MUNICH, Germany—For stable patients with a history of myocardial infarction (MI), extended use of the novel thrombin receptor antagonist vorapaxar on top of standard antiplatelet therapy reduces the risk of cardiovascular death and other thrombotic events. However, an increased bleeding risk suggests that the potent agent should be reserved for patients who are likely to reap a net benefit.

Findings from a substudy of the TRA2P-TIMI 50 trial were presented by Benjamin M. Scirica, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), August 26, 2012, at the European Society of Cardiology Congress. The data were simultaneously published online ahead of print in the Lancet.

The investigational drug vorapaxar (Merck; Whitehouse Station, NJ) antagonizes protease-activated receptor-1, a major thrombin receptor on human platelets, potently inhibiting thrombin-induced platelet aggregation.

In the main TRA2P-TIMI 50 trial, 26,449 patients with a history of atherothrombosis (MI, ischemic stroke, or PAD) were randomized to vorapaxar (2.5 mg daily) or placebo. At a median follow-up of 30 months, vorapaxar reduced the risk of cardiovascular death, MI, or stroke by 13% but increased the risk of moderate or severe bleeding by 66% (both P < 0.001)

Focusing on MI Patients

Because some data suggested a differential impact of long-term antiplatelet therapy on certain patient subsets, a prespecified subanalysis was performed on the cohort of 17,779 patients with a history of MI (n = 8,898 randomized to vorapaxar, n = 8,881 randomized to placebo). Overall, 98% of patients were being treated with aspirin and 78% with a thienopyridine (typically clopidogrel).

At a median follow-up of 30 months, patients receiving vorapaxar had lower rates of various co-primary efficacy endpoints (composites of cardiovascular death, MI, or stroke; cardiovascular death, MI, stroke, or urgent revascularization; and cardiovascular death or MI) compared with the placebo group, but similar rates of cardiovascular death (table 1).

Table 1. Kaplan-Meier Estimates of Efficacy Outcomes at 3 Years

The incidence of cardiovascular death, MI, or stroke was lower with vorapaxar regardless of the timing or type of the previous MI or whether patients planned to receive thienopyridine treatment. The advantage of vorapaxar was also seen both before (HR 0.79; P = 0.003) and after (HR 0.82; P = 0.004) a 1-year landmark.  

However, GUSTO moderate or severe bleeding, the primary safety endpoint, and TIMI non-CABG major bleeding were higher in the vorapaxar group, while intracranial hemorrhage showed a trend in that direction. In addition, more patients in the vorapxar group received transfusions for bleeding (table 2).

Table2. Kaplan-Meier Estimates of Safety Outcomes at 3 Years

Overall, the net outcome of cardiovascular death, MI, stroke, urgent revascularization, or GUSTO moderate or severe bleeding favored vorapaxar over placebo (12.5% vs. 13.4%; P = 0.038).

Profiling the Patients Most Likely to Benefit

Based on these and other data, the researchers retrospectively identified the type of patient who would be most likely to benefit from intense platelet inhibition. In individuals younger than 75 years, with no history of TIA or stroke, and a body weight of at least 60 kg—a profile that fit 84% of the cohort—vorapaxar yielded lower rates of the composite of cardiovascular death, MI, or stroke (6.8% vs. 8.6%; P < 0.0001) as well as cardiovascular death (1.5% vs. 20.0%; P = 0.02) at no cost in major or intracranial bleeding. On the other hand, among higher-risk patients with the opposite clinical characteristics, vorapaxar imparted no advantage for the efficacy or net clinical endpoints and produced higher rates of GUSTO moderate or severe bleeding.

In a commentary accompanying the Lancet publication, Stefan K. James, MD, PhD, and Claes Held, MD, PhD, both of Uppsala University (Uppsala Sweden), observe that vorapaxar “was assessed in addition to aspirin and clopidogrel in most patients, even though clopidogrel has variable and unpredictable antiplatelet effects and increases the risk of bleeding.” They suggest that “future research should assess antithrombotic drugs . . . as monotherapy or in addition to low-dose aspirin, to balance safety and efficacy for long-term secondary prevention.”

“For patients at low or moderate risk of bleeding, the ischemic benefit seems to outweigh the risk of bleeding,” Drs. James and Held say, but because those at low risk of bleeding are also often at low risk of ischemic events, “clinical characteristics or biomarkers to separate ischemic risk and bleeding risk should be defined.”

Questions Remain About Optimal Secondary Prevention

Commenting on the ESC presentation, Christoph Bode, MD, of the University of Freiburg (Freiburg, Germany), said, “Looking at the data [from TRITON TIMI 38 and PLATO], I wonder whether the substitution of prasugrel or ticagrelor [might be] as effective as vorapaxar as a third agent. In these studies, we did not see an increase in intracranial bleeding. Another question that arises is whether you need to have aspirin as the basis of treatment in all of the trials.”

Recently, a paradigm change was suggested by the ATLAS ACS 2 TIMI-51 trial, in which the addition of rivoraxaban to aspirin and clopidogrel led to a significant decrease in all-cause mortality in ACS patients, albeit at a cost of increased bleeding, Dr. Bode observed. “But [the trial’s] 1.6% reduction in all-cause mortality really stands tall, and hasn’t been shown in other studies to that extent,” he added.

The current study “puts forward a role for prolonged antiplatelet treatment in appropriately selected patients with previous myocardial infarction,” Dr. Bode said. “Further research is necessary to define the optimal combination [including] novel antithrombotic agents. But after these results, vorapxar is in my mind a viable candidate. We have to watch, though, whether some treatment options work best in certain subgroups.”

Sources:

1. Scirica BM. Vorapaxar for secondary prevention in patients with prior myocardial infarction.
2. Presented at: European Society of Cardiology Congress; August 26, 2012; Munich, Germany.
3. Scirica BM, Bonaca MP, Braunwald E, et al. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: A prespecified subgroup analysis of the TRA 2˚P-TIMI 50 trial. Lancet. 2012;Epub ahead of print.
4. James S, Held C. Improving long-term outcome after myocardial infarction. Lancet. 2012;Epub ahead of print.

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