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

Abstract

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).

PACE: randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial

“…Crucially, there was no difference in AFS between patients treated with PLX-PAD and those who received the placebo in this study. Failure to demonstrate clinical benefit may reflect the overall better prognosis observed, the high rate of ambulatory patients at baseline, or geographical distribution introducing variability in standard of care 23 .…”

Understanding Study Drug Discontinuation Through EUCLID

“…The association between region and study drug discontinuation is more difficult to grasp, as it reflects complex interplays between background patient populations, regional approaches to healthcare delivery, and attitudes surrounding clinical research. The geographic breadth of EUCLID was advantageous insofar as it increased participant diversity along many dimensions ( 12 ). However, this geographic diversity as well as data collection constraints limited our ability to understand how social determinants of health may have contributed to study drug discontinuation.…”

The EUCLIDian perspective of global peripheral artery disease (PAD)

“…Regarding trial outcomes, the total and cardiovascular mortality in EUCLID was the highest among patients in C/S America, despite younger age at enrollment, whereas fatal plus nonfatal cardiovascular event rates were the highest in North America. 2 Overall, when dividing the European countries into two regions, those enrolled in Western Europe had similar profiles and outcomes as those in North America. Regarding the limb outcomes, the probability of acute limb ischemia and lower-extremity revascularization was higher in North America and Europe, whereas amputations were more frequent in C/S America.…”

“…In brief, the comparison of data from patients enrolled in North and Central/South (C/S) America, Asia, and Western/Eastern Europe reveal some significant differences in demographic characteristics (e.g., older participants with lower body weight in Asia), risk factors (e.g., more diabetes among participants in C/S America, more hypertension and hyperlipidemia in North America), and inclusion criteria (more asymptomatic patients with history of revascularization enrolled in Asia, and more past amputees in C/S America). 2 There were also different patterns of comorbidities (higher rates of prior stroke in Asia and prior myocardial infarctions in North America) and use of cardiovascular protective drugs (high rates of statin therapy in North America and Europe and less ACE-inhibitors (ACEI) and aspirin in Asia). A high rate of ACEI intolerance due to cough has been reported among Asians, which could account for the lower usage rate of this treatment and higher usage rate of angiotensin receptor blockers.…”

“…In this issue, Norgren and co-investigators of the EUCLID (Examining Use of tiCagreLor In peripheral artery Disease) trial – an international study having recruited patients with PAD from 28 countries in four global regions – highlighted the disparities of the participants according to their geographical localization. 2 Because of the lack of difference in outcomes between the two arms of the study (i.e., ticagrelor vs clopidogrel), the authors were able to provide the overall patients’ characteristics and results, independent from the randomized allocation of enrollees. The authors report regional differences for the inclusion criteria, risk factors, associated therapies, and outcomes.…”