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

Abstract

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 (P_interaction=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.

Keywords: clopidogrel; peripheral artery disease; polyvascular disease; ticagrelor; total events.

Figure 1. Rates of second events by type of first nonfatal event.

Values above bars are the sum of the rates of acute cardiovascular and limb events and procedures as a second event. Values within bars are the rates of acute cardiovascular and limb events or the rates of procedures as a second event.

Figure 2. Treatment effects on total cardiovascular and limb events and procedures by event type.

Hazard ratios (HRs), 95% CIs, and P values from marginal proportional hazards models with death not included in a given end point treated as a competing terminal event. PAD indicates peripheral artery disease.

Figure 3. Mean cumulative functions for total cardiovascular and limb events and procedures by number of affected vascular territories.

A, One affected vascular territory. B, Two affected vascular territories. C, Three affected vascular territories. The estimated numbers of events per 100 patients in the ticagrelor and clopidogrel groups at 3 years were 40.9 and 40.7 among the subgroup with 1 affected vascular territory, 59.6 and 66.3 among the subgroup with 2 affected vascular territories, and 87.3 and 97.7 for among the subgroup with 3 affected vascular territories, 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).