Abstract
Background and Purpose—Vorapaxar is an antiplatelet agent that antagonizes thrombin-mediated activation of the protease-activated receptor-1 on platelets. We tested the efficacy and safety of vorapaxar in a prespecified analysis in the stroke subcohort from a multinational, randomized, placebo-controlled trial.
Methods—We randomly assigned patients with prior atherothrombosis (myocardial infarction, peripheral artery disease, or ischemic stroke) to receive vorapaxar (2.5 mg daily) or placebo added to standard antiplatelet therapy. Patients who qualified with stroke (N=4883) had a history of ischemic stroke in the prior 2 weeks to 12 months. The primary end point was the composite of cardiovascular death, myocardial infarction, or any stroke.
Results—The qualifying stroke was classified as large vessel in 35%, small vessel in 47%, and other/unknown in 18%. In the stroke cohort, cardiovascular death, myocardial infarction, or stroke through 3 years was not reduced with vorapaxar versus placebo (13.0% vs 11.7%; hazard ratio, 1.03; 95% confidence interval, 0.85–1.25), including recurrent ischemic stroke (hazard ratio, 0.99; 95% confidence interval, 0.78–1.25). There were no significant differences in the effect of vorapaxar based on the type or timing of the qualifying stroke. Intracranial hemorrhage at 3 years was increased with vorapaxar (2.5% vs 1.0%; hazard ratio, 2.52; 95% confidence interval, 1.46–4.36).
Conclusions—In patients with prior ischemic stroke who receive standard antiplatelet therapy, adding vorapaxar increased the risk of intracranial hemorrhage without an improvement in major vascular events, including ischemic stroke. These findings add to the accumulating evidence establishing important risks with combination antiplatelet therapy in patients with prior stroke.
Clinical Trial Registration Information—http://www.clinicaltrials.gov. Unique identifier: NCT00526474.
Introduction
In the United States, nearly 800 000 strokes occur each year, with almost 1 in 4 being recurrent events.1 Noncardioembolic ischemic strokes account for the majority of strokes and are an important target for secondary prevention. Because most noncardioembolic ischemic strokes are believed to occur as the result of atherothrombosis, antiplatelet agents are central to secondary prevention.1 Patients with ischemic stroke are also at significant risk of atherothrombotic events in the coronary and peripheral arterial beds.2 Efforts to improve antiplatelet strategies for secondary prevention after ischemic stroke have revealed a challenging balance between antithrombotic efficacy and bleeding.1 Because patients with ischemic stroke treated with contemporary antiplatelet therapy are at high risk for both recurrent ischemic and hemorrhagic events,2,3 there is a need for agents that are both more efficacious and safer.
Protease-activated receptor-1 is the predominant receptor for thrombin on human platelets. Vorapaxar is a potent antagonist of protease-activated receptor-1 that inhibits thrombin-mediated platelet activation.4 Phase 2 trials of vorapaxar suggested efficacy with acceptable safety in patients with acute ischemic stroke.4,5 We previously reported the efficacy and safety of vorapaxar among a broad group of patients with prior atherothrombosis who enrolled in the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events—Thrombolysis in Myocardial Infarction (TRA 2°P-TIMI 50) trial.6 In the overall cohort of 26 449 patients with a history of myocardial infarction (MI), ischemic stroke, or peripheral arterial disease (PAD), vorapaxar reduced the risk of cardiovascular (CV) death, MI, or stroke by 13% (P<0.001) while increasing the risk of moderate or severe bleeding (P<0.001). It should be noted that in patients who qualified for the trial with MI, vorapaxar lowered CV death, MI, or stroke by a significant 20%.7
In this prespecified analysis, we examined the efficacy and safety of vorapaxar, added to standard therapy, for secondary prevention in the 4883 patients who qualified for TRA 2°P-TIMI 50 with a prior ischemic stroke. We also evaluated the outcomes with vorapaxar in patients who qualified for the trial with MI or PAD but who also had a history of cerebrovascular disease.
Methods
Study Population
TRA 2°P-TIMI 50 was a multinational, double-blind, randomized, placebo-controlled trial. The design and primary results have been published.6,8 Between September 2007 and November 2009, 26 449 patients with prior atherothrombosis (MI, PAD, or ischemic stroke) were randomized. Patients who qualified for the trial on the basis of ischemic stroke were to have been hospitalized or evaluated in an acute stroke clinic with a final diagnosis of an ischemic (presumed thrombotic, noncardioembolic) stroke within 2 weeks to 12 months before randomization. By design, enrollment in the qualifying stroke group was completed after reaching ≈15% of the planned overall trial population. Patients were excluded if they had history at any time of intracranial hemorrhage, intracranial or spinal cord surgery, a central nervous system tumor or aneurysm, recent active abnormal bleeding, ongoing treatment with warfarin, or active hepatobiliary disease. Details of the full eligibility criteria have been reported.8 The protocol was approved by the relevant ethics committee at all participating centers. Written informed consent was obtained from all patients.
Study Protocol
Eligible patients were randomly assigned in a 1:1 ratio to receive either vorapaxar (2.5 mg daily) or placebo by a central computerized system, stratified according to the qualifying atherothrombotic disease (MI, ischemic stroke, or PAD), and whether or not the responsible physician intended to administer a thienopyridine. All concomitant medical therapy, including the use of other antiplatelet agents, was managed by the treating clinicians according to local standards of care. As described previously,6 after a median of 2 years of follow-up, the Data and Safety Monitoring Board reported an increased risk of intracranial hemorrhage with vorapaxar in participants with prior stroke and recommended that study drug be discontinued in all patients with a history of stroke before or during the trial. Patients who qualified for the trial with a prior ischemic stroke completed their participation with a final study visit at that time. Patients who qualified for the trial with an MI or PAD and discontinued study treatment because of a history of stroke continued follow-up until completion of the trial in the overall MI and PAD groups.
End Points
The data analysis plan6 defined the primary efficacy analysis to begin with the composite of CV death, MI, or stroke, followed by CV death, MI, stroke, or urgent coronary revascularization, and then CV death or MI. The definitions for each component of the efficacy composite end points have been published.8 The end point of stroke was defined as an acute focal neurological deficit of sudden onset consistent with vascular cause that was not reversible in <24 hours or that was accompanied by clear evidence of a new stroke on neuroimaging.8 Bleeding was assessed using the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) and TIMI classification systems with GUSTO moderate or severe bleeding defined as the primary safety end point.8 The subset of GUSTO severe bleeds that were intracranial hemorrhages was also reviewed and captured individually. All elements of the composite efficacy end points, and bleeding were adjudicated by a Clinical Events Committee blinded to treatment allocation.
Statistical Considerations
Analysis of the qualifying ischemic stroke cohort was prespecified in the analysis plan.8 All analyses comparing vorapaxar versus placebo for efficacy were conducted on an intent-to-treat basis with a Cox proportional hazards model using only the covariates of treatment and intent to use a thienopyridine. Event rates are presented as Kaplan-Meier failure rates at 3 years. Additional subgroups were analyzed using a Cox proportional hazards model for terms of treatment, stratification factors, subgroup, and treatment—subgroup interaction. These analyses are inherently exploratory. Analyses were performed by the TIMI Study Group, who take responsibility for and decided to submit the article.
Results
Study Participants
In total, 4883 patients qualified for the trial on the basis of a prior ischemic stroke and were randomized to vorapaxar or placebo. Their baseline characteristics are presented in Table 1. The qualifying ischemic stroke occurred 2 weeks to <3 months before randomization in 52% of patients, 3 to 6 months in 30%, and 6 to 12 months in 18%. Classification of the ischemic stroke type by the investigator is available for 4815 patients and indicates the qualifying stroke to be large vessel in 35%, small vessel (lacunar) in 47%, and other or unknown in the remainder.
Baseline Characteristics for Patients with Qualifying Stroke
Background medical therapy is shown in Table 1. The majority of patients (54%) were treated with aspirin alone, 19% with aspirin plus dipyridamole, 16% with a thienopyridine alone, 7% with aspirin and a thienopyridine, and 0.6% with dipyridamole alone. This background therapy remained quite stable over the duration of the study with >85% of patients treated with the same background antiplatelet therapy at 1 year. Lipid-lowering medications were administered to 78% of patients. The median duration of follow-up was 24 months (25th, 75th percentiles: 21, 29). Compliance with randomized study therapy was excellent with >95% of subjects receiving study therapy achieving ≥80% adherence through 2 years.
Primary Efficacy and Safety Analyses
For patients who qualified with an ischemic stroke, the 3-year incidence of CV death, MI, or stroke was 13.0% in the vorapaxar group compared with 11.7% in the placebo group; hazard ratio (HR) 1.03 (95% confidence interval [CI], 0.85–1.25; P=0.75; Figure 1A). The major additional efficacy end points and individual elements of the composite are shown in Table 2 and reveal no significant difference between vorapaxar and placebo in any of the efficacy end points examined. In particular, recurrent stroke alone was not reduced with vorapaxar (10.1% vs 7.5%; HR, 1.13; 95% CI, 0.90–1.40; P=0.30) in this cohort.
Efficacy and Safety End Points: Qualifying Stroke Cohort
Kaplan-Meier estimated rates of cardiovascular death, myocardial infarction (MI), or stroke (A), Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate or severe bleeding (B), and intracranial hemorrhage (C) in patients who qualified with ischemic stroke and were assigned to vorapaxar or placebo.
GUSTO moderate or severe bleeding was higher in patients treated with vorapaxar compared with placebo (4.2% vs 2.4%; HR, 1.93; 95% CI, 1.33–2.79; P<0.001; Table 2; Figure 1B). Intracranial hemorrhage, inclusive of intracerebral and subdural bleeding, was significantly increased with vorapaxar (2.5% vs 1.0%; HR, 2.52; 95% CI, 1.46–4.36; P<0.001; Table 2). Intracerebral bleeding was significantly increased by vorapaxar with a small number of subdural or epidural bleeding events (Table 2). The increased risk of intracranial hemorrhage emerged early and persisted (Figure 1C). Fatal bleeding was numerically higher with vorapaxar compared with placebo (Table 2).
Subgroups
Exploratory examination of clinically relevant subgroups based on the type of qualifying ischemic stroke or the timing of the stroke relative to randomization did not reveal any statistically significant differences in the effect of vorapaxar (Figure 2A). Considering background antiplatelet therapy, there was no group in which the benefit of vorapaxar was definitively apparent (Figure 2A). However, outcomes with vorapaxar compared with placebo in stroke patients tended in a more favorable direction among those managed with aspirin alone or in the small group with no other antiplatelet therapy. In patients treated with background aspirin monotherapy, the rates of CV death, MI, or recurrent stroke with vorapaxar versus placebo were 9.8% versus 10.9% (HR, 0.82; 95% CI, 0.62–1.09; P interaction versus all other antiplatelet combinations, 0.035).
There was no definitive heterogeneity in the risk of GUSTO severe or moderate bleeding (Figure 2B) or in the risk of intracranial hemorrhage (P>0.05 for each) with vorapaxar versus placebo in relation to the timing or type of stroke, or background antiplatelet therapy. In patients treated with background aspirin monotherapy, the 3-year rates of GUSTO severe or moderate bleeding with vorapaxar compared with placebo were 4.0% versus 2.4% (HR, 1.70; 95% CI, 1.00–2.87; P interaction versus all other antiplatelet combinations, 0.53), and for intracranial hemorrhage were 2.5% vs 1.3% (HR, 1.63; 95% CI, 0.80–3.33; P interaction versus all other antiplatelet combinations, 0.098).
(Continued) Cardiovascular death, myocardial infarction (MI), and stroke (A) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate or severe bleeding (B) with vorapaxar vs placebo in major subgroups. All data represent the status at the time of randomization.
Patients With MI and PAD With a History of Cerebrovascular Disease
Among the 17 779 patients who qualified for the trial with MI, 585 also had a history of prior ischemic stroke, the majority (81%) of which was >6 months preceding randomization. Within this group of patients, we observed 46 major CV events (CV death, MI, or stroke) with vorapaxar compared with 63 with placebo (HR, 0.69; 95% CI, 0.47–1.00; P=0.052; Table 3) with no heterogeneity in the effect of vorapaxar between MI patients with or without a history of stroke (P interaction=0.45). The overall number of intracranial hemorrhages in those with MI and prior stroke was very small (n=3) with 2 occurring in the vorapaxar group (0.9% vs 0.6%; P=0.56).
Major Efficacy and Safety Endpoints in Patients With Qualifying MI or PAD and History of Prior Stroke
Among the 3787 patients who qualified for the trial with PAD, 304 had a history of ischemic stroke (96% >6 months before randomization). Within this group of patients, the rate of CV death, MI, or stroke events with vorapaxar did not differ compared with placebo (HR, 1.01; 95% CI, 0.61–1.70; P=0.96; P interaction=0.73; Table 3). Five intracranial hemorrhages occurred in those with PAD and prior stroke, with a risk of intracranial hemorrhage that tended to be higher with vorapaxar (3.5% vs 0.7%; HR, 3.72; 95% CI, 0.41–33.3; P=0.24).
Combining the cohorts that qualified for the trial with MI or PAD, the risk of intracranial hemorrhage with vorapaxar tended to be higher among those with a history of stroke (2.1% vs 0.6%; HR, 2.90; 95% CI, 0.58–14.4; P=0.19) with lower absolute rates among MI or PAD patients without a history of stroke (0.6% vs 0.4%; HR, 1.55; 1.00–2.41; P=0.049; P interaction=0.45). Moreover, among the 498 patients who qualified for the trial with MI or PAD, who had a history of transient ischemic attack in the absence of a known prior stroke, the risk of intracranial hemorrhage appeared to increase similarly with vorapaxar (1.9% vs 0.5%; HR, 3.86; 95% CI, 0.43–34.5; P=0.23; P interaction versus no TIA, 0.40).
Discussion
In this randomized, placebo-controlled, multinational trial, among patients with prior noncardioembolic ischemic stroke, the addition of the protease-activated receptor-1 antagonist vorapaxar to standard therapy did not reduce the rate of major CV events but increased the risk of major bleeding, including intracerebral hemorrhage. Analyses of subgroups did not reveal any clear benefit of vorapaxar within clinically relevant groups defined by the type and timing of prior ischemic stroke, or background antiplatelet therapy. For patients who qualified for the trial with a history of MI who also had a history of ischemic stroke, vorapaxar provided benefit that was similar to benefit provided to MI patients without a prior stroke. However, the risk of intracranial hemorrhage with vorapaxar appears to be magnified in this group as it was in patients who qualified for the trial on the basis of prior stroke. In addition, a similar pattern of increased risk of intracranial hemorrhage was apparent in patients with a history of TIA in the absence of a prior known stroke. These data add to the accumulating evidence revealing important risks of combination antiplatelet therapy for long-term secondary prevention in patients with ischemic stroke or TIA.
Antiplatelet agents are a mainstay of secondary prevention in patients with prior noncardioembolic stroke. However, existing data from randomized trials are mixed and have left uncertainty regarding the optimal regimen of antiplatelet therapy. For example, more than a decade ago, the combination of low-dose aspirin and dipyridamole was found more effective than either agent alone.9 Moreover, a meta-analysis of 12 randomized trials involving 3766 patients undergoing therapy for acute stroke or TIA supported a reduction in combined vascular events with dual therapy compared with monotherapy without a significant increase in bleeding.10 It is important that this analysis was focused on the acute phase of stroke and included trials of aspirin plus dipyridamole versus aspirin or dipyridamole alone. In contrast, 3 of the more recent, and largest, randomized trials of combination antiplatelet therapy for secondary prevention after ischemic stroke have failed to show a benefit over monotherapy.11 Regimens studied included clopidogrel plus aspirin versus clopidogrel alone,11 clopidogrel plus aspirin versus aspirin alone,12 and aspirin plus extended-release dipyridamole versus clopidogrel.13 In each of these trials, antiplatelet monotherapy showed similar efficacy compared with dual therapy, and less systemic and cerebral bleeding.11–13
In our study, we found that patients who qualified for the trial with ischemic stroke were at high risk of recurrent major vascular events, compared with patients who qualified with prior MI (11.7% vs 9.6% placebo rates).6 This higher risk highlights the importance of seeking new effective therapies for secondary prevention in patients with ischemic stroke. However, the addition of the protease-activated receptor-1 antagonist vorapaxar to standard antiplatelet therapy did not improve their outcomes. Although there was a trend toward a reduction in major vascular events with vorapaxar in the subgroup of patients treated with aspirin alone as background therapy, this possible effect was not statistically significant and was accompanied by a higher risk of intracranial hemorrhage.
By its design, our trial does not address the question of whether vorapaxar could be effective as an alternative therapy administered alone in comparison with guideline-based antiplatelet therapy, especially in patients who experience a stroke while receiving standard antiplatelet therapy. The patterns in our trial of possible benefit with vorapaxar in patients who were treated with aspirin only or no other antiplatelet agent are supportive of this hypothesis but would require prospective assessment.
Our study reinforces the potential risk of intracranial bleeding with combination antiplatelet therapy for patients with prior ischemic stroke. The pattern of an increased risk of intracranial hemorrhage with vorapaxar was consistent in all major subgroups with prior stroke, including those who qualified for the trial with MI or PAD but who also had a history of stroke. Combination antiplatelet therapy with aspirin and a thienopyridine has been shown to increase the risk of intracranial hemorrhage compared with monotherapy both in patients with ischemic stroke11,12 and in patients with acute coronary syndromes with a history of stroke or TIA.14 In the latter study, a history of TIA was not examined separately from prior stroke.14 However, our findings suggest an increased risk of intracranial hemorrhage in those with prior TIA, who may be difficult to distinguish clinically from those with stroke.
Our findings also highlight the contrasting outcomes with more potent combination therapy in patients with cerebrovascular disease alone compared with patients with coronary atherothrombosis. Specifically, vorapaxar significantly reduces major vascular events in patients with MI, particularly in patients without prior stroke or TIA who are at low absolute bleeding risk,7 but showed no benefit in patients with ischemic stroke on the background of contemporary antiplatelet therapy at the dose and duration administered in this study.
Conclusions
In patients with prior ischemic stroke receiving standard antiplatelet therapy, adding vorapaxar increased the risk of intracranial hemorrhage without a reduction in either the primary efficacy end point or ischemic stroke alone. These findings add to the accumulating evidence establishing important risks with combination antiplatelet therapy in patients with prior stroke.
Source of Funding
This study was supported by Merck.
Disclosures
Dr Morrow reports that the Thrombolysis in Myocardial Infarction (TIMI) Study Group has received research grants from Abbott, AstraZeneca, Amgen, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Merck, Novartis, and Johnson & Johnson. He reports having served as a consultant for Merck, Boehringer Ingelheim, Gilead, Genentech, and Servier. Dr Alberts has received grants from Merck, been on the speaker’s bureau for Sanofi Aventis, and is a paid consultant for Sanofi Aventis, Merck, and Pozen. Dr Mohr has received consulting fees from Merck. Dr Ameriso has received grants from Merck and has served on the speaker’s bureau for Bayer, Bristol-Myers Squibb, and Boehringer Ingelheim. Dr Bonaca is a member of the TIMI Study Group. Dr Goto has received grants from Boehringer Ingelheim, Daiichi Sankyo, Sanofi Aventis, and Utsuka. He has received honoraria from AstraZeneca and Sanofi Aventis, and been a consultant to Bayer and Bristol-Myers Squibb. Dr Hankey has received honoraria for serving on the executive committee of clinical trials (Boehringer Ingelheim, Johnson & Johnson, Merck, and Sanofi Aventis). He has received honoraria from Bayer, Boehringer Ingelheim, and Pfizer Australia for speaking at sponsored symposia and consulting. S.A. Murphy is a member of the TIMI Study Group. She has been a consultant for Eli Lilly and Amarin Pharmaceuticals.Dr Scirica is a member of the TIMI Study Group. He has been a consultant for Lexicon, Arena, Gilead, and Eisai. Dr Braunwald is a member of the TIMI Study Group. He has served as a consultant for Merck (no compensation), Amorcyte, Daiichi Sankyo, Medicines Co, Ikaria, and CVRx (no compensation).
Footnotes
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.000433/-/DC1.
- Received December 10, 2012.
- Accepted December 27, 2012.
- © 2013 American Heart Association, Inc.
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- Efficacy and Safety of Vorapaxar in Patients With Prior Ischemic Stroke
