Scott D. Berkowitz

BACKGROUND: Patients with peripheral artery disease (PAD) undergoing lower extremity revascularization (LER) are at high risk of major adverse limb events (MALE) and major adverse cardiovascular events. The VOYAGER-PAD trial (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated that rivaroxaban 2.5 mg twice daily on top of antiplatelet therapy significantly reduced this risk. Whether the risk of major adverse cardiovascular events and MALE and the effect of rivaroxaban are consistent in patients with a history of prior LER versus those without has not been described. METHODS: VOYAGER-PAD randomized patients with symptomatic PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily. The history of prior LER was collected at baseline. The primary end point was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. RESULTS: A total of 6564 patients were enrolled with 2336 (35.5%) having a prior history of LER. Patients with a history of prior LER had a higher rate of MALE relative to those without prior LER (3-year Kaplan-Meier cumulative rates, 12.9% versus 8.0%; hazard ratio [HR], 1.58 [95% CI, 1.25–1.99]). Compared with placebo, rivaroxaban reduced the primary efficacy end point with a numerically greater relative benefit in those with (HR, 0.73 [95% CI, 0.60–0.88]) versus without prior LER (HR, 0.94 [95% CI, 0.81–1.10]; P _interaction =0.036). The relative increase in Thrombolysis in Myocardial Infarction major bleeding with rivaroxaban was consistent regardless of prior LER status (prior LER: HR, 1.08 [95% CI, 0.62–1.89]; no prior LER: HR, 1.88 [95% CI, 1.09–3.25]; P _interaction =0.16). CONCLUSIONS: Patients with PAD with prior LER are at particularly high risk of MALE relative to those presenting without prior LER. Rivaroxaban reduces the risk of major adverse cardiovascular events and MALE after LER for symptomatic PAD with a greater relative benefit in those with prior LER. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02504216.

Background: VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) demonstrated that antiplatelet therapy with rivaroxaban 2.5 mg twice daily compared with placebo reduced the first event in a composite end point in patients with peripheral artery disease after revascularization. The purpose of this analysis was to (1) evaluate whether rivaroxaban decreased the most severe events and (2) compare the harm and benefit of rivaroxaban on the same scale. Methods: Two exploratory, hierarchical analyses of the primary efficacy composite outcome and one exploratory analysis of the net clinical benefit composite outcome were prespecified. The global rank method and the win ratio method ranked components of the composite outcome by clinical importance. The net clinical benefit included both efficacy and safety outcomes. Results: The global rank method demonstrated that participants on rivaroxaban had fewer or later events than their placebo counterparts when events were compared in a hierarchical manner (primary ranking, P =0.0158). The win ratio approach demonstrated fewer or later fatal and nonfatal ischemic events in the rivaroxaban arm (win ratio, 1.16 [95% CI, 1.03–1.30]; P =0.0167). The net clinical benefit analysis revealed an overall beneficial effect of rivaroxaban when different efficacy and safety end points were included ( P <0.001). Conclusions: Evaluation of the VOYAGER PAD primary outcome exploring ranking of components revealed that (1) rivaroxaban decreased the most severe ischemic events and (2) that across different efficacy and safety outcomes, results consistently supported a favorable benefit–risk profile. These results help inform shared decision making on the use of rivaroxaban 2.5 mg twice daily with daily antiplatelet therapy. Registration: URL: https://www.clinicaltrials.gov ; unique identifier: NCT02504216.

Background: Days alive out of hospital (DAOH) is an objective and patient‐centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. Methods and Results: ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double‐blind, double‐dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator‐reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin ( P =0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P =0.88). Conclusions: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Background: The VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) trial compared rivaroxaban (2.5 mg twice a day) plus aspirin with aspirin alone in patients with symptomatic peripheral artery disease requiring endovascular or surgical limb revascularization, with 50% receiving clopidogrel background therapy. The New Drug Indication application includes benefit–risk assessments using clinical judgment to balance benefits against risks. During its review, the US Food and Drug Administration requested additional quantitative benefit–risk analyses with formal weighting approaches. Methods and Results: Benefits and risks were assessed using rate differences between treatment groups (unweighted analysis). To account for clinical importance of the end points, a multi‐criteria decision analysis was conducted using health state utility values as weights. Monte Carlo simulations incorporated statistical uncertainties of the event rates and utility weights. Intent‐to‐treat and on‐treatment analyses were conducted. For unweighted intent‐to‐treat analyses, rivaroxaban plus aspirin would result in 120 (95% CI, −208 to −32) fewer events of the primary composite end point (per 10 000 patient‐years) compared with aspirin alone. Rivaroxaban caused an excess of 40 (95% CI, 8–72) Thrombolysis in Myocardial Infarction major bleeding events, which was largely driven by nonfatal, nonintracranial hemorrhage Thrombolysis in Myocardial Infarction major bleeding events. For weighted analyses, rivaroxaban resulted in the utility equivalent of 13.7 (95% CI, −85.3 to 52.6) and 68.1 (95% CI, 7.9–135.7) fewer deaths per 10 000 patient‐years (intent‐to‐treat and on‐treatment, respectively), corresponding to probabilities of 64.4% and 98.7%, respectively, that benefits outweigh risks favoring rivaroxaban per Monte Carlo simulation. Conclusions: These analyses show a favorable benefit–risk profile of rivaroxaban therapy in the VOYAGER PAD trial, with findings generally consistent between the unweighted and weighted approaches.

BACKGROUND: Rivaroxaban plus aspirin compared with aspirin alone reduced major cardiac and ischemic limb events after lower extremity revascularization (LER) in the VOYAGER PAD (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) trial. The effect has not been described in patients undergoing endovascular LER. METHODS: The VOYAGER PAD trial randomized 6564 patients with symptomatic peripheral artery disease to a double-blinded treatment with 2.5 mg of rivaroxaban BID or matching placebo and 100 mg of aspirin daily. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular pathogenesis, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was Thrombolysis in Myocardial Infarction major bleeding. A prespecified subgroup of patients who underwent endovascular revascularization was included. RESULTS: Endovascular LER occurred in 4379 (66.7%) patients and surgical LER in 2185 (33.3%). Over a 3-year follow-up, rivaroxaban reduced the risk of the primary outcome by 15% (hazard ratio [HR], 0.85 [95% CI, 0.76–0.96]) with an absolute risk reduction of 0.92% at 6 months and 1.04% at 3 years and a consistent benefit in those receiving endovascular (HR, 0.89 [95% CI, 0.76–1.03]) or surgical LER (HR, 0.81 [95% CI, 0.67–0.98]; P interaction=0.43). For endovascular-treated patients, rivaroxaban reduced the risk of acute limb ischemia or major amputation of a vascular pathogenesis by 30% (HR, 0.70 [95% CI, 0.54–0.90]; P =0.005) with an absolute risk reduction of 1.0% at 6 months and 2.0% at 3 years compared with aspirin alone. Among endovascular-treated patients, the median duration of concomitant dual antiplatelet therapy with clopidogrel treatment was 31 days (interquartile range, 30–58). There was a consistent benefit for rivaroxaban regardless of background clopidogrel. Thrombolysis in Myocardial Infarction major bleeding was significantly higher for the rivaroxaban and aspirin group for the endovascular cohort (HR, 1.66 [95% CI, 1.06–2.59]) with an absolute risk increase of 0.9% at 3 years with no increase in intracranial or fatal bleeding observed (HR, 0.86 [95% CI, 0.40–1.87]; P =0.71). Mortality with rivaroxaban was higher in the endovascular-treated patients (HR, 1.24 [95% CI, 1.02–1.52]), although this finding was isolated to specific regions. CONCLUSIONS: Rivaroxaban added to aspirin or dual antiplatelet therapy after LER for peripheral artery disease reduces ischemic risk and increases major bleeding without an increased risk of intracranial or fatal bleeding. These benefits are consistent in those treated with endovascular and surgical approaches with significant benefits for major adverse limb events. These data support the use of rivaroxaban in addition to aspirin or dual antiplatelet therapy after endovascular intervention for symptomatic peripheral artery disease.

Patients with peripheral artery disease (PAD) are at an increased risk of major adverse cardiovascular events, and those with disease in the lower extremities are at risk of major adverse limb events primarily driven by atherothrombosis. Traditionally, PAD refers to diseases of the arteries outside of the coronary circulation, including carotid, visceral and lower extremity peripheral artery disease, and the heterogeneity of PAD patients is represented by different atherothrombotic pathophysiology, clinical features and related antithrombotic strategies. The risk in this diverse population includes systemic risk of cardiovascular events as well as risk related to the diseased territory (e.g., artery to artery embolic stroke for patients with carotid disease, lower extremity artery to artery embolism and atherothrombosis in patients with lower extremity disease). Moreover, until the last decade, clinical data on antithrombotic management of PAD patients have been drawn from subanalyses of randomized clinical trials addressing patients affected by coronary artery disease. The high prevalence and related poor prognosis in PAD patients highlight the pivotal role of tailored antithrombotic therapy in patients affected by cerebrovascular, aortic and lower extremity peripheral artery disease. Thus, the proper assessment of thrombotic and hemorrhagic risk in patients with PAD represents a key clinical challenge that must be met to permit the optimal antithrombotic prescription for the various clinical settings in daily practice. The aim of this updated review is to analyze different features of atherothrombotic disease as well as current evidence of antithrombotic management in asymptomatic and secondary prevention in PAD patients according to each arterial bed.

Background: Despite high female prevalence of peripheral artery disease (PAD), little is known about sex‐based outcomes after lower extremity revascularization (LER) for symptomatic PAD. The effects of rivaroxaban according to sex following LER have not been fully reported. Methods and Results: In VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease), low‐dose rivaroxaban versus placebo on a background of aspirin reduced the composite primary efficacy outcome of cardiovascular and limb events in patients with PAD undergoing LER. Unplanned index limb revascularization was prespecified and prospectively ascertained. The primary safety outcome was Thrombolysis in Myocardial Infarction major bleeding. Analyses of outcomes and treatment effects by sex were performed using Cox proportional hazards models. Among 6564 randomly assigned patients followed for a median of 28 months, 1704 (26.0%) were women. Among patients administered placebo, women were at similar risk for the primary efficacy outcome (hazard ratio [HR], 0.90; [95% CI, 0.74–1.09]; P =0.29) as men, while female sex was associated with a trend toward higher risk of unplanned index limb revascularization (HR, 1.18; [95% CI, 1.00–1.40]; P =0.0499). Irrespective of sex, effects of rivaroxaban were consistent for the primary efficacy outcome ( P ‐interaction=0.22), unplanned index limb revascularization ( P ‐interaction=0.64), and bleeding ( P ‐interaction=0.61). Women were more likely than men to discontinue study treatment (HR, 1.13; [95% CI, 1.03–1.25]; P =0.0099). Conclusions: Among >1700 women with PAD undergoing LER, women and men were at similar risk for the primary outcome, but a trend for greater risk of unplanned index limb revascularization among women was observed. Effects of rivaroxaban were consistent by sex, though women more often discontinued treatment. Better understanding of sex‐based outcomes and treatment adherence following LER is needed. Registration: URL: http://clinicaltrials.gov ; Unique identifier: NCT02504216.