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Introduction: Disparities in the care and outcomes of peripheral artery disease (PAD) have been well-established. In part this is due to disparities in enrollment of PAD trial cohorts. However, less attention has been paid to non-random protocol non-adherence after enrollment, which may lead to inaccurate estimates of treatment effects and reduce generalizability of study results. We aimed to ascertain characteristics associated with premature study drug discontinuation in a PAD cohort. Methods: Using data from EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease), factors associated with study drug discontinuation were assessed using univariable and multivariable Cox proportional hazards models with time to study drug discontinuation as the outcome of interest. Relationships between study drug discontinuation and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, ischemic stroke), major adverse limb events (MALE; acute limb ischemia, major amputation, and lower extremity revascularization), and all-cause hospitalization were assessed. Results: Of 13,842 eligible EUCLID participants, 3,886 (28.1%) prematurely and permanently discontinued study drug over a maximum follow-up of 42 months (annualized rate of 13.2 discontinuations per 100 patient-years). In a multivariable model, premature study drug discontinuation was associated with older age (aHR 1.16, 95%CI 1.14-1.19), eligibility based on prior lower extremity revascularization rather than ABI/TBI criteria (aHR 1.14, 95%CI 1.06-1.23), CLI status (aHR 1.23, 95%CI 1.06-1.42), COPD (aHR 1.36, 95%CI 1.24-1.49), and geographic region. In a multivariable analysis, study drug discontinuation was significantly associated with MACE (aHR 3.27, 95%CI 2.90-3.67, p < 0.001), MALE (aHR 1.84, 95%CI 1.63-2.07, p < 0.001), and all-cause hospitalization (aHR 2.37, 95%CI 2.21-2.54) following study drug discontinuation. Conclusions: This analysis of EUCLID demonstrates that prema

Background: Peripheral artery disease (PAD) is associated with heightened risk for major adverse cardiovascular and limb events, but data on the burden of risk for total (first and potentially subsequent) events, and the association with polyvascular disease, are limited. This post hoc analysis of the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial evaluated total cardiovascular and limb events among patients with symptomatic PAD, overall and by number of symptomatic vascular territories. Methods and Results: In the EUCLID trial, patients with symptomatic PAD (lower extremity revascularization >30 days before randomization or ankle-brachial index ≤0.80) were randomized to treatment with ticagrelor or clopidogrel. Relative effects on total events (cardiovascular death; nonfatal myocardial infarction and ischemic stroke; acute limb ischemia, unstable angina, and transient ischemic attack requiring hospitalization; coronary, carotid, and peripheral revascularization procedures; and amputation for symptomatic PAD) were summarized by hazard ratios (HRs), whereas absolute risks were estimated by incidence rates and mean cumulative functions. Among 13 885 randomized patients, 7600 total cardiovascular and limb events occurred during a median 2.7 years of follow-up, translating to 60.0 and 62.5 events per 100 patients through 3 years for the ticagrelor and clopidogrel groups, respectively (HR, 0.96; 95% CI, 0.89-1.03; P=0.27). Among 1393 patients with disease in 3 vascular territories, event accrual rates through 3 years for the ticagrelor and clopidogrel groups were 87.3 and 97.7 events per 100 patients, respectively. Absolute risk reductions for ticagrelor relative to clopidogrel at 3 years were -0.2, 6.7, and 10.3 events per 100 patients for 1, 2, and 3 affected vascular territories, respectively (Pinteraction=0.09). Conclusions: Patients with symptomatic PAD have nearly double the number of total events than first events, with rates reflecting

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 mul, Funding agencies:National Institutes of Health/National Center for Advancing Translational Sciences Colorado CTSI UL1 TR002535American Heart Association Strategically Focused Research Network in Vascular Disease 18SFRN3390085 18SFRN33960262

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 C

BACKGROUND: Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease. METHODS: In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months. RESULTS: The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49). CONCLUSIONS: In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZe, Martin Björck (Uppsala Universitet, Institutionen för kirurgiska vetenskaper, kärlkirurgi) var National Lead Investigator för den svenska delen av studien och en av dessa ”Investigators”

Background In patients with type 2 diabetes, sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to reduce glucose concentrations, blood pressure, and weight, but to increase LDL cholesterol and the incidence of urogenital infections. Protection against cardiovascular events has also been reported, as have possible increased risks of adverse outcomes such as ketoacidosis and bone fracture. We aimed to establish the effects of SGLT2 inhibitors on cardiovascular events, death, and safety outcomes in adults with type 2 diabetes, both overall and separately for individual drugs. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Library, and websites of US, European, and Japanese regulatory authorities from Jan 1, 1950, to Sept 30, 2015, for data from prospective randomised controlled trials assessing the effects of SGLT2 treatment compared with controls. We excluded duplicate reports, trials of compound drugs, trials that lasted 7 days or fewer, trials that did not report on outcomes of interest, and articles that presented pooled trial data for which the individual trials could not be identified. We extracted data in duplicate using a standardised approach. The primary outcome was major adverse cardiovascular events. Secondary outcomes were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, admission to hospital for unstable angina, heart failure, and all-cause mortality. We estimated summary relative risks with fixed-effects meta-analysis, with the I-2 statistic used to estimate heterogeneity of results beyond chance. Findings The analyses included data from six regulatory submissions (37 525 participants) and 57 published trials (33 385 participants), which provided data for seven different SGLT2 inhibitors. SGLT2 inhibitors protected against the risk of major adverse cardiovascular events (relative risk 0.84 [95% CI 0.75-0.95]; p=0.006), cardiovascular death (0.63 [0.51-0.77]; p<0.0001), h