Vorapaxar Substudy Shows Broad MI Reduction in High-Risk ACS Patients

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The novel antiplatelet agent vorapaxar reduces the total occurrence of myocardial infarction (MI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), according to a subanalysis of data from a large randomized trial published online March 25, 2013, ahead of print in the European Heart Journal. The effect was sustained over time and most pronounced for spontaneous MI.

Sergio Leonardi, MD, of the Duke Clinical Research Institute (Durham, NC), and colleagues studied the effects of vorapaxar on MI occurrence and type in 12,944 patients with NSTE-ACS enrolled in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial. Patients were randomized to vorapaxar (loading dose of 40 mg, daily maintenance dose of 2.5 mg thereafter) given at least 1 hour before any revascularization or placebo, after stratification according to the intention to use a glycoprotein IIb/IIIa inhibitor and a parenteral direct thrombin inhibitor (vs. other antithrombin agents).

Vorapaxar is a novel oral platelet protease-activated receptor (PAR)-1 antagonist that has been shown to potently inhibit thrombin-induced platelet aggregation. In 2011, the trial was terminated early after the trial’s Data and Safety Monitoring Board reported an increase in intracranial hemorrhage among patients with a history of stroke who were receiving vorapaxar. Although TRACER failed to meet its primary composite endpoint, Dr. Leonardi and colleagues analyzed the completed MI data in an effort to “better understand the potential for clinical benefit and to define a correlation between putative biology mechanisms and observed clinical phenotypes.”

Reduction in Type 1, Total MIs

Over a median follow-up of 502 days, 1,319 patients experienced 1,580 MIs, with over two-thirds (64.9%) being spontaneous type 1. Compared with the placebo group, the vorapaxar group had fewer first MIs of any type, and fewer total MIs including recurrent events. Additionally, vorapaxar reduced type 1 MIs (5.9% vs. 7.0% in the placebo group; table 1).

Table 1. Effect of Vorapaxar on MI

^a Compared with placebo.

There was no difference between the treatment and placebo groups in incidence of type 4a MIs (MI associated with PCI), which occurred in 2.6% of patients in the vorapaxar group vs. 2.8% in the placebo group (HR 0.90; P = 0.350). In addition, among patients treated with PCI (n = 7,479), there was no signal suggesting a different effect of vorapaxar on type 4a MIs according to the time from loading dose to PCI. The rates of MI associated with stent thrombosis (type 4b) were similar between the 2 treatment groups (HR 1.02; P = 0.932), as was the occurrence of type 2 MI (HR 1.17; P = 0.498).

The effect of vorapaxar on MI was consistent across key subgroups, and no interactions were statistically significant. The only trend was for thienopyridine use at baseline, where a more pronounced efficacy with vorapaxar was observed in patients who were not treated with these drugs at randomization. In the subgroup with non-procedural MI who underwent PCI within 7 days and had angiographic data available (n = 438), the treated culprit coronary lesion was mainly related to de novo lesion (61%), while restenosis (27.1%) and stent thrombosis (20.3%) were less common.

Exploratory Results May Suggest Caution

According to the study authors, the sustained effect on MI over time suggests that “continuous antagonism of PAR-1 is potentially important long-term.” This property of vorapaxar also may have contributed to the reduction of total occurrences of MI, they add.

However, Dr. Leonardi and colleagues caution that because MI was a secondary endpoint in TRACER, which failed to meet its primary objective, the results from the current study must be considered exploratory and cannot be applied to clinical practice to treat NSTE-ACS.

“Overall, the efficacy and safety balance observed in TRACER was not favorable,” they write. “Clinicians considering vorapaxar use . . . will have to carefully weigh anti-ischaemic efficacy against risk of bleeding, which included uncommon but clinically important events like intracranial hemorrhage. Future studies of vorapaxar must include strategies to reduce bleeding, which may include careful patient selection, dosing strategies, and combination therapies,” they observe.

The authors add that the results support the potential role of PAR-1 antagonism in reducing events mediated by coronary thrombosis following ACS.

Still Hope for PAR-1 Antagonists?

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), said that while the TRACER trial was disappointing as a whole, the new data demonstrate that the signal for reduction in MI events appears to be borne out for vorapaxar across all MI types.

“This drug is definitely biologically active. The issue is that the price you have to pay, which is bleeding, is a little too steep,” he said. “Many of us had high hopes for this compound and for PAR-1 drugs in general, because [they’re] different. [They] inhibit platelets at the site [of the] thrombin receptor, which is the most powerful activator of platelets.”

But Dr. Brener said other PAR-1 drugs still in the pipeline, including atopaxar, may improve upon vorapaxar by causing less bleeding.

“If that turns out to be the case, then maybe the risks and benefits may show a better balance than what we saw with vorapaxar,” he said. “There is certainly continued interest in this class of drug and it may work, but we don’t have enough data right now.”

 

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Source:
Leonardi S, Tricoci P, White HD, et al. Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRACER) trial. Eur Heart J. 2013;Epub ahead of print.

 

 

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