Efficacy and safety of prasugrel vs. clopidogrel is not affected by aspirin dose

Kohli P, Udell JA, Murphy SA, et al.
J Am Coll Cardiol. 2014 Jan 28;63(3):225-32

Background

Aspirin has long been used in the secondary prevention of patients with acute coronary syndromes (ACS), after it had been shown to reduce the incidence of re-infarction and non-fatal stroke, without a significant increase in cerebral haemorrhage [1]. Aspirin was later also found to be effective to reduce the entire spectrum of ACS, from ST-segment elevation myocardial infarction (MI) to unstable angina/non-ST-segment elevation MI (NSTEMI) [2-4]. Dosage in these studies varied considerably, thus the optimal daily dose remained unclear.
The PLATO trial had shown a benefit of the P2Y12 receptor antagonist ticagrelor over the thienopyridine clopidogrel (both combined with aspirin) in the reduction of recurrent CV events [5]. Subsequent analyses suggested that an apparent decreased efficacy of ticagrelor in North American subjects might have been related to the reduced efficacy of ticagrelor when combined with higher doses of aspirin, more commonly prescribed in North America [6]. FDA now recommends that ticagrelor be used only in combination with low doses of aspirin [7].
Prasugrel is also a potent P2Y12 receptor antagonist. This study aimed to determine whether the dose of aspirin affected the comparison between prasugrel and aspirin in the TRITON-TIMI
38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38) trial [8]. TRITON-TIMI 38 was a double-blind trial of patients with ACS, including high-risk unstable angina/NSTEMI and ST-segment elevation MI with planned percutaneous coronary intervention (PCI), randomised to either prasugrel (60 mg loading dose, 10 mg daily) or clopidogrel (300 mg loading dose, 75 mg daily).

Main results

• High-dose (>150 mg) aspirin was used more frequently in younger patients, those with unstable angina/NSTEMI as an index event, those with previous MI and in those who had a drug-eluting stent placed during PCI. 66% of patients in North America received high-dose aspirin, as opposed to 28% in other countries. Within each stratum of aspirin dosing, baseline characteristics were generally similar between prasugrel and clopidogrel.
• The strongest independent correlate of high-dose aspirin was geographical region OR: 5.19, 95%CI:4.72-5.70, P<0.001 for North America vs. other countries). Other independent correlates included previous PCI (OR: 1.18, 95% CI: 1.03- 1.35, P<0.015), systolic blood pressure (OR: 1.03 per 10-mm Hg increase, 95% CI: 1.02- 1.05, P< 0.001), and use of aspirin at randomisation (OR:1.37, 95% CI: 1.07- 1.76], p< 0.013).
• Aspirin dose did not modify the clinical effect of prasugrel vs. clopidogrel with regard to the primary efficacy endpoint of CVD, MI and stroke (HR: 0.78, 95%CI: 0.64-0.95 for aspirin <150 mg, and HR: 0.87, 95%CI: 0.69-1.10 for aspirin >150 mg, P(interaction): 0.48), nor with regard to the primary safety endpoint of TIMI major bleeding (HR: 1.47, 95%CI: 0.97-2.21 for aspirin <150 mg; HR: 1.58, 95% CI: 0.92-2.69 for aspirin >150 mg; P(interaction)=0.84).
• Prasugrel only reached superiority over clopidogrel for the primary efficacy endpoint of CVD, MI and stroke in the low-dose aspirin group. The point estimates do remain directionally consistent with the results of the overall TRITON-TIMI 38 trial.
  Similarly, in both aspirin groups, there were non-significantly fewer primary and secondary endpoint events and higher bleeding with prasugrel as compared with clopidogrel.

Conclusion

Discharge aspirin dose does not seem to modify the clinical effect of prasugrel vs. clopidogrel in patients with ACS. Prasugrel reduced the composite primary endpoint of CVD, MI and stroke significantly more than clopidogrel in the low-dose aspirin group. Other directionally consistent improvements were seen with prasugrel, that did not reach statistical significance. Prasugrel did yield higher bleeding rates than clopidogrel, irrespective of discharge aspirin dose.
Geographical differences in aspirin dose were prominent, with high-dose aspirin much more commonly being prescribed in North America. Although the ACC/AHA for ACS had been revised to recommend a low dose for discharge aspirin rather than high dose, this study does not support any interaction between prasugrel and aspirin dose.

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