Novel antiplatelet strategies in acute coronary syndromes

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= .003). The event curves for prasugrel and clopidogrel continued to diverge with time ( Figure 2 ), suggesting that prasugrel’s relative advantage in preventing ischemic events extends at least through 15 months. 15

The reduction in the primary end point with prasugrel was driven primarily by a reduction in nonfatal MI; nonsignificant trends favored prasugrel over clopidogrel on rates of cardiovascular death and all-cause mortality, but there was no difference in stroke rates. Prasugrel’s effect was consistent across subgroups based on MI type, sex, age, the type of stent used, adjunctive antithrombotic therapy, and renal function. 15

In the subgroup of patients with diabetes, the relative reduction in the primary end point with prasu­grel compared with clopidogrel was 30% ( P < .001), and the respective relative reduction among patients with diabetes who required insulin was 37%. 16

Safety. Higher antiplatelet potency carries the trade-off of increased bleeding, and this trade-off was apparent with prasugrel in TRITON-TIMI 38. 15 TIMI major bleeding (not counting bleeding related to coronary artery bypass graft surgery [CABG]) occurred significantly more often in prasugrel-treated subjects than in those receiving clopidogrel (2.4% vs 1.8%; P = .03), as did life-threatening bleeds (1.4% vs 0.9%; P = .01). Because absolute rates of major bleeding were low in each treatment group, based on these results, 167 patients would need to be treated with prasugrel rather than clopidogrel to result in 1 excess non-CABG-related major bleeding episode. Rates of intracranial hemorrhage were identical in the two treatment groups. 15

Net clinical outcome and therapeutic considerations. Overall analysis of the balance of efficacy and safety in TRITON-TIMI 38 revealed that 138 events were prevented with randomization to prasugrel instead of clopidogrel, at a cost of 35 additional TIMI major bleeds ( Figure 2 ).15

In a post hoc analysis of net clinical outcome, in which major bleeding events were added to the primary composite efficacy end point, prasugrel was associated with a 13% relative risk reduction ( P = .004). 15 Twenty-three MIs were prevented per 1,000 treated patients with the use of prasugrel instead of clopidogrel, at a cost of 6 excess non-CABG-related major bleeds. 15

Another post hoc assessment identified three subgroups who had a significantly increased risk of TIMI major bleeds with randomization to prasugrel 15:

  • Patients aged 75 years or older
  • Patients with a body weight less than 60 kg
  • Patients with a history of stroke or transient ischemic attack (TIA).

In these three subgroups, the net clinical effect either was neutral (for those aged ≥ 75years and for those weighing < 60 kg) or favored clopidogrel (for those with a history of stroke or TIA). The group with a history of stroke or TIA represented 4% of the entire cohort, and the TRITON-TIMI 38 investigators recommended avoiding prasugrel in patients with a history of these events. The other two subgroups with a significantly increased bleeding risk with prasugrel represented 16% of the entire cohort, and in these two groups the investigators suggested a pharmacokinetics-guided reduction in the maintenance dose of prasugrel, although a recommendation for such dosing is based on modeling and not actual outcomes data. 15

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