Stroke in Patients With Peripheral Artery Disease

Insights From the EUCLID Study

Brad J. Kolls, MD, PhD, MMCi; Shelly Sapp, MS; Frank W. Rockhold, PhD; J. Dedrick Jordan, MD, PhD; Keith E. Dombrowski, MD; F. Gerry R. Fowkes, MB ChB, PhD; Kenneth W. Mahaffey, MD; Jeffrey S. Berger, MD; Brian G. Katona, PharmD; Juuso I. Blomster, MD, PhD; Lars Norgren, MD, PhD; Beth L. Abramson, MD; Jose L. Leiva-Pons, MD; Juan Carlos Prieto, MD; German Sokurenko, MD; William R. Hiatt, MD; W. Schuyler Jones, MD; Manesh R. Patel, MD


Stroke. 2019;50(6):1356-1363. 

In This Article


Of the 13 885 patients enrolled in EUCLID, a total of 458 cerebrovascular events (ischemic stroke, hemorrhagic stroke, and TIA) occurred in 424 patients over a median study follow-up of 30 months. Patient demographic and clinical characteristics for those who experienced all-cause stroke and those who did not are shown in Table 1. Patients who experienced all-cause stroke were significantly older and were more likely to have had a prior stroke than those patients who did not experience a stroke. The presence of more severe PAD (as evidenced by a baseline ABI <0.60, the presence of prior amputation, or critical limb ischemia at study entry) was also associated with all-cause stroke. Additional factors including age, prior AF/flutter, diabetes mellitus, and higher systolic blood pressure were found to be significantly associated with future cerebrovascular events. Finally, residing in the Central/South America region was associated with decreased risk, whereas residing in Asia was associated with an increased risk, when compared with patients in North America.

Overall Event Rates

The occurrence of all neurological events is shown in Table 2. The cumulative incidence of ischemic stroke was 0.87 per 100 patient-years, hemorrhagic stroke was 0.11 per 100 patient-years, TIA was 0.27 per 100 patient-years, and all-cause stroke and TIA was 1.24 per 100 patient-years. A graphic representation is shown in the Figure.


The cumulative incidence of all-cause stroke and ischemic stroke by treatment group over time are plotted. Top, Cumulative incidence % for all-cause stroke by treatment group. Bottom, Cumulative incidence % for ischemic stroke by treatment group. HR indicates hazard ratio.

Risk in Patients With Coronary Artery Disease and Prior Stroke

When evaluating subgroups of patients with prior coronary artery disease and prior stroke (Table 3), those with a prior history of coronary artery disease conferred some increase in risk when compared with patients with PAD alone (rate of all-cause stroke per 100 patient-years; 0.97 PAD+coronary artery disease versus 0.84 PAD alone). Those patients with a prior history of stroke had a 2.5-fold higher rate of stroke during follow-up when compared with patients with PAD alone (rate of all-cause stroke per 100 patient years; 2.18 versus 0.84). However, patients with PAD and coronary artery disease and prior stroke had the highest rate of all-cause stroke at 2.24 per 100 patient-years.

Factors Associated With All-cause Stroke

Using multivariable competing risk hazards models, the baseline factors that were significantly associated with all-cause stroke included age, prior stroke, prior AF/flutter, diabetes mellitus, geographic region, baseline ABI <0.60, prior amputation, baseline systolic blood pressure, and treatment assignment (Table 4).

Effect of Ticagrelor When Compared With Clopidogrel

The primary end point of cardiovascular events (cardiovascular death, MI, and ischemic stroke) was similar between the ticagrelor and clopidogrel arms in the EUCLID trial.[12] The unadjusted rates of ischemic stroke (1.9% versus 2.4%) and all-cause stroke (2.2% versus 2.7%) were lower with ticagrelor when compared with clopidogrel (Table 5; Figure). After adjustment for baseline factors, the rates of ischemic stroke (adjusted hazard ratio, 0.78; 95% CI, 0.62–0.98; P=0.032) and all-cause stroke (adjusted hazard ratio, 0.80; 95% CI, 0.64–0.99; P=0.038) remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was also no significant difference in the incidence of hemorrhagic stroke (HR, 0.955; 95% CI, 0.51–1.79; P=0.886) or TIA (HR, 1.07; 95% CI, 0.72–1.60; P=0.737) between the 2 treatment groups (Table 5).

Absolute Risk Differences

The absolute risk difference, defined as the ticagrelor event percentage minus the clopidogrel event percentage, and the corresponding 95% CIs of the risk difference are shown in Table I in the online-only Data Supplement. Importantly, the risk differences for ischemic stroke (−0.54%; 95% CI, −1.02 to −0.06) and all-cause stroke (−0.55%; 95% CI, −1.07 to −0.04) favoring ticagrelor were consistent, whereas no risk difference existed for TIMI (Thrombolysis in Myocardial Infarction) major bleeding (0.06%; 95% CI, −0.35 to 0.48) or hemorrhagic stroke (−0.01%; 95% CI, −0.35 to 0.48).