Ticagrelor In Peripheral Artery Disease Research Articles

Understanding Study Drug Discontinuation Through EUCLID

IntroductionDisparities 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.MethodsUsing 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.ResultsOf 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.ConclusionsThis 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.

BackgroundPeripheral 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 ResultsIn 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 (P interaction=0.09).ConclusionsPatients 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.RegistrationURL: https://clinicaltrials.gov/; Unique identifier: NCT01732822.

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).

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.

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

Peripheral artery disease is common and associated with high mortality. There are limited data detailing causes of death among patients with peripheral artery disease. 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. 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. 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.

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. 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. 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. 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.

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). 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). 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.

Incidence and Factors Associated With Major Amputation in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial.

Peripheral artery disease (PAD) is associated with increased risk of mortality, cardiovascular morbidity, and major amputation. Data on major amputation from a large randomized trial that included a substantial cohort of patients without critical limb ischemia (CLI) have not been described. The objective was to describe the incidence and types of amputations in the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) population, subcategorize amputations in the CLI versus no CLI cohorts, and describe the events surrounding major amputation. Postrandomization major amputation was analyzed in the EUCLID trial. Patients were stratified by baseline CLI status. The occurrence of major amputation was ascertained and defined as the highest level. Perioperative events surrounding major amputation were obtained including acute limb ischemia, revascularization, and all-cause mortality. All variables were assessed for significance in univariable and multivariable models. The rate of major amputation during the course of the trial was 1.6% overall, 8.4% in the CLI at baseline group, and 1.2% in the no CLI at baseline group. The annualized rate of major amputation was 0.6% in PAD overall, 3.9% in the CLI at baseline group, and 0.5% in the no CLI at baseline group. Several factors were associated with increased risk of major amputation, including history of amputation, the presence of diabetes mellitus, baseline Rutherford category 4 to 6, and an ankle-brachial index <0.8. Factors associated with a lower risk for major amputation included prior statin use. The 30-day mortality rate after major amputation was 6.5% overall, 5.6% in the CLI at baseline group, and 6.8% in the no CLI at baseline group. The annual mortality rate following major amputation was 22.8% in the CLI at baseline group and 16.0% in the no CLI at baseline group. The risk factors for major amputation in EUCLID patients are similar to previous large registries' reports except for diabetes mellitus in patients with CLI. The mortality following major amputation is lower in the EUCLID trial compared with registry data. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

Sex-Specific Risks of Major Cardiovascular and Limb Events in Patients With Symptomatic Peripheral Artery Disease

BackgroundPatients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD. ObjectivesThe aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial. MethodsCox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection. ResultsEUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex. ConclusionsAlthough women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822)

Chronic kidney disease and risk for cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: The EUCLID trial.

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.

Acute Limb Ischemia in Peripheral Artery Disease.

Acute limb ischemia (ALI) is an important clinical event and an emerging cardiovascular clinical trial outcome. Risk factors for and outcomes after ALI have not been fully evaluated. EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized patients with peripheral artery disease to ticagrelor versus clopidogrel. Enrollment criteria included an ankle-brachial index ≤0.80 or previous lower extremity revascularization. Patients were grouped according to the primary outcome, postrandomization ALI hospitalization. Baseline factors associated with ALI were identified using Cox proportional hazards modeling. Models with ALI hospitalization as a time-dependent covariate were developed for secondary outcomes of major adverse cardiovascular events (myocardial infarction, cardiovascular death, ischemic stroke), all-cause mortality, and major amputation. Among 13 885 patients, 1.7% (n=232) had 293 ALI hospitalizations (0.8 per 100 patient-years). Patients with versus without ALI were younger and more often had previous peripheral revascularization and lower baseline ankle-brachial index. Treatment during ALI hospitalization included endovascular revascularization (39.2%, n=115), surgical bypass (24.6%, n=72), and major amputation (13.0%, n=38). After multivariable adjustment, any previous peripheral revascularization (Hazard Ratio [HR] 4.7, 95% CI 3.3-6.8, P<0.01), baseline atrial fibrillation (HR 1.8, 95% CI 1.1-3.2, P=0.03), and baseline ankle-brachial index ≤0.60 (HR 1.3 per 0.10 decrease, 95% CI 1.1-1.5, P<0.01) were associated with higher ALI risk. Older age (HR 0.8 per 10-year increase, 95% CI 0.7-1.0, P=0.02) and baseline statin use (HR 0.7, 95% CI 0.5-0.9, P<0.01) were associated with lower risk for ALI. There was no relationship between randomized treatment to ticagrelor or clopidogrel and ALI. Among patients with previous revascularization, surgical versus endovascular procedures performed more than 6 months prior were associated with ALI (adjusted HR 2.63, 95% CI 1.75-3.96). In the overall population, ALI hospitalization was associated with subsequent MACE (adjusted HR 1.4, 95% CI 1.0-2.1, P=0.04), all-cause mortality (adjusted HR 3.3, 95% CI 2.4-4.6, P<0.01), and major amputation (adjusted HR 34.2, 95% CI 9.7-20.8, P<0.01). Previous peripheral revascularization, baseline atrial fibrillation, and lower ankle-brachial index identify peripheral artery disease patients at heightened risk for ALI, an event associated with subsequent cardiovascular and limb-related morbidity and mortality. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01732822.

Stroke in Patients With Peripheral Artery Disease.

Background and Purpose- Predictors of stroke and transient ischemic attack (TIA) in patients with peripheral artery disease (PAD) are poorly understood. The primary aims of this analysis were to (1) determine the incidence of ischemic/hemorrhagic stroke and TIA in patients with symptomatic PAD, (2) identify predictors of stroke in patients with PAD, and (3) compare the rate of stroke in ticagrelor- and clopidogrel-treated patients. Methods- EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized 13 885 patients with symptomatic PAD to receive monotherapy with ticagrelor or clopidogrel for the prevention of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or ischemic stroke). Ischemic/hemorrhagic stroke and TIA were adjudicated and measured as incidence rates postrandomization and cumulative incidence (per patient-years). Post hoc multivariable competing risk hazards analyses were performed using baseline characteristics to determine factors associated with all-cause stroke in patients with PAD. Results- A total of 458 cerebrovascular events in 424 patients (317 ischemic strokes, 39 hemorrhagic strokes, and 102 TIAs) occurred over a median follow-up of 30 months, for a cumulative incidence of 0.87, 0.11, and 0.27 per 100 patient-years, respectively. Age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, geographic region, ankle-brachial index <0.60, prior amputation, and systolic blood pressure were independent baseline factors associated with the occurrence of all-cause stroke. After adjustment for baseline factors, the rates of ischemic stroke and all-cause stroke remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was no significant difference in the incidence of hemorrhagic stroke or TIA between the 2 treatment groups. Conclusions- In patients with symptomatic PAD, ischemic stroke and TIA occur frequently over time. Comorbidities such as age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, higher blood pressure, prior amputation, lower ankle-brachial index, and geographic region were each independently associated with the occurrence of all-cause stroke. Use of ticagrelor, as compared with clopidogrel, was associated with a lower adjusted rate of ischemic and all-cause stroke. Further study is needed to optimize medical management and risk reduction of all-cause stroke in patients with PAD. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01732822.

Cardiovascular and Limb Outcomes in Patients With Diabetes and Peripheral Artery Disease: The EUCLID Trial

BackgroundDiabetes confers an increased risk for atherosclerotic cardiovascular disease, but less is known about the independent risk diabetes confers on major cardiovascular and limb events in patients with symptomatic peripheral artery disease (PAD) on contemporary management. ObjectivesThe authors sought to assess the risk of cardiovascular and limb events in patients with PAD and diabetes as compared with those with PAD alone. MethodsIn the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial, 13,885 patients with symptomatic PAD were evaluated with a primary endpoint of an adjudicated composite of major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, ischemic stroke) followed over a median of ∼30 months. The diabetes subgroup was analyzed compared with the subgroup without diabetes, and further examined for diabetes-specific factors such as glycosylated hemoglobin (HbA1c) that might affect risk for major cardiovascular and limb outcomes. ResultsA total of 5,345 patients (38.5%) had diabetes; the majority (n = 5,134 [96.1%]) had type 2 diabetes. The primary endpoint occurred in 15.9% of patients with PAD and diabetes as compared with 10.4% of those without diabetes (absolute risk difference 5.5%; adjusted hazard ratio: 1.43; 95% confidence interval [CI]: 1.28 to 1.61; p < 0.001). Every 1% increase in HbA1c was associated with a 14.2% increased relative risk for MACE (95% CI: 1.09 to 1.20; p < 0.0001). ConclusionsPatients with PAD and diabetes are at high risk for cardiovascular and limb ischemic events, even on contemporary therapies. Every 1% increase in HbA1c in patients with a history of diabetes mellitus was associated with a 14.2% increased relative risk for MACE (95% CI: 1.09 to 1.20; p < 0.0001). (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822)

Polyvascular Disease and Risk of Major Adverse Cardiovascular Events in Peripheral Artery Disease

The effect of polyvascular disease on cardiovascular outcomes in the background of peripheral artery disease (PAD) is unclear. To determine the risk of ischemic events (both cardiac and limb) among patients with PAD and polyvascular disease. In this post hoc secondary analysis of the international Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, outcomes were compared among 13 885 enrolled patients with PAD alone, PAD + coronary artery disease (CAD), PAD + cerebrovascular disease (CVD), and PAD + CAD + CVD. Adjusted Cox proportional hazards regression models were implemented to determine the risk associated with polyvascular disease and outcomes, and intention-to-treat analysis was performed. The EUCLID trial was conducted from December 31, 2012, to March 7, 2014; the present post hoc analysis was performed from June 1, 2017, to February 5, 2018. EUCLID evaluated ticagrelor vs clopidogrel in preventing major adverse cardiac events (cardiovascular death, myocardial infarction [MI], or ischemic stroke) and major bleeding in patients with PAD. The primary end point was a composite of cardiovascular death, MI, or ischemic stroke. Key secondary end points included the individual components of the primary end point and acute limb ischemia leading to hospitalization, major amputation, and lower-extremity revascularization. The primary end point of Thrombolysis in Myocardial Infarction (TIMI) major bleeding was also evaluated. The EUCLID trial randomized 13 885 patients with a median age of 66 years (interquartile range, 60-73 years), of whom 3888 (28.0%) were women. At baseline, 7804 patients (56.2%) had PAD alone; 2639 (19.0%) had PAD + CAD; 2049 (14.8%) had PAD + CVD; and 1393 (10.0%) had PAD + CAD + CVD. Compared with patients with isolated PAD, the adjusted hazard ratios (aHRs) for major adverse cardiac events were 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CVD, 1.65 (95% CI, 1.43-1.91; P < .001) for PAD + CAD, and 1.99 (95% CI, 1.69-2.34; P < .001) for PAD + CAD + CVD. The aHRs for lower-extremity revascularization were 1.17 (95% CI, 1.03-1.34; P = .01) for PAD + CAD, 1.17 (95% CI, 1.02-1.35; P = .02) for PAD + CVD, and 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CAD + CVD. Polyvascular disease was not associated with an increased risk of acute limb ischemia (aHR for PAD + CVD, 0.91; 95% CI, 0.62-1.34, P = .63; PAD + CAD, 0.93; 95% CI, 0.64-1.34, P = .69; and PAD + CAD + CVD, 0.98; 95% CI, 0.63-1.53, P = .93), major amputation (aHR for PAD + CVD, 0.83; 95% CI, 0.54-1.27, P = .40; PAD + CAD, 0.74; 95% CI, 0.47-1.16, P = .19; and PAD + CAD + CVD, 1.12; 95% CI, 0.69-1.80, P = .65), or TIMI major bleeding (PAD + CVD, 0.98; 0.66-1.44, P = .91; PAD + CAD, 1.04; 0.74-1.48, P = .81; and PAD + CAD + CVD, 0.96; 95% CI, 0.62-1.51, P = .88). Compared with patients with PAD alone, the risk of major adverse cardiac events and lower-extremity revascularization increased with multiple vascular bed involvement. There was no clear increased risk of bleeding associated with polyvascular disease.

Antithrombotic therapy in peripheral artery disease: A review of the EUCLID trial results and current ongoing trials.

In addition to risk-factor modification, antithrombotic therapy is the hallmark of management to reduce cardiovascular ischemic events in patients with peripheral artery disease (PAD). Currently, the guidelines recommend long-term antiplatelet therapy with aspirin or clopidogrel in this patient population to reduce myocardial infarction, stroke, and vascular death. Past outcomes studies have shown some benefit of ticagrelor, another antiplatelet agent, as compared with clopidogrel in patients with coronary disease and concomitant PAD. However, most recently, the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial has shown no additional benefit of ticagrelor over clopidogrel. In this trial, a minority of patients had concomitant coronary artery disease, making it unique to previous studies. The EUCLID trial's evidence of neutrality between clopidogrel and ticagrelor sheds light into the complexity of studying the PAD population and the continued need to meticulously design trials to investigate the optimal therapies. The topics that will be discussed in this review include the role of antiplatelet therapy in the management of patients with PAD, a review of the EUCLID trial results and the important factors to be considered in interpreting the surprising results, and promising recent ongoing clinical trials assessing therapies in the treatment of patients with PAD.