W. Schuyler Jones

Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease.

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.)

Temporal Trends and Geographic Variation of Lower-Extremity Amputation in Patients With Peripheral Artery Disease: Results From U.S. Medicare 2000–2008

OBJECTIVES This study sought to characterize temporal trends, patient-specific factors, and geographic variation associated with amputation in patients with lower-extremity peripheral artery disease (LE PAD) during the study period. BACKGROUND Amputation represents the end-stage failure for those with LE PAD, and little is known about the rates and geographic variation in the use of LE amputation. METHODS By using data from the Centers for Medicare & Medicaid Services (CMS) from January 1, 2000, to December 31, 2008, we examined national patterns of LE amputation among patients age 65 years or more with PAD. Multivariable logistic regression was used to adjust regional results for other patient demographic and clinical factors. RESULTS Among 2,730,742 older patients with identified PAD, the overall rate of LE amputation decreased from 7,258 per 100,000 patients with PAD to 5,790 per 100,000 (p < 0.001 for trend). Male sex, black race, diabetes mellitus, and renal disease were all independent predictors of LE amputation. The adjusted odds ratio of LE amputation per year between 2000 and 2008 was 0.95 (95% CI: 0.95-0.95, p < 0.001). CONCLUSIONS From 2000 to 2008, LE amputation rates decreased significantly among patients with PAD. However, there remains significant patient and geographic variation in amputation rates across the United States.

Relationship between leg muscle capillary density and peak hyperemic blood flow with endurance capacity in peripheral artery disease

The aim of this study was to determine if skeletal muscle capillary density is lower in patients with peripheral artery disease (PAD) and if capillary density relates to functional limitations. PAD patients with intermittent claudication (IC) have a decreased exercise tolerance due to exercise-induced muscle ischemia. Despite the apparent role diminished arterial flow has in this population, the degree of walking pain and functional limitation is not entirely explained by altered hemodynamics of the affected limbs. We hypothesized that skeletal muscle capillary density is lower in PAD and is related to the functional impairment observed in this population. Sixty-four patients with PAD and 56 controls underwent cardiopulmonary exercise testing and a gastrocnemius muscle biopsy. A subset of these patients (48 PAD and 47 controls) underwent peak hyperemic flow testing via plethysmography. Capillary density in PAD patients was lower compared with controls (P < 0.001). After adjustment for several baseline demographic imbalances the model relating capillary density to peak oxygen consumption (Vo(2)) remained significant (P < 0.001). In PAD subjects, capillary density correlated with peak Vo(2), peak walking time (PWT), and claudication onset time (COT). Peak hyperemic blood flow related to peak Vo(2) in both PAD and control subjects. PAD is associated with lower capillary density, and capillary density is related to the functional impairment as defined by a reduced peak Vo(2), PWT, and COT. These findings suggest that alterations in microcirculation may contribute to functional impairment capacity in PAD.

High mortality risks after major lower extremity amputation in Medicare patients with peripheral artery disease

BACKGROUND Little is known regarding the contemporary outcomes of older patients with peripheral artery disease (PAD) undergoing major lower extremity (LE) amputation in the United States. We sought to characterize clinical outcomes and factors associated with outcomes after LE amputation in patients with PAD. METHODS Using data from the Centers for Medicare and Medicaid Services from January 1, 2000, to December 31, 2008, we examined the national patterns of mortality after major LE amputation among patients 65 years or older with PAD. Cox proportional hazards models were used to investigate the association between clinical variables, comorbid conditions, year of index amputation, geographic variation, and major LE amputation. RESULTS Among 186,338 older patients with identified PAD who underwent major LE amputation, the mortality rate was 13.5% at 30 days, 48.3% at 1 year, and 70.9% at 3 years. Age per 5-year increase (hazard ratio [HR] 1.29, 95% CI 1.29-1.29), history of heart failure (HR 1.71, 95% CI 1.71-1.72), renal disease (HR 1.84. 95% CI 1.83-1.85), cancer (HR 1.71, 95% CI 1.70-1.72), and chronic obstructive pulmonary disease (HR 1.33, 95% CI, 1.32-1.33) were all independently associated with death after major LE amputation. Subjects who underwent above knee amputation had a statistically higher hazard of death when compared with subjects who underwent LE amputation at more distal locations (HR with above the knee amputation 1.31, 95% CI 1.25-1.36). CONCLUSIONS Older patients with PAD undergoing major LE amputation still face a slightly high mortality risk, with almost half of all patients with PAD dying within a year of major LE amputation.

Erythropoietin Activates Mitochondrial Biogenesis and Couples Red Cell Mass to Mitochondrial Mass in the Heart

Rationale: Erythropoietin (EPO) is often administered to cardiac patients with anemia, particularly from chronic kidney disease, and stimulation of erythropoiesis may stabilize left ventricular and renal function by recruiting protective effects beyond the correction of anemia. Objective: We examined the hypothesis that EPO receptor (EpoR) ligand-binding, which activates endothelial NO synthase (eNOS), regulates the prosurvival program of mitochondrial biogenesis in the heart. Methods and Results: We investigated the effects of EPO on mitochondrial biogenesis over 14 days in healthy mice. Mice expressing a mitochondrial green fluorescent protein reporter construct demonstrated sharp increases in myocardial mitochondrial density after 3 days of EPO administration that peaked at 7 days and surpassed hepatic or renal effects and anteceded significant increases in blood hemoglobin content. Quantitatively, in wild-type mice, complex II activity, state 3 respiration, and mtDNA copy number increased significantly; also, resting energy expenditure and natural running speed improved, with no evidence of an increase in left ventricular mass index. Mechanistically, EPO activated cardiac mitochondrial biogenesis by enhancement of nuclear respiratory factor-1, PGC-1&agr; (peroxisome proliferator-activated receptor &ggr; coactivator 1&agr;), and mitochondrial transcription factor-A gene expression in wild-type but not in eNOS−/− or protein kinase B (Akt1)−/− mice. EpoR was required, because EpoR silencing in cardiomyocytes blocked EPO-mediated nuclear translocation of nuclear respiratory factor-1. Conclusions: These findings support a new physiological and protective role for EPO, acting through its cell surface receptor and eNOS-Akt1 signal transduction, in matching cardiac mitochondrial mass to the convective O2 transport capacity as erythrocyte mass expands.

Conflicting Results Between Randomized Trials and Observational Studies on the Impact of Proton Pump Inhibitors on Cardiovascular Events When Coadministered With Dual Antiplatelet Therapy Systematic Review

Background— Discordant results have been reported on the effects of concomitant use of proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT) for cardiovascular outcomes. We conducted a systematic review comparing the effectiveness and safety of concomitant use of PPIs and DAPT in the postdischarge treatment of unstable angina/non–ST-segment–elevation myocardial infarction patients. Methods and Results— We searched for clinical studies in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, from 1995 to 2012. Reviewers screened and extracted data, assessed applicability and quality, and graded the strength of evidence. We performed meta-analyses of direct comparisons when outcomes and follow-up periods were comparable. Thirty-five studies were eligible. Five (4 randomized controlled trials and 1 observational) assessed the effect of omeprazole when added to DAPT; the other 30 (observational) assessed the effect of PPIs as a class when compared with no PPIs. Random-effects meta-analyses of the studies assessing PPIs as a class consistently reported higher event rates in patients receiving PPIs for various clinical outcomes at 1 year (composite ischemic end points, all-cause mortality, nonfatal MI, stroke, revascularization, and stent thrombosis). However, the results from randomized controlled trials evaluating omeprazole compared with placebo showed no difference in ischemic outcomes, despite a reduction in upper gastrointestinal bleeding with omeprazole. Conclusions— Large, well-conducted observational studies of PPIs and randomized controlled trials of omeprazole seem to provide conflicting results for the effect of PPIs on cardiovascular outcomes when coadministered with DAPT. Prospective trials that directly compare pharmacodynamic parameters and clinical events among specific PPI agents in patients with unstable angina/non–ST-segment–elevation myocardial infarction treated with DAPT are warranted.

Comparative effectiveness of endovascular and surgical revascularization for patients with peripheral artery disease and critical limb ischemia

BACKGROUND For patients with critical limb ischemia (CLI), the optimal treatment to enhance limb preservation, prevent death, and improve functional status is unknown. We performed a systematic review and meta-analysis to assess the comparative effectiveness of endovascular revascularization and surgical revascularization in patients with CLI. METHODS We systematically searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for relevant English-language studies published from January 1995 to August 2012. Two investigators screened each abstract and full-text article for inclusion, abstracted the data, and performed quality ratings and evidence grading. Random-effects models were used to compute summary estimates of effects, with endovascular treatment as the control group. RESULTS We identified a total of 23 studies, including 1 randomized controlled trial, which reported no difference in amputation-free survival at 3 years (odds ratio [OR] 1.22, 95% CI 0.84-1.77) and all-cause mortality (OR 1.07, 0.73-1.56) between the 2 treatments. Meta-analysis of the observational studies showed a statistically nonsignificant reduction in all-cause mortality at 6 months (11 studies, OR 0.85, 0.57-1.27) and amputation-free survival at 1 year (2 studies, OR 0.76, 0.48-1.21) in patients treated with endovascular revascularization. There was no difference in overall death, amputation, or amputation-free survival at ≥2 years. CONCLUSIONS The currently available literature suggests that there is no difference in clinical outcomes for patients with CLI treated with endovascular or surgical revascularization. There is a paucity of high-quality data available to guide clinical decision making, especially as it pertains to patient subgroups or anatomical considerations.

Alteration in angiogenic and anti-angiogenic forms of vascular endothelial growth factor-A in skeletal muscle of patients with intermittent claudication following exercise training.

The aims of this study were twofold: (1) to identify whether peripheral artery disease (PAD) patients had increased muscle concentration of angiogenic VEGF-A, anti-angiogenic VEGF165b or VEGF receptor 1 (VEGF-R1) when compared with control subjects, and (2) to evaluate whether exercise training in PAD patients was associated with changes in muscle concentration of VEGF-A, VEGF165b or VEGF-R1. At baseline, 22 PAD and 30 control subjects underwent gastrocnemius muscle biopsy. Twelve PAD patients were treated with supervised exercise training (SET) and underwent muscle biopsy after 3 weeks and 12 weeks of training and had sufficient tissue to measure VEGF-A, VEGF165b and VEGF-R1 concentrations in skeletal muscle lysates by ELISA. Muscle concentrations of VEGF-A and VEGF165b were similar in PAD patients versus controls at baseline. At both time points after the start of SET, VEGF-A levels decreased and there was a trend towards increased VEGF165b concentrations. At baseline, VEGF-R1 concentrations were lower in PAD patients when compared with controls but did not change after SET. Skeletal muscle concentrations of VEGF-A are not different in PAD patients when compared with controls at baseline. SET is associated with a significant reduction in VEGF-A levels and a trend towards increased VEGF165b levels. These somewhat unexpected findings suggest that further investigation into the mechanism of vascular responses to exercise training in PAD patients is warranted.

Ticagrelor Compared With Clopidogrel in Patients with Prior Lower Extremity Revascularization for Peripheral Artery Disease.

Background: In patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for long-term management is unknown. Methods: The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ⩽0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. Results: Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98–1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08–1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86–6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were found for the primary efficacy end point (11.4% vs 11.3%; HR 1.01, 95% CI 0.88–1.15; P=0.90), all-cause mortality (9.2% vs 9.2%; HR 0.99, 95% CI 0.86–1.15; P=0.93), acute limb ischemia (2.5% vs 2.5%; HR 1.03, 95% CI 0.78–1.36; P=0.84), or major bleeding (1.9% vs 1.8%; HR 1.15, 95% CI 0.83–1.59; P=0.41). The median duration of follow-up was ≈30 months. Conclusions: After adjustment for baseline characteristics, patients enrolled based on previous revascularization for peripheral artery disease had higher rates of myocardial infarction and acute limb ischemia, with similar composite rates of cardiovascular death, myocardial infarction, and stroke when compared with patients enrolled based on the ankle-brachial index criterion. No significant differences were found between ticagrelor and clopidogrel for reduction of cardiovascular or acute limb events. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01732822.

The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease

Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these advances, there remains a substantial need for more high-quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institutes National Patient-Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial.