Current Drug Therapy

Prasugrel for acute coronary syndromes: Faster, more potent, but higher bleeding risk

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ABSTRACTPrasugrel (Effient) has been approved for reducing the risk of thrombotic complications in patients with acute coronary syndromes who are to undergo percutaneous coronary intervention. In a large clinical trial (N Engl J Med 2007; 357:2001–2005), prasugrel was superior to clopidogrel (Plavix), another drug of its class, in this situation. However, bleeding complications were more frequent with prasugrel, and so this drug should be avoided in patients at higher risk of bleeding.

KEY POINTS

  • The thienopyridines—ticlopidine (Ticlid), clopidogrel (Plavix), and now prasugrel—reduce the risk of death from and serious complications of acute coronary syndromes by inhibiting platelet aggregation.
  • Compared with clopidogrel, prasugrel is more potent, faster in onset, and more consistent in inhibiting platelets.
  • Prasugrel should be avoided in patients at higher risk of bleeding, including those with a history of stroke or transient ischemic attack, those age 75 or older, or those who weigh less than 60 kg.


 

References

Prasugrel (Effient) is more potent and consistent in its effects than clopidogrel (Plavix), thus preventing more thrombotic events—but at a price of more bleeding. Therefore, the drugs must be appropriately selected for the individual patient.

Over the last 9 years, the thienopyridines—ticlopidine (Ticlid), clopidogrel, and now prasugrel—have become essential tools for treating acute coronary syndromes.

The usual underlying mechanism of acute coronary syndromes is thrombosis, caused by rupture of atherosclerotic plaque.1 Accordingly, antithrombotic agents—aspirin, heparin, lowmolecular-weight heparin, glycoprotein IIb/IIIa inhibitors, the direct thrombin inhibitor bivalirudin (Angiomax), and thienopyridines—have all been shown to reduce the risk of major adverse cardiac outcomes in this setting.

In this article, we review the pharmacology and evidence of effectiveness of the thienopyridine drugs, focusing on prasugrel, the latest thienopyridine to be approved by the US Food and Drug Administration (FDA).

THIENOPYRIDINES INHIBIT PLATELET ACTIVATION AND AGGREGATION

Thienopyridines are prodrugs that require conversion by hepatic cytochrome P450 enzymes. The active metabolites bind irreversibly to platelet P2Y12 receptors. Consequently, they permanently block signalling mediated by platelet adenosine diphosphate-P2Y12 receptors, thereby inhibiting glycoprotein IIb/IIIa receptor activation and platelet aggregation.

Aspirin, in contrast, inhibits platelets by blocking the thromboxane-mediated pathway. Therefore, the combination of aspirin plus a thienopyridine has an additive effect.2

The effect of thienopyridines on platelets is irreversible. Therefore, although the half-life of prasugrel’s active metabolite is 3.7 hours, its inhibitory effects last for 96 hours, essentially the time for half the body’s circulating platelets to be replaced.

TICLOPIDINE, THE FIRST THIENOPYRIDINE

Ticlopidine was the first thienopyridine to be approved by the FDA. Its initial studies in unstable angina were small, their designs did not call for patients to concurrently receive aspirin, and all they showed was that ticlopidine was about as beneficial as aspirin. Consequently, the studies had little impact on clinical practice.3

In a pivotal trial,4 patients who received coronary stents were randomized to afterward receive either the combination of ticlopidine plus aspirin or anticoagulation therapy with heparin, phenprocoumon (a coumarin derivative available in Europe), and aspirin. At 30 days, an ischemic complication (death, myocardial infarction [MI], repeat intervention) had occurred in 6.2% of the anticoagulation therapy group vs 1.6% of the ticlopidine group, a risk reduction of 75%. Rates of stent occlusion, MI, and revascularization were 80% to 85% lower in the ticlodipine group. This study paved the way for widespread use of thienopyridines.

Ticlopidine’s use was limited, however, by a 2.4% incidence of serious granulocytopenia and rare cases of thrombocytopenic purpura.

BENEFIT OF CLOPIDOGREL

Although prasugrel is the focus of this review, the trials of prasugrel all compared its efficacy with that of clopidogrel. Furthermore, many patients should still receive clopidogrel and not prasugrel, so it is important to be familiar with the evidence of clopidogrel’s benefit.

Once approved for clinical use, clopidogrel was substituted for ticlopidine in patients undergoing coronary stenting on the basis of studies showing it to be at least as effective as ticlopidine and more tolerable. A series of trials of clopidogrel were done in patients across a spectrum of risk groups, from those at high risk of coronary heart disease to those presenting with ST-elevation MI. The time of pretreatment in the studies ranged from 3 hours to 6 days before percutaneous coronary intervention, and the duration of treatment following intervention ranged from 30 days to 1 year.

Clopidogrel in non-ST-elevation acute coronary syndromes

The CURE trial2 (Clopidogrel in Unstable Angina to Prevent Recurrent Events), published in 2001, established clopidogrel as a therapy for unstable ischemic syndromes, whether treated medically or with revascularization. In that trial, 12,562 patients with acute coronary syndromes without ST elevation (ie, unstable angina or non-ST-elevation MI), as defined by electrocardiographic changes or positive cardiac markers, were randomized to receive clopidogrel (a 300-mg loading dose followed by 75-mg maintenance doses) or placebo for a mean duration of 9 months. All patients also received aspirin 75 mg to 325 mg daily.

The composite outcome of death from cardiovascular causes, nonfatal MI, or stroke occurred in 20% fewer patients treated with clopidogrel than with placebo (9.3% vs 11.4%). The benefit was similar in patients undergoing revascularization compared with those treated medically.

Although there were significantly more cases of major bleeding in the clopidogrel group than in the placebo group (3.7% vs 2.7%), the number of episodes of life-threatening bleeding or hemorrhagic strokes was the same.

PCI-CURE5 was a substudy of the CURE trial in patients who underwent a percutaneous coronary intervention. Patients were pretreated with clopidogrel or placebo for a mean of 6 days before the procedure. Afterward, they all received clopidogrel plus aspirin in an unblinded fashion for 2 to 4 weeks, and then the randomized study drug was resumed for a mean of 8 months.

Significantly fewer adverse events occurred in the clopidogrel group as tallied at the time of the intervention, 1 month later, and 8 months later.

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