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CADTH Health Technology Review
Authors; Chantelle C. Lachance, and Monika Mierzwinski-Urban.
Mental health conditions, including bipolar disorders, generalized anxiety disorders, major depressive disorders, and schizophrenia, affect about one-third of the Canadian population.1 In Canada, schizophrenia affects approximately 1% of the population over the age of 10 years old, and the all-cause mortality rate in those with the condition is 2.8 times higher than those without it.2 Different pharmacological and psychological therapy options are available for patients with mental health conditions; the most appropriate therapy option for patients depends on the type (e.g., generalized anxiety disorders versus schizophrenia) and degree (i.e., mild, moderate, or severe) of their mental health condition.3 For example, first-line therapy for those diagnosed with schizophrenia or bipolar disorder is often pharmacological therapy.4,5
Clozapine is a second-generation antipsychotic drug indicated for patients with psychotic disorders, including delusional disorder, schizophrenia, schizoaffective disorder, and bipolar disorder.6,7 Clozapine has shown clinical efficacy; for example, clozapine has shown benefits over other antipsychotic drugs for patients with treatment-resistant schizophrenia and in reducing the risk of suicide in patients with schizophrenia.4,8-10 Typically, clozapine is prescribed to patients who are resistant to first-line antipsychotic drugs due to the risk of unpredictable and serious adverse drug reactions, such as myocarditis and cardiomyopathy.6,11,12 Resistance to first-line antipsychotic drugs is common: for patients with schizophrenia, it is estimated that 50% do not respond adequately (i.e., partial or no response) after receiving their prescribed pharmacotherapy.13
Myocarditis is defined as inflammation of the heart muscle and typically develops within the first 4 weeks after initiating clozapine.10,14 Cardiomyopathy is a disease of the heart muscle that makes it harder for the heart to pump blood to the rest of the body and has a later onset.15,16 The incidence of clozapine-related myocarditis in Australia and Canada over the last few decades has been variably reported at between 0.01% and 3.88%, which is a higher incidence rate than that of clozapine-related cardiomyopathy.10,17-19 Recognizing how fatal these adverse events can be, health care providers require guidance around how to monitor for myocarditis and cardiomyopathy, as well as appropriate courses of action for when myocarditis or cardiomyopathy are detected (e.g., stop clozapine use and switch to a different antipsychotic).
There are different ways to screen and diagnose myocarditis and cardiomyopathy, including clinical examination, endomyocardial biopsy, electrocardiogram (ECG), echocardiogram, cardiac MRI, and biochemical markers of myocardial injury.20 A simply blood test can assess biochemical markers of myocardial injury, including cardiac troponin I and T, which can be less invasive for the patient and cost-saving for the health care system.21,22 However, concerns about the diagnostic test accuracy of high-sensitivity cardiac troponin assays still prevail.21,23
In 2021, CADTH produced a report providing a reference list of publications concerning the diagnostic accuracy of high-sensitivity troponin I testing versus troponin T testing for detecting myocarditis or cardiomyopathy in patients receiving clozapine for psychotic disorders.24 In addition, the report provided a reference list of evidence-based guidelines on the use of clozapine for patients with psychotic disorders.24 The aim of this rapid review is to summarize and critically appraise the full text of relevant evidence regarding the diagnostic accuracy of high-sensitivity troponin I testing versus troponin T testing for detecting myocarditis or cardiomyopathy in patients receiving clozapine for psychotic disorders. This report also aims to summarize and critically appraise the recommendations from evidence-based guidelines regarding the use of clozapine for patients with psychotic disorders.
A limited literature search was conducted by an information specialist on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were high-sensitivity troponin I testing and clozapine. No filters were applied to limit the retrieval by study type for question 1. CADTH-developed search filters were applied to limit retrieval to guidelines for question 2. Conference abstracts were excluded from the search results. The search was completed on April 20, 2022, and limited to English-language documents published since January 1, 2016.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Selection Criteria.
Articles were excluded if they did not meet the selection criteria outlined in Table 1, if they were duplicate publications, or if they were published before 2016. Guidelines with unclear methodologies were also excluded.
The included guidelines were critically appraised by 1 reviewer using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument.25 Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
A total of 119 citations were identified in the literature search. Following screening of titles and abstracts, 106 citations were excluded and 13 potentially relevant reports from the electronic search were retrieved for full-text review. Nineteen potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 29 publications were excluded for various reasons, and 3 publications, all of which were evidence-based guidelines,26-28 met the inclusion criteria and were included in this report. Appendix 1 presents the PRISMA29 flow chart of the study selection.
Additional references of potential interest are provided in Appendix 5.
No health technology assessments, systematic reviews, randomized controlled trials (RCTs), or non-randomized studies were identified regarding the diagnostic accuracy of high-sensitivity troponin I testing versus troponin T testing for detecting myocarditis or cardiomyopathy in patients receiving clozapine for psychotic disorders. Three guidelines, published between 2016 and 2020, were identified regarding the use of clozapine for patients with psychotic disorders.26-28 The Royal Australian and New Zealand College of Psychiatrists (RANZCP) guideline26 is an update for the previous 2005 clinical practice guidelines for the management of schizophrenia and related disorders.30 The German Association for Psychiatry, Psychotherapy and Psychosomatics (in German called Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde [DGPPN]) guideline28 is also an update to a previous guideline, but it is not clear when the last version was published.
Additional details regarding the characteristics of the included guidelines are provided in Appendix 2.
The 3 guidelines were developed by the National Institute for Health and Care Excellence (NICE),27 DGPPN,28 and RANZCP.26
For the NICE27 and DGPPN28 guidelines, evidence informing the recommendations were collected through a well-defined literature search. The RANZCP group drafted its recommendations with reference to existing systematic reviews, informal literature reviews, and relevant international clinical practice guidelines.26
The guidelines used rating schemes to convey the quality of the evidence.26-28 Evidence informing the NICE guideline27 was rated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology as being of high, moderate, low, or very low quality. Evidence informing the DGPPN guideline28 ranged from 1++ (highest; i.e., high-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias) to 4 (lowest; i.e., expert opinion). For the RANZCP guideline,26 evidence for intervention studies was assigned grades ranging from I (highest; i.e., systematic review of RCTs) to IV (lowest; i.e., case series), according to Australian National Health and Medical Research Council levels of evidence. Grading recommendations for the DGPPN guideline28 were based on the methodology of the Scottish Intercollegiate Guidelines Network (Grade A [highest] to D [lowest]). Neither the NICE27 nor the RANZCP26 guidelines were clear on their rating schemes for strength of recommendations.
All 3 guidelines provide details on how their recommendations were developed and evaluated. For the NICE guideline,27 recommendations were drafted based on the committee’s interpretation of the available evidence, taking into account the trade-off between the benefits and harms, costs, or implications compared with the economic benefits, current practices, recommendations made in other relevant guidelines, people’s preferences, and equality issues. When evidence was of poor quality, or was conflicting or absent, the committee drafted recommendations based on expert opinion.27 The DGPPN guideline28 was developed in full accordance with the Working Group of Scientific Medical Societies (i.e., in German called Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften [AWMF]) Guidance Manual and Rules for Guideline Development.31 The DGPPN guideline28 is an evidence- and consensus-based guideline (i.e., with a representative committee, systematic review and synthesis of the evidence, and structured consensus development), classified as a level S3 guideline (i.e., the highest quality level for guidance development in Germany). Evidence-based recommendations for the RANZCP guideline26 were formulated when the guideline group judged that there was sufficient evidence on a topic. Where evidence was weak or lacking, consensus-based recommendations were formulated by a group of experts.26
Each guideline group took a slightly different approach to validate their guidelines. The NICE group conducted a stakeholder review of the draft guideline through a 6-week public consultation and feedback process; all comments received from registered key stakeholders were responded to in writing and posted on the NICE website.27 For the revision process, the DGPPN group involved experts within topic-specific, module working groups to update and expand the guideline texts.26 The RANZCP group invited review by its committees and members, an expert advisory committee, and key stakeholders (e.g., professional bodies, special interest groups).26
The NICE guideline27 is intended for those living in the UK; the DGPPN guideline28 is intended for those living in Germany; and the RANZCP guideline26 is intended for those living in Australia and New Zealand.
The intended users of the NICE guideline27 are health care professionals, social care practitioners, and other practitioners providing public services for people with complex psychosis; commissioners and providers of mental health services; and people using mental health services, their families, and carers. The target population of this guideline is adults with complex psychosis (i.e., primary diagnosis of a psychotic illness with severe and treatment-resistant symptoms of psychosis and functional impairment).27
The intended users of the DGPPN guideline28 are practitioners who treat people with schizophrenia. The target population of this guideline is people with schizophrenia.28
The intended users of the RANZCP guideline26 are psychiatrists, psychiatry trainees, resident medical officers, and hospital interns in psychiatry. The authors mentioned that the guideline may also be useful to general practitioners, mental health nurses, other clinicians who work with people with schizophrenia and related psychoses, and policy-makers. The target population of this guideline is people with schizophrenia and related disorders.26
The included guidelines considered a range of evidence-based practices for the clinical management and rehabilitation of people with psychotic disorders. The relevant intervention for all included guidelines was clozapine for people with psychotic disorders (i.e., complex psychosis,27 schizophrenia,26,28 and related disorders26).
The relevant outcomes of the included guidelines were evidence about rates of physical and mental health conditions and substance misuse in this population;27 augmenting clozapine with a co-prescription,26,27 electroconvulsive therapy (ECT),26 or switching to another drug;26 drug treatment resistance comparing combination treatment with monotherapy;28 adverse events;26 metabolic and adverse event monitoring;26 prescriptions to reduce adverse events related to taking clozapine;26 lower value of therapeutic reference range for clozapine;28 efficacy and safety of different doses of clozapine;26 other guidelines and studies;27,28 the committee’s experience and knowledge;27 and clinical consensus.28
All included guidelines26-28 were clear and specific with describing their overall objectives, health questions, population to whom the guideline is meant to apply, and target users of the guideline. The included guidelines all involved guideline development groups of relevant professions.26-28 The NICE27 and RANZCP26 guideline developers sought the views and preferences of the target population (e.g., patients, public), but this was unclear from the abbreviated English version of the DGPPN guideline.28 The NICE27 and DGPPN31 guidelines used systematic methods to search for evidence, which is a strategy that increases reproducibility and reduces potential bias. The RANZCP26 guideline used a different approach to search for evidence: the guideline development group used existing systematic reviews, informal literature reviews, and relevant international clinical practice guidelines to draft its recommendations. All guidelines26-28 described strengths and limitations of the body of evidence; described methods for formulating the recommendations; considered the health benefits, side effects, and risks in the formulation of the recommendations; provided an explicit link between the recommendations and the supporting evidence; were reviewed by external experts before its publication; and provided a procedure for updating the guideline. The 1 exception was that the RANZCP26 guideline did not indicate a procedure for updating the guideline. All guidelines26-28 provided specific and unambiguous recommendations, presented different options for management of the condition, and presented key recommendations in a way that is easily identifiable. The included guidelines26-28 provided advice or tools on how the recommendations can be put into practice and the potential resource implications of applying the recommendations have been considered. The NICE27 and RANZCP26 guidelines described facilitators and barriers to the application, but this was unclear for the DGPPN guideline.28 It was also unclear if any of the guidelines26-28 presented monitoring and/or auditing criteria. Regarding editorial independence, all guidelines26-28 were not clear nor did they provide an explicit statement that the funding body did not influence the content of the guideline. Moreover, while conflicts of interest for contributing authors were provided in the NICE27 and RANZCP26 guidelines, they were not clearly addressed in the DGPPN guideline.28 Given that guidelines were intended for use in the UK,27 Germany,28 Australia,26 and New Zealand,26 the recommendations may not be generalizable to Canadian settings.
Although the views and preferences of the target population, facilitators and barriers to the application, and competing interests were not mentioned in the abbreviated English version of the DGPPN guideline,28 it is possible these were addressed in the long version, published in German. For example, the DGPPN guideline was developed in full accordance with the AWMF Guidance Manual and Rules for Guideline Development,31 and this guidance advises that representatives of target users and patient target population should be included in the guideline development at an early stage. Thus, it is likely that the DGPPN followed this recommendation and included pertinent details about target user involvement in its long version of the guideline, published in German.31
Overall, the guidelines were clearly presented, were grounded in a generally comprehensive and transparently assessed evidence base, and appeared to provide unbiased recommendations on current clinical practice for clinical audiences. Additional details regarding the strengths and limitations of the included publications are provided in Appendix 3.
Appendix 4 presents the detailed recommendations and supporting evidence that are relevant to the current report.
No relevant evidence regarding high-sensitivity troponin I testing for detecting myocarditis or cardiomyopathy in patients receiving clozapine for psychotic disorders was identified; therefore, no summary can be provided.
The NICE guideline27 provides a list of considerations for the rehabilitation service to examine during the initial physical comprehensive assessment (e.g., full blood count, drug levels where appropriate, ECG). An exhaustive list is provided in Table 4. This guideline also suggests that medicines should be reviewed regularly to manage complex psychosis and monitor effectiveness, adverse effects, and drug interactions, including monitoring for continence and constipation for those taking clozapine. Moreover, drug levels should be monitored to check adherence and guide dosing: at least annually and as needed for clozapine and mood-stabilizing anti-epileptic medicines. All of the NICE recommendations are derived from committee consensus based on evidence from the literature, expert opinions, and existing guidelines (the strength of this recommendation is not reported and unclear; the quality of the supporting evidence is not reported and unclear).27
The DGPPN guideline28 provides 3 recommendations regarding clozapine management with testing and assessment of health parameters. These recommendations are based on good clinical practice informed by clinical consensus (the strength of this recommendation is not reported and unclear; the quality of the supporting evidence is not reported and unclear). The DGPPN guideline28 recommends providing laboratory tests and recording an ECG before starting pharmacotherapy. This guideline also suggests the decision about the suitable antipsychotic drug and route of administration is made jointly by the service user and treating doctor and recommends considering and discussing a variety of health parameters. Moreover, the guideline recommends informing service users, family members, and close confidants, as well as carers, about the necessary monitoring tests, and recommends implementing the monitoring tests as part of the overall treatment plan. The full list of recommended tests is located in Table 9 of the DGPPN guideline.28
The RANZCP guideline26 suggests that clozapine monitoring protocols should be followed rigorously. This recommendation is based on level III-1 evidence from pseudo-RCT findings (the strength of this recommendation is not reported and unclear). This guideline also suggests that metabolic monitoring and interventions to manage the metabolic side effects of clozapine are essential. This recommendation is based on level II evidence from RCT findings (the strength of this recommendation is not reported and unclear).26
The NICE guideline27 provides 2 recommendations regarding clozapine management in patients with co-prescriptions. Both NICE recommendations are derived from committee consensus based on evidence from the literature, expert opinions, and existing guidelines (the strength of this recommendation is not reported and unclear; the quality of the supporting evidence is not reported and unclear).27 For people with complex psychosis whose symptoms have not responded adequately to an optimized dose of clozapine alone, NICE recommends augmenting clozapine with the following, depending on target symptoms: (1) an antipsychotic drug (e.g., aripiprazole for schizophrenia and related psychoses); (2) a mood stabilizer for psychosis with significant affective symptoms; and/or (3) an antidepressant if there are significant depressive symptoms in addition to the psychotic condition. NICE also recommends the following:
Only use multiple medicines, or doses above British National Formulary or summary of product characteristics limits, to treat complex psychosis: (i) if this is agreed and documented by the multidisciplinary team and the person (and their family, carer or advocate, as appropriate); (ii) as a limited therapeutic trial, returning to conventional dosages or monotherapy after 3 months, unless the clinical benefits of higher doses or combined therapy clearly outweigh the risks; (iii) if the medicines are being used to treat specific symptoms that are disabling or distressing; (iv) after taking into account drug interactions and side effects, for example be cautious when adding an antidepressant to clozapine for someone who has experienced symptoms of mania; (v) if systems and processes are in place for monitoring the person's response to treatment and side effects (monitoring may include physical examination, ECG and appropriate hematological tests) (p. 33).27
The DGPPN guideline28 provides various recommendations regarding clozapine management in patients with co-prescriptions. The guideline states treatment with olanzapine or risperidone may be suggested if clozapine is not tolerated. This recommendation is based on good clinical practice informed by clinical consensus (the strength of this recommendation is not reported and unclear; the quality of the supporting evidence is not reported and unclear). In case of drug treatment resistance, DGPPN suggests first offering treatment with an antipsychotic in monotherapy; this comes from level 1++ evidence (i.e., high-quality meta-analysis) and a grade A recommendation (i.e., highest grade). A combination of 2 antipsychotic drugs may be suggested, with monitoring of side effects and interactions, if adequate response is not achieved with monotherapy with 3 different antipsychotic drugs, including clozapine strategy (good clinical practice informed by clinical consensus; the strength of this recommendation is not reported and unclear; the quality of the supporting evidence is not reported and unclear). The DGPPN guideline recommends documenting this approach and, if there is still no treatment response, discontinuing this strategy (good clinical practice informed by clinical consensus; the strength of this recommendation is not reported and unclear; the quality of the supporting evidence is not reported and unclear). The DGPPN guideline recommends that the combination of IV or sublingual lorazepam and clozapine should be avoided.28 This recommendation is adapted from another guideline, based on 4 original studies, and classified as a grade B recommendation.28
The RANZCP guideline26 also provides 3 recommendations for this outcome. The RANZCP guideline26 advises the consideration of either of the following treatment options if positive symptoms persist despite an adequate trial of clozapine: continue clozapine and prescribe adjunctive medication; or reinstate the previous regimen that was most effective and well tolerated and prescribe adjunctive medication.26 This recommendation is based on level II evidence from RCT findings (the strength of this recommendation is not reported and unclear).26 The addition of ECT may be considered in people with treatment-resistant schizophrenia who have an inadequate response to clozapine. This is also based on level II evidence from RCT findings (the strength of this recommendation is not reported and unclear).26 Where clozapine monotherapy is ineffective, augmentation with other medicines or ECT can be considered (level III-1 evidence from pseudo-RCT findings; the strength of this recommendation is not reported and unclear).26
The DGPPN guideline28 suggests reaching a serum level of clozapine of at least 350 ng/mL in case of treatment resistance as long as there are no tolerability issues (grade B recommendation based on level 2++ evidence [i.e., high-quality systematic reviews of case-control or cohort studies, and high-quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal]).28
The RANZCP guideline26 suggests 12.5 mg as the daily starting dose and 900 mg as the maximum recommended dose with the caveat that these doses may not be tolerated by some people. This recommendation is adapted from product information approved by “Australian Therapeutic Goods Administration, product information approved by Medsafe (the New Zealand Medicines and Medical Devices Safety Authority) and Therapeutic Guidelines – Psychotropic version 7 (Psychotropic Writing Group, 2013).” The strength of this recommendation is not reported and unclear.26
The findings in this report are limited by the quantity of relevant evidence. No studies were identified that evaluated the diagnostic accuracy of high-sensitivity troponin I testing versus troponin T testing for detecting myocarditis or cardiomyopathy in patients receiving clozapine for psychotic disorders; therefore, the diagnostic accuracy of high-sensitivity troponin I testing is unknown.
Three evidence-based guidelines26-28 were identified that included recommendations on the use of clozapine for patients with psychotic disorders; however, these guidelines did not provide specific recommendations for monitoring clozapine-induced cardiomyopathy or clozapine-induced myocarditis (e.g., physical symptoms to identify, type and magnitude of vital sign changes). This report identified 1 strong recommendation based on high-quality evidence, with several other recommendations that were based on sources of evidence that may not be considered highest quality, with the strength of recommendation not reported and unclear. The included guidelines were specific to the UK,27 Germany,28 Australia,26 and New Zealand;26 therefore, it is unclear whether the results summarized in this report are generalizable to Canada.
These limitations warrant the use of caution when interpreting the findings of this report.
This rapid review is an upgrade of a 2021 CADTH report24 that provided a reference list of relevant studies on the topic identified from the literature. This report identified 3 evidence-based guidelines published since 2016 that captured current recommendations regarding the use of clozapine for patients with psychotic disorders.26-28 The included guidelines were generally well developed and clearly presented.26-28 No relevant studies were identified regarding diagnostic accuracy of high-sensitivity troponin I testing versus troponin T testing for detecting myocarditis or cardiomyopathy in patients receiving clozapine for psychotic disorders.
The 3 included guidelines provide recommendations for testing and assessment of key health parameters for patients who are prescribed clozapine.26-28 Two guidelines27,28 describe which assessments should be considered before initiating pharmacotherapy, including clozapine. These recommendations are based on evidence from the literature, expert opinions, and existing guidelines27 and good clinical practice informed by clinical consensus.28 Three guidelines highlight the importance of rigorously following clozapine monitoring protocols; monitoring medicines and drug levels; checking adherence; guiding dosing; monitoring effectiveness, adverse effects, and drug interactions (recommendations from level II [i.e., RCT] and III-1 [i.e., pseudo-RCT] evidence as well as committee consensus on evidence from the literature, expert opinions, and existing guidelines).26-28 Together, this guidance provides key information on which tests and assessments should be considered for monitoring the potential side effects of clozapine.
The 3 guidelines also provide recommendations of co-prescription and adjunct treatment for patients who have not responded adequately to an optimized dose of clozapine alone.26-28 Derived from varying levels of evidence, the guidelines recommend continuing clozapine and prescribing adjunctive medication, with the type dependent on target symptoms (e.g., antipsychotic, mood stabilizer, antidepressant);26-28 reinstating the previous regimen that was most effective and well tolerated and prescribing adjunctive medication26; and/or augmenting with ECT.26
Two guidelines provide recommendations about clozapine dosing. One guideline suggests 12.5 mg as the daily starting dose and 900 mg as the maximum recommended dose with an important caveat that these doses may not be tolerated by individuals.26 Based on level 2++ evidence (i.e., highest quality), 1 guideline suggests reaching a serum level of clozapine of at least 350 ng/mL in case of treatment resistance if there are no tolerability issues.28
Overall, the recommendations put forward by these different guideline groups were consistent; however, several of the recommendations were derived from sources of evidence that may not be considered highest quality, with the strength of recommendation not reported and unclear. Given that the guidelines were produced by guideline groups in other countries, it is unclear whether the recommendations summarized in this report are generalizable to Canada. New primary research on the diagnostic accuracy of high-sensitivity troponin I testing for detecting myocarditis or cardiomyopathy may further inform the research questions addressed in this report.
Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (German)
English translation: Working Group of Scientific Medical Societies
Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (German)
English translation: German Association for Psychiatry, Psychotherapy and Psychosomatics
electrocardiogram
electroconvulsive therapy
National Institute for Health and Care Excellence
Royal Australian and New Zealand College of Psychiatrists
randomized controlled trial
Selection of Included Studies.
Characteristics of Included Guidelines.
Note that this appendix has not been copy-edited.
Strengths and Limitations of Guidelines Using AGREE II.
Summary of Recommendations in Included Guidelines.
Note that this appendix has not been copy-edited.
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While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up to date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
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About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
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