FAQ
Prasugrel: a thienopyridine drug on the horizon
Background
Recent literature has addressed a cause for concern regarding clopidogrel resistance, which puts patients at risk for increased thrombotic events. Due to this phenomenon, researchers began to look for alternatives that would overcome this issue. This led to the development of prasugrel, a member of the thienopyridine class of oral platelet aggregation inhibitors similar to clopidogrel and ticlopidine. Platelets are activated by a variety of endogenous agonists such as adenosine disph/b>>osphate (ADP), collagen, and thrombin.
Clopidogrel requires 2 cytochrome P450 (CYP) dependant oxidative steps to form its thiol containing active metabolite, which then binds irreversibly to P2Y12 receptors. Prasugrel, on the other hand, only requires 1 CYP450 dependant oxidative step, which results in a more effective conversion of the parent molecule to the active metabolite. This mechanism allows for greater and more efficient platelet inhibition compared to the existing thienopyridines. The Food and Drug Administration (FDA) granted prasugrel a 6-month priority review in February.
Platelet activation and aggregation play an important role after spontaneous plaque disruption in acute coronary syndromes or mechanical disruption of coronary artery plaques caused by percutaneous coronary intervention (PCI). Since coronary intervention can increase the risk of thrombosis, dual antiplatelet therapy with aspirin and a thienopyridine has become standard therapy. Current American College of Cardiology and American Heart Association (ACC/AHA) practice guidelines for unstable angina/non ST-elevation myocardial (UA/NSTEMI) infarction and ST-elevation myocardial infarction (STEMI) recommend the use of clopidogrel 300 or 600 mg loading dose (LD) followed by 75 mg daily and aspirin 162 to 325 mg daily before PCI and to be continued after the procedure (duration varies based on type of stent and patient’s risk for bleeding). The role of prasugrel in these situations has been investigated in randomized controlled trials. Phase 1 studies have shown prasugrel to have dose-dependent inhibition of platelet aggregation. Prasugrel also demonstrated a rapid onset and long duration of action in single and multiple dose human studies. These studies warranted further safety and efficacy evaluation as well as comparison to standard therapy.
Literature Review
Wiviott and colleagues compared prasugrel with clopidogrel in patients undergoing elective or urgent PCI in a dose ranging, multicenter, randomized, parallel group, double-dummy, active-comparator safety trial (JUMBO-TIMI 26). The study enrolled 900 subjects who were randomized to receive standard clopidogrel therapy (n=250) or prasugrel low-dose (40 mg LD followed by 7.5 mg daily; n=200), intermediate-dose (60 mg LD followed by 10 mg daily; n=200) or high-dose (60 mg LD followed by 15 mg daily; n=250). Patients were excluded if they had bleeding risks, stroke within 2 years, or use of various anticoagulants prior to PCI. The primary outcome measure was non-CABG (coronary artery bypass grafting) related significant hemorrhage at 30 days defined as composite major or minor hemorrhage. Bleeding events were defined and classified as per standard TIMI procedure. A clinically overt hemorrhage with a hemoglobin drop > 5 g/dL was considered major, and a clinically overt hemorrhage with a hemoglobin drop of 3 to ≤5 g/dL was considered minor. Additional safety and efficacy endpoints were also measured such as all-cause mortality, myocardial infarction (MI), stroke, clinical target vessel thrombosis, and recurrent myocardial ischemia requiring hospitalization. Results of the study revealed that among all groups the rates of major and minor bleeding were low. Rates for major bleeding in the combined prasugrel group were 0.5% vs. 0.8% for clopidogrel (p=0.544). The primary endpoint showed a 1.7% vs. 1.2% rate of bleeding for the prasugrel group compared to the clopidogrel group (p=0.590). The study did find a higher incidence of minimal bleeding in the high-dose prasugrel group (3.6%) compared with low-dose (2.0%), intermediate-dose (1.5%) groups and the clopidogrel group (2.4%, p values not reported). The incidence of MI, thrombosis, and recurrent ischemia was less frequent in the prasugrel group but this was not statistically significant.
Despite these findings, there were several limitations to this study. The trial was not statistically powered to determine differences in efficacy endpoints so the results must be used with caution. In addition, the authors comment that their power was reduced based on the low event rate of bleeding in the control group. The exclusion of elderly patients, those undergoing PCI for STEMI, and patients receiving anticoagulants prior to PCI limits the ability to extrapolate the results to patient populations seen at numerous institutions. The authors concluded that use of prasugrel showed low rates of bleeding and the results would be used in a larger trial discussed below that examines safety and efficacy of prasugrel.
TRITON-TIMI 38 study was conducted by the same authors involved in the JUMBO TIMI trial and was powered to find differences between groups for safety and efficacy. The study was a multicenter, randomized, parallel-group, double-dummy trial that compared prasugrel with clopidogrel in patients undergoing PCI. A total of 10,074 patients with UA/NSTEMI and 3534 patients with STEMI were randomized to either prasugrel 60 mg LD followed by 10 mg daily (n=6813) and clopidogrel 300 mg LD followed by 75 mg (n=6795) daily along with aspirin 162 to 325 mg daily. Patients were treated for 6 to 15 months with primary endpoint being a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke, and the main secondary endpoint was major bleeding. Ninety-nine percent of these patients had PCI at the time of randomization.
The findings showed a statistically significant difference in primary efficacy endpoint favoring prasugrel (9.9%) vs. clopidogrel (12.1%, hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.73 to 0.90, p<0.001). The rate of MI with subsequent cardiac-related death was reduced in prasugrel recipients vs. clopidogrel (0.4% vs. 0.7%, HR 0.58, 95% CI 0.36 to 0.93, p=0.02). The rate of a composite secondary endpoint (death from cardiac causes, nonfatal MI, or urgent revascularization) at 30 and 90 days was lower for prasugrel recipients (HR 0.78, 95% CI 0.69 to 0.89 and HR 0.79, 95% CI 0.70 to 0.90, p<0.001 for both). Prasugrel recipients had a lower incidence of stent thrombosis vs. clopidogrel (1.1% vs. 2.4%; HR 0.48, 95% CI 0.36 to 0.64, p<0.001).
The safety endpoint of major bleeding showed a statistically significant difference in major hemorrhage among patients treated with prasugrel 146 (2.4%) compared with clopidogrel 111 (1.8%, HR 1.32, 95% CI 1.03 to 1.68, p=0.03). This included a higher rate of life threatening bleeding in the prasugrel group (1.4%) compared to the clopidogrel groups (0.9%, HR 1.52, 95% CI 1.08 to 2.13, p=0.01). Comparing the 2 groups showed no statistically significant difference in death from cardiovascular causes or fatal hemorrhage (prasugrel 2.2% vs. clopidogrel 2.4%, HR 0.94, 95% CI 0.75 to 1.18, p=0.31) or nonfatal stroke (prasugrel 1% vs. clopidogrel 1%; p=0.93) alone.
Overall, the authors concluded that prasugrel therapy was superior to clopidogrel in terms of efficacy for preventing ischemic events/stent thrombosis, but at the cost of an increased incidence of major bleeding.
Conclusion
The role of prasugrel for platelet inhibition in patients undergoing PCI will need to be clearly defined once the drug hits the market. It may be prudent to limit use to patients < 75 years old, with no previous history of cardiovascular accidents due to the risk of life threatening bleeding evidenced by the TRITON-TIMI study. Clopidogrel should remain the mainstay of therapy for UA/NSTEMI and STEMI patients undergoing PCI as indicated by the current guidelines.
References
American College of Cardiology. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction. http://www.acc.org/qualityandscience/clinical/topic/topic.htm#anginapectoris. Accessed April 30, 2008.
American College of Cardiology. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. http://www.acc.org/qualityandscience/clinical/topic/topic.htm#M. Accessed April 30, 2008.
Jakubowski JA, Payne CD, Brandt JT et al. The platelet inhibitory effects and pharmacokinetics of prasugrel after administration of loading and maintenance doses in healthy subjects. J Cardiovasc Pharmacol. 2006;47(3):377-384.
Wiviott S, Braunwald E, McCabe C et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.
Niitsu Y, Jakubowski J, Sugidahci A et al. Pharmacology of CS-747 (Prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost. 2005;31(2):184-194.
Wiviott S, Antman E, Winters K. Randomized comparison of prasugrel (CS-747), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the joint utilization of medications to block platelets optimally (JUMBO)-TIMI 26 trial. Circulation. 2005;111(25):3366-3373