervention to aid sleep unless: Sleep problems persist despite following the sleep plan. Sleep problems are having a negative impact on the child or young person and their family or carers. If a pharmacological intervention is used to aid sleep it should: Only be used following consultation with a specialist paediatrician or psychiatrist with expertise in the management of autism or paediatric sleep medicine Be used in conjunction with non-pharmacological interventions Be regularly reviewed to evaluate the ongoing need for a pharmacological intervention and to ensure that the benefits continue to outweigh the side effects and risks If the sleep problems continue to impact on the child or young person or their parents or carers, consider: Referral to a paediatric sleep specialist and Short breaks and other respite care for one night or more. Short breaks may need to be repeated regularly to ensure that parents or carers are adequately supported. Agree the frequency of breaks with them and record this in the care plan. Transition to Adult Services Local autism teams should ensure that young people with autism who are receiving treatment and care from child and adolescent mental health services (CAMHS) or child health services are reassessed at around 14 years to establish the need for continuing treatment into adulthood. If continuing treatment is necessary, make arrangements for a smooth transition to adult services and give information to the young person about the treatment and services they may need. The timing of transition may vary locally and individually but should usually be completed by the time the young person is 18 years. Variations should be agreed by both child and adult services. As part of the preparation for the transition to adult services, health and social care professionals should carry out a comprehensive assessment of the young person with autism. The assessment should make best use of existing documentation about personal, educational, occupational, social, and communication functioning, and should include assessment of any coexisting conditions, especially depression, anxiety, ADHD, obsessive-compulsive disorder (OCD), and global delay or intellectual disability in line with the NGC summary of the NICE guideline Autism: recognition, referral, diagnosis and management of adults on the autism spectrum (NICE clinical guideline 142). For young people aged 16 or older whose needs are complex or severe, use the care programme approach in England, or care and treatment plans in Wales, as an aid to transfer between services. Involve the young person in the planning and, where appropriate, their parents or carers. Provide information about adult services to the young person, and their parents or carers, including their right to a social care assessment at age 18. During transition to adult services, consider a formal meeting involving health and social care and other relevant professionals from child and adult services. Definitions: Strength of Recommendations Some recommendations can be made with more certainty than others. The Guideline Development Group (GDG) makes a recommendation based on the trade-off between the benefits and harms of an intervention, taking into account the quality of the underpinning evidence. For some interventions, the GDG is confident that, given the information it has looked at, most patients would choose the intervention. The wording used in the recommendations in this guideline denotes the certainty with which the recommendation is made (the strength of the recommendation). Interventions That Must (or Must Not) Be Used The GDG usually uses 'must' or 'must not' only if there is a legal duty to apply the recommendation. Occasionally 'must' (or 'must not') is used if the consequences of not following the recommendation could be extremely serious or potentially life threatening. Interventions That Should (or Should Not) Be Used a 'Strong' Recommendation The GDG uses 'offer' (and similar words such as 'refer' or 'advise') when confident that, for the vast majority of patients, an intervention will do more good than harm, and be cost effective. Similar forms of words (for example, 'Do not offer') are used when the GDG is confident that an intervention will not be of benefit for most patients. Interventions That Could Be Used The GDG uses 'consider' when confident that an intervention will do more good than harm for most patients, and be cost effective, but other options may be similarly cost effective. The choice of intervention, and whether or not to have the intervention at all, is more likely to depend on the patient's values and preferences than for a strong recommendation, and so the healthcare professional should spend more time considering and discussing the options with the patient.

A National Institute for Health and Care Excellence (NICE) pathway titled "Autism Overview" is available from the NICE Web site.

The type of evidence supporting the recommendations is not specifically stated.

Appropriate management and support of children and young people on the autism spectrum See the "From Evidence to Recommendations" sections of the full version of the original guideline document for additional details about benefits of specific interventions.

Side effects of medications See the "From Evidence to Recommendations" sections and Chapter 9 in the full version of the original guideline document for additional details about potential harms of specific interventions.

The National Institute for Health and Care Excellence (NICE) has developed tools to help organisations implement this guidance. These are available on the NICE Web site (see also the "Availability of Companion Documents" field). Key Priorities for Implementation The following recommendations have been identified as priorities for implementation. Access to Health and Social Care Services Ensure that all children and young people with autism have full access to health and social care services, including mental health services, regardless of their intellectual ability or any coexisting diagnosis. Knowledge and Competence of Health and Social Care Professionals Health and social care professionals working with children and young people with autism in any setting should receive training in autism awareness and skills in managing autism, which should include: The nature and course of autism The nature and course of behaviour that challenges in children and young people with autism Recognition of common coexisting conditions, including: Mental health problems such as anxiety and depression Physical health problems such as epilepsy Sleep problems Other neurodevelopmental conditions such as attention deficit hyperactivity disorder (ADHD) The importance of key transition points, such as changing schools or health or social care services The child or young person's experience of autism and its impact on them The impact of autism on the family (including siblings) or carers The impact of the social and physical environment on the child or young person How to assess risk (including self-harm, harm to others, self-neglect, breakdown of family or residential support, exploitation, or abuse by others) and develop a risk management plan The changing needs that arise with puberty (including the child or young person's understanding of intimate relationships and related problems that may occur, for example, misunderstanding the behaviour of others) How to provide individualised care and support and ensure a consistent approach is used across all settings Skills for communicating with a child or young person with autism Making Adjustments to the Social and Physical Environment and Processes of Care Take into account the physical environment in which children and young people with autism are supported and cared for. Minimise any negative impact by: Providing visual supports, for example, words, pictures or symbols that are meaningful for the child or young person Making reasonable adjustments or adaptations to the amount of personal space given Considering individual sensory sensitivities to lighting, noise levels, and the colour of walls and furnishings Make adjustments or adaptations to the processes of health or social care, for example, arranging appointments at the beginning or end of the day to minimise waiting time, or providing single rooms for children and young people who may need a general anaesthetic in hospital (for example, for dental treatment). Psychosocial Interventions Consider a specific social-communication intervention for the core features of autism in children and young people that includes play-based strategies with parents, carers and teachers to increase joint attention, engagement and reciprocal communication in the child or young person. Strategies should: Be adjusted to the child or young person's developmental level Aim to increase the parents', carers', teachers' or peers' understanding of, and sensitivity and responsiveness to, the child or young person's patterns of communication and interaction Include techniques of therapist modelling and video-interaction feedback Include techniques to expand the child or young person's communication, interactive play, and social routines The intervention should be delivered by a trained professional. For pre-school children consider parent, carer or teacher mediation. For school-aged children consider peer mediation. Anticipating and Preventing Behaviour That Challenges Assess factors that may increase the risk of behaviour that challenges in routine assessment and care planning in children and young people with autism, including: Impairments in communication that may result in difficulty understanding situations or in expressing needs and wishes Coexisting physical disorders, such as pain or gastrointestinal disorders Coexisting mental health problems such as anxiety or depression and other neurodevelopmental conditions such as ADHD The physical environment, such as lighting and noise levels The social environment, including home, school and leisure activities Changes to routines or personal circumstances Developmental change, including puberty Exploitation or abuse by others Inadvertent reinforcement of behaviour that challenges The absence of predictability and structure Psychosocial Interventions for Behaviour That Challenges If no coexisting mental health or behavioural problem, physical disorder or environmental problem has been identified as triggering or maintaining the behaviour that challenges, offer the child or young person a psychosocial intervention (informed by a functional assessment of behaviour) as a first-line treatment. Pharmacological Interventions for Behaviour That Challenges Consider antipsychotic medication1 for managing behaviour that challenges in children and young people with autism when psychosocial or other interventions are insufficient or could not be delivered because of the severity of the behaviour. Antipsychotic medication should be initially prescribed and monitored by a paediatrician or psychiatrist who should: Identify the target behaviour. Decide on an appropriate measure to monitor effectiveness, including frequency and severity of the behaviour and a measure of global impact. Review the effectiveness and any side effects of the medication after 3 to 4 weeks. Stop treatment if there is no indication of a clinically important response at 6 weeks. 1At the time of publication (August 2013), no antipsychotic medication had a UK marketing authorisation for use in children for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Families and Carers Offer families (including siblings) and carers an assessment of their own needs, including whether they have: Personal, social, and emotional support Practical support in their caring role, including short breaks and emergency plans A plan for future care for the child or young person, including transition to adult services Transition to Adult Services For young people aged 16 or older whose needs are complex or severe, use the care programme approach (CPA) in England, or care and treatment plans in Wales, as an aid to transfer between services. Involve the young person in the planning and, where appropriate, their parents or carers. Provide information about adult services to the young person, and their parents or carers, including their right to a social care assessment at age 18. From National Clinical Guidelines to Local Protocols Once a national guideline has been published and disseminated, local healthcare groups will be expected to produce a plan and identify resources for implementation, along with appropriate timetables. Subsequently, a multidisciplinary group involving commissioners of healthcare, primary care, and specialist mental health professionals, service users, and carers should undertake the translation of the implementation plan into local protocols, taking into account both the recommendations set out in this guideline and the priorities in the National Service Framework for Mental Health and related documentation. The nature and pace of the local plan will reflect local healthcare needs and the nature of existing services; full implementation may take a considerable time, especially where substantial training needs are identified.

Clinical Algorithm;Mobile Device Resources;Patient Resources;Resources

Living with Illness;Staying Healthy

Effectiveness;Patient-centeredness

Not applicable: The guideline was not adapted from another source.

2013 Aug

National Institute for Health and Care Excellence (NICE)

Guideline Development Group

Guideline Development Group Members: Gillian Baird (Chair), Consultant Paediatrician and Professor of Paediatric Neurodisability, Guy's and St Thomas' NHS Foundation trust and King's Health partners, London; Tim Kendall (Facilitator), Medical Director and Consultant Psychiatrist, Sheffield Health and Social Care, NHS Foundation Trust and Director, National Collaborating Centre for Mental Health; Nick Gould (Co-facilitator), Emeritus Professor of Social Work, University of Bath, Consultant, Social Care Institute for Excellence; Virginia Bovell, Patient and carer member; Carole Buckley, General Practitioner, Bristol; Tony Charman, Chair in Clinical Child Psychology, King's College London; Jonathan Green, Professor of Child and Adolescent Psychiatry, University of Manchester and Royal Manchester Children's Hospital; Patricia Howlin, Emeritus Professor of Clinical Child Psychology, King's College London; Glenys Jones, Lecturer in Autism, University of Birmingham; Ann Le Couteur, Professor of Child and Adolescent Psychiatry, Newcastle University, Honorary Child and Adolescent Consultant Psychiatrist, Northumberland Tyne and Wear NHS Foundation Trust; Robin Mackenzie, Patient and carer member, Medical Law and Ethics, University of Kent; Barbara Parker, Patient and carer member; Emily Simonoff, Academic lead, Child and Adolescent Mental Health, Institute of Psychiatry; Stephen Simpson, Community Learning Disability Nurse, South West Yorkshire Partnership NHS Foundation Trust; Vicky Slonims, Clinical Lead Speech and Language Therapist, Guy's and St Thomas' NHS Foundation Trust, Honorary Senior Lecturer, Kings College London; Alison Stewart, Manager, Speech and Language Therapy Service to Education, Central London Community Healthcare Trust, Honorary Lecturer City University; Katy Strudwick, Clinical Specialist Paediatric Occupational Therapist, St Thomas' Hospital; Gabriel Whitlingum, Consultant Paediatrician, Hampshire Hospitals Foundation Trust

All Guideline Development Group (GDG) members made formal declarations of interest at the outset, which were updated at every GDG meeting, and service user and carer concerns were routinely discussed as a standing agenda item. See Appendix 2 in the full version of the original guideline document (see the "Availability of Companion Documents" field) for declarations of interests by GDG members.

Electronic copies: Available from the National Institute for Health and Care Excellence (NICE) Web site. Also available for download as a Kindle or EPUB ebook from the NICE Web site.

The following are available: Autism. The management and support of children and young people on the autism spectrum. Full guideline. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 866 p. (Clinical guideline; no 170). Electronic copies: Available in Portable Document Format (PDF) from the NICE Web site. Autism. The management and support of children and young people on the autism spectrum. Appendices 1-13. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. (Clinical guideline; no 170). Electronic copies: Available in PDF from the NICE Web site. Autism. The management and support of children and young people on the autism spectrum. Appendices 14-19. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. (Clinical guideline; no 170). Electronic copies: Available in PDF from the NICE Web site. Autism. The management and support of children and young people on the autism spectrum. Baseline assessment tool. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. (Clinical guideline; no 170). Electronic copies: Available from the NICE Web site. Autism. The management and support of children and young people on the autism spectrum. Costing statement. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 9 p. (Clinical guideline; no 170). Electronic copies: Available in PDF from the NICE Web site. Autism overview. NICE pathway. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. Electronic copies: Available from the NICE Web site The guidelines manual 2009. London (UK): National Institute for Health and Care Excellence (NICE); 2009 Jan. Electronic copies: Available in PDF from the NICE Archive Web site.

The following is available: Managing autism in children and young people. Information for the public. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. Electronic copies: Available from the National Institute for Health and Care Excellence (NICE) Web site. Also available for download as a Kindle or EPUB ebook from the NICE Web site. Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

10011

Everolimus in combination with exemestane for treating advanced HER2-negative hormone-receptor-positive breast cancer after endocrine therapy.

National Institute for Health and Care Excellence (NICE). Everolimus in combination with exemestane for treating advanced HER2-negative hormone-receptor-positive breast cancer after endocrine therapy. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 62 p.(Technology appraisal guidance; no. 295).

This is the current release of the guideline.

Advanced human epidermal growth factor receptor 2 (HER2)-negative hormone-receptor-positive breast cancer

Assessment of Therapeutic Effectiveness;Treatment

Endocrinology;Family Practice;Internal Medicine;Obstetrics and Gynecology;Oncology

Advanced Practice Nurses;Nurses;Physician Assistants;Physicians

To assess the clinical effectiveness and cost-effectiveness of everolimus in combination with exemestane for treating advanced human epidermal growth factor receptor 2 (HER2)-negative hormone-receptor-positive breast cancer after endocrine therapy

Postmenopausal women with advanced human epidermal growth factor receptor 2 (HER2)-negative hormone-receptor-positive breast cancer that has recurred or progressed following a non-steroidal aromatase inhibitor (NSAI)

Everolimus in combination with exemestane (not recommended)

Clinical effectiveness Progression-free survival/time to progression (PFS/TTP) Overall survival (OS) Overall response rate Health-related quality of life (HRQoL) Duration of response Time to response Clinical benefit rate Adverse events Cost-effectiveness

Hand-searches of Published Literature (Primary Sources);Hand-searches of Published Literature (Secondary Sources);Searches of Electronic Databases;Searches of Unpublished Data

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Care Excellence (NICE) commissioned an independent academic centre to perform an assessment of the manufacturer's submission on the technology considered in this appraisal and prepare an Evidence Review Group (ERG) report. The ERG report for this technology appraisal was prepared by the Liverpool Reviews and Implementation Group (see the "Availability of Companion Documents" field). Clinical Effectiveness Searches Systematic Review The following databases were searched by the manufacturer, 8 to 9 March 2012: MEDLINE and MEDLINE In-Process (OvidSP) EMBASE (OvidSP) Science Citation Index (ISI Web of Science) Conference Proceedings Citation Index Science (ISI Web of Science) Cochrane Library (Wiley Interscience): Cochrane Database of Systematic Reviews Cochrane Central Register of Controlled Trials Database of Abstracts of Reviews of Effects (DARE) Health Technology Assessment Database (HTA) ClinicalTrials.gov (www.clinicaltrials.gov) International Clinical Trials Registry Platform (http://www.who.int/ictrp/en/) metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/) US Food and Drug Administration (www.fda.gov/) European Medicines Agency (www.ema.europa.eu/) National Institute for Health and Care Excellence (http://www.nice.org.uk/) American Society for Clinical Oncology (ASCO) annual meeting (www.asco.org) European Society for Medical Oncology (ESMO) annual meeting (www.esmo.org/) International Society for Pharmacoeconomics and Outcomes Research (www.ispor.org) European CanCer Organisation (ECCO) and European Breast Cancer Conference (EBCC) annual meeting (www.ecco-org.eu/) San Antonio Breast Cancer Symposium (SABC) (www.sabcs.org/) For all databases, search terms included the term 'everolimus'. For MEDLINE and MEDLINE In-Process, EMBASE and Science Citation Index, searches were also limited to second line or recurrent advanced breast cancer or metastatic breast cancer. No language, study or date restrictions were employed, nor were any search filters used. The search strategies employed appear to be comprehensive. The ERG also conducted its own searches of MEDLINE and MEDLINE In-Process (Ovid SP), EMBASE (Ovid SP), ASCO and SABCS on 5 December 2012 and did not identify any additional potentially relevant studies. Mixed Treatment Comparison A series of searches was undertaken by the manufacturer on 22 March 2012 to identify systematic reviews and trials which could be used to provide indirect comparisons. The first searches were undertaken in the following databases: MEDLINE and MEDLINE In-Process (OvidSP) EMBASE (OvidSP) The Cochrane Library (Wiley Interscience) ClinicalTrials.gov (http://clinicaltrials.gov/) ICTRP (www.who.int/ictrp/) A second series of searches were undertaken on 26 March 2012 in the Cochrane Library databases via the Wiley Interscience interface, specifically the Cochrane Database of Systematic Reviews (CDSR) and the DARE and HTA database. Searches were also undertaken on the National Horizon Scanning Centre website and the NICE website. For all databases, search terms were limited to identify breast cancer studies and, where databases allowed, attempts were made to limit the searches to identify randomised controlled trials (RCTs) and systematic reviews/meta-analyses. No language, study or drug restrictions were employed. Date restrictions were only employed for searches of the DARE and HTA databases (to 2010-2012 publications). The search strategies employed appear to be appropriate. The ERG also conducted its own searches of the Cochrane Library (Wiley Interscience), MEDLINE and MEDLINE In-Process (Ovid SP) on 16 November 2012 and did not identify any additional potentially relevant studies. Nave Chained Indirect Analysis In order to conduct the 'nave chained indirect analysis', a 'rapid search' of the Cochrane Library (Cochrane Database of Systematic Reviews, DARE and HTA databases) was conducted to identify systematic reviews and health technology assessments of chemotherapy and advanced or metastatic breast cancer. The precise detail of the search strategy is not provided in the manufacturer's submission (MS) but it is stated that it 'was designed to be sensitive in order to identify all systematic reviews and health technology assessments about advanced or metastatic breast cancer' and, for DARE and HTA, limited to reviews published from 2010 to 2012. It is not possible to assess the appropriateness of the search strategy employed from the level of detail provided. However the ERG conducted its own searches of the Cochrane Library (Wiley Interscience), MEDLINE and MEDLINE In-Process (Ovid SP) on 16 November 2012 and did not identify any additional potentially relevant reviews. Inclusion Criteria Systematic Review The MS presented the inclusion and exclusion criteria for its systematic review. These are reproduced in the Table below. Clinical Effectiveness Inclusion Criteria Population: postmenopausal women with hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer whose disease had recurred or progressed following endocrine therapy, including treatment with non-steroidal aromatase inhibitors Intervention: everolimus in combination with exemestane, fulvestrant or tamoxifen Comparator: exemestane, fulvestrant or tamoxifen Outcomes: clinical benefit rate (CBR), response rate (complete, partial, stable disease), overall survival (OS), progression-free survival (PFS) or time to progression (TTP), adverse events (AEs) and discontinuations due to AEs, health-related quality of life (HRQoL), time to treatment discontinuation Study design: randomised controlled trials (RCTs) of any duration and crossover RCTs if data were presented at crossover; non-randomised comparative and uncontrolled studies reporting AEs were also eligible for inclusion Language: there was no language restriction applied to the search; studies with English abstracts, but whose full reports were in languages other than English were not extracted but were listed for information only Publication status: published, unpublished and grey literature was eligible; studies published as abstracts or conference presentations were included if an associated published full paper could not be found and adequate data were presented Exclusion Criteria None specified Mixed Treatment Comparison The search results were assessed for relevance to drug interventions for women with HR-positive advanced or metastatic breast cancer. To achieve a network, the following eligibility criteria were relaxed for record selection from the results of the second searches: HER2-negative status: trials with mixed populations and where the HER2 status was not reported were considered eligible. Treatment lines other than second line were considered eligible. Nave Chained Indirect Analysis Explicit inclusion and exclusion criteria for the 'nave chained indirect analysis' were not presented in the MS. However, it is stated that having identified potentially relevant reviews, these 'were then sifted to remove those reviews that were not about drug interventions for advanced or metastatic breast cancer: surgery, radiotherapy, non-drug treatments, screening, prevention, etc.' Without greater detail, it is not possible to comment on the appropriateness of the inclusion and exclusion criteria employed. However, the ERG does not believe that any relevant reviews were excluded. Cost-effectiveness Objective of the Manufacturer's Cost-effectiveness Literature Review The manufacturer carried out a search to identify studies reporting the cost-effectiveness of everolimus in postmenopausal women with HR-positive, HER2-negative, advanced (locally advanced or metastatic) breast cancer who had already received endocrine therapy. The databases searched included: MEDLINE, MEDLINE In-Process, EMBASE, EconLit and the National Health Service Economic Evaluation Database (NHS EED). All searches were carried out on 8 and 9 March 2012. The search strategy used did not include an economic search filter because scoping searches had indicated that the amount of literature for everolimus was very small. The search strategies comprised the drug name in combination with search terms for advanced or metastatic breast cancer. No date or language limits were applied. Full details of the search strategies, as well as the databases and resources searched, are provided in the MS. Conclusions of the Cost-effectiveness Literature Review The manufacturer's search to identify studies reporting the cost-effectiveness of everolimus in postmenopausal women with HR-positive, HER2-negative, advanced (locally advanced or metastatic) breast cancer who had already received endocrine therapy did not identify any relevant cost-effectiveness studies. The ERG is satisfied with the manufacturer's search strategy and is reasonably confident that the manufacturer did not miss any relevant published articles.

Clinical Effectiveness One randomised controlled trial (RCT) was identified for inclusion in the systematic review. One other open-label phase II trial provided supporting evidence. Three more studies were included for mixed treatment comparison. Cost-effectiveness No relevant cost-effectiveness studies were identified. The manufacturer submitted an economic evaluation.

Expert Consensus

Not applicable

Review of Published Meta-Analyses;Systematic Review with Evidence Tables

Expert Consensus

Not applicable

Summary of Appraisal Committee's Key Conclusions on Cost-effectiveness Availability and Nature of Evidence The Committee considered the manufacturer's economic model and the Evidence Review Group (ERG)'s critique of the manufacturer's comparison of everolimus plus exemestane and exemestane alone. The Committee noted that the incremental cost-effectiveness ratios (ICERs) were most sensitive to the modelling of overall survival and progression-free survival assessment method. Uncertainties Around and Plausibility of Assumptions and Inputs in the Economic Model The Committee agreed that the most plausible ICER should be based on an analysis using the following assumptions: using exponential functions to estimate progression-free survival and the non-parallel model of overall survival; omitting the adjustment factor from Beauchemin et al. (2012); using locally assessed trial data; including adverse reactions; using rates of adverse reactions as documented in the European Public Assessment Report; recalculating time on treatment; including costs of monitoring disease that has not progressed; correcting discounting and utility values for stable disease; using the utility value for 'progressed disease' from Lloyd et al. (2006); and omitting extra mortality from non-cancer causes. Incorporation of Health-Related Quality-of-Life Benefits and Utility Values The Committee concluded that neither valuation of utility for the 'progressed disease' health state was without uncertainty, but that the data from Lloyd et al. (2006) were more appropriate than the data from Launois et al. (1997). Have Any Potential Significant and Substantial Health-Related Benefits Been Identified That Were Not Included in the Economic Model, and How Have They Been Considered? Although the Committee acknowledged that the mechanism of action of everolimus may offer a step change in treatment by restoring sensitivity of the tumour to endocrine therapy, it concluded that the manufacturer had not submitted convincing evidence that everolimus (plus exemestane) provides health-related quality-of-life benefits exceeding that calculated in the quality-adjusted life year (QALY). Are There Specific Groups of People for Whom the Technology Is Particularly Cost-effective? The Committee concluded that the available evidence did not allow it to make any recommendations specific to subgroups of patients. What Are the Key Drivers of Cost-effectiveness? Using local or central assessment for progression-free survival in the modelling: The Committee concluded that it was more appropriate to use effectiveness data derived from local assessment in the modelling than from central assessment because local assessment represented the primary end point of the trial, reflected clinical practice and minimised the potential for bias from informative censoring. Choice of survival modelling: The Committee agreed that the manufacturer's estimated 10.5 months' survival benefit with the Weibull analysis was likely to be optimistic, and that the estimated 1.4 months' survival benefit with the ERG's exploratory parallel exponential model was likely to be pessimistic. It acknowledged that the overall survival benefit of everolimus plus exemestane is uncertain but probably lies between these estimates. The Committee noted that it is also similar to the overall survival benefit from the ERG's non parallel exponential model (4.6 months), which reflects the longer progression-free survival with everolimus plus exemestane than with exemestane alone. Most Likely Cost-Effectiveness Estimate (Given as an ICER) The Committee concluded that the ERG's estimate of the ICER (including the patient access scheme for everolimus) of 68,000 per QALY gained for everolimus plus exemestane compared with exemestane alone was more plausible than the manufacturer's base-case estimate.

External Peer Review

Consultee organisations from the following groups were invited to comment on the draft scope, Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination. Manufacturer/sponsors Professional/specialist and patient/carer groups Commentator organisations (without the right of appeal) In addition, individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.

Everolimus, in combination with exemestane, is not recommended within its marketing authorisation for treating postmenopausal women with advanced human epidermal growth factor receptor 2 (HER2)-negative hormone-receptor-positive breast cancer that has recurred or progressed following treatment with a non-steroidal aromatase inhibitor (NSAI). Women currently receiving everolimus for advanced breast cancer should be able to continue treatment until they and their clinician consider it appropriate to stop.

None provided

The type of evidence supporting the recommendations is not specifically stated for each recommendation. The Appraisal Committee considered clinical and cost-effectiveness evidence submitted by the manufacturer and a review of this submission by the Evidence Review Group. For clinical effectiveness, one randomised controlled trial was the main source of evidence. For cost-effectiveness, the manufacturer's model was considered.

Appropriate recommendation for the use of everolimus in combination with exemestane for treating advanced human epidermal growth factor receptor 2 (HER2)-negative hormone-receptor-positive breast cancer after endocrine therapy

The summary of product characteristics lists the following as the most frequently reported grade 3 or 4 adverse reactions: anaemia, fatigue, diarrhoea, infections, stomatitis, hyperglycaemia, thrombocytopenia, lymphopenia, neutropenia, hypophosphataemia, hypercholesterolaemia, diabetes mellitus and pneumonitis. For full details of adverse reactions and contraindications, see the summary of product characteristics.

Everolimus is contraindicated in people who are hypersensitive to the active substance, to derivatives of rapamycin, or to any of the excipients used to make everolimus. For full details of adverse reactions and contraindications, see the summary of product characteristics.

The National Institute for Health and Care Excellence (NICE) has developed a costing statement explaining the resource impact of this guidance. This tool is available from the NICE Web site (see also the Availability of Companion Documents" field).

Foreign Language Translations;Patient Resources;Resources

Getting Better;Living with Illness

Effectiveness;Patient-centeredness

Not applicable: The guideline was not adapted from another source.

2013 Aug

National Institute for Health and Care Excellence (NICE)

Appraisal Committee

Committee Members: Dr Amanda Adler (Chair), Consultant Physician, Addenbrooke's Hospital; Professor Ken Stein (Vice Chair), Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter; Dr Ray Armstrong, Consultant Rheumatologist, Southampton General Hospital; Dr Jeff Aronson, Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford; Professor John Cairns, Professor of Health Economics Public Health and Policy, London School of Hygiene and Tropical Medicine; David Chandler, Lay Member; Mark Chapman, Health Economics and Market Access Manager, Medtronic UK; Professor Fergus Gleeson, Consultant Radiologist, Churchill Hospital, Oxford; Robert Hinchliffe, HEFCE Clinical Senior Lecturer in Vascular Surgery and Honorary Consultant Vascular Surgeon, St George's Vascular Institute; Professor Daniel Hochhauser, Consultant in Medical Oncology, UCL Cancer Institute; Dr Neil Iosson, General Practitioner; Anne Joshua, Associate Director of Pharmacy, NHS Direct; Dr Rebecca Kearney, Clinical Lecturer, University of Warwick; Terence Lewis, Lay Member; Professor Ruairidh Milne, Director of Strategy and Development and Director for Public Health Research at the National Institute for Health Research (NIHR) Evaluation, Trials and Studies Coordinating Centre at the University of Southampton; Dr Elizabeth Murray, Reader in Primary Care, University College London; Dr Peter Norrie, Principal Lecturer in Nursing, DeMontfort University; Professor Stephen Palmer, Professor of Health Economics, Centre for Health Economics, University of York; Dr Sanjeev Patel, Consultant Physician Senior Lecturer in Rheumatology, St Helier University Hospital; Dr John Pounsford, Consultant Physician, Frenchay Hospital, Bristol; Dr Danielle Preedy, Lay Member; Cliff Snelling, Lay Member; Marta Soares, Research Fellow, Centre for Health Economics, University of York; Professor Andrew Stevens, Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham; Dr Nerys Woolacott, Senior Research Fellow, Centre for Health Economics, University of York; Dr Nicky Welton, Senior Lecturer in Biostatistics/Health Technology Assessment, University of Bristol

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

Electronic copies: Available from the National Institute for Health and Care Excellence (NICE) Web site.

The following are available: Fleeman N, Bagust A, Beale S, Blundell M, Dwan K, Pilkington G, Proudlove C, Dundar Y, Vecchio F, Thorp N. Everolimus in combination with an aromatase inhibitor for the treatment of breast cancer after prior endocrine therapy: a single technology appraisal. Liverpool (UK): LRiG, The University of Liverpool; 2013. 101 p. Electronic copies: Available in Portable Document Format (PDF) from the National Institute for Health and Care Excellence (NICE) Web site. Everolimus in combination with exemestane for treating advanced HER2-negative hormone-receptor-positive breast cancer after endocrine therapy. Costing statement. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 3 p. (Technology appraisal guidance; no. 295). Electronic copies: Available in PDF from the NICE Web site.

The following is available: Everolimus given with exemestane for advanced breast cancer. Information for the public. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Aug. 6 p. (Technology appraisal guidance; no. 295). Electronic copies: Available in Portable Document Format (PDF) from the National Institute for Health and Care Excellence (NICE) Web site. Also available in Welsh from the NICE Web site. Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

This NGC summary was completed by ECRI Institute on November 20, 2013. The National Institute for Health and Care Excellence (NICE) has granted the National Guideline Clearinghouse (NGC) permission to include summaries of their Technology Appraisal guidance with the intention of disseminating and facilitating the implementation of that guidance. NICE has not verified this content to confirm that it accurately reflects the original NICE guidance and therefore no guarantees are given by NICE in this regard. All NICE technology appraisal guidance is prepared in relation to the National Health Service in England and Wales. NICE has not been involved in the development or adaptation of NICE guidance for use in any other country. The full versions of all NICE guidance can be found at www.nice.org.uk.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

10012

Intrauterine growth restriction: screening, diagnosis, and management.

Lausman A, Kingdom J, Maternal Fetal Medicine Committee. Intrauterine growth restriction: screening, diagnosis, and management. J Obstet Gynaecol Can. 2013 Aug;35(8):741-8. [55 references] PubMed

This is the current release of the guideline.

Intrauterine growth restriction

Counseling;Diagnosis;Management;Risk Assessment;Screening

Family Practice;Internal Medicine;Obstetrics and Gynecology

Advanced Practice Nurses;Nurses;Physician Assistants;Physicians

To provide summary statements and recommendations and to establish a framework for screening, diagnosis, and management of pregnancies affected with intrauterine growth restriction (IUGR)

Pregnant women with clinical risk factors for intrauterine growth restriction (IUGR) or with a confirmed diagnosis of IUGR

Screening for clinical risk factors for intrauterine growth restriction (IUGR) by means of a complete history Counseling on smoking cessation at any time during pregnancy First and second trimester screening tests for aneuploidy Ultrasound examination of the placenta and uterine artery Dopplers at 19 to 23 weeks Maternalfetal medicine consultation Comprehensive third trimester ultrasound examination including biophysical profile, fetal biometry, amniotic fluid volume, and umbilical artery Doppler studies (not recommended in women without risk factors for IUGR) Low-dose aspirin in at-risk women Invasive testing to rule out aneuploidy Maternal screening for infectious etiology Surveillance of IUGR, including serial ultrasound estimation of fetal weight, umbilical artery Doppler studies, placental assessment, and other Doppler studies such as middle cerebral artery, umbilical vein, and ductus venosus Increased surveillance (e.g., 2 to 3 times per week) or admission to hospital and delivery planning as required Antenatal cardiotocography (non-stress testing) as a test of fetal well-being (not recommended in isolation to monitor fetuses with IUGR) Maternal administration of corticosteroids Expectant management with close fetal and maternal surveillance versus delivery after 37 weeks Choosing site of planned delivery, taking into consideration facilities and expertise available

Risk of intrauterine growth restriction (IUGR) and stillbirth in the third trimester Perinatal morbidity and mortality

Searches of Electronic Databases;Searches of Unpublished Data

Published literature in English was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in January 2013 using appropriate controlled vocabulary via MeSH terms (fetal growth restriction and small for gestational age) and key words (fetal growth, restriction, growth retardation, IUGR, low birth weight, small for gestational age). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Quality of Evidence Assessment* I: Evidence obtained from at least one properly randomized controlled trial II-1: Evidence from well-designed controlled trials without randomization II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees *Adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.

Review of Published Meta-Analyses;Systematic Review

Expert Consensus

Classification of Recommendations A. There is good evidence to recommend the clinical preventive action B. There is fair evidence to recommend the clinical preventive action C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making Adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.

A formal cost analysis was not performed and published cost analyses were not reviewed.

Internal Peer Review

This clinical practice guideline has been prepared by the Maternal Fetal Medicine Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.

The quality of evidence (I-III) and classification of recommendations (A-E, L) are defined at the end of the "Major Recommendations" field. Summary Statements The definition of small-for-gestational age for a fetus in utero is an estimated fetal weight that measures 10th percentile on ultrasound. This diagnosis does not necessarily imply pathologic growth abnormalities, and may simply describe a fetus at the lower end of the normal range. (III) Intrauterine growth restriction (IUGR) refers to a fetus with an estimated fetal weight 10th percentile on ultrasound that, because of a pathologic process, has not attained its biologically determined growth potential. (III) A clinical estimation of fetal weight or symphysis-fundal height has poor sensitivity and specificity and should not be relied upon to diagnose IUGR. IUGR should be considered in the differential diagnosis when the fetus is found to be small for gestational age. (II-1) Effective screening for IUGR requires accurate dating and includes a review of the mother's menstrual history, relevant assisted reproductive technology information, and either a first trimester or early second trimester dating ultrasound. (I) Symphysis-fundal height determination is of limited value in routine obstetrical care, but continues to be the only physical examination screening test available. (I) Fetal weight determination in fetuses between the 10th and 90th percentiles by ultrasound biometry alone has at least a 10% error rate across gestation, but is effective equally when measuring with abdominal circumference alone or in combination with head size (biparietal diameter or head circumference) and/or femur length to establish an estimated fetal weight. (II-2) Determining whether IUGR is symmetric or asymmetric is of less clinical importance than careful re-evaluation of fetal anatomy and uterine and umbilical artery Doppler studies. (I) In women with risk factors for IUGR, uterine artery Doppler screening at 19 to 23 weeks may identify pregnancies at risk of antepartum stillbirth and preterm delivery due to IUGR and placental disease. (II-2) In pregnancies in which IUGR due to uteroplacental vascular insufficiency is diagnosed, maternal surveillance for the development of severe preeclampsia with adverse features is warranted. (II-1) Once surveillance of a fetus with IUGR is instituted, umbilical artery Doppler studies and biophysical profile scoring can be used as short-term predictors of fetal well-being. (I) In the presence of abnormal umbilical artery Doppler studies, further investigation of the fetal circulatory system by Doppler examination of the middle cerebral artery, ductus venosus, and umbilical vein can be considered. (II-2) For a fetus with IUGR, the decision for obstetrical intervention, including Caesarean section, in cases of abnormal fetal heart rate or malpresentation is largely based on fetal viability, as assessed by ultrasound. (II-2) Maternal surveillance for the development of preeclampsia is warranted. (II-2) Recommendations Women should be screened for clinical risk factors for IUGR by means of a complete history. (II-2B) Women should be counseled on smoking cessation at any time during pregnancy. (II-2A) First and second trimester screening tests for aneuploidy maybe useful tests of placental function. If two screening test results are abnormal, health care providers should be aware that the fetus is at increased risk of preterm IUGR and associated stillbirth. (II-1A) If IUGR is suspected, further assessment can assist in making the diagnosis. If available, detailed ultrasound examination of the placenta (looking for evidence of a small, thickened placenta, or abnormal morphology) and uterine artery Dopplers should be considered at 19 to 23 weeks. In the absence of available diagnostic testing, closer surveillance should be offered. A maternal-fetal medicine consultation can be considered if the placenta appears abnormal on ultrasound, especially in the context of a growth-restricted fetus and abnormal uterine artery Doppler. In a rural setting, the caregiver needs to decide whether the patient should be delivered immediately, or whether transfer to a tertiary center is appropriate. A telephone consultation and telemedicine may help. (II-2A) In women without risk factors for IUGR, comprehensive third trimester ultrasound examination including biophysical profile, fetal biometry, amniotic fluid volume, and umbilical artery Doppler studies is not recommended. (II-2D) Low-dose aspirin should be recommended to women with a previous history of placental insufficiency syndromes including IUGR and preeclampsia. It should be initiated between 12 and 16 weeks' gestation and continued until 36 weeks. (I-A) Low-dose aspirin should also be recommended to women with two or more current risk factors in pregnancy including, but not limited to, pre-gestational hypertension, obesity, maternal age 40 years, history of use of artificial reproductive technology, pre-gestational diabetes mellitus (type I or II), multiple gestation, previous history of placental abruption, and previous history of placental infarction. It should be initiated between 12 and 16 weeks' gestation and continued until 36 weeks. (I-A) Umbilical artery Doppler studies are not recommended as a routine screening test in uncomplicated pregnancies. (I-E) An ultrasound examination for estimated fetal weight and amniotic fluid volume should be considered after 26 weeks if the symphysis-fundal height measurement in centimeters deviates by 3 or more from the gestational age in weeks or there is a plateau in symphysis-fundal height. (II-2B) In cases in which the fetus measures 10th percentile by estimated fetal weight or abdominal circumference measurement, the underlying cause of IUGR may be established by an enhanced ultrasound examination to include a detailed review of fetal anatomy, placental morphology, and Doppler studies of the uterine and umbilical arteries. (II-2A) In cases of IUGR, determination of amniotic fluid volume should be performed to aid in the differential diagnosis of IUGR and increase the accuracy of the diagnosis of placental insufficiency. (II-2B) Umbilical artery Doppler should be performed in all fetuses with an estimated fetal weight or an abdominal circumference 10th percentile. (I-A) In pregnancies affected by IUGR, umbilical artery Doppler studies after 24 weeks may prompt intervention that reduces perinatal mortality and severe perinatal morbidity due to IUGR. (I-A) In pregnancies in which IUGR has been identified, invasive testing to rule out aneuploidy may be offered where fetal abnormalities are suspected, soft markers are seen, or no supportive evidence of underlying placental insufficiency is evident. (II-2A) In patients presenting with IUGR, maternal screening for infectious etiology may be considered. (II-2A) When IUGR is diagnosed, surveillance should be initiated. Serial ultrasound estimation of fetal weight (every 2 weeks), along with umbilical artery Doppler studies should be initiated. If available, a placental assessment and other Doppler studies such as middle cerebral artery, umbilical vein, and ductus venosus can be performed. Increased frequency of surveillance may be required. (II-2A) If fetal growth starts to plateau, amniotic fluid index starts to decline, or fetal tone or gross movements are diminished or absent, then more intensive surveillance (e.g., 2 to 3 times per week) or admission to hospital and delivery planning is required. (II-2A) Abnormal umbilical cord Doppler (e.g., absent or reversed end-diastolic flow) in the presence of IUGR is an ominous finding that requires intervention and possible delivery. (I-A) Cardiotocography (non-stress testing) performed antenatally as a test of fetal well-being should not be used in isolation to monitor fetuses with IUGR. (II-2E) Maternal administration of corticosteroids is indicated if there is a significant possibility of delivery at 34 weeks' gestation, as administration may positively affect umbilical Doppler studies. (I-A) If delivery was not indicated prior to 37 weeks in a patient diagnosed with IUGR, expectant management with close fetal and maternal surveillance versus delivery should be discussed after 37 weeks. (I-A) Site of planned delivery should take into consideration facilities and expertise available at each institution including obstetricians, pediatricians or neonatologists as appropriate, anesthesiologists, and access to Caesarean section. (III-A) Definitions: Quality of Evidence Assessment* I: Evidence obtained from at least one properly randomized controlled trial II-1: Evidence from well-designed controlled trials without randomization II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees *Adapted from the Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care. Classification of Recommendations A. There is good evidence to recommend the clinical preventive action B. There is fair evidence to recommend the clinical preventive action C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making Adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.

None provided

The type of supporting evidence is identified and graded for each recommendation (see the "Major Recommendations" field).

Implementation of the recommendations in this guideline should increase clinician recognition of intrauterine growth restriction (IUGR) and guide intervention where appropriate. Optimal long-term follow-up of neonates diagnosed as IUGR may improve their long-term health.

Not stated

An implementation strategy was not provided.

Foreign Language Translations

Getting Better;Staying Healthy

Effectiveness;Patient-centeredness

Not applicable: The guideline was not adapted from another source.

2013 Aug

Society of Obstetricians and Gynaecologists of Canada

Maternal Fetal Medicine Committee

Principal Authors: Andrea Lausman, MD, Toronto ON; John Kingdom, MD, Toronto ON Maternal Fetal Medicine Committee: Robert Gagnon, MD (Chair), Verdun QC; Melanie Basso, RN, Vancouver BC; Hayley Bos, MD, London ON; Joan Crane, MD, St. John's NL; Gregory Davies, MD, Kingston ON; Marie-France Delisle, MD, Vancouver BC; Lynda Hudon, MD, Montreal QC; Savas Menticoglou, MD, Winnipeg MB; William Mundle, MD, Windsor ON; Annie Ouellet, MD, Sherbrooke QC; Tracy Pressey, MD, Vancouver BC; Christy Pylypjuk, MD, Saskatoon SK; Anne Roggensack, MD, Calgary AB; Frank Sanderson, MD, Saint John NB

Disclosure statements have been received from all members of the committee.

Electronic copies: Available from the Society of Obstetricians and Gynaecologists of Canada (SOGC) Web site. Also available in French from the SOGC Web site. Print copies: Available from the Society of Obstetricians and Gynaecologists of Canada, La socit des obsttriciens et gyncologues du Canada (SOGC) 780 promenade Echo Drive Ottawa, ON K1S 5R7 (Canada); Phone: 1-800-561-2416.

None available

This NGC summary was completed by ECRI Institute on November 19, 2013. The information was verified by the guideline developer on December 13, 2013.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.