Search

Jemi Galani,1 Hillary Mulder,2 Frank W Rockhold,2 E Hope Weissler,2,3 Iris Baumgartner,4 Jeffrey S Berger,5 Juuso I Blomster,6 F Gerry R Fowkes,7 William R Hiatt,8,9 Brian G Katona,10 Lars Norgren,11 Kenneth W Mahaffey,12 Jennifer K Quint,13 Manesh R Patel,1,2 W Schuyler Jones1,2 1Department of Medicine, Duke University Medical Center, Durham, NC, USA; 2Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; 3Department of Surgery, Division of Vascular Surgery, Duke University Health System, Durham, NC, USA; 4Department of Medicine, Swiss Cardiovascular Center, University of Bern, Bern, Switzerland; 5Departments of Medicine and Surgery, New York University School of Medicine, New York, NY, USA; 6University of Turku, Turku, Finland; 7Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK; 8Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA; 9CPC Clinical Research, Aurora, CO, USA; 10AstraZeneca, Gaithersburg, MD, USA; 11Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 12Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, CA, USA; 13Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, UKCorrespondence: W Schuyler JonesDuke University Medical Center, Box 3330, Durham, NC, 27710, USATel +1 919-668-8917Fax +1 919-668-7026Email schuyler.jones@duke.eduBackground: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of developing lower extremity peripheral artery disease (PAD) and suffering PAD-related morbidity and mortality. However, the effect and burden of COPD on patients with PAD is less well defined. This post hoc analysis from EUCLID aimed to analyze the risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with PAD and concomitant COPD compared with those without COPD, and to describe the adverse events specific to patients with COPD.Methods: EUCLID randomized 13,885 patients with symptomatic PAD to monotherapy with either ticagrelor or clopidogrel for the prevention of MACE. In this analysis, MACE, MALE, mortality, and adverse events were compared between groups with and without COPD using unadjusted and adjusted Cox proportional hazards model.Results: Of the 13,883 patients with COPD status available at baseline, 11% (n=1538) had COPD. Patients with COPD had a higher risk of MACE (6.02 vs 4.29 events/100 patient-years; p< 0.001) due to a significantly higher risk of myocardial infarction (MI) (3.55 vs 1.85 events/100 patient-years; p< 0.001) when compared with patients without COPD. These risks persisted after adjustment (MACE: adjusted hazard ratio (aHR) 1.30, 95% confidence interval [CI] 1.11– 1.52; p< 0.001; MI: aHR 1.45, 95% CI 1.18– 1.77; p< 0.001). However, patients with COPD did not have an increased risk of MALE or major bleeding. Patients with COPD were more frequently hospitalized for dyspnea and pneumonia (2.66 vs 0.9 events/100 patient-years; aHR 2.77, 95% CI 2.12– 3.63; p< 0.001) and more frequently discontinued study drug prematurely (19.36 vs 12.54 events/100 patient-years; p< 0.001; aHR 1.34, 95% CI 1.22– 1.47; p< 0.001).Conclusion: In patients with comorbid PAD and COPD, the risks of MACE, respiratory-related adverse events, and premature study drug discontinuation were higher when compared with patients without COPD.Registration: ClinicalTrials.gov: NCT01732822.Keywords: peripheral artery disease, chronic obstructive pulmonary disease, major adverse cardiovascular events

BackgroundThe ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS.DesignAn analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events.MethodsSubjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events.ResultsIn predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p

Context: Randomized trials have shown that aspirin decreases the risk of cardiovascular events in patients with symptomatic coronary and cerebrovascular disease. Despite guideline recommendations for secondary prevention in peripheral artery disease (PAD), the effect of aspirin in this population is not well established.Objective: To investigate the effect of aspirin on cardiovascular event rates in patients with PAD.Data Sources and Study Selection: MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, Science Citation Index (1966 to December 2008), and unpublished studies from the supplemental index of the Antithrombotic Trialists' Collaboration. Eligible studies were prospective, randomized controlled trials of aspirin therapy, with or without dipyridamole that reported cardiovascular event rates. Eighteen trials involving 5269 individuals were identified.Data Extraction: Studies were reviewed to determine the number of participants, mean follow-up, and the primary end point of cardiovascular events (nonfatal myocardial infarction [MI], nonfatal stroke, and cardiovascular death). Data on the secondary end points of all-cause mortality, major bleeding, and the individual components of the primary outcome measure were also abstracted. For the primary end point, the analysis had 88% power to detect a 25% reduction and 70% power to detect a 20% reduction in cardiovascular events in the aspirin group compared with the control group.Data Synthesis: Among 5269 participants, cardiovascular events were experienced by 251 (8.9%) of 2823 patients taking aspirin (alone or with dipyridamole) and by 269 (11.0%) of 2446 in the control group (pooled relative risk [RR], 0.88; 95% confidence interval [CI], 0.76-1.04). Aspirin therapy was associated with a reduction in the secondary outcome of nonfatal stroke (52 of 2823 vs 76 of 2446; RR, 0.66; 95% CI, 0.47-0.94) but was not associated with significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding. In the subset of 3019 participants taking aspirin alone vs control, aspirin was associated with a nonsignificant reduction in cardiovascular events (125 of 1516 vs 144 of 1503; RR, 0.75; 95% CI, 0.48-1.18), a significant reduction in nonfatal stroke (32 of 1516 vs 51 of 1503; RR, 0.64; 95% CI, 0.42-0.99), but no statistically significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding.Conclusions: In patients with PAD, treatment with aspirin alone or with dipyridamole resulted in a statistically nonsignificant decrease in the primary end point of cardiovascular events and a significant reduction in nonfatal stroke. Results for the primary end point may reflect limited statistical power. Additional randomized controlled trials of aspirin therapy are needed to establish the net benefit and bleeding risks in PAD. [ABSTRACT FROM AUTHOR]

Objectives: In the current study, we hypothesized that beraprost would: 1) improve treadmill exercise performance and quality of life; and 2) decrease rates of ischemic events in patients with intermittent claudication.Background: Previous trials with beraprost sodium, an orally active prostaglandin I(2) analogue, in the treatment of claudication in patients with peripheral arterial disease (PAD) have been inconsistent.Methods: Patients with intermittent claudication (n = 897) were randomized to receive either 40 microg three times a day of beraprost with meals (n = 385) or placebo (n = 377) in a double-blinded manner for one year. The primary efficacy parameter was treadmill-measured maximum walking distance, as assessed at three and six months after randomization. Secondary efficacy parameters included treadmill-measured pain-free walking distance and change in quality of life.Results: There was no significant improvement in maximum walking distance in the beraprost group (16.7%) as compared with the placebo group (14.6%, p = NS). Administration of beraprost did not improve the pain-free walking distance (p = NS between treatment groups), and there was no improvement in the quality-of-life measures between the treatment groups. The incidence of critical cardiovascular events was 7.3% in the beraprost group and 11.4% in the placebo group (p = NS). There was a significant reduction in the combination of cardiovascular death and myocardial infarction in the beraprost group (p = 0.01).Conclusions: Despite previous investigations suggesting efficacy, these results indicate that beraprost is not an effective treatment to improve symptoms of intermittent claudication in patients with PAD. The potential benefit of beraprost on critical cardiovascular events would require confirmation in a larger prospective investigation. [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis strongly associated with cardiovascular (CV) morbidity and mortality. Approximately 12% of the US adult population is affected. Despite its prevalence, the disease has received little attention from clinicians. The primary causes of death in patients with PAD are myocardial infarction and stroke; thus, current treatment strategies for symptomatic PAD include aggressive modification of risk factors for CV disease such as cessation of smoking, treatment of hypertension and diabetes, and normalization of low-density lipoprotein cholesterol levels. All patients with PAD should be receiving antiplatelet therapy to prevent ischemic events. Medical treatment for patients with claudication includes exercise rehabilitation and drug therapy. Although many therapies for claudication have been thoroughly investigated, research continues on new treatments. In contrast, more prospective, randomized trials are needed to evaluate various therapies for treating patients with PAD. [ABSTRACT FROM AUTHOR]

Background  The MARINER trial evaluated whether postdischarge thromboprophylaxis with rivaroxaban could reduce the primary outcome of symptomatic venous thromboembolism (VTE) or VTE-related death in acutely ill medical patients at risk for VTE. Although aspirin use was not randomized, approximately half of the enrolled patients were receiving aspirin at baseline. We hypothesized that thromboprophylaxis with once-daily rivaroxaban (10 mg or, if creatinine clearance was 30-49 mL/min, 7.5 mg) plus aspirin (R/A) would be superior to placebo without aspirin (no thromboprophylaxis [no TP]). Methods  We compared the primary and major secondary outcomes in the intention-to-treat population in four subgroups defined at baseline: (1) R/A ( N  = 3,159); (2) rivaroxaban alone ( N  = 2,848); (3) aspirin alone ( N  = 3,046); and (4) no TP ( N  = 2,966). Major bleeding (MB) and nonmajor clinically relevant (NMCR) bleeding were assessed in the safety population on treatment plus 2 days. Results  Patients on R/A had reduced symptomatic VTE and VTE-related death compared with no TP (0.76 vs 1.28%, p  = 0.042), and experienced less symptomatic VTE and all-cause mortality ( p  = 0.005) and all-cause mortality alone ( p  = 0.01) compared with no TP. Event incidences for rivaroxaban alone (0.91%) or aspirin alone (0.92%) were similar. MB was low in all groups but lowest in the no TP group. NMCR bleeding was increased with R/A compared with no TP ( p  = 0.009). Limitations  Aspirin use was not randomized. Conclusion  Extended postdischarge thromboprophylaxis with R/A was associated with less symptomatic VTE and VTE-related death compared with no TP in previously hospitalized medical patients at risk for VTE. NMCR bleeding was increased with R/A compared with no TP. These post hoc findings need confirmation in a prospective trial., Competing Interests: Conflict of Interest Alex C. Spyropoulos: Janssen Research & Development LLC, Bayer, Portola, Boehringer Ingelheim, Daiichi Sankyo, ATLAS group; Mark Goldin: Janssen Research & Development LLC; Walter Ageno: Janssen Research & Development LLC, Bayer, Portola, Daiichi Sankyo, Aspen, BMS, Pfizer, Sanofi, Leo Pharma; Gregory W. Albers: Janssen Research & Development LLC, Bayer; C. Greg Elliott: Janssen Research & Development LLC, Bayer; Jonathan L. Halperin: Janssen Research & Development LLC, Abbott, Bayer, Boehringer Ingelheim, National Institute of Health, ATLAS group, Johnson & Johnson, Ortho-McNeil-Janssen; William R. Hiatt: Janssen Research & Development LLC, Bayer, NIH; Gregory Maynard: Janssen Research & Development LLC; P. Gabriel Steg: Janssen Research & Development LLC, Bayer, Merck, Sanofi, Servier, Amarin, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron, Lilly, AstraZeneca, Idorsia, Novo-Nordisk; Jeffrey I. Weitz: Janssen Research & Development LLC, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis, Merck, Novartis, Pfizer, Portola, Anthos, Servier; Theodore E. Spiro: Bayer U.S. LLC; Wentao Lu, Janssen Research and Development LLC; Jessica Marsigliano, Janssen Research and Development LLC; Gary E. Raskob: Janssen Research & Development LLC, Bayer, BMS, Daiichi Sankyo, Boehringer Ingelheim, Eli Lilly, Pfizer, Portola, Novartis, Anthos, Tetherex; Elliot S. Barnathan: Janssen Research & Development LLC., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients because of bleeding concerns. The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) and MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism without increased bleeding. We hypothesized that patients with major bleeding but not those with nonmajor clinically relevant bleeding would be at an increased risk of all-cause mortality (ACM)., Methods: We evaluated all bleeding events in patients taking at least 1 dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) nonmajor clinically relevant bleeding, (3) major bleeding, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events., Results: Compared with patients with no bleeding, the risk of ACM for patients with nonmajor clinically relevant bleeding was not increased in MARINER (hazard ratio, 0.43; P =0.235) but was increased in MAGELLAN (hazard ratio, 1.74; P =0.021). Major bleeding was associated with a higher incidence of ACM in both studies, whereas trivial bleeding was not associated with ACM in either study., Conclusions: Patients with major bleeding had an increased risk of ACM, whereas nonmajor clinically relevant bleeding was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: MAGELLAN, NCT00571649. URL: https://www., Clinicaltrials: gov; Unique identifier: MARINER, NCT02111564.

Regional variations exist in the epidemiology of peripheral artery disease (PAD), in comorbidities, use of secondary prevention, and outcomes. Large studies of these variations in worldwide populations are rare. The EUCLID (Examining Use of tiCagreLor In peripheral artery Disease) trial included 13,885 patients with PAD from four geographical regions (Central/South America, Europe, Asia, North America) and compared monotherapy with ticagrelor and clopidogrel. Inclusion criteria were either an ankle-brachial index < 0.80 or a prior revascularization. The primary efficacy endpoint was time to first occurrence of any event in the composite of cardiovascular death, myocardial infarction, or ischemic stroke and did not differ between the study arms. This post hoc analysis of EUCLID confirmed that regional differences occurred in the inclusion criteria with more prior revascularization in North America (73.9%) and Asia (72.5%) compared with Central/South America (34.0%) and Europe (51.6%). The characteristics of patients also differed. Prior amputation at baseline was most frequent in Central/South America (6.3%) compared with other regions (1.6-2.8%). A history of stroke was most common in Asia, coronary heart disease in North America, and diabetes in Central/South America compared with other regions. The incidence of outcomes in patients with PAD varied by region. North America had the highest rate of the primary combined endpoint (5.97 events/100 patient-years). Corresponding rates were 4.80, 3.95, and 3.87 for Asia, Europe, and Central/South America, respectively. Hospitalization for acute limb ischemia (events/100 patient-years) was most frequent in Europe (0.75) and North America (0.74) compared with Asia (0.60) and Central/South America (0.33). Adjustment for inclusion criteria and relevant PAD characteristics did not have a major impact on these regional differences. Further adjustment for concomitant disease, risk factors, and preventive medication modified the regional differences only marginally. In conclusion, substantial regional differences were found in cardiovascular and limb outcomes in patients with PAD and were not explained by variation in the category of included patients, concomitant disease, risk factors, and prevention. Such differences, which may be due to variation in other factors such as background population rates or clinical care, need to be considered when designing and interpreting large international studies ( ClinicalTrials.gov Identifier: NCT01732822 ).

Objective: Amputation remains a frequent and feared outcome in patients with peripheral artery disease (PAD). Although typically characterized as major or minor on the extent of tissue loss, the etiologies and outcomes after amputation by extent are not well-understood. In addition, emerging data suggest that the drivers and outcomes of amputation in patients with PAD may differ in those with and without diabetes mellitus (DM)., Methods: The EUCLID trial randomized 13,885 patients with symptomatic PAD, including 5345 with concomitant diabetes, to ticagrelor or clopidogrel and followed them for long-term outcomes. Amputations were prospectively reported by trial investigators. Their primary and contributing drivers were adjudicated using safety data, including infection, ischemia, or multifactorial etiologies. Outcomes following major and minor amputations were analyzed, including recurrent amputation, major adverse limb events, adverse cardiovascular events, and mortality. Multivariable logistic regression models were used to identify independent predictors of minor amputations. Analyses were performed overall and stratified by the presence or absence of DM at baseline., Results: Of the patients randomized, 398 (2.9%) underwent at least one lower extremity nontraumatic amputation, for a total of 511 amputations (255 major and 256 minor) over a median of 30 months. A history of minor amputation was the strongest independent predictor for a subsequent minor amputation (odds ratio, 7.29; 95% confidence interval, 5.17-10.30; P < .001) followed by comorbid DM (odds ratio, 4.60; 95% confidence interval, 3.16-6.69; P < .001). Compared with patients who had a major amputation, those with a minor amputation had similar rates of subsequent major amputation (12.2% vs 13.6%), major adverse limb events (15.1% vs 14.9%), and major adverse cardiovascular events (17.6% vs 16.3%). Ischemia alone was the primary driver of amputation (51%), followed by infection alone (27%), and multifactorial etiologies (22%); however, infection was the most frequent driver in those with DM (58%) but not in those without DM (15%)., Conclusions: Outcomes after amputation remain poor regardless of whether they are categorized as major or minor. The pattern of amputation drivers in PAD differs by history of DM, with infection being the dominant etiology in those with DM and ischemia in those without DM. Greater focus is needed on the prognostic importance of minor amputation and of the multifactorial etiologies of amputation in PAD. Nomenclature with anatomical description of amputations and eliminating terms "major" or "minor" would seem appropriate., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease-2019 (COVID-19) has been associated with significant risk of venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality particularly among hospitalized patients with critical illness and elevated D-dimer (Dd) levels. Conflicting data have yet to elucidate optimal thromboprophylaxis dosing. HEP-COVID (NCT04401293) is a phase 3, multicenter, pragmatic, prospective, randomized, pseudo-blinded, active control trial to evaluate efficacy and safety of therapeutic-dose low-molecular-weight heparin (LMWH) versus prophylactic-/intermediate-dose LMWH or unfractionated heparin (UFH) for prevention of a primary efficacy composite outcome of VTE, ATE, and all-cause mortality 30 ± 2 days post-enrollment. Eligible patients have COVID-19 diagnosis by nasal swab or serologic testing, requirement for supplemental oxygen per investigator judgment, and Dd >4 × upper limit of normal (ULN) or sepsis-induced coagulopathy score ≥4. Subjects are randomized to enoxaparin 1 mg/kg subcutaneous (SQ)/two times a day (BID) (creatinine clearance [CrCl] ≥ 30 mL/min) or 0.5 mg/kg (CrCl 15-30 mL/min) versus local institutional prophylactic regimens including (1) UFH up to 22,500 IU (international unit) daily (divided BID or three times a day), (2) enoxaparin 30 and 40 mg SQ QD (once daily) or BID, or (3) dalteparin 2,500 IU or 5,000 IU QD. The principal safety outcome is major bleeding. Events are adjudicated locally. Based on expected 40% relative risk reduction with treatment-dose compared with prophylactic-dose prophylaxis, 308 subjects will be enrolled (assuming 20% drop-out) to achieve 80% power. Distinguishing design features include an enriched population for the composite endpoint anchored on Dd >4 × ULN, stratification by intensive care unit (ICU) versus non-ICU, and the ability to capture asymptomatic proximal deep venous thrombosis via screening ultrasonography prior to discharge., Competing Interests: M.G.: research grant from Janssen; M.C.: speakers bureau Sanofi; A.T.: educational grant: Janssen, research grant: Janssen, Bristol Meyers Squibb, Idorsia, consultant: Recovery Force, J.M.K.: consultant for Bayer Healthcare, Jansen, the ATLAS Group, AMAG pharmaceuticals, Agile Therapeutics for advisory and steering committee activities. Data and safety monitoring committees for Cystic Fibrosis Foundation Therapeutics, Novo Nordisk, Pfizer, Genentech, and BioMarin pharmaceuticals. M.B.: research grant support to CPC Clinical Research from Amgen, AstraZeneca, Bayer, Janssen, Merck, NovoNordisk; J.L.H.: consultancies with the ATLAS Group, Bayer Healthcare, Boehringer Ingelheim, and Population Health Research Institute; J.I.W.: consultant for Anthos, ATLAS Group, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Johnson and Johnson, Merck, Pfizer, PhaseBio, and Servier, institutional research grants from Bayer and Boehringer Ingelheim; A.C.S.: Janssen, Boehringer Ingelheim, Bayer, BMS, Portola, ATLAS Group: consultancy; Janssen, Boehringer Ingelheim: research funding. D.G., W.D., J.W., S.K., G.S., J.M.L., A.M., E.G., P.A.L., K.C., M.L., C.P.S., H.R., K.O., W.R.H., R.A.D., V.E.A.: no conflict of interest., (Thieme. All rights reserved.)

Patients with chronic kidney disease may develop new or more severe anemia when treated with antiplatelet agents due to blood loss in conjunction with impaired erythropoiesis. Because anemia independently predicts limb amputation and mortality among patients with peripheral artery disease (PAD), we evaluated the relationship between estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) levels in the EUCLID trial in which patients with symptomatic PAD were randomized to ticagrelor or clopidogrel. At baseline, 9025, 1870, and 1000 patients had eGFR ⩾ 60, 45-59, and < 45 mL/min/1.73 m 2 , respectively. The mean fall in Hb during the trial was 0.46 ± 1.68 g/dL and did not differ by baseline eGFR category, although Hb fall ⩾ 10% was more frequent among patients with lower eGFR ( p for trend < 0.0001). On-study treatment with iron, erythropoiesis-stimulating agents, and/or red blood cell transfusion was reported for 479 (5.3%), 165 (8.8%), and 129 (12.9%) patients in the three eGFR categories, respectively ( p for trend < 0.0001). After adjustment for baseline and post-randomization effects, those not receiving anemia treatment had a smaller reduction in Hb from baseline than those receiving anemia treatment ( p < 0.0001). Other determinants of Hb reduction included absence of on-study myocardial infarction, coronary or peripheral revascularization, residence outside North America, male sex, and baseline eGFR. We conclude that among patients with PAD treated with P2Y 12 inhibitors, lower baseline eGFR was associated with a greater reduction in Hb. ClinicalTrials.gov Identifier: NCT01732822 .

Background: Paclitaxel drug-coated devices (DCDs) were developed to improve lower extremity revascularization (LER) patency in peripheral artery disease (PAD) but have been associated with long-term mortality., Objectives: This study assessed DCD safety and effectiveness in LER for PAD., Methods: VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) randomized patients with PAD who underwent LER to rivaroxaban or placebo. The primary VOYAGER PAD study efficacy and safety outcomes were composite cardiovascular and limb events and Thrombolysis In Myocardial Infarction major bleeding. For prespecified DCD analyses, primary safety and effectiveness outcomes were mortality and unplanned index limb revascularization (UILR). Major adverse limb events (MALE) were a secondary outcome. Inverse probability treatment weighting was used to account for each subject's propensity for DCD treatment. Effects of rivaroxaban were assessed with Cox proportional hazards models., Results: Among 4,316 patients who underwent LER, 3,478 (80.6%) were treated for claudication, and 1,342 (31.1%) received DCDs. Median follow-up was 31 months, vital status was ascertained in 99.6% of patients, and there were 394 deaths. After weighting, DCDs were not associated with mortality (HR: 0.95; 95% CI: 0.83-1.09) or MALE (HR: 1.08; 95% CI: 0.90-1.30) but were associated with reduced UILR (3-year Kaplan-Meier: 21.5% vs 24.6%; HR: 0.84; 95% CI: 0.76-0.92). Irrespective of DCD use, consistent benefit of rivaroxaban for composite cardiovascular and limb events (P interaction  = 0.88) and safety of rivaroxaban with respect to bleeding (P interaction  = 0.57) were observed., Conclusions: In >4,000 patients with PAD who underwent LER, DCDs were not associated with mortality or MALE but were associated with persistent reduction in UILR. These findings provide insight into the safety and effectiveness of DCDs in PAD. (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD [VOYAGER PAD]; NCT02504216)., Competing Interests: Funding Support and Author Disclosures VOYAGER PAD was funded by Bayer and Janssen Pharmaceuticals. A Pan-Industry Consortium (Medtronic, Boston Scientific, Cook, Philips, Bard, Surmodics, TriReme) provided funding through a grant to CPC Clinical Research to support statistical analyses performed at CPC Clinical Research. Dr Bonaca was supported by the American Heart Association Strategically Focused Research Network in Vascular Disease under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project). Dr Hess has received grants to CPC Clinical Research from Bayer, Janssen, and Amgen during the conduct of the study; and has received grants from Merck and Amgen outside the submitted work. Dr Patel has received grants and personal fees from Bayer and from Janssen during the conduct of the study; has received grants and personal fees from AstraZeneca and Heartflow, outside the submitted work; and has received grants from the National Heart, Lung, and Blood Institute, Medtronic, and Phillips Healthcare. Dr Bauersachs has received personal fees from Bayer during the conduct of the study; and has received personal fees from Bristol Myers Squibb, Daiichi-Sankyo, and Pfizer, outside the submitted work. Dr Anand has received personal fees from Bayer AG and Janssen during the conduct of the study; and has received personal fees from Bayer AG and Janssen outside the submitted work. Dr Debus has received grants and personal fees from Bayer AG; and has received grants from Cook LTD and Terumo Aortic during the conduct of the study. Dr Nehler has received grants from Bayer and Janssen; and has received salary support from CPC Clinical Research during the conduct of the study. Dr Yeh has been a consultant and has received grants from Abbott Vascular, Boston Science, and Medtronic; and has received grants from BD Bard, Cook Medical, and Philips Medical. Dr Secemsky has received research grants to BIDMC from the NIH/NHLBI K23HjL150290, Harvard Medical School’s Shore Faculty Development Award, AstraZeneca, BD, Boston Scientific, Cook, CSI, Laminate Medical, Medtronic, and Philips; and has received consulting/speaking fees from Abbott, Bayer, BD, Boston Scientific, Cook, CSI, Inari, Janssen, Medtronic, Philips, and Venture Medical. Dr Beckman has been a consultant for Janssen and Bayer during the conduct of the study. Dr. Capell has received grants from Bayer and Janssen to CPC Clinical Research during the conduct of the study. Dr Berkowitz has received personal fees from Bayer U.S., LLC during the conduct of the study and outside of the submitted work from employment as a Clinical Research Physician. Dr Haskell was employed by Janssen Pharmaceuticals LLC during the conduct of the study; and holds stock in Johnson & Johnson. Dr Hiatt has received grants to CPC Clinical Research from Bayer and Janssen during the conduct of this study. Dr Bonaca has received grants to CPC Clinical Research from Bayer AG and Janssen Pharmaceuticals during the conduct of the study; and has received grants from Amgen, AstraZeneca, Merck, NovoNordisk, Pfizer, and Sanofi outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Although older patients are at increased risk for venous thromboembolism (VTE), thromboprophylaxis is underused because of bleeding concerns. The MARINER trial evaluated whether rivaroxaban reduced symptomatic postdischarge VTE in acutely ill medical patients., Objectives: We hypothesized that rivaroxaban would have a favorable benefit/risk profile in patients ≥75 years of age., Methods: Patients were randomized in a double-blind manner at hospital discharge to rivaroxaban (10 mg/day for creatinine clearance ≥50 ml/min; 7.5 mg/day for ≥30-<50 ml/min) or placebo for 45 days. Using a Cox proportional hazard model including treatment as a covariate, we compared the risk of the primary efficacy outcome (symptomatic VTE plus VTE-related death in the intention-to-treat population) and safety outcome (International Society on Thrombosis and Haemostasis major bleeding in the safety population) in the prespecified subgroups of patients ≥ and <75 years of age., Results: The primary event rate in patients ≥75 years of age was 2-fold higher than that in those <75 years. The incidence of the primary efficacy outcomes in both age groups was numerically lower with rivaroxaban than with placebo (≥75: 1.2% and 1.6%, HR 0.73, 95% CI 0.43-1.22; <75 0.6% and 0.8%, HR 0.78, 95% CI 0.46-1.32; interaction p-value for age group = .85). The incidence of major bleeding was low and similar in the two age and treatment groups (interaction p value for age group = .35)., Conclusion: Symptomatic VTE and VTE-related death occur frequently in older patients with acute medical illness. The benefit/risk profile of rivaroxaban in patients ≥75 years of age appears consistent with that observed in the general population., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Aims: In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk-benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described., Methods and Results: The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan-Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding)., Conclusion: Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER., Methods: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee., Results: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method ( P -interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67-0.98]; P =0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding ( P -interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding ( P -interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; P =0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage ( P =0.95) and postprocedural bleeding requiring intervention ( P =0.93) was not significantly increased., Conclusions: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.

Background: Patients with peripheral artery disease (PAD) treated with lower extremity revascularization are at increased risk of major atherothrombotic vascular events (acute limb ischemia (ALI), major non-traumatic lower-limb amputation, myocardial infarction (MI), ischemic stroke, and cardiovascular (CV)-related death). This study assessed the incidence of major atherothrombotic vascular events, venous thromboembolism (VTE) events and rates of subsequent lower extremity revascularizations in the real-world among patients with PAD after revascularization., Methods: Patients aged ≥50 years with PAD who underwent peripheral revascularization were identified from Optum Clinformatics Data Mart claims database (Q1/2014-Q2/2019). The first lower extremity revascularization after PAD diagnosis was defined as index date. Incidence rates of major atherothrombotic vascular events (i.e., composite of ALI, major non-traumatic lower-limb amputation, MI, ischemic stroke, and CV-related death) and VTE were assessed during follow-up as the number of events divided by patient-years of observation (censored at the first event). Rates of subsequent revascularizations and VTE were estimated overall and compared between patients with major atherothrombotic vascular events and those without., Results: Of the 38,439 patients included, 6,675 (17.4%) had a major atherothrombotic vascular event during a median follow-up of 1.0 year. The composite major atherothrombotic vascular and VTE incidence rates were 13.81/100 patient years and 1.77/100 patient years, respectively, and 40.2% of patients experienced subsequent revascularizations. Patients with a post-revascularization major atherothrombotic vascular event had significantly higher rates of subsequent revascularizations (64.6% vs. 35.1%, standardized difference [SD] ≥10%) and VTE (4.6% vs. 2.1%, SD ≥10%) versus those without., Conclusion: One-in-six PAD patients aged ≥50 years who underwent peripheral revascularization experienced a major atherothrombotic vascular event within one year, and consequently, experienced higher rates of subsequent revascularizations compared with those without a major atherothrombotic vascular event post-revascularization. These findings highlight the need to improve strategies to prevent major atherothrombotic vascular events after revascularization., (Copyright © 2021 Janssen Scientific Affairs, LLC. Published by Elsevier Inc. All rights reserved.)