Rationale and design for the Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD).

BACKGROUND: Patients with peripheral artery disease (PAD) undergoing a lower-extremity revascularization are at heightened risk for ischemic cardiac and limb events. Although intensification of antithrombotic therapy after revascularization has demonstrated benefit in coronary disease populations, this approach has not been well studied or shown consistent benefit in PAD. Recent trial evidence demonstrated that a treatment strategy of rivaroxaban added to background antiplatelet therapy reduced ischemic risk in patients following recent acute coronary syndromes, as well as in patients with stable atherosclerotic vascular disease. Whether these benefits extend to the population of patients with symptomatic lower-extremity PAD undergoing revascularization is the objective of the VOYAGER PAD trial. STUDY DESIGN: VOYAGER PAD is an international randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rivaroxaban in symptomatic PAD patients undergoing a peripheral surgical and/or endovascular revascularization. Patients are randomized in a 1:1 ratio to either rivaroxaban 2.5 mg twice daily or placebo, on a background of low-dose aspirin (100 mg daily). In addition, the use of a limited course of P2Y12 inhibition is allowed at the discretion of the site investigator. The primary efficacy end point is a novel composite of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia, and major amputation of vascular etiology. The primary safety end point is major bleeding according to the Thrombolysis in Myocardial Infarction definition. Enrolment began in August 2015 and will complete randomization of at least 6,500 patients by January 2018. This event-driven trial is expected to observe outcomes over a mean patient follow-up of 30 months. CONCLUSIONS: VOYAGER PAD is evaluating the efficacy of rivaroxaban added to background antiplatelet therapy to reduce major cardiovascular and limb ischemic vascular outcomes in the high-risk population of PAD patients undergoing peripheral revascularization.

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

SUMMARY BACKGROUND Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. METHODS This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle­brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57­0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35­0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69­1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45­1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12­2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17­2·40; p=0·0043). INTERPRETATION Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding.

Rationale, design and baseline characteristics of participants in the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial

BACKGROUND: Long-term aspirin prevents vascular events but is only modestly effective. Rivaroxaban alone or in combination with aspirin might be more effective than aspirin alone for vascular prevention in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). Rivaroxaban as well as aspirin increase upper gastrointestinal (GI) bleeding and this might be prevented by proton pump inhibitor therapy. METHODS: Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) is a double-blind superiority trial comparing rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg once daily or rivaroxaban 5 mg twice daily vs aspirin 100 mg once daily for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD. Patients not taking a proton pump inhibitor were also randomized, using a partial factorial design, to pantoprazole 40 mg once daily or placebo. The trial was designed to have at least 90% power to detect a 20% reduction in each of the rivaroxaban treatment arms compared with aspirin and to detect a 50% reduction in upper GI complications with pantoprazole compared with placebo...

Effect of age on efficacy and safety of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial.

BACKGROUND: Antithrombotic therapy plays an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS) but is associated with bleeding risk. Advanced age may modify the relationship between efficacy and safety. METHODS: Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding. RESULTS: The median age of the population was 64years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435). Similar to what was observed for efficacy outcomes, we did not observe any interaction between vorapaxar and age on bleeding outcomes. For the composite of moderate or severe bleeding according to the GUSTO classification, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were 1.73 (0.89-3.34), 1.39 (1.04-1.86), 1.10 (0.85-1.42), and 1.73 (1.29-2.33), respectively (P value for interaction = .574). CONCLUSION: Older patients had a greater risk for ischemic and bleeding events; however, the efficacy and safety of vorapaxar in NSTE ACS were not significantly influenced by age.

Effect of age on efficacy and safety of vorapaxar in patients with non–ST-segment elevation acute coronary syndrome: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial

Methods: Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding. ResultsThe median age of the population was 64 years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54 years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75 years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75 years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54 years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435)...