TITLE: Clopidogrel, Prasugrel and Ticagrelor in Adults with Acute Coronary Syndrome: A Review of the Clinical Effectiveness DATE: 15 August 2011 CONTEXT AND POLICY ISSUES: Acute coronary syndrome (ACS) is a collective term used to describe the acute onset of myocardial ischemia resulting from the occlusion of coronary arteries and includes the following designations: ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA).1 When patients present with sign and symptoms of ACS, they receive an immediate oral administration of dual antiplatelet therapy consisting of acetylsalicylic acid (aspirin; ASA) and a thienopyridine.2 Thienopyridines are a class of P2Y12 platelet ADP receptor antagonists and the one that is most commonly administered to ACS patients is clopidogrel.3 ACS (STEMI, or NSTEMI/UA) is classified based on the characteristics of electrocardiograms (ECG) and the level of cardiac enzymes circulating in the blood.4 STEMI patients receive immediate care, which may include percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or management by drug alone.5,6 NSTEMI patients receive similar treatment options, but the administration of these treatments are less time-critical than in STEMI patients.6,7 Currently, dual therapy with clopidogrel and ASA is the standard treatment for ACS patients in Canada.6 Clopidogrel has many limitations including a slow onset of action, incomplete platelet inhibition, poor antiplatelet response to some patients, and an irreversible antiplatelet effect.8 A new thienopyridine, prasugrel, has been observed to provide a faster response and better clinical efficacy than clopidogrel, at the expense of an increased risk of major bleeding.9 Like clopidogrel, prasugrel irreversibly inhibits platelet aggregation by binding to the P2Y12 platelet ADP receptor for the entire 8-9 day life span. ACS patients who are on clopidogrel or prasugrel are at a higher risk of bleeding during emergency CABG procedures or other surgical interventions.10,11 Ticagrelor, a cyclopentyltriazolopyridine, has different properties than thienopyridines.3 Since it is not a prodrug requiring metabolic activation, ticagrelor has a faster 12 onset response than clopidogrel. In addition, it binds reversibly to P2Y12 platelet ADP receptor, Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions. which allows for the restoration of platelet aggregation upon termination of therapy.12 The rapid and reversible effect of ticagrelor makes it a promising option for the treatment of ACS patients including those managed medically or with PCI and/or CABG.13 This report reviews the clinical effectiveness and the comparative clinical effectiveness of clopidogrel, prasugrel and ticagrelor in adults with ST elevation or non-ST elevation acute coronary syndrome. Treatment cost per day of antiplatelet agents used for ACS, based on the recommended daily dose, will be also provided. RESEARCH QUESTIONS: 1. What is the clinical effectiveness of clopidogrel, prasugrel and ticagrelor in adults with ST elevation or non-ST elevation ACS? 2. What is the comparative clinical effectiveness of clopidogrel, prasugrel and ticagrelor in adults with ST elevation or non-ST elevation ACS? 3. What are the comparative treatment costs per day of antiplatelet agents used for ACS, based on the recommended daily dose? KEY MESSAGE: Compared to aspirin alone, dual therapy (clopidogrel plus aspirin) produces a significant reduction in major cardiovascular events in ACS patients and in those undergoing PCI, with an increased risk of major bleeding. Compared to the standard loading dose (300 mg), an increased loading dose of clopidogrel (600 mg) reduces the incidence of major cardiovascular events without an increase in major bleeding in patients undergoing PCI. Compared to clopidogrel, prasugrel decreases the rates of ischemic events including stent thrombosis, but increases the risk of major and fatal bleeding in patients undergoing PCI, without changes in overall mortality. Compared to clopidogrel, ticagrelor decreases the rate of all-cause mortality, vascular mortality, or myocardial infarction, without an increase in the rate of major bleeding, but with an increase in the risk of major non-CABG bleeding. Prasugrel and ticagrelor have similar efficacy and safety, except prasugrel is more protective for stent thrombosis, with an increased risk of major bleeding. METHODS: Literature search strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2011, Issue 5), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and abbreviated list of major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses and randomized controlled trials. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2006 and June 3, 2011. Clopidogrel, Prasugrel and Ticagrelor in Adults with Acute Coronary Syndrome 2 Selection criteria and method One reviewer screened the titles and abstracts of the retrieved publications and evaluated the full-text publication for the final article selection, according to selection criteria presented in Table 1. Table 1: Selection Criteria Population Adults (≥ 18 years of age) with either ST-elevation ACS or non-ST- elevation ACS Intervention Clopidogrel, prasugrel or ticagrelor [with or without aspirin or acetylsalicylic acid (ASA)] Comparator Q1: placebo or ASA Q2: clopidogrel, prasugrel or ticagrelor [with or without aspirin or acetylsalicylic acid (ASA)] Outcomes Primary outcome: composite of death, MI or stroke Secondary (individual) outcome: all-cause mortality, cardiovascular mortality, MI, stroke Harm: major and minor bleeding (as defined in individual RCTs) Study Designs Health technology assessments (HTAs), systematic reviews, meta- analysis, randomized controlled trials (RCTs) Exclusion criteria Studies were excluded if they did not meet the selection criteria, were sub-studies of the main trials, were included in the selected systematic reviews/meta-analyses, or were published prior to 2006. Critical appraisal of individual studies The quality of included HTAs and systematic reviews was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) tool.14 RCT and non-randomized study quality were evaluated using the Downs and Black instrument.15 A numeric score was not calculated for each study. Instead, strengths and weaknesses of each study were summarized and described. SUMMARY OF EVIDENCE: Quantity of research available The literature search yielded 290 citations. Upon screening titles and abstracts, 246 citations were excluded and 44 potentially relevant articles were retrieved for full-text review. Two additional relevant reports were retrieved from other sources. Of the 46 potentially relevant articles, 13 were included in this review. They are two HTAs,16,17 eight systematic reviews18-25 and three RCTs.9,26,27 The study selection process is outlined in a PRISMA flowchart (Appendix 1). Clopidogrel, Prasugrel and Ticagrelor in Adults with Acute Coronary Syndrome 3 Summary of study characteristics A summary of study characteristics can be found in Appendix 2. Of the included HTAs and systematic reviews, six compared dual antiplatelet therapy (clopidogrel plus aspirin) versus monotherapy (aspirin alone or clopidogrel alone),16-18,23-25 one compared high clopidogrel loading dose (600 mg) versus standard clopidogrel loading dose (300 mg),22 and three 19-21 compared new P2Y12 inhibitors (prasugrel or ticagrelor) versus clopidogrel. The reported primary outcomes varied among the systematic reviews, but they were usually composite endpoint