Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE Viewpoint based on presentations during the Canadian Cardiovascular Conference 2008

Toronto, Ontario / October 25-29, 2008

Reviewed by:

Shamir R. Mehta, MD, MSc

Associate Professor of Medicine, McMaster University

Interventional Cardiologist, Hamilton Health Sciences , Hamilton, Ontario

Platelet activation and aggregation play an important role in thrombus formation following disruption of an atherosclerotic plaque. Antiplatelet therapy was one of several pivotal developments contributing to the improvement in cardiovascular (CV) morbidity and mortality observed over the last few decades. Today, oral antiplatelet agents, especially ASA, are among the most extensively used medicines throughout the world. Their widespread use reflects the well-known finding that compared with no treatment or placebo, any antiplatelet therapy decreases the patient’s likelihood of experiencing a major CV event by about 25%.

Antiplatelet Therapy in Current Guidelines

Since the 1980s, evidence-based guidelines for management of acute coronary syndromes (ACS) have emphasized the benefits of antiplatelet therapy in both early and long-term management of patients with ST-segment elevation myocardial infarction (STEMI) or unstable angina/non-ST-segment elevation MI (UA/NSTEMI).

Based on an extensive systematic overview and meta-analysis of data from the Antithrombotic Trialists’ Collaboration, it is strongly recommended that after an initial loading dose, all individuals with an ACS receive ASA 75 to 162 mg/day. In most cases, this should be given indefinitely. Allergy to ASA or very high risk of bleeding are the only absolute contraindications. Other agents may be employed in patients who cannot tolerate ASA or for additional antithrombotic effects in the short term (for example, to enhance antiplatelet activity during angiography or invasive therapy), for longer-term CV protection, or both. The antiplatelet regimen selected depends on specific clinical situations (the nature of the event, type of therapy, patient age, risk of bleeding, and concomitant factors such as diabetes). This article reviews the use of ASA and clopidogrel and emerging therapies investigated in or destined for similar clinical applications.

Considerable data also support early use of the thienopyridine clopidogrel across the spectrum of ACS, including unstable angina, NSTEMI and STEMI. While clopidogrel is an alternative to ASA in patients who are hypersensitive to or unable to tolerate ASA, dual antiplatelet therapy with both ASA and clopidogrel is indicated for patients with ACS. Simultaneously targeting two platelet surface receptors (thromboxane A2 by ASA and ADP P2Y12 with clopidogrel) results in a synergistic antiplatelet effect.

In patients with UA/NSTEMI, clopidogrel is beneficial irrespective of whether the patient is treated with medical therapy alone or if patients receive revascularization with either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery. Data supporting the use of clopidogrel in addition to ASA in this broad group of patients were largely based on the results of the landmark CURE trial (CURE trial investigators. N Engl J Med 2001;345(7):494-502). In this study, which included 12,562 patients, the combination of clopidogrel (300 mg followed by 75 mg/day) and ASA (75 to 325 mg/day) reduced the relative risk of CV death/MI/stroke by 20% over ASA alone (9.3% vs. 11.4%, P<0.001), over a maximum of one year of follow-up (mean nine months). For the end point of CV death/MI/stroke/severe ischemia within the first 24 hours after randomization, the relative risk reduction was 34% (P=0.003). The efficacy of clopidogrel was observed regardless of ASA dose.

Numerous trials have confirmed that pretreatment with clopidogrel convincingly reduces CV events before and after PCI. For example, the PCI-CURE substudy of the CURE trial (Mehta et al. Lancet 2001;358(9281):527-33) showed that pretreatment with clopidogrel reduced the post-procedure 30-day risk of CV death/MI/urgent revascularization by 30%. Similar results were reported in the STEMI population in the PCI-CLARITY trials (Sabatine et al. JAMA 2005; 294(10):1224-32). The clinical advantage for patients receiving clopidogrel in addition to ASA and other standard therapies was maintained out to one year. From randomization until a maximum of one year, the clopidogrel-treated group had a 31% lower incidence of MI or CV death than those in the placebo group (8.8% vs. 12.6%, P=0.002). These data emphasize the importance of early initiation of clopidogrel and long-term treatment for up to one year.

Clopidogrel, when added to ASA, is also beneficial in patients with STEMI, irrespective of whether they have undergone reperfusion therapy. Patients aged <75 years should generally receive a loading dose of 300 mg. (Based on new data, some physicians now administer a loading dose of 600 mg; however, the optimal dose has yet to be definitively established.) Individuals of any age receive maintenance dosing of 75 mg/day for at least two weeks and up to one year. These recommendations emanate primarily from findings in COMMIT (Chen et al. Lancet 2005;366(9497):1607-21), in which clopidogrel added to ASA significantly reduced the relative risk of death (14%) or reinfarction (19%) in the month following the index event; and CLARITY (Scirica et al. J Am Coll Cardiol 2006; 48(1):37-42), in which clopidogrel added to a thrombolytic agent led to a 36% decrease in the risk of an occluded infarct-related artery/death/MI.

In CURE, clopidogrel significantly increased the risk of major bleeding (3.7% vs. 2.7%; relative risk, 1.38; P=0.001) but not of life-threatening bleeding. The risk of bleeding is significantly minimized if lower doses of ASA (75 to 100 mg) are used and if clopidogrel is withheld for several days (ideally five days) before CABG surgery. In patients undergoing PCI in the CURE trial, bleeding rates were similar between the groups. Similarly, clopidogrel use did not seem to increase the risk of bleeding in STEMI patients enrolled in the CLARITY and COMMIT trials.

Dual Antiplatelet Therapy in Canada

Investigators compiling data for the GRACE registry recently reported that the first-line use of clopidogrel (i.e. within 24 hours of a patient’s presentation with ACS) has increased over the last several years, but that a gap persists between evidence-based recommendations and their “real-world” application. About 25% to 30% of eligible patients do not receive dual antiplatelet therapy (Yan et al. CCC 2008, Toronto, abstract 1004). Additional analysis suggested that clopidogrel was most widely used in patients undergoing invasive management but underutilized in patients treated conservatively—an important group of patients who, according to the CURE trial, are likely to derive benefit (Banihashemi et al. CCC 2008, Toronto, abstract 1000).

Dosing Strategies

Despite their documented clinical benefits, contemporary antiplatelet agents are associated with potential limitations including delayed onset of action, variability of platelet inhibition in different individuals (i.e. response/resistance to therapy) and irreversibility. In addition, some patients experience thrombotic events despite taking recommended antiplatelet therapy. Much of the current research on antiplatelet therapy is focused on optimized dosing and development of new agents that will expand the pool of therapeutic options. Ideally, this work will help ensure treatment can be customized for specific patient profiles and clinical situations.

Solid evidence indicates that pretreatment (e.g. prehospital administration of a rapidly dispersible form of ASA, early administration of clopidogrel) can help offset a delay in antiplatelet activity. New dosing strategies may also help address delayed and incomplete platelet inhibition. As mentioned above, there is emerging evidence for employing a 600-mg loading dose or even a double 600-mg bolus of clopidogrel, as well as for higher maintenance doses. Montalescot et al. showed that 600- and 900-mg doses of clopidogrel led to more rapid and greater platelet inhibition than the 300-mg dose (J Am Coll Cardiol 2006;48(5):931-8). Moreover, Canadian investigators recently determined that two 600-mg doses of clopidogrel given 24 hours apart achieved significantly greater platelet inhibition than a single loading dose (L’Allier et al. J Am Coll Cardiol 2008;51(11):1066-72). Another study has demonstrated that in patients with ACS previously exposed to chronic clopidogrel treatment, a loading dose of 900 mg is more effective than lower doses at inhibiting platelet aggregation and reduces poor or slow response to the drug (Collet et al. Circulation 2008;118(12):1219-22). A recent pilot study also showed that a 150-mg maintenance dose provided greater platelet inhibition in patients with diabetes and a suboptimal response to the 75-mg dose (Angiolillo et al. Circulation 2007;115(6):708-16).

These higher doses may also have an improved clinical impact. The ARMYDA study demonstrated that in 255 patients undergoing PCI, the incidence of death/MI/revascularization was more than 50% lower in patients receiving 600 mg compared with 300 mg of clopidogrel (Patti et al. Circulation 2005; 111(16):2099-106). The much larger CURRENT-OASIS 7 study now in progress will help provide more information on the relative clinical benefits of a higher clopidogrel dose. In this trial, approximately 20,000 patients with ACS (including STEMI) managed with an invasive strategy will be randomly assigned to a high-dose regimen (600 mg, then 150 mg/day for seven days, then 75 mg/day) or the current standard dose of 300 mg followed by 75 mg/day. The primary efficacy outcome is CV death/MI/stroke at 30 days; bleeding complications will also be evaluated. The trial also includes an assessment of 30-day outcomes related to ASA at doses >300 mg and <100 mg per day, given that the optimal ASA/clopidogrel dosing regimen also requires clarification. Results from CURRENT-OASIS 7 are expected in 2009.

New Agents

Like clopidogrel, the new agents prasugrel and AZD6140 target the P2Y12 platelet receptor but have a faster onset of action, greater potency and are associated with less response variability.

The efficacy and safety of clopidogrel and prasugrel were initially compared in the TRITON-TIMI 38 trial (Wiviott et al. N Engl J Med 2007;357(20):2001-15), which included 13,608 moderate- to high-risk ACS patients undergoing PCI. The antiplatelet therapies (prasugrel 60 mg loading dose followed by 10 mg/day; clopidogrel 300 mg then 75 mg/day) were administered for six to 15 months. Over the follow-up period, the primary efficacy end point of CV death/MI/stroke occurred in 9.9% of the prasugrel-treated group and 12.1% of those receiving clopidogrel, for a relative risk reduction of 19% (P<0.001). Patients receiving prasugrel also experienced significantly less stent thrombosis and required fewer urgent target vessel revascularization procedures. However, the heightened efficacy of the study drug came at a safety cost. There was a significant 32% increased risk of major bleeding (2.4% with prasugrel vs. 1.8% with clopidogrel, P=0.03) and life-threatening bleeding (1.4% vs. 0.9, P=0.01), both fatal and nonfatal.

Two points to consider when interpreting the TRITON-TIMI 38 trial include the lack of clopidogrel pretreatment, which is currently standard practice in Canada and has been shown to lead to approximately a 30% reduction in important clinical events; and the use of a 300-mg loading dose/75 mg per day which may eventually be superseded by the higher doses discussed above. In addition, the study did not include patients with ACS receiving conservative therapy, so the potential role of prasugrel in this large patient population is as yet unknown. Finally, the higher rates of bleeding with prasugrel (including TIMI major and minor bleeding, fatal and nonfatal bleeding, intracranial hemorrhage in patients with prior stroke and bleeding during CABG surgery) suggest that further study of this novel agent may be necessary, particularly in patients at higher risk of bleeding.

The multinational TRILOGY (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial now underway will help answer some of the questions raised by TRITON-TIMI 38, including whether long-term clopidogrel or prasugrel therapy (expected median duration 18 months) is more clinically advantageous for approximately 10,000 medically managed patients with ACS. This double-blind, randomized controlled study will also evaluate the impact of clopidogrel and prasugrel in patients already receiving chronic clopidogrel therapy. To help address the issue of bleeding observed in TRITON-TIMI 38, the trial will employ a lower prasugrel dose (30 mg loading dose followed by 5 to 10 mg/day).

Still more studies in progress or in planning stages are aimed at enhancing current antiplatelet regimens and care of patients with ACS. Among these is the large PLATO study, which is comparing the direct-acting, reversible P2Y₁₂ inhibitor AZD6140 with clopidogrel in about 18,000 ACS and STEMI patients. The intravenous ADP receptor antagonist cangrelor is being evaluated in the CHAMPION PCI and PLATFORM trials and two studies are assessing the use of a novel thrombin receptor antagonist in addition to ASA with or without clopidogrel.

Summary

While we look forward to an expanded range of therapeutic options, defining optimal efficacy and safety balance with current and new antiplatelet therapies will require rigorous evaluation in large-scale clinical trials. Clinicians initiating antiplatelet therapy should continue to refer to the latest evidence-based guidelines for ACS.