Correspondence

Platelet Activation and Atherothrombosis

N Engl J Med 2008; 358:1638-1639April 10, 2008

Article

To the Editor:

In their review of platelet activation and atherothrombosis, Davì and Patrono (Dec. 13, 2007, issue)1 state that “the clinical benefit associated with P2Y₁₂ blockade by clopidogrel in patients receiving aspirin is relatively modest and inconsistent.” However, combining aspirin and clopidogrel is beneficial in certain subgroups. In one study, after percutaneous coronary intervention, combination therapy for 1 year was associated with a 26.9% relative reduction in the combined risk of death, myocardial infarction, or stroke.2 The addition of clopidogrel (300 mg in a loading dose, then 75 mg daily) to aspirin also improved patency rates for the infarct-related artery and reduced ischemic complications in patients with ST-segment elevation.3 The composite end point of arterial occlusion, death, or recurrent myocardial infarction in the study by Sabatine et al.3 was reduced by 36% with clopidogrel. Combination therapy also reduced the composite end point of death, reinfarction, or stroke as well as all-cause mortality and reinfarction among 45,852 patients presenting with an acute myocardial infarction.4 The clinical benefits of the combination therapy were not associated with an increased risk of bleeding. Thus, the beneficial role of dual antiplatelet therapy should not be underestimated.

John R. Kapoor, M.D., Ph.D.
Stanford University, Stanford, CA 94305
jkapoor@stanford.edu

4 References

1. 1

   Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482-2494
   Full Text | Web of Science | Medline

2. 2

   Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-2420[Erratum, JAMA 2003;289:987.]
   CrossRef | Web of Science | Medline

3. 3

   Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179-1189
   Full Text | Web of Science | Medline

4. 4

   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 2005;366:1607-1621
   CrossRef | Web of Science | Medline

Author/Editor Response

In response to Kapoor's comments, the relative risk reduction of major vascular events associated with the combination of clopidogrel and aspirin, as compared with single antiplatelet therapy, is relatively modest and inconsistent in the major areas of high cardiovascular risk (Figure 1Figure 1Relative Risk Reductions for the Combined End Point of Major Vascular Events.).2-4 The additional benefit of dual antiplatelet therapy versus aspirin alone is only a fraction of the benefit associated with aspirin versus placebo in the same clinical setting.1,5 In our article, we also suggest that the role of adenosine diphosphate (ADP) in atherothrombosis may have been underestimated on the basis of trials of ticlopidine and clopidogrel because of incomplete and variable blockade of ADP-induced platelet aggregation by these drugs. The results of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 386 are consistent with this hypothesis. A new thienopyridine, prasugrel, which causes a higher level of inhibition of ADP-induced platelet aggregation and a less variable response than standard-dose clopidogrel, further reduced major vascular events by about one fifth in patients with acute coronary syndromes and scheduled percutaneous coronary intervention.

Carlo Patrono, M.D.
Catholic University School of Medicine, 00168 Rome, Italy
carlo.patrono@rm.unicatt.it

Giovanni Davì, M.D.
G. d'Annunzio University Foundation, 66013 Chieti, Italy

5 References

1. 1

   Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86[Erratum, BMJ 2002;324:141.]
   CrossRef | Web of Science

2. 2

   Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717
   Full Text | Web of Science | Medline

3. 3

   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 2005;366:1607-1621
   CrossRef | Web of Science | Medline

4. 4

   The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502[Erratum, N Engl J Med 2001;345:1506, 1716.]
   Full Text | Web of Science | Medline

5. 5

   ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-360
   Web of Science | Medline

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