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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 There are limited data on health status instruments in patients with peripheral artery disease and cardiovascular and limb events. We evaluated the relationship between health status changes and cardiovascular and limb events. Methods and Results In an analysis of the EUCLID (Examining Use of Ticagrelor in Symptomatic Peripheral Artery Disease) trial, we examined the characteristics of 13 801 patients by tertile of health status instrument scores collected in the trial (EuroQol 5-Dimensions [EQ-5D], EQ visual analog scale [VAS], and peripheral artery questionnaire). We assessed the association between the baseline health status measurements and major adverse cardiovascular events, major adverse limb events, and lower-extremity revascularization procedures during trial follow-up and the association between 12-month health status change scores and subsequent end points during follow-up. There were 13 217 (95%) patients with EQ-5D scores, 13 533 (98%) with VAS scores, and 4431 (32%) with peripheral artery questionnaire scores. Patients in the lowest baseline EQ-5D tertile (0 to <0.69) were more likely to be female with severe claudication compared with the highest tertile (0.79-1.0; P <0.01). Patients in the lowest VAS (0-60) and peripheral artery questionnaire (0-49) tertiles had lower ankle-brachial indices compared with the highest tertiles (80-100 and 76-108, respectively; P <0.01). There was a significant association between baseline EQ-5D, VAS, and peripheral artery questionnaire scores and adjusted major adverse cardiovascular events, major adverse limb events, and lower-extremity revascularization ( P <0.05). Improved EQ-5D and VAS scores over 12 months were associated with reduced risk of subsequent major adverse cardiovascular events or lower-extremity revascularization (all P <0.01). Conclusions Although health status instruments are rarely used in clinical practice, these measures are associated with outcomes, including major adverse cardiovascular events, major adverse limb events, and lower-extremity revascularization. Further research is needed to determine the relationship between changes in these instruments, revascularization, and outcomes.

Background: Patients with peripheral artery disease have a high risk of future cardiovascular disease events and mortality. Little is known about the changes in symptom classification over time in patients with peripheral artery disease and the association of changes in symptom classification with subsequent cardiovascular disease events., Methods: In this analysis of the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease), we examined the changes in Rutherford classification (RC) of patients over 12 months. We examined the baseline characteristics of patients by change in symptom classification at 12 months (improved=decreased RC, no change, or worsened=increased RC), and the association between changes in symptom classification (RC) at 12 months and subsequent cardiovascular disease events., Results: Among 12 759 patients, 3240 (25%) were classified as improved by RC at 12 months, 8132 (64%) as no change, and 1387 (11%) as worsened. At 12 months, many patients who were asymptomatic or had mild/moderate claudication at enrollment had no change in symptom classification over 12 months (73.7% and 70.9%). Patients who worsened over 12 months were more likely to have comorbidities (diabetes mellitus and prior myocardial infarction) and more events (myocardial infarction, amputation, and major bleeding) by 12 months postrandomization, all P <0.001. Worsened symptom classification over 12 months was associated with increased risk of all-cause death (adjusted hazard ratio, 1.29 [95% CI, 1.03-1.62]), major amputation (adjusted hazard ratio, 4.12 [95% CI, 2.46-6.88]), and a composite of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio, 1.30 [95% CI, 1.05-1.62]), all P <0.05 after 12 months postrandomization., Conclusions: Patients with comorbidities and prior history of cardiovascular disease events at baseline and within the first 12 months of the trial were more likely to have worsened symptom classification at 12 months. Worsening symptom classification over 12 months was associated subsequently with an increased risk of all-cause death, amputation, and a composite of cardiovascular death, myocardial infarction, or stroke. Graphic Abstract: A graphic abstract is available for this article.

Background: Rates and predictors of major bleeding in patients with peripheral artery disease (PAD) treated with antiplatelets have not been well studied. This post hoc analysis of EUCLID aimed to determine the incidence of major/minor bleeding, predictors of major bleeding, and risk of major adverse cardiovascular events (MACE) following major bleeding events., Methods: EUCLID, a multicenter randomized controlled trial of 13,885 patients with symptomatic PAD, compared ticagrelor with clopidogrel for the prevention of MACE. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Baseline characteristics were used to develop a multivariable model to determine factors associated with TIMI major bleeding. The occurrence and timing of MACE relative to a first major bleeding event were determined., Results: TIMI major bleeding occurred in 2.3% of participants overall (0.94 event/100 patient-years). There was no significant difference in major bleeding rates by treatment assignment. Factors associated with TIMI major bleeding included older age, geographic region, Rutherford class, and β-blocker use. Patients with TIMI major bleeding postrandomization had an increased risk of MACE (hazard ratio [HR] 4.46; 95% CI 3.40-5.84; P < .0001) compared with those without major bleeding; the association was strongest within 30 days after a bleeding event., Conclusions: In patients with symptomatic PAD, 0.94 major bleeding event/100 patient-years was observed and associated with older age, residing in North America, disease severity, and β-blocker use. Patients who had a major bleeding event were significantly more likely to experience MACE, especially within the first 30 days, when compared with patients who did not have major bleeding., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Observational, genetic, and experimental data indicate that triglyceride rich lipoproteins (TRLs) likely participate causally in atherothrombosis. Yet, robust clinical trial evidence that triglyceride (TG) lowering therapy reduces cardiovascular events remains elusive. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARM-α), pemafibrate, will be used to target residual cardiovascular risk remaining after treatment to reduce low-density lipoprotein cholesterol (LDL-C) in individuals with the dyslipidemia of type 2 diabetes mellitus (T2). The PROMINENT study will randomly allocate approximately 10,000 participants with T2D, mild-to-moderate hypertriglyceridemia (TG: 200-499 mg/dl; 2.26-5.64 mmol/l) and low high-density lipoprotein cholesterol levels (HDL-C: ≤40 mg/dl; 1.03 mmol/l) to either pemafibrate (0.2 mg twice daily) or matching placebo with an average expected follow-up period of 3.75 years (total treatment phase 5 years; 24 countries). At study entry, participants must be receiving either moderate-to-high intensity statin therapy or meet specified LDL-C criteria. The study population will be one-third primary and two-thirds secondary prevention (established cardiovascular disease). The primary endpoint is a composite of nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for unstable angina requiring urgent coronary revascularization, and cardiovascular death. This event-driven study will complete when 1092 adjudicated primary endpoints have accrued with at least 200 occurring in women. Statistical power is at least 90% to detect an 18% reduction in the primary endpoint. Pre-specified secondary and tertiary endpoints include all-cause mortality, hospitalization for heart failure, new or worsening peripheral artery disease, new or worsening diabetic retinopathy and nephropathy, and change in biomarkers including select lipid and non-lipid biomarkers, inflammatory and glycemic parameters., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

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 AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .).

The U.S. Food and Drug Administration (FDA) issued a Guidance for Industry in 2008 defining preapproval and postapproval requirements for the demonstration of cardiovascular safety for all new medications developed for glycemic management in type 2 diabetes. Seventeen large, prospective, randomized, controlled clinical trials involving more than 140,000 subjects thus far have been completed or are ongoing in accordance with this guidance. All five of the completed trials, involving three different drug classes, have met their primary objective to exclude an unacceptable level of ischemic cardiovascular risk as defined in the FDA guidance. Additionally, one trial found an increased risk of hospitalization for heart failure, and another demonstrated decreases in cardiovascular mortality and hospitalization for heart failure. Given that a heightened risk of cardiovascular ischemic events has not been demonstrated across several classes of new diabetes drugs, we believe it is time for the scientific community and the FDA to consider a more targeted approach to what is, in effect, a global cardiovascular safety trial requirement for all new type 2 diabetes medications in development., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

This White Paper provides a summary of presentations and discussions at a Cardiovascular Safety Outcome Trials Think Tank cosponsored by the Cardiac Safety Research Consortium, the US Food and Drug Administration, and the American College of Cardiology, held at American College of Cardiology's Heart House, Washington, DC, on February 19, 2014. Studies to assess cardiovascular (CV) risk of a new drug are sometimes requested by regulators to resolve ambiguous safety signals seen during its development or among other members of its class. Think Tank participants thought that important considerations in undertaking such studies were as follows: (1) plausibility-how likely it is that a possible signal indicating risk is real, based on strength of evidence, and/or whether a plausible mechanism of action for potential CV harm has been identified; (2) relevance-what relative and absolute CV risk would need to be excluded to determine that the drug had an acceptable benefit-to-risk balance for its use in the intended patient population; and (3) how plausibility and relevance influence the timing and approach to further safety assessment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To determine the prevalence of an abnormal ankle-brachial index (ABI) among subjects not considered to be at high risk for cardiovascular disease (CVD) based on the Framingham Risk Score (FRS)., Materials and Methods: Data from the Population-Based Examinations to Determine Ankle-brachiaL index (PEDAL) Study (2007-2009), a cross-sectional study at 23 U.S. sites, in conjunction with Legs for Life, a national ABI screening program, were analyzed. This study includes data from 822 participants (average age 64.3 years ± 11.6, 69.7% women, 89.7% non-Hispanic white) without known CVD or diabetes, who were screened for peripheral artery disease (PAD) with an ABI and for whom all FRS variables were available. Participants' 10-year coronary heart disease (CHD) risk was estimated from the FRS, and three risk categories were defined: low (< 10%), intermediate (10%-19%), and high (≥ 20%). ABI < 0.90 or > 1.4 in either leg was considered abnormal., Results: The prevalence of abnormal ABI was 14.2% (95%confidence interval [CI] 11.9%-16.8%). According to the FRS, 463 (56.3%) participants were at low risk, 212 (25.8%) were at intermediate risk, and 147 (17.9%) were at high risk. Among participants with a low FRS (n = 463; without CVD or diabetes or both) and an intermediate FRS (n = 212; without CVD or diabetes or both), 12.3% and 12.2% had an abnormal ABI., Conclusions: The prevalence of abnormal ABI, a CHD equivalent, is high among individuals not identified as high risk by conventional Framingham-based risk assessment., (Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.)

Background: The benefit of aspirin to prevent cardiovascular events in subjects without clinical cardiovascular disease relative to the increased risk of bleeding is uncertain., Methods: A meta-analysis of randomized trials of aspirin versus placebo/control to assess the effect of aspirin on major cardiovascular events (MCEs) (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), individual components of the MCE, stroke subtype, all-cause mortality, and major bleeding. Nine trials involving 102,621 patients were included: 52,145 allocated to aspirin and 50,476 to placebo/control., Results: Over a mean follow-up of 6.9 years, aspirin was associated with a reduction in MCE (risk ratio [RR] 0.90, 95% CI 0.85-0.96, P < .001). There was no significant reduction for myocardial infarction, stroke, ischemic stroke, or all-cause mortality. Aspirin was associated with hemorrhagic stroke (RR 1.35, 95% CI 1.01-1.81, P = .04) and major bleeding (RR 1.62, 95% CI 1.31-2.00, P < .001). In meta-regression, the benefits and bleeding risks of aspirin were independent of baseline cardiovascular risk, background therapy, age, sex, and aspirin dose. The number needed to treat to prevent 1 MCE over a mean follow-up of 6.9 years was 253 (95% CI 163-568), which was offset by the number needed to harm to cause 1 major bleed of 261 (95% CI 182-476)., Conclusions: The current totality of evidence provides only modest support for a benefit of aspirin in patients without clinical cardiovascular disease, which is offset by its risk. For every 1,000 subjects treated with aspirin over a 5-year period, aspirin would prevent 2.9 MCE and cause 2.8 major bleeds., (Copyright © 2011 Mosby, Inc. All rights reserved.)

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.

Objectives: The purpose of this study is to determine if an ankle-brachial index (ABI) >or=1.40 is associated with reduced quality of life (QoL)., Background: Ankle-brachial index values >or=1.40 have been associated with some cardiovascular disease (CVD) risk factors and increased mortality, but the relationship to other disease morbidity such as reduced QoL has not been previously evaluated., Methods: The PARTNERS (PAD Awareness, Risk and Treatment: New Resources for Survival) program was a national cross-sectional study of 7,155 patients age >50 years recruited from 350 primary care sites. All sites performed the ABI using a Doppler device and a standardized technique., Results: A total of 296 subjects had an ABI >or=1.40 in at least 1 leg, and 4,420 had an ABI between 0.90 and 1.40. Diabetes, male gender, and waist circumference were positively associated with a high ABI, and smoking and dyslipidemia were inversely associated with a high ABI. After adjustment for age, gender, and the traditional CVD risk factors, and accounting for multiple comparisons, the high ABI group had significantly higher odds for foot ulcers (p < 0.005) and borderline associations with heart failure, stroke, and neuropathy. After the same adjustments and adjusting for patients with other CVD, the high ABI group scored 2.0 points lower on the physical component scale on the Medical Outcomes Study Standard Form-36 and 5.5 points lower on the Walking Impairment Questionnaire walking distance domain (p < 0.05 for both)., Conclusion: Individuals with a high ABI have higher odds for foot ulcers and neuropathy, as well as lower scores on some physical functioning QoL domains.

This study tested the hypothesis that patients with PAD have impaired health-related quality of life (HRQoL) to a degree similar to that of patients with other types of cardiovascular disease (other-CVD), and also evaluated the clinical features of PAD associated with impaired HRQoL. This was a cross-sectional study in 350 primary care practice sites nationwide with 6,499 participants. The reference group had no clinical or hemodynamic evidence of PAD or other-CVD; the PAD group had an ankle-brachial index < 0.90 or a prior history of PAD; the other-CVD group had a clinical history of cardiac or cerebral vascular disease (but no PAD), and the combined PAD-other-CVD group included both diagnoses. Individuals were assessed using four HRQoL questionnaires including the Walking Impairment Questionnaire (WIQ), Medical Outcomes Study SF-36 (SF-36), Cantril Ladder of Life and the PAD Quality of Life questionnaire. PAD patients had lower WIQ distance scores than the other-CVD group. Both the PAD and other-CVD groups had significantly lower SF-36 Physical Function scores compared with the reference group. The WIQ revealed that PAD patients were more limited by calf pain, whereas other-CVD patients were more limited by chest pain, shortness of breath and palpitations. In conclusion, in this nationwide study, one of the first to directly compare the HRQoL burden of CVD with that of PAD, the evaluation of PAD in office practice revealed a HRQoL burden as great in magnitude as in patients with other forms of CVD.

Office-based cardiovascular risk prediction continues to challenge practitioners in primary and secondary risk stratification settings. In patients with established peripheral arterial disease (PAD), the risk of cardiovascular events (i.e. death or morbidity due to coronary heart disease and/or cerebrovascular disease) is high, yet traditional risk factors and the ankle-brachial index (ABI) do not provide a complete secondary risk prediction. In this population, office-based cardiovascular risk stratification may be improved by surrogate markers of the systemic atherosclerotic burden, as well as markers of systemic inflammation. This review will evaluate the utility of the ABI, clinical stage of disease, and the emerging role of C-reactive protein (CRP) and other inflammatory markers in secondary risk prediction in PAD. Defining which patients are in the highest category of risk may direct health care providers to emphasize secondary preventive measures, and facilitate patient adherence to recommended medical therapies and smoking cessation.

Pharmacological and non-pharmacological interventions to improve function and quality of life in patients with claudication are being evaluated in clinical research trials. An important component of clinical development programs is assessing the safety of the intervention and monitoring for adverse impact of the therapy on research participants. The conduct of both of these safety assessments is facilitated by the ability to estimate the anticipated rates of cardiovascular events and death in the target population. To obtain estimates of these rates, data were abstracted from randomized, double-blind, placebo-controlled trials performed in patients with claudication and designed to show functional improvement, and which have been published since 1990. Patient-year exposures and the number of deaths, serious adverse events and cardiovascular serious adverse events in the placebo arms of these trials were tabulated, and summed event rates calculated. The mortality rate was 1.9 deaths per hundred patient-years (27 deaths observed in 1446 patient-years). The mortality rate in claudication trials is lower than that reported in natural history studies. Cardiovascular serious adverse events in claudication trials were observed at a rate of 8.5 per hundred patient-years (65 events in 762 patient-years). Thus, cardiovascular morbidity and mortality should be expected in clinical trials enrolling claudicants. The current analyses provide benchmark data for ensuring that development programs are large enough to allow meaningful safety conclusions, and to assist in data and safety monitoring of these trials.

Current data and guidelines recommend treating abnormal blood lipids (ABL) to goal. This is a complex process and requires involvement from various healthcare professionals with a wide range of expertise. The model of a multidisciplinary case management approach for patients with ABL is well documented and described. This collaborative approach encompasses primary and secondary prevention across the lifespan, incorporates nutritional and exercise management as a significant component, defines the importance and indications for pharmacological therapy, and emphasizes the importance of adherence. Use of this collaborative approach for the treatment of ABL ultimately will improve cardiovascular and cerebrovascular morbidity and mortality.

Background: Peripheral arterial disease (PAD) and diabetes are both associated with a high risk of ischemic events, but the role of intensive blood pressure control in PAD has not been established., Methods and Results: The Appropriate Blood Pressure Control in Diabetes study followed 950 subjects with type 2 diabetes for 5 years; 480 of the subjects were normotensive (baseline diastolic blood pressure of 80 to 89 mm Hg). Patients randomized to placebo (moderate blood pressure control) had a mean blood pressure of 137+/-0.7/81+/-0.3 mm Hg over the last 4 years of treatment. In contrast, patients randomized to intensive treatment with enalapril or nisoldipine had a mean 4-year blood pressure of 128+/-0.8/75+/-0.3 mm Hg (P<0.0001 compared with moderate control). PAD, which is defined as an ankle-brachial index <0.90 at the baseline visit, was diagnosed in 53 patients. In patients with PAD, there were 3 cardiovascular events (13.6%) on intensive treatment compared with 12 events (38.7%) on moderate treatment (P=0.046). After adjustment for multiple cardiovascular risk factors, an inverse relationship between ankle-brachial index and cardiovascular events was observed with moderate treatment (P=0.009), but not with intensive treatment (P=0.91). Thus, with intensive blood pressure control, the risk of an event was not increased, even at the lowest ankle-brachial index values, and was the same as in a patient without PAD., Conclusions: In PAD patients with diabetes, intensive blood pressure lowering to a mean of 128/75 mm Hg resulted in a marked reduction in cardiovascular events.

Despite a worse cardiovascular disease (CVD) risk profile, Hispanics have lower CVD mortality than non-Hispanic Whites in studies based on death certificates. This study examined 310 deaths that occurred between 1984 and 1998 among 1,862 Hispanic and non-Hispanic White participants in the San Luis Valley Diabetes Study, using medical records to classify cause of death. Among persons without diabetes, the age-adjusted all-cause mortality rate was 6.1/1,000 person-years in non-Hispanic Whites and 7.4/1,000 person-years in Hispanics. Among persons with diabetes, it was 24.3/1,000 person-years in non-Hispanic Whites and 21.9/1,000 person-years in Hispanics. Among nondiabetics, the age-adjusted CVD mortality rate was 2.5/1,000 person-years in non-Hispanic Whites and 1.6/1,000 person-years in Hispanics. Among diabetics, it was 12.9/1,000 person-years in non-Hispanic Whites and 8.8/1,000 person-years in Hispanics. Among nondiabetics, the adjusted hazard ratio for CVD death in Hispanics compared with non-Hispanic Whites was 0.65 (95% confidence interval (CI): 0.34, 1.23). The hazard ratio for coronary heart disease death was 0.95 (95% CI: 0.35, 2.59). Among diabetics, the hazard ratio for CVD death, after adjustment for conventional and diabetes risk factors, was 0.44 (95% CI: 0.26, 0.74), and for coronary heart disease death it was 0.43 (95% CI: 0.21, 0.91). A statistically significant decreased risk of CVD death was observed only in male Hispanics with diabetes. Competing mortality or factors that interact with diabetes may explain these differences.

In patients with symptomatic peripheral artery disease (PAD), the impact of chronic kidney disease (CKD) on major adverse cardiovascular events has not been fully evaluated. The Examining Use of Ticagrelor In PAD (EUCLID) trial randomized 13,885 patients with PAD to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. This post hoc analysis compared the incidence of the primary composite endpoint (cardiovascular death, myocardial infarction (MI), or ischemic stroke) in patients with CKD (eGFR < 60 mL/min/1.73 m2) with those without CKD (eGFR ⩾ 60 mL/min/1.73 m2). The primary safety endpoint was thrombolysis in MI (TIMI) major bleeding. A total of 13,483 patients were included; 3332 (25%) had CKD, of whom 237 had stage 4/5 disease. Median follow-up was approximately 30 months. After statistical adjustment, patients with CKD had a higher rate of the primary endpoint compared with those without CKD (6.75 vs 3.72 events/100 patient-years; adjusted hazard ratio (HR) 1.45, 95% CI 1.30–1.63). CKD was not associated with increased risk of hospitalization for acute limb ischemia (ALI) (adjusted HR 0.96, 95% CI 0.69–1.34) or major amputation (adjusted HR 0.92, 95% CI 0.66–1.28). CKD was not associated with a significantly increased risk of major bleeding (adjusted HR 1.21, 95% CI 0.89–1.64), but minor bleeding was significantly increased (adjusted HR 1.51, 95% CI 1.07–2.15). In conclusion, patients with PAD and CKD had higher rates of cardiovascular death, MI, and ischemic stroke, but similar rates of ALI, major amputation, and TIMI major bleeding when compared with patients without CKD. ClinicalTrials.gov Identifier: NCT01732822 [ABSTRACT FROM AUTHOR]

Prior studies have assessed the prognostic value of a decrease, not an increase, of the post-exercise ankle-brachial index (ABI) among patients with normal resting results. Thus, we sought to evaluate the prognostic significance of an increase in post-exercise ABI among these patients. From a single center vascular laboratory database between September 2005 and January 2010, we retrospectively identified 1437 consecutive patients with a normal resting ABI (1.00-1.40) and available post-exercise results. We classified them into group 1 (normal subjects; post-exercise ABI drop > 20%, 58%) and group 2 (post-exercise ABI increase, 42%) after excluding those with an ABI drop > 20% (peripheral artery disease) as they had known disease (n=192). The primary outcome was to assess the risk of ischemic events, defined as a composite of unadjudicated death, stroke, or myocardial infraction (MACE). Associations between groups and outcomes were examined using multivariable Cox proportional hazard and propensity analyses. Both groups had similar prevalence of cardiovascular comorbidities. In unadjusted analysis, group 2 was more likely to have MACE (p = 0.001). After adjusting for all baseline characteristics, an increase in post-exercise ABI compared to normal subjects was associated with a higher MACE (adjusted HR: 1.70, 95% CI: 1.14-2.53; p=0.009). This association stayed statistically significant after propensity matching (adjusted HR: 1.80, 95% CI: 1.17-2.76; p=0.007). This hypothesis-generating analysis showed that an increase in post-exercise ABI appears to identify a population with a higher risk for MACE. A prospective study of this association and mechanisms of risk should be conducted. [ABSTRACT FROM AUTHOR]

The article discusses the effectiveness of the treadmill walking performance in the treatment of patients with peripheral artery disease (PAD). Topics highlighted include the effect of the disease on the person's ability to walk, a description of the exercise method and the difference between the treadmill walking test and the 6-minute walk test.

Propionyl-l-carnitine (PLC) may improve exercise performance in patients with peripheral artery disease, but results from clinical trials have been inconsistent. The safety and efficacy of PLC for treatment of claudication was evaluated by a systematic review and meta-analysis of clinical trials for which data were available through September 2010. Eighty-five studies were identified, of which 13 were randomized controlled trials. Owing to database availability for the six phase III studies carried out with PLC (1 g orally, twice daily), a patient-level meta-analysis was conducted as the primary analysis. Treadmill performance data from these six studies were harmonized to peak walking distance (PWD) on a 7% grade at a speed of 3 km/hour. PLC (n = 440) was associated with a net 16 meter improvement (95% CI, 8–20 meters) in PWD as compared with placebo (n = 427) in the primary analysis (p = 0.002). The effect of PLC was similar in subpopulations defined using clinical and demographic variables, with possible enhanced benefit in patients engaged in an exercise program or enrolled at study sites in Russia. The systematic review of the effect of PLCs on claudication identified seven additional randomized controlled trials for a total of 13 trials, which included 681 patients on placebo and 672 on PLC. This meta-analysis confirmed a 45 meter net improvement on PLC using a random-effects model. In conclusion, oral PLC is associated with a statistically significant increase in PWD in patients with claudication, which may be clinically relevant. [ABSTRACT FROM PUBLISHER]

Many protocols have been used in clinical and research settings for collecting systolic blood pressure (SBP) measurements to calculate the ankle-brachial index (ABI); however, it is not known how useful it is to replicate measurements and which measures best reflect cardiovascular risk. Standardized measurements of ankle and arm SBP from 5140 overweight or obese individuals with type 2 diabetes were used to estimate sources of variation. Measurement characteristics of leg-specific ABI, as calculated using a standard algorithm based on the highest SBP of the dorsalis pedis or posterior tibial arteries, were projected using simulations. Coefficients of variability ranged from 2% to 3% when single SBP measurements were used and ABI was overestimated by 2-3%. Taking two SBP measurements at each site reduced standard errors and bias each by 30-40%. The sensitivity of detecting low ABI ranges exceeded 90% for ABI within 0.05 of the 0.90 clinical cut-point. The average and the minimum of the two (i.e. right and left) leg-specific ABI values had similar U-shaped relationships with Framingham risk scores; however, the average leg ABI had slightly greater precision. Replicating SBP measurements reduces the error and bias of ABI. Averaging leg-specific values may increase power for characterizing cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

The time course of muscle oxygen desaturation (StO2 kinetics) following exercise onset reflects the dynamic interaction between muscle blood flow and muscle oxygen consumption. In patients with peripheral arterial disease (PAD), muscle StO2 kinetics are slowed during walking exercise; potentially reflecting altered muscle oxygen consumption relative to blood flow. This study evaluated whether StO2 kinetics measured using near infrared spectroscopy (NIRS) would be slowed in PAD during low work rate calf exercise compared with healthy subjects under conditions in which blood flow did not differ. Eight subjects with PAD and eight controls performed 3 min of calf exercise at 5, 10, 30, and 50% of maximal voluntary contraction (MVC). Calf blood flow responses were measured by plethysmography. Power outputs were similar between groups for all work rates. In PAD, the time constants of StO2 kinetics were significantly slower than controls during 5% MVC (13.5 ± 1.7 vs. 6.9 ± 1.2 s, P < 0.05) and 10% MVC work rates (14.5 ± 2.7 vs. 6.8 ± 1.1 s, P < 0.05). Blood flow assessed when exercise was interrupted after 30 s did not differ between PAD and control subjects at these work rates. In contrast, the StO2 time constants were not different between groups during 30 and 50% MVC work rates, where blood flow responses in PAD subjects were lower as compared with controls. Thus in PAD, the slowed StO2 kinetic responses under conditions of unimpaired calf blood flow reflect slowed muscle oxygen consumption in PAD skeletal muscle during low work rate plantar flexion exercise as compared with healthy skeletal muscle. [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD) is a chronic, lifestyle-limiting disease and is an independent predictor of cardiovascular and cerebrovascular ischemic events. Despite the recognition that PAD is associated with a marked increase in the risk of ischemic events, this particular manifestation of systemic atherosclerosis is largely underdiagnosed and undertreated. The risk of PAD is markedly increased among individuals with diabetes, and ischemic event rates are higher in diabetic individuals with PAD than in comparable non-diabetic populations. Consequently, early diagnosis and treatment of PAD in patients with diabetes is critically important in order to reduce the risk of cardiovascular events, minimize the risk of long-term disability, and improve quality of life. A diagnosis of PAD in patients with diabetes mandates a multi-faceted treatment approach, involving aggressive risk-factor modification, antiplatelet therapy, and revascularization procedures. The American Diabetes Association recently issued a consensus statement on the epidemiology, pathophysiology, diagnosis, and management of PAD in patients with diabetes. This article will review the clinical implications of the consensus statement and highlight the treatment options available in order to help prevent future ischemic events in diabetic individuals with PAD. [Copyright &y& Elsevier]

Peripheral arterial disease is prevalent, associated with increased cardiovascular morbidity and mortality, and is underdiagnosed. Nevertheless, systematic efforts to provide early office-based peripheral arterial disease detection are not routinely implemented in office practice. The PARTNERS Program implemented the ankle–brachial index (ABI) measurement in primary care outpatient clinics in order to model practical dissemination of this technique and thus improve office-based peripheral arterial disease detection. The objective of this study was to identify clinician-defined factors that were perceived to foster acceptance of, or create barriers to, the use of the ABI in office practice. The ABI Utilization Survey was administered to primary care clinicians who participated in the PARTNERS Program, as well as to additional primary care clinicians who participated in the PARTNERS Preceptorship. The survey assessed six parameters: pre- and post-participation office ABI utilization; perceived clinical utility of the ABI; perceived value of the ABI data relative to other commonly used office disease detection methods; feasibility of implementing office-based ABI testing; definition of factors limiting utilization of the ABI in office practice; and the role of office staff in performing the ABI test. Survey data were obtained from 886 respondents. A total of 68% of respondents did not measure the ABI prior to participation in the PARTNERS Program. After Program participation, the frequency of office ABI use increased from 12% to 43% weekly and 13% to 39% monthly. The few participants who reported using the ABI only once a year (annually) did not significantly change after the program. Most clinicians believed that the ABI was useful in the diagnosis and management of both symptomatic (96%) and asymptomatic (89%) peripheral arterial disease. Moderate to major barriers to use of the ABI included time constraints (56%), lack of reimbursement (45%), and staff availability (45%). Nearly all (88%) clinicians believed that it was feasible to incorporate ABI into daily practice. Overall, most clinicians (57 – 75%) believed that ABI was equal to, or more useful, than other widely available and reimbursed screening tests in preserving their patients' health. In conclusion, the ABI was perceived by primary care clinicians to be a clinically useful diagnostic test. Limited reimbursement and time were identified as the primary barriers to its widespread use. Once learned, most clinicians stated that the ABI would continue to be frequently used in their office practice. The ABI is a simple peripheral arterial disease detection tool that can be successfully applied in primary care office practices. [ABSTRACT FROM AUTHOR]

There is a paucity of trials that specifically evaluate the benefits of cardiovascular risk reduction therapies in patients with peripheral arterial disease. We therefore sought to describe the data supporting the use of therapies for lowering cardiovascular risk, preventing ischemic events, as well as managing intermittent claudication, in these patients. A search for randomized, placebo-controlled trials in peripheral arterial disease was conducted using Medline and reference lists of relevant articles. These trials served as the primary sources of data and treatment recommendations, while observational studies and case series were included as sources of commonly accepted treatment recommendations that were not fully supported by the randomized trial. Data from the primary sources support the use of antiplatelet therapy and, potentially, of angiotensin-converting enzyme inhibitors, for preventing ischemic events. In contrast, the evidence demonstrates a nonsignificant trend for treating dyslipidemia to prevent mortality and does not specifically support intensive glycemic control in persons with diabetes or estrogen use in these patients. However, observational data and data derived from trials in persons with other manifestations of cardiovascular disease may be generalized to support the importance of treating key risk factors, such as smoking, diabetes, dyslipidemia, and hypertension. Data supporting the use of estrogen to reduce cardiovascular risk are less clear. Studies do demonstrate improvement in walking ability resulting from exercise rehabilitation programs, as well as from use of cilostazol and, to a more modest degree, pentoxifylline. The consensus is to treat risk factors of peripheral arterial disease patients similarly to patients with other manifestations of atherosclerosis and to use exercise rehabilitation or cilostazol to treat the subset of patients with claudication. [Copyright &y& Elsevier]

Information about several topics discussed at a meeting of the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration held from March 28-29, 2012 on the risk assessment of cardiovascular events in development of new drugs for obesity, is presented. Several strategies have been suggested by the committee members for assessing cardiovascular risk.

Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently available drugs or approaches. In the setting of multifactorial risk reduction with statins and other lipid-lowering agents, antihypertensive therapies, and antihyperglycemic treatment strategies, cardiovascular complication rates are falling, yet remain higher for patients with diabetes mellitus than for those without. This review considers the mechanisms, history, controversies, new pharmacological agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care in the patient with diabetes mellitus and heart disease outside of the acute care setting. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein cholesterol (LDL-C) is associated with heightened risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in peripheral artery disease (PAD). Lipid-lowering therapies (LLT) that reduce LDL-C decrease this risk.Objectives: The authors examined LLT use and actual achieved LDL-C in PAD.Methods: PAD patients in MarketScan from 2014 to 2018 were identified. Outcomes included LLT use, defined as high-intensity (HI) (high-intensity statin, statin plus ezetimibe, or PCSK9 inhibitor), low-intensity (any other lipid regimen), or no therapy, and follow-up LDL-C. Factors associated with LDL-C <70 mg/dl were identified with multivariable logistic regression.Results: Among 250,103 PAD patients, 20.5% and 39.5% were treated at baseline with HI and low-intensity LLT, respectively; 40.0% were on no LLT. Over a 15-month median follow-up period, HI LLT use increased by 1.5%. Among 18,747 patients with LDL-C data, at baseline, 25.1% were on HI LLT, median LDL-C was 91 mg/dl, and 24.5% had LDL-C <70 mg/dl. Within the HI LLT subgroup, median LDL-C was 81 mg/dl, and 64% had LDL-C ≥70 mg/dl. At follow-up, HI LLT use increased by 3.7%, median LDL-C decreased by 4.0 mg/dl, and an additional 4.1% of patients had LDL-C <70 mg/dl. HI LLT use was greater after follow-up MACE (55.0%) or MALE (41.0%) versus no ischemic event (26.1%). After MACE or MALE, LDL-C was <70 mg/dl in 41.5% and 36.1% of patients, respectively, versus 27.1% in those without an event. Factors associated with follow-up LDL-C <70 mg/dl included smoking, hypertension, diabetes, prior lower extremity revascularization, and prior myocardial infarction but not prior acute or critical limb ischemia.Conclusions: In PAD, LLT use is suboptimal, LDL-C remains elevated, and LLT intensity is a poor surrogate for achieved LDL-C. Less aggressive lipid management was observed in PAD versus cardiovascular disease, highlighting missed opportunities for implementation of proven therapies in PAD. [ABSTRACT FROM AUTHOR]

Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits, using clinically-evident cardiovascular endpoints. To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, regulatory bodies, and government agencies convened for a think tank meeting in July 2014 in Washington, DC. This paper summarizes the proceedings of the meeting and aims to delineate the current adverse trends in cardiovascular drug development, understand the key issues that underlie these trends within the context of a recognized need for a rigorous regulatory review process, and provide potential solutions to the problems identified. [ABSTRACT FROM AUTHOR]

Abstract: Background: Non-valvular atrial fibrillation is associated with an increase in thromboembolism, i.e. stroke, and atherosclerotic events, i.e. myocardial infarction. Vitamin E possesses anti-coagulant as well as anti-atherosclerotic properties. Our aim was to assess whether vitamin E is associated with cardiovascular events in patients with non-valvular atrial fibrillation. Methods: Serum levels of cholesterol-adjusted vitamin E were measured in 1012 patients with non-valvular atrial fibrillation. Patients were followed for a mean time of 27.0months, and cardiovascular events, such as cardiovascular death and fatal and nonfatal stroke or myocardial infarction, were recorded. Results: During the follow-up period, cardiovascular events occurred in 109 (11%) patients (18 fatal and 14 nonfatal myocardial infarction; 13 fatal and 19 nonfatal ischemic strokes; 45 cardiovascular deaths). Lower vitamin E serum levels were found in patients who experienced cardiovascular events compared to those who did not (3.8±1.2 vs. 4.4±1.8μmol/mmol cholesterol; p<0.001). Using a Cox proportional hazard model, age, diabetes, history of stroke and myocardial infarction and vitamin E serum levels (HR 0.77; 95% CI: 0.67–0.89; p=0.001) independently predicted cardiovascular events. Patients with vitamin E<4.2μmol/mmol cholesterol (median values) had an increased risk of cardiovascular events (HR 1.87; 95% CI: 1.25–2.80: p=0.002). Conclusions: Low vitamin E serum levels are associated with an increased risk of cardiovascular events in patients with non-valvular atrial fibrillation. [Copyright &y& Elsevier]