AFP Journal Club
The Story Behind the Study
Is Prasugrel More Effective Than Clopidogrel in Patients with Acute Coronary Syndrome Scheduled for PCI?
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Am Fam Physician. 2008 Dec 1;78(11):1252-1253.
Each month, three presenters review an interesting journal article in a conversational manner. These articles involve “hot topics” that affect family physicians or “bust” commonly held medical myths. The presenters give their opinions about the clinical value of the individual study discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP.
This Month's Article
Wiviott SD, Braunwald E, McCabe CH, et al., for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–2015.
Is prasugrel better than clopidogrel in patients with acute coronary syndrome who are scheduled for percutaneous coronary intervention ?
Mark: Prasugrel (Effient), which is still in development, will likely be marketed in the future as the more effective prodigal son of clopidogrel (Plavix). Should we stop using clopidogrel in favor of prasugrel?
What does this article say?
Mark: This is a double-blind study of 13,608 patients; 10,074 with high-risk unstable angina or non-ST segment elevation myocardial infarction (non-STEMI) and 3,534 with STEMI. Patients were administered prasugrel 60 mg or clopidogrel 300 mg. Importantly, all patients were scheduled for percutaneous coronary intervention (PCI). To be included in the study, those with unstable angina or non-STEMI had to have coronary anatomy known to be amenable to treatment by PCI. The primary end point was a composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke. Secondary end points included all of the primary end points, plus need for urgent revascularization.
The conclusion of the authors is that, in patients with acute coronary syndrome with scheduled PCI, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. So, does this mean that prasugrel should be preferred because of fewer ischemic events and fewer stent thromboses? Not based on this study.
Should we believe this study?
Mark: No. There are a couple of major problems. One is that the dose of clopidogrel is too low. We know that the loading dose of clopidogrel should be 600 mg to get platelet inhibition within two hours and that prasugrel 60 mg is not equivalent to clopidogrel 300 mg.1,2 Thus, it is a “straw man comparison.” They compared an optimal dose of prasugrel against a suboptimal dose of clopidogrel.
Andrea: A second problem is that the coronary anatomy had to be known to be amenable to PCI before patients were included in the study. This is selection bias. Because we don't know the coronary anatomy ahead of time in many patients with acute coronary syndrome, it is likely that if the drug was started in all persons going to the cath lab (some of whom would turn out not to have optimal coronary anatomy and would not benefit from PCI), the overall benefit would be less and there would be at least the same amount of bleeding.
Bob: Taking these two limitations into account, what about the results? The authors report a benefit in cardiovascular outcomes at 14.5 months in patients with a high-risk acute coronary syndrome who undergo PCI. However, for each cardiovascular death prevented by the use of prasugrel, its use resulted in approximately one additional episode of fatal bleeding. How is that for a risk/benefit ratio? Further, prasugrel needs to be avoided in patients with a history of stroke or transient ischemic attack. In these patients, prasugrel produced a significant increase in intracranial bleeding (2.3 versus 0 percent).
Mark: It gets worse. It turns out that there is no benefit over clopidogrel in persons with a creatinine clearance less than 60 mL per minute, persons older than 65 years, and women. This is a major part of the cohort that needs PCI! If we don't use prasugrel in these groups, the applicability of this drug is going to be very limited.
Andrea: If the authors had used a 600-mg clopidogrel loading dose, one could speculate whether the bleeding would likely have been higher in the clopidogrel group as well.
Bob: The final annoying aspect of this paper is its misleading title. It claims to compare prasugrel with clopidogrel in patients with acute coronary syndrome. This has nothing to do with patients with acute coronary syndrome whom we are planning to treat. It would have been more accurate to mention that these are patients who had acute coronary syndrome and were scheduled for PCI and in whom the coronary anatomy was known before the drug was started.
What should the family physician do?
Mark: For now, continue to use at least 325 mg of aspirin as a loading dose for most patients with acute coronary syndrome. If the patient is truly allergic to aspirin, load with clopidogrel 300 mg. For those undergoing PCI with stenting, clopidogrel remains the drug of choice. The currently recommended dose is 300 mg, even though it may take a bit longer to get optimal platelet inhibition than with the 600-mg dose. The discussion above with regard to the 600-mg dose of clopidogrel versus prasugrel 60 mg is to illustrate the bias in the study and is not meant to suggest we should use clopidogrel 600 mg. As noted by Andrea, bleeding would likely have been higher with a clopidogrel dose of 600 mg.
Use aspirin 325 mg as a loading dose in all patients with acute coronary syndrome. If patients are allergic to aspirin or undergoing PCI with stenting, a loading dose of clopidogrel 300 mg is a reasonable alternative.
Prasugrel has so many groups in whom the benefit does not outweigh the risk that it should not be widely adopted based on this study.
Comparing a study drug to a suboptimal dose of a competing drug or to a placebo is called a “straw man comparison.” Obviously, if you use an adequate dose of a study drug and a suboptimal comparison, the study drug is going to win. In this study, the dose of prasugrel and clopidogrel were not equivalent.
Selection bias occurs when the patients in a study are not the same as the patients you see in practice. In this case, all patients had to have coronary anatomy that was known to be amenable to PCI. Thus, the benefit is overestimated because some patients who undergo PCI won't have amenable coronary anatomy.
1. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation. 2005;111(20):2560–2564.
2. Jernberg T, Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J. 2006;27(10):1166–1173.
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