More than 22 million Americans are estimated to take aspirin daily; 3–5% of patients covered by health insurance in France received a prescription for antiplatelet drugs in 2006, representing an estimated 200,000 to 300,000 new patients each year. Aspirin, which inhibits the formation of platelet thromboxane, is a major treatment to reduce ischaemic complications in patients with atherothrombotic disease. Clopidogrel, a thienopyridine derivative, selectively inhibits the platelet adenosine phosphate receptor and is a potent inhibitor of platelet aggregation. Dipyridamole reduces platelet aggregation by raising the antiplatelet level of cyclic adenosine monophosphate and cyclic guanosine monophosphate, but has non-bleeding side effects. Cilostazol, a phosphodiesterase 3 inhibitor, is an alternative to aspirin for the prevention of stent restenosis, which works through a different mechanism.
When clopidogrel is used with aspirin, the antiplatelet effect is synergistic . The clinical benefit of this combination comes mainly from its use in the management of patients with unstable angina and non-ST or ST-elevation myocardial infarction as well as patients undergoing a percutaneous coronary intervention (PCI) . Clopidogrel added to aspirin is considered a standard regimen in acute coronary syndromes (ACS) . Accordingly, most patients who receive long-term dual antiplatelet therapy have undergone either stent PCI or had an ACS. However, some patients still experience cardiovascular events in spite of treatment with aspirin and/or clopidogrel. This may be caused by low responsiveness, which has been reported to range from 1–45% for the two drugs . In particular, clopidogrel is a prodrug that needs to be metabolized to the active thiol metabolite by the cytochrome P450 system. This activation is a source of significant inter-individual variability in clopidogrel responsiveness.
When considering the long-term or chronic condition of atherothrombosis, it is unclear whether dual antiplatelet therapy provides superior efficacy over single antiplatelet therapy. Moreover, the risk/benefit balance could be unacceptable because of the increased haemorrhagic risk of dual antiplatelet therapy. The aim of this review is to clarify chronic atherothrombosis situations in which dual antiplatelet therapy can bring additional benefit compared with monotherapy. We will not discuss here the benefit of dual antiplatelet therapy in ACS or in atrial fibrillation or haemodialysis graft patency, as described recently elsewhere .
Four recent randomized controlled trials–namely the MATCH, CHARISMA, PROFESS and ESPRIT studies–compared dual antiplatelet therapy with monotherapy in patient populations at high risk of atherothrombotic events . Selected populations were similar, except that patients in the CHARISMA trial had multiple risk factors. Moreover, in the ESPRIT and PROFESS studies, diabetes and prior stroke were less prevalent. In these trials, efficacy was assessed using a composite endpoint consisting of myocardial infarction, stroke or death from cardiovascular causes, except in the MATCH trial where efficacy was assessed using these three same events plus rehospitalization for an acute ischaemic event. In the PROFESS and ESPRIT studies, the composite outcome was a secondary endpoint. In all studies, major bleeding was considered as a safety outcome and was defined as any intracranial bleeding, any fatal bleeding or any bleeding requiring hospital admission. The results of these trials are summarized in Table 1 and Fig. 1 .
| Dual therapy | Monotherapy | Follow-up (months) | Outcome | Effect size [95% confidence interval] | |
|---|---|---|---|---|---|
| CHARISMA, 2006 | Aspirin + clopidogrel | Aspirin | 28 | MI, stroke or CV death | 0.93 [0.83–1.05] |
| 534/7802 | 573/7801 | ||||
| ESPRIT, 2006 | Aspirin + dipyridamole | Aspirin | 24 | CV death, non-fatal stroke, non-fatal MI | 0.80 [0.66–0.98] |
| 173/1363 | 216/1376 | ||||
| PROFESS, 2008 | Aspirin + dipyridamole | Clopidogrel | 25 | Stroke, retinal infarction, or death from any cause | 0.99 [0.92–1.07] |
| 1333/10181 | 1333/10,151 | ||||
| MATCH, 2004 | Aspirin + clopidogrel | Clopidogrel | 30 | Stroke, MI, CV death | 0.94 [0.84–1.05] |
| 596/3797 | 636/3802 | 18 | Ischaemic stroke, MI, CV death, or rehospitalization for acute ischaemia | ||
| Safety endpoint: major bleedings | |||||
|---|---|---|---|---|---|
| Dual therapy | Monotherapy | Effect size [95% confidence interval] | |||
| CHARISMA, 2006 | Aspirin + clopidogrel | Aspirin | Fatal bleeding and intracranial haemorrhage, or bleeding that caused haemodynamic compromise requiring blood or fluid replacement, inotropic support or surgical intervention | 1.25 [0.97–1.61] | |
| 130/7802 | 104/7801 | ||||
| ESPRIT, 2006 | Aspirin + dipyridamole | Aspirin | All intracranial or fatal bleeding, any bleeding requiring hospital admission | 0.67 [0.44–1.03] | |
| 35/1363 | 53/1376 | ||||
| PROFESS, 2008 | Aspirin + dipyridamole | Clopidogrel | Haemorrhagic event that resulted in clinically significant disability, symptomatic intracranial haemorrhage, intraocular bleeding causing loss of vision, the need for a transfusion of ≥ 2 units of red cells or the equivalent amount of whole blood, or the need for hospitalization | 1.15 [1.00–1.32] | |
| 419/10181 | 365/10151 | ||||
| MATCH, 2004 | Aspirin + clopidogrel | Clopidogrel | Any fatal bleeding event; a drop in haemoglobin of 50 g/L; significant hypotension with need for inotropes [haemorrhagic shock]; symptomatic intracranial haemorrhage, or transfusion of 4 units of red blood cells or equivalent amount of whole blood | 3.34 [2.09–5.34] | |
| 73/3797 | 22/3802 | ||||
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