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.

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.

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.

Incidence, Characteristics, and Outcomes of Myocardial Infarction in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial.

Importance: Patients with peripheral artery disease (PAD) are at high risk for myocardial infarction (MI). Objective: To characterize the incidence and types of MI in a PAD population, identify factors associated with MI, and determine the association of MI with cardiovascular mortality and acute limb ischemia. Design, Setting, and Participants: The Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease (EUCLID) was a double-blind randomized clinical trial conducted at 811 sites in 28 countries that randomized 13 885 patients with symptomatic PAD to monotherapy with ticagrelor or clopidogrel. Participants had an ankle-brachial index (ABI) of 0.80 or less or previous lower extremity revascularization. Median follow-up was 30 months. For these analyses, patients were evaluated for MI occurrence during follow-up irrespective of treatment. Data were analyzed from June 2017 to September 2018. Main Outcomes and Measures: An adjudication clinical events committee classified MI as type 1 (spontaneous), type 2 (secondary), type 3 (sudden cardiac death), type 4a (less than 48 hours after percutaneous coronary intervention), type 4b (definite stent thrombosis), or type 5 (less than 72 hours after coronary artery bypass graft). A multivariate regression model was developed by stepwise selection to identify factors associated with MI, and a time-dependent multivariate Cox regression analysis was performed to determine the association of MI with cardiovascular death and acute limb ischemia requiring hospitalization. Results: Of the 13 885 patients included in this analysis, 9997 (72.0%) were male, and the median (interquartile range) age was 66 (60-73) years. Myocardial infarction occurred in 683 patients (4.9%; 2.4 events per 100 patient-years) during a median follow-up of 30 months. Patients experiencing MI were older (median [interquartile range] age, 69 [62-75] vs 66 [60-72] years), more likely to have diabetes (349 of 683 [51.1%] vs 4996 of 13 202 [37.8%]) or a previous lower extremity revascularization (466 of 683 [68.2%] vs 7409 of 13 202 [56.1%]), and had a lower ABI (if included by ABI) compared with censored patients. Of the 683 patients with MI during follow-up, the most common MI type was type 1 (405 [59.3%]), followed by type 2 (236 [34.6%]), type 4a (14 [2.0%]), type 3 (12 [1.8%]), type 4b (11 [1.6%]), and type 5 (5 [0.7%]). Postrandomization MI was independently associated with cardiovascular death (adjusted hazard ratio, 9.0; 95% CI, 7.3-11.2; P < .001) and acute limb ischemia requiring hospitalization (adjusted hazard ratio, 2.5; 95% CI, 1.3-5.0; P = .008). Conclusions and Relevance: Approximately 5% of patients with symptomatic PAD had an MI during a median follow-up of 30 months. Type 1 MI (spontaneous) was the most common MI type; however, one-third of MIs were type 2 MI (secondary). More research is needed to identify therapies to reduce the risk of MI in patients with PAD and to improve management of type 2 MI. Trial Registration: ClinicalTrials.gov Identifier: NCT01732822.

Ticagrelor versus clopidogrel in patients with symptomatic peripheral artery disease and prior coronary artery disease: Insights from the EUCLID trial.

Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular morbidity and mortality. We sought to evaluate the risk of concomitant coronary artery disease (CAD) in patients with symptomatic PAD versus PAD without diagnosed CAD, and whether ticagrelor was superior to clopidogrel in reducing that risk. The EUCLID trial randomized 13,885 patients with PAD to antithrombotic monotherapy with ticagrelor or clopidogrel. CAD was defined as prior myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) surgery. Median follow-up was 30 months. Among 4032 (29%) patients with PAD and CAD, 63% had prior MI, 54% prior PCI, and 38% prior CABG. After adjustment for baseline characteristics, patients with PAD and CAD had significantly higher rates of the primary endpoint (cardiovascular death/MI/stroke, 15.3% vs 8.9%, hazard ratio (HR) 1.50, 95% CI: 1.13-1.99; p=0.005), but no statistically significant increase in acute limb ischemia (HR 1.28, 95% CI: 0.57-2.85; p=0.55) or major bleeding (HR 1.10, 95% CI: 0.49-2.48; p=0.81) versus PAD without CAD. Among patients with PAD and CAD, there was no differential treatment effect between ticagrelor versus clopidogrel for the primary efficacy endpoint (HR 1.02, 95% CI: 0.87-1.19; p=0.84), acute limb ischemia (HR 1.03, 95% CI: 0.63-1.69; p=0.89), or major bleeding (HR 1.06, 95% CI: 0.66-1.69; p=0.81). There was a statistically significant interaction between prior coronary stent placement and study treatment ( p=0.03) with a numerical reduction in the primary efficacy endpoint with ticagrelor versus clopidogrel (13.8% vs 16.8%, HR 0.82, 95% CI: 0.65-1.03; p=0.09). Patients with PAD and prior CAD had higher composite rates of cardiovascular death, MI, and ischemic stroke versus PAD without diagnosed CAD. There were no significant differences between ticagrelor and clopidogrel in cardiovascular events or major bleeding. ClinicalTrials.gov Identifier: NCT01732822.

Outcomes of Patients with Critical Limb Ischaemia in the EUCLID Trial.

OBJECTIVES: Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established. DESIGN, MATERIALS, METHODS: The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss. RESULTS: In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI. CONCLUSIONS: Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI. CLINICALTRIALS.GOV: NCT01732822.

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 .).

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.

Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial.

BACKGROUND: Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y12 receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events. STUDY DESIGN: EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction-defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur. CONCLUSIONS: The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.

Coronary flow reserve as a link between exercise capacity, cardiac systolic and diastolic function.

BACKGROUND: Decreased coronary flow reserve (CFR) is associated with increased risk of adverse cardiovascular events. We sought to investigate how CFR from left anterior descending (LAD) coronary artery reflects clinical markers of cardiac function. METHODS: We enrolled 400 patients referred for myocardium perfusion scintigraphy due to chest pain at Sahlgrenska University Hospital in Gothenburg, Sweden. Transthoracic echocardiography including adenosine-assisted CFR in LAD was performed at a separate occasion. RESULTS: Median age was 62years (range 32-83) and 47% were female. Prior myocardial infarction had occurred in 28% of the population. In adjusted multivariate models, CFR in LAD was associated with echocardiography left ventricle ejection fraction at rest (ß=0.97, p=0.033) as well as under stress (ß=1.52, p=0.0056) and maximum exercise capacity (ß=6.27, p=0.026). CFR in LAD outweighed left ventricle ejection fraction as the determinant of maximum exercise capacity. Hyperaemic diastolic mitral annulus peak velocity measured by vector velocity imaging was inversely associated with LAD CFR (ß=-0.39, p=0.0077). In subgroup analyses these findings were associated with normal coronary perfusion in myocardium perfusion scintigraphy. CONCLUSIONS: In patients with angina-like symptoms CFR measured in LAD reflects well both systolic and diastolic cardiac function emphasizing the essential role of myocardial microvascular circulation in cardiac physiology.

The harms of smoking and benefits of smoking cessation in women compared with men with type 2 diabetes: an observational analysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial.

OBJECTIVES: In general populations, the adverse effects of smoking on coronary risk have been demonstrated to be greater in women than in men; whether this is true for individuals with diabetes is unclear. DESIGN: Cohort study. SETTING: 20 countries worldwide participating in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial. PARTICIPANTS: 11,140 patients with type 2 diabetes aged ≥ 55 years and in cardiovascular risk at the time of randomisation. PRIMARY AND SECONDARY OUTCOME MEASURES: Major cardiovascular events (death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction (MI)), all cardiovascular events (major cardiovascular event or peripheral arterial disease or transient ischaemic attack), and all-cause mortality. Secondary outcome measures were major coronary events (fatal and non-fatal MI), major cerebrovascular events (fatal and non-fatal stroke), nephropathy (new or worsening renal disease), and all cancer. RESULTS: At baseline, 6466 (56% women) participants were never-smokers, 1550 (28% women) were daily smokers and 3124 (21% women) were former smokers. Median follow-up time was 5 years. In Cox regression models after multiple adjustments, compared with never smoking, daily smoking was associated with increased risk of all primary and secondary outcomes with the exception of major cerebrovascular disease. Only for major coronary events was there any evidence of a stronger effect in women than in men (ratio of the adjusted HRs women:men; 1.64 (0.83 to 3.26) p=0.08). For all other outcomes considered, the hazards of smoking were similar in men and women. Quitting smoking was associated with a 30% reduction in all-cause mortality (p=0.001) in both sexes. CONCLUSIONS: In individuals with diabetes, the effects of smoking on all major forms of cardiovascular disease are equally as hazardous in women and men with the possible exception of major coronary events where there was some evidence of a greater hazard in women. TRIAL REGISTRATION NUMBER: NCT00145925.