Atherothrombosis resulting in recurrent ischemia and stent thrombosis remain major problems in the secondary prevention of coronary artery disease and after percutaneous coronary intervention (PCI). Recruitment of activated platelets to sites of plaque rupture and within arterial stents plays a central role in thrombotic complications. Accordingly, dual antiplatelet therapy with aspirin and a thienopyridine has resulted in improved outcomes following acute coronary syndromes (ACS) and PCI.1-3 Limitations in currently available thienopyridines include a delayed onset of action, need for activation (as current drugs are prodrugs), and variable and incomplete antiplatelet effects.4 Some data support that this interpatient variability may result in increased risk of adverse outcomes following stent placement,5,6 and further justifies the need for drug development in the antiplatelet arena.
Mechanism of action
Prasugrel is a novel member of the thienopyridine class of oral antiplatelet agents that includes ticlopidine and clopidogrel. Early clinical trials have demonstrated that prasugrel is highly orally active, with a quicker onset of action and less variability in platelet inhibitory activity than clopidogrel or ticlopidine.7 Following oral administration, prasugrel first undergoes hydrolysis to thiolactone, then cytochrome P-450 (CYP) oxidation to its biologically active metabolite, resulting in noticeable adenosine diphosphate (ADP) inhibition within 30 minutes.8 This metabolite, like other thienopyridine metabolites, binds irreversibly to the platelet P2Y12 receptor, inhibiting ADP-mediated platelet activation and aggregation. The duration of effect is similar to clopidogrel at 3 to 5 days. One notable pharmacodynamic desire this drug lacks is reversibility. Other pertinent pharmacokinetic data are included in the Table.
The first phase 2 clinical trial was the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 study,9 a dose-ranging, safety trial comparing the primary end point of clinically significant bleeding (TIMI minor or major) in patients taking prasugrel versus clopidogrel. Nine hundred four patients undergoing PCI were treated with enteric-coated aspirin 325 mg and randomized to clopidogrel (300 mg/75 mg) or prasugrel (40 mg/7.5 mg, 60 mg/10 mg, or 60 mg/15 mg). At 30 days, bleeding rates were 2.4% with clopidogrel and 1.5%, 2.0%, and 3.6% across the range of prasugrel doses, respectively. Evaluation of secondary efficacy end points revealed a nonsignificant reduction in major adverse cardiovascular events. The findings from the JUMBO trial allowed care providers to postulate if greater inhibition of P2Y12 would result in improved outcomes, and if so, at what cost.
The recently published Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON) was a randomized, double-blind, double-dummy trial designed to answer a similar question. The authors hypothesized that prasugrel would be superior to clopidogrel in ACS patients undergoing PCI.10 Unstable angina or non-ST-elevation myocardial infarction (NSTEMI) patients who were included in the study were required to have a TIMI risk score ≥3 and to be seen within 72 hours of the index event. All of these patients had to have PCI or angiography planned, while ST-segment elevation myocardial infarction (STEMI) patients could be within 12 hours of the event with PCI planned or within 14 days of a medically managed event. Patients were excluded from the study if they had an increased risk of bleeding, anemia, thrombocytopenia, history of pathologic intracranial findings, or had taken any thienopyridine within 5 days. The primary end point was a composite of cardiovascular death, and nonfatal myocardial infarction (MI) or stroke, which was the same used in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.3,10 Prespecified secondary end points included urgent target-vessel revascularization, rehospitalization, and stent thrombosis, while safety outcomes were TIMI major and minor bleeding.
The trial enrolled 10,074 patients with unstable angina or NSTEMI and 3,534 patients with STEMI. Patients were randomized to prasugrel, 60-mg loading dose, followed by 10 mg daily, or the Food and Drug Administration (FDA)-approved dose of clopidogrel (300 mg loading and 75 mg daily). During the 15 month follow-up, 12.1% of clopidogrel patients and 9.9% of prasugrel patients experienced the primary end point (< .01). Statistical significance appeared to be driven by an absolute difference of 2.2% in nonfatal MI. There was also a significant reduction in stent thrombosis and urgent target-vessel revascularization in the prasugrel arm. There was no apparent difference in cardiovascular death or all-cause mortality, which may be due to the fact that the trial was not adequately powered to detect a difference in these end points. The benefit observed with prasugrel, likely the product of greater antiplatelet effect, must be balanced with the resultant increase in clinically significant bleeding. In TRITON, prasugrel was associated with a statistically significant increase in TIMI major and minor bleeding rates. Excluding bleeding events associated with coronary artery bypass graft (CABG) surgery, the prasugrel arm also had a 0.5% absolute increase in life-threatening bleeding events (= .01) and fatal bleeding was increased by 0.3% (= .002). Prasugrel treatment also resulted in a near 5-fold increase in CABG surgery-related bleeding. Subgroup analyses were performed to identify patient populations who did not benefit from prasugrel or had increased bleeding. Analysis revealed a decreased benefit and potential harm in subjects older than 75 years, those with low body weight (< 60 kg), or those with a history of ischemic stroke.10 In the patients who had a history of stroke or transient ischemic attack, prasugrel resulted in an excess of intracranial hemorrhage (2.3% vs 0% in the clopidogrel group; = .02)
According to the results of the TRITON trial alone, not everyone should receive prasugrel after PCI. Although reductions in the primary end point were seen, safety concerns were also observed. The inclusion and exclusion criteria of the TRITON trial should be used to help guide decisions about which patients are good candidates for prasugrel therapy as an alternative to clopidogrel. Until further data are available, the available data should not be extrapolated to other patient populations, including patients who do not receive PCIs.
With greater ADP-induced platelet inhibition of prasugrel compared with clopidogrel, it is not surprising that bleeding was increased. However, these events are particularly concerning considering patients at the highest risk of bleeding were excluded from the TRITON trial. Given the results of the subanalysis, and the increased risk of intracranial hemorrhage, prasugrel should not be used in patients with known cerebrovascular disease. Although subgroup analysis is merely hypothesis generating until further safety evaluations are performed, elderly patients and those with low body weights should be avoided in addition to previously mentioned populations.
If approved by the FDA, prasugrel will be marketed under the trade name Effient. Patients at the highest risk of stent thrombosis or ischemic events, but at a low risk for bleeding, should be considered for dual antiplatelet therapy with prasugrel as an alternative to clopidogrel plus aspirin.
Following these criteria, if 1,000 patients are treated with prasugrel, 22 events (cardiovascular death, MI, or stroke) will be avoided, 6 patients will experience non—CABG surgery-related major bleeding, and 3 patients will have fatal bleeding. While prasugrel may be an answer for some patients and physicians, still newer agents are being developed to treat the complications of MI. Most will promise further decrease in platelet aggregation, quicker onsets of action, and even reversibility. Only time will tell which agents will be able to accomplish these things without compromising safety. Based on available data, if prasugrel was available today, it would appear to benefit patients at high risk of ischemic events—for example, those with diabetes or with inadequate platelet inhibition despite taking clopidogrel.