Clopidogrel in acute coronary syndromes

Patients with non-ST elevation myocardial infarction

The CURE randomised trial established the role of clopidogrel in the treatment of patients with non-ST elevation myocardial infarction.4 In the trial, 12 562 patients with unstable angina or non-ST elevation myocardial infarction, who were largely medically managed, received aspirin and were randomly assigned to clopidogrel (300 mg loading dose, followed by 75 mg daily) or placebo. The absolute risk reduction in the composite end point of cardiovascular death, non-fatal myocardial infarction, and stroke for those who took both aspirin and clopidogrel was 2.1% (P<0.001; relative risk 0.8, 95% confidence interval 0.72 to 0.9). This benefit of clopidogrel was also seen in patients who received subsequent coronary artery bypass surgery or percutaneous coronary intervention. Despite a 1% absolute increase in major bleeding with dual aspirin and clopidogrel treatment, such treatment has become standard clinical practice in the management of non-ST elevation myocardial infarction. The latest guidance from the American College of Cardiology, American College of Chest Physicians, and European Society of Cardiology on non-ST elevation myocardial infarction strongly recommends the use of clopidogrel (level I A recommendation; see box).5 6 7

Patients with ST elevation myocardial infarction

Two landmark trials established the role of clopidogrel in the treatment of patients with ST elevation myocardial infarction. CLARITY randomised 3491 patients who presented with ST elevation myocardial infarction within 12 hours of the onset of chest pain to receive a 300 mg clopidogrel loading dose, followed by 75 mg daily, or matching placebo for 30 days.8 All patients received aspirin, heparin, and fibrinolytics and then proceeded to coronary angiography. The primary composite end point (death, myocardial infarction, and infarct related occluded artery flow) was lower in the clopidogrel arm than in the placebo arm, with no difference in bleeding between the two groups.

Subsequently, the COMMIT randomised trial enrolled 45 852 patients who presented with ST elevation myocardial infarction within 24 hours of onset of ischaemic pain but did not undergo percutaneous coronary intervention.9 Patients were randomised to clopidogrel 75 mg daily or matching placebo for four weeks or until hospital discharge. All patients received aspirin, and fibrinolytic agents were used if clinically appropriate. The clopidogrel group had a 0.9% absolute risk reduction in the composite end point of death, reinfarction, and stroke (P=0.002; odds ratio 0.91, 0.86 to 0.97) and a 0.6% reduction in absolute risk of death (P=0.03; 0.93, 0.87 to 0.99) compared with the placebo group at 28 days. Subgroup analysis of COMMIT showed that the effects of clopidogrel were consistent across a wide range of patients and independent of other drugs used. No excess major bleeding or cerebral haemorrhage was seen in the clopidogrel group.

The findings of the CLARITY and COMMIT trials have led to clopidogrel becoming standard treatment for ST elevation myocardial infarction. Guidelines from the American College of Cardiology strongly recommend the use of clopidogrel in addition to aspirin for the management of ST elevation myocardial infarction (level I A recommendation).10 A loading dose of clopidogrel 300 mg is encouraged in patients under 75 years, although this recommendation is based on expert opinion alone.

Patients undergoing percutaneous coronary intervention with coronary stenting

The CLASSICS trial established the role of clopidogrel after percutaneous coronary intervention by showing that clopidogrel was equivalent to ticlodipine in reducing adverse cardiac events after coronary stenting but had a better safety and tolerability profile.11 12

The PCI-CURE study, a subgroup analysis of the CURE trial, further established the role of clopidogrel after coronary stenting.13 In this trial, 2658 patients with non-ST elevation myocardial infarction who subsequently underwent percutaneous coronary intervention with stenting were randomised to a 300 mg loading dose of clopidogrel, followed by 75 mg daily clopidogrel or matching placebo. All patients received aspirin. The use of clopidogrel reduced the composite end point (death from cardiac disease, myocardial infarction, and target vessel revascularisation at 30 days) compared with the placebo group. The role of clopidogrel in reducing adverse cardiac events after coronary stenting is established, and treatment with clopidogrel has become standard clinical practice.

After acute coronary syndromes

The ideal duration of clopidogrel treatment for non-ST elevation myocardial infarction is unclear, although the average length of treatment in the CURE trial was nine months. The latest American College of Cardiology and American College of Chest Physicians guidelines for ST elevation myocardial infarction recommend a 14 day course of clopidogrel treatment (level I B recommendation) on the basis of the average duration of treatment in the COMMIT trial.10 14 These guidelines also suggest that up to one year of clopidogrel may be beneficial in ST elevation myocardial infarction, although this is based on extrapolation from other clopidogrel studies in coronary artery disease and expert opinion (level II C recommendation).

CHARISMA, a trial that randomised 15 603 patients with multiple cardiac risk factors and clinically evident cardiovascular disease to either clopidogrel 75 mg daily or placebo plus background aspirin for two years, showed that prolonged treatment with clopidogrel did not reduce cardiac adverse events.15 This trial enrolled a heterogeneous group of patients with cardiac disease, so it is difficult to know whether patients with documented coronary artery disease would benefit from long term dual antiplatelet therapy with aspirin and clopidogrel. Routine prolonged treatment with clopidogrel beyond current recommendations is not warranted at this time.

After coronary stenting

The optimal duration of clopidogrel after coronary stenting was still unclear at the end of the PCI-CURE study, which looked at the use of clopidogrel only up to 30 days after stenting. The CREDO trial randomised 2116 patients who underwent percutaneous coronary intervention with stenting to a 300 mg loading dose of clopidogrel, followed by 75 mg daily for 12 months or a placebo loading dose, followed by clopidogrel 75 mg daily for 28 days.16 The composite end point of death, myocardial infarction, and stroke at 12 months was lower in the 12 month clopidogrel arm than in the 28 day clopidogrel arm. This showed that a longer rather than shorter course of treatment with clopidogrel is best after coronary stenting. Major bleeding at 12 months was not significantly different between the 12 month and 28 day clopidogrel groups. On the basis of PCI-CURE and CREDO, the most recent guidance from the American College of Cardiology, European Society of Cardiology, and American College of Chest Physicians on percutaneous coronary intervention strongly recommends clopidogrel for at least one month after bare metal stent insertion (level I A recommendation), with an ideal duration of one year (level I B recommendation).17 18 19

After drug eluting coronary stent placement

A longer duration of dual antiplatelet treatment with aspirin and clopidogrel is needed after placement of a drug eluting stent than a bare metal stent. Previous percutaneous coronary intervention guidelines recommended six to 12 months of such treatment, largely on the basis of randomised clinical trials of drug eluting stent studies and registry data.20 Concerns have recently emerged about late stent thrombosis and subsequent adverse cardiac events with drug eluting stents. Several small observational studies and registry data suggest that mortality and the incidence of myocardial infarction may be higher with drug eluting stents than with bare metal stents, probably because of the greater chance of late stent thrombosis with drug eluting stents.21 22 Observational studies and analysis of registry data show that premature discontinuation of clopidogrel is the biggest risk factor for late stent thrombosis.22 23 The possibility of higher cardiac event rates associated with drug eluting stents has sparked much concern and debate.24

Because of these concerns, the American College of Cardiology has recommended that patients receive at least one year of dual antiplatelet treatment with aspirin and clopidogrel after implantation of any drug eluting stent. These recommendations are based largely on observational data and expert opinion (level I B recommendation).22 The use of dual antiplatelet treatment is crucial and patients should be told about the importance of adhering to treatment with clopidogrel before implantation of a drug eluting stent.

The optimal treatment beyond one year is unknown, but studies to determine the optimal duration of clopidogrel after placement of a drug eluting stent are under way. Patients who are allergic to aspirin should take clopidogrel indefinitely.