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

Abstract and Introduction


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.


Stroke affects millions of people annually worldwide.[1,2] In the United States, stroke is the fifth leading cause of death and annually affects over 795 000 people.[1] More than one-third of those who experience a stroke are left permanently disabled; making stroke the leading cause of long-term disability.[1,2] Treatment with antiplatelet agents is the current best practice to prevent ischemic stroke in all cardiovascular patients without known atrial fibrillation (AF), including those with lower extremity peripheral artery disease (PAD) and prior stroke.[3] However, the rates of stroke and primary risk factors for stroke in the setting of PAD are not well studied and may require an alternative approach to prevention. Indeed, many prior studies have failed to show consistent advantages for specific antiplatelet agents across populations at risk.[4–8] There is increasing evidence that more potent antiplatelet therapy may be beneficial in patients with PAD and in patients with vascular disease in multiple beds. Ticagrelor in combination with aspirin was found to be superior to aspirin alone in reducing all-cause stroke risk in patients with prior myocardial infarction (MI).[6,8] Ticagrelor was also superior to clopidogrel in reducing stroke events in patients with an index acute coronary syndrome (including the subgroup of patients with PAD).[6,9] Similar advantages in stroke prevention were seen for clopidogrel compared with aspirin in patients at high risk for atherosclerotic events, especially those patients with PAD.[8–10] These prior data suggest there may be an important role for more potent and dual antiplatelet therapy in the prevention of stroke or transient ischemic attack (TIA) and in patients with symptomatic PAD. Further characterization of stroke rates and risk factors in this population would be helpful in understanding the main stroke risk drivers in this population and lend further insight into prevention strategies.

In the current substudy from the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease), there are 3 primary aims: (1) to determine the incidence of all-cause stroke (ischemic and hemorrhagic) and TIA in patients with symptomatic PAD; (2) to determine the factors associated with all-cause stroke in patients with PAD; and (3) to evaluate the effect of ticagrelor compared with clopidogrel on the occurrence of stroke or TIA in the overall trial population.