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Since the discovery that low-dose aspirin can reduce the risk of heart attack, anti-platelet agents have become an increasingly important tool for preventing cardiovascular events. While aspirin is the most widely used and best studied anti-platelet agent, the use of clopidogrel (Plavix) and combination dipyridamole-aspirin (Aggrenox) have increased substantially in recent years, and a 2007 study introduced a new agent, prasugrel (Effient). Heavy marketing to physicians and direct-to-consumer advertising have made Plavix the second best-selling drug in the world. But how do the efficacy and safety of these newer drugs compare to aspirin? At a much higher cost ($160 per month for clopidogrel and $180 per month for dipyridamole-aspirin),when should these drugs routinely be used to replace aspirin at $1.30 per month?
A number of large randomized controlled trials have evaluated various antiplatelet regimens,and have produced widely varying results for different clinical conditions. The major studies are reviewed below, along with their implications for practice.
Acute coronary syndromes (ACS): The CURE, COMMIT, and CLARITY trials showed that the combination of clopidogrel and aspirin is more effective than aspirin alone for patients with unstable angina or who have had a myocardial infarction (both non-ST-segment elevation MI ("NSTEMI") and ST-elevation MI ("STEMI")).1,2,3 Combining aspirin and clopidgrel does not appear to increase the risk of bleeding in the short-term, but longer-term trials all found substantially higher risks of bleeding with this dual therapy4; therefore, the combination should be used with caution in patients for whom the benefits of this approach do not clearly outweigh their risks.
A new antiplatelet agent, prasugrel (Effient), when combined with aspirin was recently found to be superior to clopidogrel combined with aspirin in ACS patients who underwent percutaneous coronary intervention (PCI) (rate of primary study end point: 9.9% v. 12.1%, p<0.001).5 The combination of prasugrel and aspirin also caused a higher risk of major bleeding than clopidogrel plus aspirin (2.4% v. 1.8%, p=0.03). However, some patients, such as those with a low body weight, age ≥ 75, or a history of stroke, appeared to benefit less and had higher risks of bleeding; these subgroups are less likely to benefit from this new combination.
Elective percutaneous coronary intervention (PCI): Dual antiplatelet therapy with clopidogrel and aspirin is the standard of care for patients undergoing elective PCI. A common duration of treatment is up to 12 months6 though the upper limit of duration has not been defined. There is ongoing debate about whether the benefits of prolonged antiplatelet therapy outweigh its risks.
In patients with ACS or elective PCI, there is good evidence for use of clopidogrel + aspirin for at least 1 year. Prasugrel + aspirin for 15 months may be a better alternative for some ACS patients who have undergone PCI, but the benefit-risk profile is worse with this drug for some patient groups, including those who are older or weigh less.
The value of dual antiplatelet therapy is less clear for patients with stable coronary artery disease (including those with stable angina and a history of MI).
In the CHARISMA trial7 of patients with symptomatic vascular disease (including ahistory of MI and stable angina) or multiple risk factors, combining clopidogrel with aspirinproduced vascular outcomes that were equivalent to those seen with aspirin alone. Thesubgroup of patients with symptomatic vascular disease showed a slight benefit fromcombination therapy vs. aspirin alone, but this result was of only borderline statisticalsignificance and must be interpreted cautiously in light of the higher rate of bleeding thesepatients experienced.
The CAPRIE trial found only minimal differences between aspirin and clopidogrel inpatients with recent, but not acute, MI.8,9
However, there were some subgroups of patients in the CAPRIE trial who seemed tobenefit more from clopidogrel than from aspirin, though many of these subgroups weredefined after the study was completed. Clopidogrel (Plavix) may be a reasonable choice insuch patients: those with a history of coronary artery disease, stroke, or TIA, and any of the following: bypass surgery, events involving multiple vascular beds, two or more ischemicevents, diabetes, or high cholesterol.10
There is little evidence to support the routine use of clopidogrel for most post-MI patients whose infarcts are not recent.9 In most patients with stable coronary artery disease, it is reasonable to reserve clopidogrel for high-risk patients, and use aspirin for all others.
For patients who have had a stroke or a transient ischemic attack, several trials have compared aspirin or clopidogrel alone with an aspirin-clopidogrel or aspirin-dipyridamole combination.7,11-14
In patients with ischemic stroke or TIA within the prior 3 months, the evidence favors clopidogrel or aspirin-dipyridamole. Use aspirin for most patients with a more remote history of stroke.
The CAPRIE trial indicated that clopidogrel is more effective than aspiring for patients with severe PAD.8 However the CHARISMA trial assessed an aspirin-clopidogrel combination in these patients and found that it was no better than aspirin alone.7
An overview of these trials warrants using clopidogrel monotherapy in patients with PAD.
Six large trials have evaluated the role of aspirin for the primary prevention of vascular disease (i.e., in patients who have not yet had a cardiovascular event). The results of a metaanalysis of these trials are summarized below.15 While the use of aspirin is one of the most time-honored means of preventing MI, recent studies suggest that its use is not as simple a decision as it once seemed to be, especially for patients without existing heart disease and/or an increased risk of bleeding. Further, all antiplatelet agents increase the risk of gastrointestinal and intracranial bleeding, even aspirin at low doses.16
Because of the bleeding risk caused by antiplatelet therapy, aspirin should be prescribed for primary prevention only in patients for whom the benefits of therapy outweigh its potential harm.
The cost of clopidogrel (Plavix), dipyridamole-aspirin (Aggrenox), and prasugrel (Effient) are more than 100 times that of aspirin. Despite this, it can still be economically reasonable to prescribe these drugs in appropriately chosen patients. For example, one economic analysis found that clopidogrel (Plavix) used alone in patients with peripheral vascular disease appears to be highly cost-effective.9
Differences in cost may be particularly relevant when choosing between agents that are equally effective or equally safe. This is especially important in patients for whom an unaffordable drug will result in non-compliance.
This material was produced by Niteesh K. Choudhry, M.D., Ph.D.,Assistant Professor of Medicine, Harvard Medical School, with consultative input from Michael A. Fischer, M.D., M.S.,Assistant Professor of Medicine, Harvard Medical School; Leslie Jackowski, B.Sc.(Hon)., MBBS, Research Fellow, Harvard University;William H. Shrank, M.D., M.S.H.S., Assistant Professor of Medicine, Harvard Medical School. Series editor: Jerry Avorn, M.D., Professor of Medicine, Harvard Medical School. Drs Avorn, Choudhry, Fischer, and Shrank are all physicians at the Brigham and Women’s Hospital in Boston. None of the authors receives any personal compensation from any drug company. These are general recommendations only; specific clinical decisions should be made by the treating physician based on assessment of the individual patient.
References:
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2. Chen ZM, Jiang LX, Chen YP, et al.Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet.Nov 5 2005;366(9497):1607-1621.
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8. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet.Nov 16 1996;348(9038):1329-1339.
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13. Halkes PH, van Gijn J, Kappelle LJ,Koudstaal PJ,Algra A.Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia ofarterial origin (ESPRIT): randomised controlled trial. Lancet.May 20 2006;367(9523):1665-1673.
14. Sacco RL, Diener HC,Yusuf S, et al.Aspirin and extendedrelease dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. Sep 18 2008;359(12):1238-1251.
15. Berger JS, Roncaglioni MC,Avanzini F, Pangrazzi I,Tognoni G, Brown DL.Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. Jan 18 2006;295(3):306-313.
16.Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding.BMJ. Apr 1 1995;310(6983):827-830.
17. Baigent C, Blackwell L, Collins R, et al.Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet.May 30 2009;373(9678):1849-1860.