Decision Support on Clopidogrel, Prasugrel, and Ticagrelor in Acute
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As contributors to a publicly funded health care system, Canada’s public drug plans must balance the potential benefits of new drugs with ensuring the best value for limited health care budgets. But deciding which drugs to cover, in which situations and for which patients, is never an easy task. CADTH’s Decision Support series provides an overview of relevant drug review issues and highlights sources of evidence to support decision-making. Please refer to the CADTH reports cited for full details on any of the issues discussed. Acute coronary syndrome (ACS) is a term used for any condition caused by sudden, reduced blood flow to the heart. It most commonly occurs when a coronary artery is partially or completely blocked due to blood clot formation. Partial blockage of blood flow can cause unstable angina (chest pain which comes and goes) and a more complete or total block can cause myocardial infarction (MI); that is, a heart attack. MI can be further defined as ST segment elevation MI (STEMI) or as non-ST segment elevation MI (NSTEMI), depending upon the degree of damage to the heart. STEMI is a more severe heart attack than NSTEMI. In Canada, patients presenting with symptoms of ACS generally receive immediate dual antiplatelet therapy, typically acetylsalicylic acid (ASA), or aspirin, and clopidogrel (Plavix and generics). Some patients are managed in the acute setting with medications alone, while others may atherothrombotic events in adults with ACS; in undergo percutaneous coronary intervention other words, for patients who have experienced (PCI), or “ballooning,”or coronary artery bypass unstable angina or MI to prevent stroke or grafting (CABG) (bypass surgery) to reopen the additional MIs. The potential advantages of these blocked artery. Some patients undergoing PCI new agents over clopidogrel are faster onset of may also receive a coronary stent to help keep the action, and lower variability between patients in artery open. Each year, Canadian hospitals admit the degree of platelet inhibition. 60,000 people with ACS and this number is expected to rise as the Canadian population ages.1 CADTH provides unbiased, evidence-based information to Canada’s decision-makers, who Health Canada recently approved two new often have tough choices to make about funding antiplatelet agents — prasugrel (Effient) and health technologies. On the topic of dual ticagrelor (Brilinta) — for use in combination with antiplatelet therapy in ACS, CADTH has recently ASA for the secondary prevention of published the following reports: 1 CDEC Final Recommendation: prasugrel2 faster onset of action of prasugrel, compared to CDEC Final Recommendation: ticagrelor3 clopidogrel, has less clinical benefit if patients Clopidogrel, Prasugrel and Ticagrelor in Adults receive an antiplatelet early in their treatment with Acute Coronary Syndrome: A Review of pathway. the Clinical Effectiveness, Cost Effectiveness and Guidelines, June 20124 A loading dose of 300 mg of clopidogrel was used in TRITON-TIMI 38, which is a lower dose than is What did the Common Drug Review find? often used in Canadian hospitals. CDEC noted this may have resulted in an overestimation of the The Canadian Drug Expert Committee (CDEC), 2 which makes recommendations on drugs for comparative efficacy of prasugrel. Recent meta- Canada’s publicly funded drug plans, recommends analyses have shown that a loading dose of that prasugrel and ticagrelor not be listed at the 600 mg of clopidogrel provides a reduction in MI, submitted prices. The specific reasons for these stroke, and CV death, without an increase in major bleeding, compared with a 300 mg clopidogrel recommendations differed between the two 6 drugs, although in both cases CDEC was not loading dose. persuaded that the newer agents would have clinical benefits over clopidogrel in Canadian The efficacy of ticagrelor was compared with practice. standard dose (75 mg daily) clopidogrel in the PLATO study, which included 18,624 patients with How do the drugs compare? ACS regardless of management strategy (i.e., Indications: Prasugrel, co-administered with ASA, medical, PCI, or CABG). Following up to 12 months is indicated for use only in ACS patients who will of therapy, the rate at which patients experienced be managed with PCI. In contrast, ticagrelor and the primary composite outcome of MI, stroke, or clopidogrel, co-administered with ASA, are CV death was lower for ticagrelor (9.3%) than indicated in ACS patients managed with clopidogrel (10.9%); HR 0.8 (95% confidence medication alone, or managed with PCI and/or interval [CI] 0.8 to 0.9). However, when looking with CABG. only at the North American patients in the study, there was no statistically significant difference 7 Efficacy: The efficacy of prasugrel was compared between treatments; HR 1.3 (95% CI 0.9 to 1.7). with standard dose (75 mg daily) clopidogrel in the clinical trial TRITON-TIMI 38, which involved New information: In addition to CADTH’s 13,608 patients with ACS undergoing PCI. systematic review, a recent network meta-analysis Following up to 15 months of therapy, the rate at used data from 14 clinical trials (including TRITON- which prasugrel-treated patients experienced the TIMI 38 and PLATO) to indirectly compare primary composite outcome of MI, stroke, or prasugrel, ticagrelor, and clopidogrel high-dose (≥ 150 mg daily) and standard dose (75 mg daily) death from cardiovascular (CV) cause was lower 8 (9.4%) than experienced by clopidogrel-treated in patients undergoing PCI. A subgroup analysis patients (11.5%), with a hazard ratio (HR) of was also conducted that focused on trials in 0.8 (95% CI 0.7 to 0.9).5 patients with ACS. No significant differences between prasugrel, ticagrelor, and high-dose CDEC noted that the benefit of prasugrel may not clopidogrel were observed for MI, stroke, CV be realized in a Canadian setting due to the timing death, or major adverse cardiac events (MACE) in of antiplatelet therapy in the TRITON-TIMI 38 trial either the overall analysis or the ACS subgroup. All and the dose of clopidogrel used. In the trial, 74% three strategies were more effective than of patients received the antiplatelet loading dose standard dose clopidogrel. As with all network during PCI. Only 2% of patients received the meta-analyses, differences between trials may loading dose more than six hours prior to PCI. But introduce bias. In the cited analysis, such in Canada, the majority of ACS patients receive a differences included dose and timing of antiplatelet loading, dose of ASA, and variation in loading dose of clopidogrel (300 mg to 600 mg) 8 upon hospital arrival.2 This is important, as the outcome definitions. 2 In a recently published paper, prasugrel was Stroke: While the overall risk of stroke was not compared with standard-dose clopidogrel statistically significantly different between the (75 mg daily) in a new trial (TRILOGY) involving ticagrelor and clopidogrel arms in PLATO (relative 7,243 ACS patients managed with medication risk [RR] 1.17 [95% CI 0.91 to 1.52]), the incidence alone. Currently, this use is not an approved of stroke (unknown cause) was higher for indication for prasugrel. The study authors found ticagrelor-treated patients compared with no significant difference between prasugrel and clopidogrel-treated patients (RR 4.98 [95% CI 1.01 clopidogrel on the primary composite end point of to 22.71]). The risks for other types of stroke MI, stroke, or CV death.9 (hemorrhagic stroke, non-hemorrhagic stroke) were higher with ticagrelor, but were not What are the potential harms? statistically different.3 Antiplatelet therapy increases bleeding risk because it reduces clotting. For patients Neoplasms: Analysis of the TRITON-TIMI 38 data undergoing surgical interventions such as PCI and by the Food and Drug Administration (FDA) found CABG, bleeding risk is an especially serious a statistically significant increase in the incidence consideration. of new or worsened neoplasm with prasugrel compared with clopidogrel (2.2% versus 1.6%, Bleeds: Bleeding in TRITON-TIMI 38 was assessed P = 0.01; calculated by CDR). 2,5 The FDA using the thrombosis in myocardial infarction concluded that the trend may be spurious, but (TIMI) criteria. Patients treated with prasugrel had required enhanced surveillance of cancer events a statistically significantly higher rate of non– in future trials. The Canadian product monograph CABG-related bleeding (2.4% versus 1.8%), CABG- for prasugrel warns prescribers about the related bleeding (13.4% versus 3.2%), and life- increased frequency of malignancy in the TRITON- threatening or fatal bleeding (1.4% versus 0.9%) TIMI 38 trial and that the causality is currently compared with clopidogrel.6 unknown.11 The percentage of patients with ACS having a Breathing difficulties: In PLATO, ticagrelor-treated major bleed, defined by TIMI criteria, were similar patients had a higher incidence of dyspnea with ticagrelor (7.9%) compared with clopidogrel (breathing difficulties) (12.0% versus 6.5%), and (7.7%) in the PLATO study.10 However, compared severe dyspnea (0.7% versus 0.4%), compared with clopidogrel, ticagrelor-treated patients had a with clopidogrel.3 higher frequency of major bleeds unrelated to CABG (2.8% versus 2.2%).6 What are the costs of treatment? Costs may vary by jurisdiction. The costs New information: In the network meta-analysis compared by CDEC in December 20113 and June discussed earlier, some differences were observed 20122 were: regarding bleeding risks. Firstly, prasugrel was associated with a higher risk of major bleeding Treatment Dose Daily Cost than ticagrelor and standard dose clopidogrel, but Ticagrelor3 90 mg twice there was no significant difference versus high- $2.96 dose clopidogrel. The risk of major bleeding was (Brilinta) daily not significantly different between ticagrelor and Prasugrel 2 10 mg daily $2.66 low-dose or high-dose clopidogrel, nor was there (Effient) a significant difference between the two doses of 3 8 Clopidogrel clopidogrel.