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Age, Weight May Define Benefits, Risks of Vorapaxar After MI

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Need More Data to Separate Risks

The findings of the TIMI Study Group’s TRA 2°P–TIMI 50 trial subgroup analysis support the addition of long-term antithrombotic treatment following MI, Dr. Stefan James and Dr. Claes Held wrote in an accompanying editorial.

However, it remains to be seen whether doctors, patients, health care providers, and funding agencies will accept the use of an expensive drug that reduces MI risk and possibly death, but also increases the risk of severe bleeding.

"For patients at low or moderate risk of bleeding, the ischemic benefit seems to outweigh the risk of bleeding. But patients at low risk of bleeding are also often at low risk of ischemic events. Therefore, clinical characteristics or biomarkers to separate ischemic risk and bleeding risk should be defined," they wrote (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61383-X]).

"Future research should assess antithrombotic drugs, such as inhibitors of protease-activated receptor 1, as monotherapy or in addition to low-dose aspirin, to balance safety and efficacy for long-term secondary prevention. Also, the effect of a lower dose of vorapaxar than that used in TRA 2°P-TIMI 50 should be investigated," they wrote.

Although the results of the TRA 2°P-TIMI 50 trial "provide data that [aid] our understanding of this topic and offer a step in the right direction," further research on blockade of protease-activated receptor 1 and other antithrombotic drugs is needed to optimize long-term, post-MI secondary prevention strategies, they concluded.

Dr. James and Dr. Held are with Uppsala (Sweden) Clinical Research Center at Uppsala University. Dr. James disclosed receiving institutional research grants from and/or serving on advisory boards for AstraZeneca, Eli Lilly, Merck, Bristol-Myers Squibb, Terumo, Medtronic, and Vascular Solutions. He also has received honoraria from AstraZeneca, Eli Lilly, and the Medicines Company. Dr. Held disclosed receiving institutional research grants from and/or serving on the advisory board for AstraZeneca, Merck, Bristol-Myers Squibb, GlaxoSmithKline, Roche, and Pfizer, and has received honoraria from AstraZeneca.



The investigational antiplatelet drug vorapaxar reduced the risk of cardiovascular death and ischemic events when it was added to standard antiplatelet treatment in a large, randomized, placebo-controlled trial of patients who had a previous myocardial infarction.

The findings, from a prespecified subgroup analysis of the TRA 2°P (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events)–TIMI 50 (Thrombolysis in Myocardial Infarction 50) trial, were most pronounced in patients younger than age 75 years with a body weight of at least 60 kg. Therefore, the benefits of treatment in this group may outweigh the risk of moderate or severe bleeding seen with treatment in this study, Dr. Benjamin M. Scirica of Harvard Medical School, Boston, and his colleagues from the TIMI Study Group reported Aug. 26 in the Lancet.

The study findings – the first to demonstrate the benefit of adding intense antiplatelet treatment to aspirin for long-term, secondary prevention of post-MI thrombotic events – were simultaneously presented at the annual congress of the European Society of Cardiology.

Of 26,449 patients in the TRA2°P–TIMI 50 trial, 17,769 experienced a qualifying MI and thus constituted the subgroup for the current analysis. These patients were randomized to receive treatment with 2.5 mg of a daily oral dose of either vorapaxar or placebo. In each group, 98% of patients concomitantly took aspirin, 78% took a thienopyridine, and 96% took a lipid-lowering agent. During a median follow-up of 2.5 years, cardiovascular death, MI, or stroke occurred in 610 of the 8,898 patients who received active treatment, compared with 750 of 8,881 patients who received placebo (3-year Kaplan-Meier estimates of 8.1% vs. 9.7%; hazard ratio, 0.80), the investigators said (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61269-0]).

However, the principal safety end point of moderate or severe bleeding, as defined by GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries), occurred significantly more often in the treatment group than in the placebo group, with 241 of 8,880 vorapaxar patients experiencing such bleeding, compared with 151 of 8,849 placebo patients (3-year Kaplan-Meier estimates of 3.4% vs. 2.1%; HR, 1.61).

Among those younger than age 75 years with no history of transient ischemic attack or stroke, and with a body weight of at least 60 kg (which represented 84% of the study subgroup), cardiovascular death, MI, or stroke occurred in 431 of 7,449 patients who received active treatment, compared with 570 of 7,640 who received placebo (3-year Kaplan Meier estimates of 6.8% vs. 8.6%; HR, 0.75), they noted.

"Moreover, cardiovascular death, myocardial infarction, stroke, urgent coronary revascularization, or GUSTO moderate or severe bleeding was less likely in the vorapaxar group than in the placebo group in these patients [HR, 0.86]. By contrast, for patients aged 75 years and older, with a history of transient ischemic attack or stroke, or patients weighing less than 60 kg, net clinical outcome was not significantly different with vorapaxar compared with placebo," the investigators wrote.

Patients in the multinational, double-blind TRA 2°P-TIMI 50 trial were adults with a history of atherothrombosis who were enrolled between September, 2007, and November, 2009. Those enrolled on the basis of MI had had a spontaneous MI in the 2 weeks to 12 months prior to enrollment.

Vorapaxar is a potent and selective antagonist of protease-activated receptor 1, which is the main receptor for thrombin on human platelets. The findings suggest that inhibiting this receptor "is a novel therapeutic target for long-term secondary prevention after myocardial infarction. The incremental benefit of vorapaxar existed even with high adherence to guidelines," the investigators wrote, noting that the findings add to existing evidence of a benefit of long-term antiplatelet treatment in addition to aspirin for reducing the risk of thrombotic events, and they also confirm the increased risk of bleeding with vorapaxar treatment.

"Identification of patients appropriate for treatment therefore depends on balance of the competing risks of ischemia and bleeding, which are largely based on the clinical setting, patient characteristics, concomitant anticoagulants, and drug dosing," they wrote.

Specifically, the findings of this and other studies indicate that clinical characteristics such as advanced age and low body weight are consistent predictor of increased bleeding risk with potent antithrombotic treatments.

"These simple clinical criteria seem to be useful for selection of patients with better potential for improved net clinical outcomes with vorapaxar," they wrote.

The TRA 2°P-TIMI 50 trial was supported by Merck. The TIMI Study Group and individual members of the group reported numerous disclosures with respect to grant funding, consulting work, and advisory board participation for various pharmaceutical companies. Details are available with the full text of the article at

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