Vorapaxar May Protect Against Incident Ischemic Stroke, Stent Thrombosis

When added to single or dual antiplatelet therapy, vorapaxar lowers the risk of new ischemic stroke in patients with MI or PAD and no history of cerebrovascular disease. The drug also protects against stent thrombosis in patients with stable atherosclerotic disease and a history of coronary stenting. The findings come from two analyses of the TRA 2°P-TIMI 50 trial published in the December 9, 2014, issue of the Journal of the American College of Cardiology. 

The main results of the 26,449-patient trial, which were presented at the American College of Cardiology/i2 Scientific Session in March 2012 and published simultaneously in the New England Journal of Medicine, showed that vorapaxar (Zontivity; Merck, Sharp & Dohme), a protease-activated receptor (PAR)-1 antagonist, reduced the risk of cardiovascular death, MI, or stroke in patients with established vascular disease compared with a placebo.

However, that benefit came at the expense of an increase in intracranial hemorrhage, particularly among patients who qualified for the trial based on a history of stroke. For that reason, the drug received a contraindication for patients with prior stroke when it was approved by the FDA. 

Vorapaxar Prevents New Ischemic Strokes

In one of the 2 new analyses, Marc P. Bonaca, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), and colleagues examined the risk of incident ischemic stroke and resulting death, as well as intracerebral hemorrhage, among the 20,170 trial participants who had MI or PAD and no history of cerebrovascular disease, most of whom (69%) were on dual antiplatelet therapy (DAPT). 

Vorapaxar lowered the risk of a first ischemic stroke through a median follow-up of 2.6 years (0.88% vs 1.47%; HR 0.57; 95% CI 0.43-0.75); the association held true regardless of whether patients entered the trial with a history of MI or PAD. Among those who had a new ischemic stroke, vorapaxar did not increase the risk of hemorrhagic conversion or death after the stroke.

Vorapaxar heightened the risk of hemorrhagic stroke (0.17% vs 0.06%; HR 2.79; 95% CI 1.00-7.73), but because of the infrequency of the outcome, it still reduced the risk of any stroke (1.20% vs 1.65%; HR 0.67; 95% CI 0.52-0.87). 

The reductions in all strokes and ischemic strokes and the increase in hemorrhagic stroke were consistent regardless of background thienopyridine use.

As for functional outcomes, there were no differences in modified Rankin Scale (mRS) scores after ischemic stroke between the vorapaxar and placebo groups. In addition, vorapaxar cut the risk of incident ischemic stroke across mRS categories. 

Stent Thrombosis Lower With Vorapaxar

In the other analysis, Dr. Bonaca and colleagues evaluated vorapaxar’s effect on definite stent thrombosis among 14,491 trial participants who either had a history of coronary stent implantation before randomization or received a stent during follow-up. Slightly fewer than half (47%) had DES and 83% were on DAPT in which the thienopyridine was clopidogrel in nearly all cases. 

During a median follow-up of 2.5 years, there were 152 cases of definite stent thrombosis; 92% occurred either late (30 days to 1 year) or very late (> 1 year) after PCI.

Compared with placebo, vorapaxar reduced the overall risk (1.1% vs 1.4%; HR 0.71; 95% CI 0.51-0.98). That finding was consistent regardless of history of diabetes, STEMI, or stroke; smoking status; DES use; DAPT use and duration; trial qualification due to MI or PAD; aspirin dose; and the time since PCI. In particular, very late stent thrombosis was reduced by 35% with vorapaxar (HR 0.65; 95% CI 0.43-0.97). 

Vorapaxar also lowered the rate of the trial’s primary endpoint (cardiovascular death, MI, or stroke) in the stent subgroup (HR 0.83; 95% CI 0.74-0.93), mostly resulting from reductions in MI and ischemic stroke. The drug increased GUSTO moderate or severe bleeding (HR 1.57; 95% CI 1.26-1.94) but did not affect the risks of intracranial hemorrhage or fatal bleeding, which occurred infrequently.

“[O]ur findings provide important evidence for PAR-1 antagonism as a viable target for reducing late and very late [stent thrombosis] and indicate that a reduction in definite [stent thrombosis] is an antithrombotic benefit of vorapaxar to be considered in weighing its potential benefits versus risks for the individual patient,” the authors say. 

Why Vorapaxar May Not Mix With a History of Stroke

In an accompanying editorial, Robert G. Hart, MD, of McMaster University (Hamilton, Canada), and colleagues focus on the stroke analysis, saying, “It is intriguing that triple antiplatelet therapy reduced ischemic stroke more than dual antiplatelet therapy, an observation that raises the possibility that even 2 antiplatelet agents with differing mechanisms of action provide submaximal protection against ischemic stroke.” 

However, they add, because the finding derives from a subanalysis, it requires independent validation “before addition of vorapaxar to standard antiplatelet drug therapy for stroke prevention can be recommended with confidence.”

The editorialists highlight that vorapaxar lowered the risk of ischemic stroke in patients without prior stroke but not in those with such a history. The most likely explanation, they say, revolves around stroke type. 

“In a cohort with a high prevalence of previous lacunar strokes, recurrent strokes are overwhelmingly likely to have lacunar mechanisms, and lacunar ischemic stroke may be less responsive to dual antiplatelet therapy,” Dr. Hart and colleagues explain. “In those without prior ischemic stroke or [transient ischemic attack], who had clinical manifestations of atherosclerosis, vorapaxar prevented ischemic strokes, with only a minority likely to be lacunar.”

“To verify this possibility and to better understand the underlying mechanisms, more information is needed about the proportion of lacunar and nonlacunar ischemic strokes,” they write. “Such details about ischemic stroke subtypes and associated risk factors are important to identify patients who would benefit most from vorapaxar, considering the risk of hemorrhage associated with this agent.” 

1. Bonaca MP, Scirica, BM, Braunwald E, et al. New ischemic stroke and outcomes with vorapaxar versus placebo: results from the TRA 2°P-TIMI 50 trial. J Am Coll Cardiol. 2014;64:2318-2326.

2. Bonaca MP, Scirica BM, Braunwald E, et al. Coronary stent thrombosis with vorapaxar versus placebo: results from the TRA 2°P-TIMI 50 trial. J Am Coll Cardiol. 2014;64:2309-2317.

3. Hart RG, Halperin JL, Weitz JI, et al. Vorapaxar, combination antiplatelet therapy, and stroke [editorial]. J Am Coll Cardiol. 2014;64:2327-2329.

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