Regional variation in cause of death in patients with type 2 diabetes: Insights from EXSCEL.

AIMS: Type 2 diabetes (T2D) is a risk factor for cardiovascular and non-cardiovascular mortality. However, global distribution of cause-specific deaths in T2D is poorly understood. We characterized cause-specific deaths by geographic region among individuals with T2D at risk for cardiovascular disease (CVD). METHODS AND RESULTS: The international EXSCEL trial included 14,752 participants with T2D (73% with established CVD). We identified the proportion of deaths over 5-year follow-up attributed to cardiovascular and non-cardiovascular causes, and associated risk factors. During median 3.2-year follow-up, 1,091 (7.4%) participants died. Adjudicated causes of death were 723 cardiovascular (66.3% of deaths), including 252 unknown, and 368 non-cardiovascular (33.7%). Most deaths occurred in North America (N = 356/9.6% across region) and Eastern Europe (N = 326/8.1%), with fewest in Asia/Pacific (N = 68/4.4%). The highest proportional cause-specific deaths by region were sudden cardiac in Asia/Pacific (23/34% of regional deaths) and North America (86/24%); unknown in Eastern Europe (90/28%) and Western Europe (39/21%); and non-malignant non-cardiovascular in Latin America (48/31%). Cox proportional hazards model for adjudicated causes of death showed prognostic risk factors (hazard ratio [95% CI]) for cardiovascular and non-cardiovascular deaths, respectively: heart failure 2.04 (1.72-2.42) and 1.86 (1.46-2.39); peripheral artery disease 1.83 (1.54-2.18) and 1.78 (1.40-2.26); and current smoking status 1.61 (1.29-2.01) and 1.77 (1.31-2.40). CONCLUSIONS: In a contemporary T2D trial population, with and without established CVD, leading causes of death varied by geographic region. Underlying mechanisms leading to variability in cause of death across geographic regions and its impact on clinical trial endpoints warrant future research.

Evaluation of the effect of sodium zirconium cyclosilicate on arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with hyperkalaemia: protocol for the multicentre, randomised, controlled DIALIZE-Outcomes study.

INTRODUCTION: Patients with kidney failure receiving chronic haemodialysis have elevated risk of arrhythmias potentially increasing the likelihood of sudden cardiac death, stroke and hospitalisation. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an efficacious and well-tolerated treatment for predialysis hyperkalaemia in patients undergoing haemodialysis. The DIALIZE-Outcomes study evaluates the effect of SZC on sudden cardiac death and arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with recurrent hyperkalaemia. METHODS AND ANALYSIS: International, multicentre, randomised, double-blind, placebo-controlled study conducted at 357 study sites across 25 countries. Adults (≥18 years) receiving chronic haemodialysis three times per week with recurrent predialysis serum potassium (K+) ≥5.5 mmol/L post long interdialytic interval (LIDI) are eligible. Patients (~2800) will be randomised 1:1 to SZC or placebo, starting at 5 g orally once daily on non-dialysis days and titrated weekly in 5 g increments (maximum 15 g) to target predialysis serum K+ 4.0-5.0 mmol/L post LIDI. The primary objective is to evaluate efficacy of SZC versus placebo in reducing occurrence of the primary composite endpoint of sudden cardiac death, stroke or arrhythmia-related hospitalisation, intervention or emergency department visit. Secondary endpoints include efficacy of SZC versus placebo in maintaining normokalaemia (serum K+ 4.0-5.5 mmol/L post LIDI) at the 12-month visit, preventing severe hyperkalaemia (serum K+ ≥6.5 mmol/L post LIDI) at the 12-month visit and reducing the incidence of individual cardiovascular outcomes. Safety of SZC will be evaluated. The study is event driven, with participants remaining in the study until 770 primary endpoint events have occurred. Average time in the study is expected to be ~25 months. ETHICS AND DISSEMINATION: Approval was obtained from the relevant institutional review board/independent ethics committee from each participating site (approving bodies in supplementary information). The results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2020-005561-14 and clinicaltrials.gov identifier NCT04847232.

Understanding Study Drug Discontinuation Through EUCLID.

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 premature, permanent discontinuation of study drug is relatively common in more than a quarter of PAD patients, is unevenly distributed based on geography and other baseline characteristics, and is associated with worse outcomes in a clinical trial context. Study teams leading future PAD trials may want to address the possibility of study drug discontinuation prospectively, as a proactive approach may help investigators to maintain study cohort diversity and representativeness without sacrificing power and precision.

Total Cardiovascular and Limb Events and the Impact of Polyvascular Disease in Chronic Symptomatic Peripheral Artery Disease.

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 the number of affected vascular territories. These findings highlight the clinical relevance of quantifying disease burden in terms of total events and the need for long-term preventive treatments in high-risk patient populations. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT01732822.

Etiology and outcomes of amputation in patients with peripheral artery disease in the EUCLID trial.

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.

World regional differences in outcomes for patients with peripheral artery disease: Insights from the EUCLID trial.

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).

Polyvascular disease and increased risk of cardiovascular events in patients with type 2 diabetes: Insights from the EXSCEL trial.

BACKGROUND AND AIMS: Polyvascular disease is an independent predictor of major adverse cardiovascular events (MACE). The relationship between the number of diseased arterial beds and MACE is unknown. How MACE risk changes in individuals with type 2 diabetes (T2D) is also understudied. Furthermore, it is unknown whether heart failure (HF) status and hemoglobin A1c (HbA1c) levels influence outcomes in polyvascular disease. This analysis from the Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL) aimed to examine the risk associated with increasing number of diseased arterial beds on MACE and all-cause mortality (ACM). METHODS: Cox models were used to test associations between the number of diseased arterial beds and MACE and ACM. Prespecified interaction testing between number of diseased arterial beds with baseline HF, HbA1c (≤8% vs. >8%), and treatment assignment was performed. RESULTS: Overall, 14,751 participants were included; 26.5% were without atherosclerosis, 58.9% had 1-bed, 12.3% had 2-bed, and 2.3% had 3-bed disease. An increasing burden of atherosclerotic disease was associated with increasing risk of MACE (adjusted HR [aHR] 1.71 [95% CI 1.46-2.02]; 2.61 [2.17-3.15]; 3.46 [2.69-4.45] for 1, 2, and 3 beds, respectively, p < 0.001 for all) and ACM (1.94 [1.56-2.42]; 3.03 [2.33-3.95]; 3.66 [2.59-5.18] for 1, 2, and 3 beds, respectively, p < 0.001 for all). Prespecified interaction testing did not reveal any significant associations. CONCLUSIONS: In patients with T2D, compared to those without atherosclerotic vascular disease, risk of MACE and ACM increases incrementally with each additional diseased arterial bed.

Ankle-Brachial Index for Risk Stratification in Patients With Symptomatic Peripheral Artery Disease With and Without Prior Lower Extremity Revascularization: Observations From the EUCLID Trial.

[Figure: see text].

Impact of chronic kidney disease on hemoglobin among patients with peripheral artery disease treated with P2Y12 inhibitors: Insights from the EUCLID trial.

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 m2, 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 P2Y12 inhibitors, lower baseline eGFR was associated with a greater reduction in Hb. ClinicalTrials.gov Identifier: NCT01732822.

Association of Heart Failure With Outcomes Among Patients With Peripheral Artery Disease: Insights From EUCLID.

Background Peripheral artery disease (PAD) and heart failure (HF) are each independently associated with poor outcomes. Risk factors associated with new-onset HF in patients with primary PAD are unknown. Furthermore, how the presence of HF is associated with outcomes in patients with PAD is unknown. Methods and Results This analysis examined risk relationships of HF on outcomes in patients with symptomatic PAD randomized to ticagrelor or clopidogrel as part of the EUCLID (Examining Use of Ticagrelor in Peripheral Arterial Disease) trial. Patients were stratified based on presence of HF at enrollment. Cox models were used to determine the association of HF with outcomes. A separate Cox model was used to identify risk factors associated with development of HF during follow-up. Patients with PAD and HF had over twice the rate of concomitant coronary artery disease as those without HF. Patients with PAD and HF had significantly increased risk of major adverse cardiovascular events (hazard ratio [HR], 1.31; 95% CI, 1.13-1.51) and all-cause mortality (HR, 1.39; 95% CI, 1.19-1.63). In patients with PAD, the presence of HF was associated with significantly less bleeding (HR, 0.65; 95% CI, 0.45-0.96). Characteristics associated with HF development included age ≥66 (HR, 1.29; 95% CI, 1.18-1.40 per 5 years), diabetes mellitus (HR, 1.85; 95% CI, 1.41-2.43), and weight (bidirectionally associated, ≥76 kg, HR, 0.77; 95% CI, 0.64-0.93; <76 kg, HR, 1.12; 95% CI, 1.07-1.16). Conclusions Patients with PAD and HF have a high rate of coronary artery disease with a high risk for major adverse cardiovascular events and death. These data support the possible need for aggressive treatment of (recurrent) atherosclerotic disease in PAD, especially patients with HF.

Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk: A Secondary Analysis of the STRENGTH Trial.

IMPORTANCE: In patients treated with ω-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes. OBJECTIVE: To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of ω-3 fatty acids compared with corn oil placebo. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020). INTERVENTIONS: Participants were randomized to receive 4 g daily of ω-3 carboxylic acid (CA) or an inert comparator, corn oil. MAIN OUTCOMES AND MEASURES: The primary prespecified end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients treated with the ω-3 CA compared with corn oil for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization. RESULTS: Of the 13 078 total participants, 6539 (50%) were randomized to receive ω-3 CA and 6539 (50%) randomized to corn oil. ω-3 Fatty acid levels were available at both baseline and 12 months after randomization in 10 382 participants (5175 ω-3 CA patients [49.8%] and 5207 corn oil-treated patients [50.2%]; mean [SD] age, 62.5 [8.9] years, 3588 [34.6%] were women, 9025 [86.9%] were White, and 7285 [70.2%] had type 2 diabetes). The median plasma levels at 12 months in ω-3 CA patients were 89 µg/mL (interquartile range [IQR], 46-131 µg/mL) for EPA and 91 µg/mL (IQR, 71-114 µg/mL) for DHA with top tertile levels of 151 µg/mL (IQR, 132-181 µg/mL) and 118 µg/mL (IQR, 102-143 µg/mL), respectively. Compared with corn oil, the adjusted hazard ratios for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83-1.16; P = .81) for EPA, and 1.02 (95% CI, 0.86-1.20; P = .85 for DHA. Sensitivity analyses based on changes in plasma and red blood cell levels of EPA and DHA and primary and secondary prevention subgroups showed similar results. CONCLUSIONS AND RELEVANCE: Among patients treated with ω-3 CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02104817.

Association of Chronic Obstructive Pulmonary Disease with Morbidity and Mortality in Patients with Peripheral Artery Disease: Insights from the EUCLID Trial.

BACKGROUND: 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.

Predicting major adverse limb events in individuals with type 2 diabetes: Insights from the EXSCEL trial.

AIMS: Although models exist to predict amputation among people with type 2 diabetes with foot ulceration or infection, we aimed to develop a prediction model for a broader range of major adverse limb events (MALE)-including gangrene, revascularization and amputation-among individuals with type 2 diabetes. METHODS: In a post-hoc analysis of data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial, we compared participants who experienced MALE with those who did not. A multivariable model was constructed and translated into a risk score. RESULTS: Among the 14,752 participants with type 2 diabetes in EXSCEL, 3.6% experienced MALE. Characteristics associated with increased risk of MALE were peripheral artery disease (PAD) (HRadj 4.83, 95% CI: 3.94-5.92), prior foot ulcer (HRadj 2.16, 95% CI: 1.63-2.87), prior amputation (HRadj 2.00, 95% CI: 1.53-2.64), current smoking (HRadj 2.00, 95% CI: 1.54-2.61), insulin use (HRadj 1.86, 95% CI: 1.52-2.27), coronary artery disease (HRadj 1.67, 95% CI: 1.38-2.03) and male sex (HRadj 1.64, 95% CI: 1.31-2.06). Cerebrovascular disease, former smoking, age, glycated haemoglobin, race and neuropathy were also associated significantly with MALE after adjustment. A risk score ranging from 6 to 96 points was constructed, with a C-statistic of 0.822 (95% CI: 0.803-0.841). CONCLUSIONS: The majority of MALE occurred among participants with PAD, but participants without a history of PAD also experienced MALE. A risk score with good performance was generated. Although it requires validation in an external dataset, this risk score may be valuable in identifying patients requiring more intensive care and closer follow-up.

Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial.

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. Design, Setting, and Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. Main Outcomes and Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%). Conclusions and Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

Cause of Death Among Patients With Peripheral Artery Disease: Insights From the EUCLID Trial.

BACKGROUND: Peripheral artery disease is common and associated with high mortality. There are limited data detailing causes of death among patients with peripheral artery disease. METHODS: EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) was a randomized clinical trial that assigned patients with peripheral artery disease to clopidogrel or ticagrelor. We describe the causes of death in EUCLID using mortality end points adjudicated through a clinical events classification process. The association between baseline factors and cardiovascular death was evaluated by Cox proportional hazards modeling. The competing risk of noncardiovascular death was assessed by the cumulative incidence function for cardiovascular death and the Fine and Gray method to ascertain the association between baseline characteristics and cardiovascular mortality. RESULTS: A total of 1263 out of 13 885 (9.1%) patients died (median follow-up: 30 months). There were 706 patients (55.9%) with a cardiovascular cause of death and 522 (41.3%) with a noncardiovascular cause of death. The most common cause of cardiovascular death was sudden cardiac death (20.1%); while myocardial infarction (5.2%) and ischemic stroke (3.2%) were uncommon. The most common causes of noncardiovascular death were malignancies (17.9%) and infections (11.9%). The factor most associated with a higher risk of cardiovascular death was age per 5 year increase (HR, 1.26 [95% CI, 1.20-1.32]). Female sex was associated with a lower risk of cardiovascular death (HR, 0.68 [95% CI, 0.56-0.82]). To evaluate the effect of noncardiovascular death as a competing risk, we superimposed the cumulative incidence function curve with the Kaplan-Meier curve. These curves closely approximated each other. After accounting for the competing risk of noncardiovascular death, the magnitude and direction of the factors associated with cardiovascular death were minimally changed. CONCLUSIONS: Among patients with symptomatic peripheral artery disease, noncardiovascular causes of death reflected a high proportion (40%) of deaths. Accounting for noncardiovascular deaths as a competing risk, there was not a significant change in the risk estimation for cardiovascular death. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

Association of Disease Progression With Cardiovascular and Limb Outcomes in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial.

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.

Association of Hypertension and Arterial Blood Pressure on Limb and Cardiovascular Outcomes in Symptomatic Peripheral Artery Disease: The EUCLID Trial.

BACKGROUND: Current guidelines recommend aggressive management of hypertension. Recent evidence suggested potential harm with low blood pressure targets in patients with peripheral artery disease. We investigated the association of a history of hypertension and office systolic blood pressure (SBP) with major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs). METHODS AND RESULTS: The EUCLID trial (Examining the Use of Ticagrelor in Peripheral Artery Disease) included 13 885 participants with symptomatic peripheral artery disease; median follow-up was 30 months. Cox proportional hazards regression was used to calculate hazard ratios (HRs) for any MACE, MALE, and MALE including lower extremity revascularization. A clinical history of arterial hypertension was present in 10 857 (78%) participants, and these participants were older and more likely to be female when compared with the 3026 (22%) patients without hypertension. In patients with a history of hypertension, the adjusted hazard ratio for MACE was 0.94, 95% CI, 0.82-1.08; P=0.39, and the adjusted hazard ratio for MALE was 1.08, 95% CI, 0.96-1.23; P=0.21. During follow-up, average SBP was 135 mm Hg (125-145). Every 10 mmHg increase in SBP>125 mmHg was associated with an increased risk of MACE (HR, 1.10 [95% CI, 1.06-1.14]; P<0.001), a marginally increased risk of MALE (HR, 1.07 [95% CI, 1.00-1.15]; P=0.062), and an increased risk of MALE/lower extremity revascularization (HR, 1.08 [95% CI, 1.04-1.11]; P<0.001). Every decrease in 10 mmHg SBP ≤125 mmHg was associated with an increased risk of MACE (HR, 1.19 [95% CI, 1.09-1.31]; P<0.001) but not MALE or MALE/lower extremity revascularization (HR, 1.02 [95% CI, 0.84-1.23], P=0.824; HR, 1.04 [95% CI, 0.95-1.13], P=0.392, respectively). CONCLUSIONS: History of hypertension was not associated with higher hazard for MACE or MALE in patients with peripheral artery disease. In contrast, there was a higher hazard of MACE in patients with out-of-target low and high SBP. High but not low SBP was associated with an increased risk of ischemic limb events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

Association of Health Status Scores With Cardiovascular and Limb Outcomes in Patients With Symptomatic Peripheral Artery Disease: Insights From the EUCLID (Examining Use of Ticagrelor in Symptomatic Peripheral Artery Disease) Trial.

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.