Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial

Abstract

AimsIn the TRITON-TIMI 38 trial, greater platelet inhibition with prasugrel reduced the first occurrence of the primary endpoint (cardiovascular death, MI, or stroke) compared with clopidogrel in patients with an acute coronary syndrome (ACS) undergoing planned percutaneous coronary intervention. We hypothesized that prasugrel would reduce not only first events but also recurrent primary endpoint events and therefore total events compared with clopidogrel.Methods and resultsPoisson regression analysis was performed to compare the number of occurrences of the primary endpoint between prasugrel and clopidogrel in TRITON-TIMI 38. Landmark analytic methods were used to evaluate the risk of a recurrent primary endpoint event following an initial non-fatal endpoint event. Among patients with an initial non-fatal event, second events were significantly reduced with prasugrel compared to clopidogrel (10.8 vs. 15.4%, HR 0.65, 95% CI 0.46–0.92; P = 0.016), as was CV death following the non-fatal event (3.7 vs. 7.1%, HR 0.46, 95% CI 0.25–0.82; P = 0.008). Overall there was a reduction of 195 total primary efficacy events with prasugrel vs. clopidogrel (rate ratio 0.79, 95% CI 0.71–0.87; P < 0.001). Recurrent bleeding events occurred infrequently (TIMI major non-CABG bleeds: four with prasugrel and two with clopidogrel). Study drug discontinuation was frequent following the initial major bleeding event (42% of patients discontinued study drug).ConclusionWhile standard statistical analytic techniques for clinical trials censor patients who experience a component of the primary composite endpoint, total cardiovascular events remain important to both patients and clinicians. Prasugrel, a more potent anti-platelet agent, reduced both first and subsequent cardiovascular events compared with clopidogrel in patients with ACS.

Review of Prasugrel for the Secondary Prevention of Atherothrombosis

“…For example, competition for CYP 3A4 may explain why the antiplatelet effect of clopidogrel is reduced when given concomitantly with atorvastatin or dihydropyridine calcium channel blockers (CCBs). 46,47 Concomitant administration of dihydropyridine CCBs and clopidogrel also increased the risk of an adverse cardiovascular outcome (adjusted hazard ratio determined platelet activity that had safety and antiplatelet activity end points, and (2) [23][24][25][26][27][28] The studies were selected for this review with a focus on comparative data from randomized, controlled studies relating to the pharmacological and/or clinical properties of prasugrel, and data/commentary from the FDA review document were also included. 12 However, in order to place the prasugrel data into context within current clinical practice, comparative information on the pharmacologic and clinical profile of clopidogrel from smaller studies was also identified via PubMed.…”

“…[24][25][26][27][28] Three examined patient subgroupsstent recipients, 27 patients with STEMI, 28 and patients with diabetes 26 -and 2 examined end points-recurrent events 25 and early/late events. 24 In all 3 TRITON patient subgroup analyses, prasugrel was randomized, double-blind trial involving 13,608 patients with moderate-to high-risk ACS with scheduled PCI.…”

“…24 In addition to the patients experiencing a first event (cardiovascular death, nonfatal MI, or stroke) reported in the primary TRITON results, 58 patients in the prasugrel group and 115 patients in the clopidogrel group experienced a second event (P < 0.001). 25 When both the first and recurrent events were considered, the overall incidence of the primary composite end point in TRITON was 701 in the prasugrel group and 896 in the clopidogrel group (rate ratio [RR] = 0.79, 95% CI = 0.71-0.87, P < 0.001). 25 …”

“…25 When both the first and recurrent events were considered, the overall incidence of the primary composite end point in TRITON was 701 in the prasugrel group and 896 in the clopidogrel group (rate ratio [RR] = 0.79, 95% CI = 0.71-0.87, P < 0.001). 25 …”

“…25 Prasugrel significantly reduced the occurrence of MI during the first 3 days (periprocedural period) relative to clopidogrel (4.27% vs. 5.24%, HR = 0.81, 95% CI = 0.70-0.95, P = 0.008), as well as during the maintenance dosing period from day 3 to the end of the trial (3.40% vs. 4.79%, HR = 0.69, 95% CI = 0.58-0.83, P < 0.001). 24 Significant reductions were also seen in early and late occurrences of stent thrombosis and urgent target vessel revascularization.…”