vorapaxar and Ischemia

Oral antiplatelet therapies for secondary prevention of ischemic recurrences in patients with atherosclerotic disease manifestations include aspirin and P2Y12 receptor antagonists. Despite the use of these therapies, patients remain at risk for recurrent ischemic events, which may be attributed to other platelet signaling pathways which continue to be activated. More intense antithrombotic strategies have been investigated, including identifying additional targets to modulate platelet activation. Among these, thrombin-mediated platelet activation through PAR-1 has been subject to broad clinical investigation. Vorapaxar is the only PAR-1 receptor antagonists that completed large-scale clinical investigations and is approved for clinical use. This manuscript provides an overview of the pharmacology and clinical trial development of vorapaxar as well as its role in clinical practice.

Topics: Atherosclerosis; Blood Platelets; Clinical Trials as Topic; Humans; Ischemia; Lactones; Platelet Activation; Platelet Aggregation Inhibitors; Pyridines; Receptors, Thrombin; Secondary Prevention

Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02-0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65%.

Topics: Acute Coronary Syndrome; Aged; Female; Genetic Variation; Genotype; Hemorrhage; Humans; Ischemia; Lactones; Male; Middle Aged; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide; Pyridines; Randomized Controlled Trials as Topic; Receptor, PAR-1; Receptors, Thrombin

Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a morbid event that may result in limb loss. We investigated the causes, sequelae, and predictors of ALI in a contemporary population with symptomatic PAD and whether protease-activated receptor 1 antagonism with vorapaxar reduced ALI overall and by type.. The Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in stable patients, including 3787 with symptomatic PAD. ALI was a prespecified adjudicated end point using a formal definition. A total of 150 ALI events occurred in 108 patients during follow-up (placebo 3-year rate, 3.9%; 1.3% annualized). For patients with symptomatic PAD, previous peripheral revascularization, smoking, and the ankle-brachial index were predictive of ALI. The majority of ALI events occurred as a result of surgical graft thrombosis (56%), followed by native vessel in situ thrombosis (27%). Stent thrombosis and thromboembolism caused ALI in 13% and 5%, respectively. Amputation occurred in 17.6% presenting with ALI. Vorapaxar reduced first ALI events by 41% (hazard ratio, 0.58; 95% confidence interval, 0.39-0.86; P=0.006) and total ALI events by 41% (94 versus 56 events; risk ratio, 0.59; 95% confidence interval, 0.38-0.93; P=0.022). The efficacy of vorapaxar was consistent across types of ALI.. In selected patients with symptomatic PAD and without atrial fibrillation, ALI occurs at a rate of 1.3%/y, is most frequently caused by acute bypass graft thrombosis or in situ thrombosis of a diseased vessel, and often results in limb loss. Vorapaxar reduces ALI in patients with symptomatic PAD with consistency across type, including PAD resulting from surgical graft thrombosis and in-situ thrombosis.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526474.

Topics: Acute Disease; Aged; Atherosclerosis; Coronary Artery Bypass; Double-Blind Method; Extremities; Female; Follow-Up Studies; Humans; Ischemia; Lactones; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prospective Studies; Pyridines; Stroke; Thrombolytic Therapy; Treatment Outcome

Clinical trials traditionally use time-to-first-event analysis embedded within the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke. However, many patients have >1 event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER.. TRACER randomized 12 944 patients with non-ST-segment elevation acute coronary syndromes to placebo or to protease-activated receptor 1 antagonist vorapaxar with a median follow-up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD, MI, or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD, MI, stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD, MI, or stroke (14.7% vorapaxar vs. 16.4% placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.02; number needed to treat [NNT], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent (HR, 0.88; 95% CI, 0.80 to 0.98; P=0.02; NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia (HR, 0.92; 95% CI, 0.84 to 1.01; P=0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding (HR, 1.42; 95% CI, 1.21 to 1.66; P<0.001) and Thrombolysis in Myocardial Infarction clinically significant bleeding (HR, 1.550; 95% CI, 1.403 to 1.713; P<0.001).. Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events.. ClinicalTrials.gov. Unique identifier: NCT00527943.

Topics: Acute Coronary Syndrome; Aged; Cardiovascular Diseases; Double-Blind Method; Female; Hemorrhage; Humans; Ischemia; Lactones; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Proportional Hazards Models; Pyridines; Recurrence; Secondary Prevention; Stroke; Treatment Outcome

Vorapaxar is a novel antagonist of protease-activated receptor-1, the primary receptor for thrombin on human platelets that is also present on vascular endothelium and smooth muscle. Patients with peripheral artery disease are at risk of systemic atherothrombotic events, as well as acute and chronic limb ischemia and the need for peripheral revascularization.. The Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26 449 patients with stable atherosclerotic vascular disease (myocardial infarction, stroke, or peripheral artery disease). Patients with qualifying peripheral artery disease (n=3787) had a history of claudication and an ankle-brachial index of <0.85 or prior revascularization for limb ischemia. The primary efficacy end point was cardiovascular death, myocardial infarction, or stroke, and the principal safety end point was Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) bleeding. In the peripheral artery disease cohort, the primary end point did not differ significantly with vorapaxar (11.3% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.78-1.14; P=0.53). However, rates of hospitalization for acute limb ischemia (2.3% versus 3.9%; hazard ratio, 0.58; 95% confidence interval, 0.39-0.86; P=0.006) and peripheral artery revascularization (18.4% versus 22.2%; hazard ratio, 0.84; 95% confidence interval, 0.73-0.97; P=0.017) were significantly lower in patients randomized to vorapaxar. Bleeding occurred more frequently with vorapaxar compared with placebo (7.4% versus 4.5%; hazard ratio, 1.62; 95% confidence interval, 1.21-2.18; P=0.001).. Vorapaxar did not reduce the risk of cardiovascular death, myocardial infarction, or stroke in patients with peripheral artery disease; however, vorapaxar significantly reduced acute limb ischemia and peripheral revascularization. The beneficial effects of protease-activated receptor-1 antagonism on limb vascular events were accompanied by an increased risk of bleeding.

Topics: Aged; Ankle Brachial Index; Cohort Studies; Comorbidity; Double-Blind Method; Extremities; Female; Follow-Up Studies; Hemorrhage; Humans; Ischemia; Kaplan-Meier Estimate; Lactones; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Pyridines; Receptor, PAR-1; Risk Factors; Stroke; Thrombin; Treatment Outcome

Background Patients with peripheral artery disease are at increased risk of both major adverse cardiovascular events (MACEs) and limb events. The pathobiology of limb events is likely multifactorial. Observational studies suggest a benefit of statin therapy for reducing the risk of limb ischemic events while randomized trials demonstrate a benefit with more potent antithrombotic therapies, particularly those targeting thrombin. Whether the effects of these therapeutic pathways are independent and complementary is not known. Methods and Results The TRA 2°P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50) trial demonstrated that vorapaxar significantly reduced MACEs and limb events. The purpose of the current analysis was to evaluate the association of statin use and intensity and the occurrence of MACEs and limb events in 5845 patients with symptomatic peripheral artery disease randomized in TRA 2°P-TIMI 50 and then to understand whether statin use modified the benefits of vorapaxar for MACEs or limb ischemic events. We found that statin therapy was associated with significantly lower risk of MACEs (hazard ratio [HR], 0.77; 95% CI, 0.66-0.89;

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemia; Lactones; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Pyridines; Stroke; Thrombin; Treatment Outcome

Topics: Disease Progression; Humans; Ischemia; Lactones; Lower Extremity; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Pyridines; Treatment Outcome; Vascular Patency