vorapaxar and Intracranial-Hemorrhages

Recent clinical trial data suggest that protease-activated receptor-1 (PAR-1) antagonists may increase the risk of intracranial hemorrhage. Our objective was to investigate the qualitative and quantitative risks of intracranial hemorrhage in patients receiving PAR-1 antagonist therapy.. Pubmed, EMBASE, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov from 1966 to May 2012, were searched to identify relevant studies. We included randomized controlled trials that included a comparison of PAR-1 antagonist with placebo and in which the total number of patients and intracranial hemorrhage events were reported separately for active treatment and control groups. Summary incidence rates, relative risks, and 95% confidence intervals (CIs) were calculated using random-effects models. Between-study heterogeneity was assessed using the I2 statistic.. In 9 PAR-1 antagonist trials with 42000 patients with a history of thrombotic vascular disease or acute coronary syndrome, PAR-1 antagonist treatment was associated with increased risk of intracranial hemorrhage (0.59% vs 0.30%; relative risk, 1.98; 95% CI, 1.46-2.68; P<0.00001; number needed to harm, 345). There was no heterogeneity across trials (P=0.84; I2=0%), PAR-1 antagonist agent (P=0.52), treatment duration (P=0.38), or trial-qualifying event (P=0.59). Risk of death from any cause or a cardiovascular cause did not differ between active treatment and control groups.. In a pooled analysis of data from 9 trials, PAR-1 antagonist therapy was associated with an increased risk for intracranial hemorrhage.

Topics: Acute Coronary Syndrome; Humans; Imines; Incidence; Intracranial Hemorrhages; Lactones; Placebos; Pyridines; Randomized Controlled Trials as Topic; Receptor, PAR-1; Risk Factors; Thrombosis

In contrast to the vast majority of pharmaceuticals on the market, antiplatelet agents are widely prescribed in a uniform, 'one size fits all' manner, without conventional dose adjustments. However, strong evidence yielded from clinical trials repeatedly suggests that patients with a low body weight (LBW), the elderly and those with renal or hepatic impairment may benefit from reduced doses, while younger, heavier patients, males and diabetics may benefit from a dose escalation. Vorapaxar, a thrombin protease-activated receptor-1 inhibitor, has been tested in the TRA2P and TRACER clinical trials, but its efficacy and safety in patients with a LBW is unclear.. To determine the impact of LBW on primary end point rates (PER) and bleeding risk after vorapaxar, as yielded from the TRA2P and TRACER secondary FDA review.. The LBW (<60 kg) groups in TRA2P (n = 1,852; 7%) and TRACER (n = 1,046; 8%) were small. However, the PER repeatedly suggested inferiority of vorapaxar over placebo in both the successful TRA2P study (10.6 vs. 8.4%; p = 0.012) and the failed TRACER study (19.3 vs. 18.2%; p = not significant). In TRA2P, the PER monotonically escalated with increasing weight for placebo, while those in the vorapaxar arm formed a flat U- or J-shaped distribution across the weight quintiles. In TRACER, the PER by weight quintile appear much higher, but also more random than in TRA2P. The bleeding rates in TRA2P were higher for the 2 lowest-weight quintiles with both placebo and vorapaxar. In TRACER, bleeding rates were more than doubled when compared to TRA2P, and they varied little by weight quintile, with a slight decrease for the heaviest patients in the placebo population and being the highest in the 2 lowest-weight quintiles after vorapaxar.. The FDA analyses revealed no definite proof that LBW is associated with reduced efficacy of vorapaxar. While these data are striking, they can be explained by better outcomes in LBW placebo patients already sufficiently treated with dual-antiplatelet therapy. In contrast to efficacy, both TRA2P and TRACER definitely suggest that bleeding rates after vorapaxar are higher in patients with LBW. Dose adjustment for antiplatelet agents may soon become a reality.

Topics: Body Weight; Double-Blind Method; Humans; Intracranial Hemorrhages; Lactones; Logistic Models; Platelet Aggregation Inhibitors; Pyridines; Thinness; Treatment Outcome

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.. 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.. 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).. 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.

Topics: Aged; Double-Blind Method; Female; Humans; International Cooperation; Intracranial Hemorrhages; Kaplan-Meier Estimate; Lactones; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1; Risk Factors; Stroke; Treatment Outcome

Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.. In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.. Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups.. In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

Topics: Acute Coronary Syndrome; Aged; Angioplasty; Cardiovascular Diseases; Combined Modality Therapy; Coronary Artery Bypass; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Humans; Intracranial Hemorrhages; Kaplan-Meier Estimate; Lactones; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1

Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.. We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.. At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).. Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).

Topics: Aged; Brain Ischemia; Cardiovascular Diseases; Double-Blind Method; Female; Hemorrhage; Humans; Intracranial Hemorrhages; Kaplan-Meier Estimate; Lactones; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1; Retreatment; Risk; Secondary Prevention; Stroke

Background Vorapaxar, a protease-activated receptor-1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. Methods and Results TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow-up, 477 days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan-Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22-6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2 years [hazard ratio, 0.79; 95% confidence interval, 0.58-1.07]), and similar for stroke overall (1.93% versus 2.13% at 2 years [hazard ratio, 0.94; 95% confidence interval, 0.71-1.24]). Conclusions Stroke occurred in <2% of patients. Vorapaxar-assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.

Topics: Acute Coronary Syndrome; Aged; Clinical Trials, Phase III as Topic; Female; Humans; Incidence; Intracranial Hemorrhages; Lactones; Male; Middle Aged; Multicenter Studies as Topic; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Risk Factors; Secondary Prevention; Stroke; Treatment Outcome

Topics: Humans; Imines; Intracranial Hemorrhages; Lactones; Pyridines; Receptor, PAR-1