Prasugrel for acute coronary syndromes: Faster, more potent, but higher bleeding risk
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.
Clopidogrel in ST-elevation acute MI
The CLARITY-TIMI 28 trial6 (Clopidogrel as Adjunctive Reperfusion Therapy—Thrombolysis in Myocardial Infarction 28) showed that adding clopidogrel (a 300-mg loading dose, then 75 mg daily) to aspirin benefitted patients with ST-elevation MI receiving fibrinolytic therapy. At 30 days, cardiovascular death, recurrent MI, or urgent revascularization had occurred in 11.6% of the clopidogrel group vs 14.1% of the placebo group, a statistically significant difference. The rates of major or minor bleeding were no higher in the clopidogrel group than in the placebo group, an especially remarkable finding in patients receiving thrombolytic therapy.
PCI-CLARITY.7 About half of the patients in the CLARITY trial ultimately underwent a percutaneous coronary intervention after fibrinolytic therapy, with results reported as the PCI-CLARITY substudy. Like those in PCI-CURE, these patients were randomized to receive pretreatment with either clopidogrel or placebo before the procedure, in this study for a median of 3 days. Both groups received clopidogrel afterward. At 30 days from randomization, the outcome of cardiovascular death, MI, or stroke had occurred in 7.5% of the clopidogrel group compared with 12.0% of the placebo group, which was statistically significant, without any significant excess in the rates of major or minor bleeding.
COMMIT8 (the Clopidogrel and Metoprolol in Myocardial Infarction Trial) also showed clopidogrel to be beneficial in patients with acute MI. This trial included more than 45,000 patients in China with acute MI, 93% of whom had ST-segment elevation. In contrast to CLARITY, in COMMIT barely more than half of the patients received fibrinolysis, fewer than 5% proceeded to percutaneous interventions, and no loading dose was given: patients in the clopidogrel group received 75 mg/day from the outset.
At 15 days, the incidence of death, reinfarction, or stroke was 9.2% with clopidogrel compared with 10.1% with placebo, a small but statistically significant difference. Again, the rate of major bleeding was not significantly higher, either overall or in patients over age 70.
Of note, patients over age 75 were excluded from CLARITY, and as mentioned, no loading dose was used in COMMIT. Thus, for patients receiving fibrinolysis who are over age 75, there is no evidence to support the safety of a loading dose, and clopidogrel should be started at 75 mg daily.
Clopidogrel in elective percutaneous coronary intervention
The CREDO trial9 (Clopidogrel for the Reduction of Events During Observation) was in patients referred for elective percutaneous coronary intervention. Three to 24 hours before the procedure, the patients received either a 300-mg loading dose of clopidogrel or placebo; afterward, all patients received clopidogrel 75 mg/day for 28 days. All patients also received aspirin.
A clopidogrel loading dose 3 to 24 hours before the intervention did not produce a statistically significant reduction in ischemic events, although a post hoc subgroup analysis suggested that patients who received the loading dose between 6 and 24 hours before did benefit, with a relative risk reduction of 38.6% in the composite end point (P = .051).
After 28 days, the patients who had received the clopidogrel loading dose were continued on clopidogrel, while those in the placebo group were switched back to placebo. At 1 year, the investigators found a significantly lower rate of the composite end point with the prolonged course of clopidogrel (8.5% vs 11.5%).
In summary, these studies found clopidogrel to be beneficial in a broad spectrum of coronary diseases. Subgroup analyses suggest that pretreatment before percutaneous coronary intervention provides additional benefit, particularly if clopidogrel is given at least 6 hours in advance (the time necessary for clopidogrel to cause substantial platelet inhibition).
SOME PATIENTS RESPOND LESS TO CLOPIDOGREL
The level of platelet inhibition induced by clopidogrel varies. In different studies, the frequency of clopidogrel “nonresponsiveness” ranged from 5% to 56% of patients, depending on which test and which cutoff values were used. The distribution of responses to clopidogrel is wide and fits a normal gaussian curve.10
A large fraction of the population carries a gene that may account for some of the interpatient variation in platelet inhibition with clopidogrel. Carriers of a reduced-function CYP2C19 allele—approximately 30% of people in one study—have significantly lower levels of the active metabolite of clopidogrel, less platelet inhibition from clopidogrel therapy, and a 53% higher rate of death from cardiovascular causes, MI, or stroke.11
