Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA·CER) trial.

Leonardi S, Tricoci P, White HD et al.
Eur Heart J. 2013 Jun;34(23):1723-31. doi: 10.1093/eurheartj/eht104

Background

Vorapaxar is a potent inhibitor of thrombin-induced platelet aggregation as a selective antagonist of the protease-activated receptor (PAR)-1. This novel antiplatelet agent yields consistent inhibition of thrombin-receptor agonist peptide (TRAP)-induced platelet aggregation [1].
In the large phase III trials TRA·CER [2] and TRA 2P·-TIMI 50 [3] vorapaxar was primarily associated with a reduced rate of myocardial infarct (MI), as compared to placebo, in patients with non-ST segment elevation acute coronary syndrome (NSTE ACS) or atherosclerotic disease. MI represents a group of events with different pathophysiologies, sizes, and clinical and prognostic implications. It is therefore important to characterise a drug’s effect on a certain type of MI.
This study analysed the effect of vorapaxar on different types of MI as currently classified by the Universal Definition of MI-document, analysed the effect of vorapaxar on total occurrence of MI and across MIs of various sizes and over time [4]. This is an analysis of the TRA·CER study results, a multicentre, randomised, double-blind, placebo-controlled event-driven trial  that studied vorapaxar at 40 mg loading dose followed by a daily 2.5 mg maintenance dose in 12944 patients with NSTE ACS at high risk for ischemic events [2,5]. Median follow-up time was 502 days (IQR: 349-667), during which 1319 patients experienced an MI, of which 186 patients had two or more events.

Main results

• As compared to placebo, vorapaxar reduced the risk of a first MI of any type (HR: 0.88, 95%CI: 0.79-0.98, P=0.021). Including recurrent MIs, vorapaxar yielded a similar risk reduction (HR: 0.86, 95%CI: 0.77-0.97, P=0.014). The cumulative incidence curves started to separate about 1 month after randomisation and continued to diverge over time.
• Type 1 (spontaneous) MIs were most common and occurred in 382 of 6473 patients receiving vorapaxar (5.9%) and in 455 out of 6471 patients in the placebo group (7.0%)(HR: 0.83, 95%CI: 0.73-0.95, P=0.007).
• The incidences of MIs of different sizes, as assessed by troponin or creatine kinase-MB peak data, were consistently lower in vorapaxar treated patients as compared to the placebo group..
• Type 4a (PCI-related) Mis occurred in 166 (2.6%) patients in the vorapaxar group as opposed to 183 (2.8%) in the placebo group (HR: 0.90, 95%CI: 0.73-1.12, P=0.350). Rates of MI between the two treatment groups were also similar for type 4b (stent thrombosis-related), type 2 (secondary MI due to disturbed oxygen levels) or type 5 (CABG-related).

Conclusion

Vorapaxar reduces the incidence of MI in high-risk NSTE-ACS patients, mostly treated with concomitant dual antiplatelet therapy. Although this effect was most evident for spontaneous MI, it appeared directionally consistent across various MI sizes and it was stable in time. This study suggests that PAR-1 is important in the development of clinically evident coronary thrombosis in the presence of plaque disruption and that PAR-1 antagonism is a viable mechanism to reduce symptomatic thrombosis in such an event.
It should however be noted that the TRA·CER trial did not meet its primary objective, and that MI was a secondary endpoint. The increase in bleeding seen after vorapaxar in the TRA·CER trial should also be taken into account. Therefore, these results should be considered exploratory and should be confirmed before they can be applied in clinical practice to treat patients with NSTE-ACS.

References

1. Leonardi S, Tricoci P, Mahaffey KW. Promises of PAR-1 inhibition in acute coronary syndrome. Curr Cardiol Rep 2012;14:32–39.
2. Tricoci P, Huang Z, Held C et al. TRACER Investigators. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012;366:20–33.
3. Morrow DA, Braunwald E, Bonaca MP, et al. TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012;366:1404–1413.
4. Thygesen K, Alpert JS, White HD, Joint ESC/ACCF/AHA/WHF Task Force for
the Redefinition of Myocardial Infarction et al. Universal definition of myocardial infarction. Circulation 2007;116:2634–2653.
5. TRA.CER Executive and Steering Committees. The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale. Am Heart J 2009;158:327–334.

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