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More information on prasugrel (Effient)

Prasugrel (Effient) STEMI Subgroup Analysis Published in the Lancet

Prasugrel STEMI Subgroup Analysis – Authors' Reply


May 30, 2009

The Lancet, Volume 373, Issue 9678, 30 May 2009-5 June 2009, Pages 1846-1848, Gilles Montalescot, Stephen D Wiviott, Eugene Braunwald, Sabina A Murphy, Elliott M Antman

In Gilles Montalescot and colleagues’ report on the subgroup with ST-segment-elevation myocardial infarction(STEMI) from TRITON-TIMI 38(Feb 28, p 723 ),[1] non-fatal myocardial infarction was not adequately defined. This outcome drove most of the reduction in the primary composite endpoint seen with prasugrel versus clopidogrel. Food and Drug Administration Advisory Committee documents [2] reveal that asymptomatic elevations in cardiac enzymes accounted for many events, and that in all patients presenting with acute coronary syndrome (ACS) most non-fatal myocardial infarctions were periprocedural (table). Furthermore, when only site-reported events were counted, the reduction in the primary outcome with prasugrel was no longer significant, neither for the STEMI subgroup nor the overall ACS cohort.

Also, Montalescot and colleagues claim that the bleeding risk was similar with prasugrel and clopidogrel. However, the STEMI subgroup was underpowered to detect a meaningful difference in this safety outcome. Given the lack of heterogeneity between the STEMI patients and the rest of the ACS cohort with regard to both risk and benefit, the risk estimate calculated from the entire study population is more appropriate. In this larger group, both thrombolysis in myocardial infarction (TIMI) major haemorrhage (hazard ratio 1·32, 95% CI 1·03–1·68) and fatal haemorrhage (4·19, 1·58–11·1) unrelated to coronary-artery bypass grafting were significantly increased with prasugrel .[3]

Lastly, although the STEMI subgroup analysis was prespecified, TRITON-TIMI 38 was not prospectively designed to assess the superiority of prasugrel over clopidogrel in this population .[4] Because α was not adjusted to account for the multiple planned and post-hoc comparisons that were made, it is likely that some of the positive findings are type 1 errors.[1] Thus, any conclusions drawn from these data must be regarded as exploratory at best.

We declare that we have no conflicts of interest.

James Floyd, Sidney Wolfe

Health Research Group, Public Citizen, Washington, DC 20009, USA


 

 Clopidogrel (n=529)

 Prasugrel (n=432)

≤24 h

308 (58%)

 266 (62%)

>24 h to 30 days

48 (9%)

 34 (8%)

>30 days to 1 year

154 (29%)

119 (28%)

>1 year

16 (3%)

10 (2%)

Unknown

 3 (1%)

 3 (1%)

Table: Non-fatal myocardial infarctions not associated with stent thrombosis in all patients with acute coronary syndrome, by time from percutaneous coronary intervention[2]


[1] Montalescot G, Wiviott SD, Braunwald E, et al, for the TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction(TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723–31.

[2] FDA. Briefing materials from Feb 3, 2009, meeting of FDA Cardiovascular and Renal Drugs Advisory Committee. http://www.fda.gov/ohrms/dockets/ac/09/briefi ng/2009-4412b1-01-FDA.pdf (accessed March 20, 2009).

[3] Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–15.

[4] Wiviott SD, Antman EM, Gibson CM, et al, for the TRITON-TIMI 38 investigators. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitionN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J 2006; 152: 627–35.

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