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Randomized Controlled Trial
. 2015 Mar 19;4(3):e001505.
doi: 10.1161/JAHA.114.001505.

Efficacy and safety of vorapaxar as approved for clinical use in the United States

Giulia Magnani  1 , Marc P Bonaca  1 , Eugene Braunwald  1 , Anthony J Dalby  2 , Keith A A Fox  3 , Sabina A Murphy  1 , José Carlos Nicolau  4 , Ton Oude Ophuis  5 , Benjamin M Scirica  1 , Jindrich Spinar  6 , Pierre Theroux  7 , David A Morrow  1
Affiliations
Randomized Controlled Trial

Efficacy and safety of vorapaxar as approved for clinical use in the United States

Giulia Magnani et al. J Am Heart Assoc. .

Erratum in

Abstract

Background: Vorapaxar is a protease-activated receptor-1 antagonist approved by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD), without a previous stroke or transient ischemic attack (TIA).

Methods and results: We examined the efficacy and safety of vorapaxar in the intended use population, considering 20,170 patients randomized in the multinational, double-blinded, placebo-controlled TRA 2°P-TIMI 50 trial. Of these, 16,897 qualified with a history of MI in the prior 2 weeks to 1 year and 3273 with PAD. At baseline 97% of the patients were treated with aspirin, 71% with a thienopyridine, and 93% a statin. At 3 years, the endpoint of CV death, MI, or stroke was significantly reduced with vorapaxar compared with placebo (7.9% versus 9.5%, HR, 0.80; 95% CI 0.73 to 0.89; P<0.001). Vorapaxar also significantly reduced the composite of CV death, MI, stroke, and urgent coronary revascularization (10.1% versus 11.8%, HR, 0.83; 95% CI 0.76 to 0.90; P<0.001), as well as the rate of CV death or MI (P<0.001). The safety endpoint of GUSTO moderate or severe bleeding, was increased in the vorapaxar group (3.7 versus 2.4, HR, 1.55; 95% CI 1.30 to 1.86, P<0.001). Intracranial bleeding (ICH) was 0.6% versus 0.4%, P=0.10 with vorapaxar versus placebo, with fatal bleeding 0.2% versus 0.2%; P=0.70.

Conclusions: In patients with prior MI or PAD who have not had a previous stroke or TIA, vorapaxar added to standard therapy is effective for long-term secondary prevention of thrombotic CV events, while increasing moderate or severe bleeding.

Clinical trial registration: URL: clinicaltrials.gov Unique Identifier: NCT00526474.

Keywords: antiplatelet therapy; atherosclerosis; myocardial infarction; peripheral arterial disease; secondary prevention; vorapaxar.

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Figures

Figure 1.
Figure 1.
Kaplan–Meier estimated occurrence of CV death, MI, or stroke. CI indicates confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
Figure 2.
Figure 2.
Kaplan–Meier estimates of CV death, MI, or stroke according to time from qualifying MI to randomization; (A) <3 months (N=7456), (B) 3 to 6 months (N=4907), and (C) >6 months (N=4462) in the population with no history of stroke or TIA and a nonmissing date. CI indicates confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; TIA, transient ischemic attack.
Figure 3.
Figure 3.
Kaplan–Meier estimated occurrence of GUSTO moderate or severe bleeding. CI indicates confidence interval; GUSTO, Global Utilization of Streptokinase and t‐PA for Occluded Coronary Arteries; HR, hazard ratio.
Figure 4.
Figure 4.
Efficacy, safety, and net clinical outcomes according to the qualifying atherosclerosis (MI or PAD). CI indicates confidence interval; CVD, cardiovascular disease; MI, myocardial infarction; PAD, peripheral artery disease; TIA, transient ischemic attack; UCR, urgent coronary revascularization.
Figure 5.
Figure 5.
CV death, MI, or stroke in major subgroups. CI indicates confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction.
Figure 6.
Figure 6.
GUSTO moderate or severe bleeding in major subgroups. CI indicates confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GUSTO, Global Utilization of Streptokinase and t‐PA for Occluded Coronary Arteries; HR, hazard ratio; MI, myocardial infarction.
Figure 7.
Figure 7.
Outcomes for every 1000 patients treated for 3 years. The net clinical outcome of CV death, MI, stroke, or GUSTO severe bleeding was 8.55% with vorapaxar versus 10.08% with placebo (HR 0.82; 95% CI 0.75 to 0.91). The P values below each column are those generated by the Cox proportional model over the duration of follow‐up in the trial. CI indicates confidence interval; CV, cardiovascular; GUSTO, Global Utilization of Streptokinase and t‐PA for Occluded Coronary Arteries; HR, hazard ratio; MI, myocardial infarction.
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Comment in

References

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