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


In the current study, we report 3 key findings about all-cause stroke in patients with PAD enrolled in the EUCLID study. First, the rate of all-cause stroke was 2.4% among patients with symptomatic PAD during a mean study follow-up of 30 months. Second, baseline characteristics that were independently associated with all-cause stroke included many known clinical comorbidities including older age, prior stroke, prior AF/flutter, diabetes mellitus, geographic region, more severe PAD (including baseline ABI <0.60 and history of amputation), and baseline systolic blood pressure. Finally, ticagrelor was associated with overall lower rates of all-cause stroke and ischemic stroke, and the rate of hemorrhagic stroke was similar in patients treated with ticagrelor and clopidogrel.

The rate of stroke events in the current study (2.4% over 30 months) is similar to the rate reported in other trials of patients at risk for stroke with documented vascular disease on potent antiplatelet agents (2%–5%).[10,17] Risk of stroke is highest in the acute period following a stroke or TIA, ranging from 6% to 11% of study participants[5,7,18] compared with patients outside of the acute poststroke setting and patients with multiple cardiovascular risk factors for which the rates are somewhat lower (3%–6%). The lowest rates have been observed in the post-MI setting (≤2%).[8,19] These differences in event rates likely reflect the differences in the enrolled populations and the risk related to the various mechanisms of stroke. This is evidenced by the high rate of all-cause stroke in the patients with a prior history of stroke (5.2%) when compared with patients without a prior history of stroke (2.2%), and the differences in rates between the different cohorts within the EUCLID study (Table 3).

In our assessment of factors that confer risk for all-cause stroke, we found that baseline factors including age, prior stroke, prior AF/flutter, diabetes mellitus, geographic region, baseline ABI <0.60, prior amputation, and baseline systolic blood pressure were significant predictors of the occurrence of all-cause stroke in patients with PAD. These factors are similar to prior reports of at-risk populations, including patients with PAD, treated with antiplatelet therapy.[3,19] It is interesting to note that many of these factors are not directly responsive to antiplatelet therapy (ie, age and AF), or are associated with small vessel stroke types (ie, diabetes mellitus), which are also generally considered less responsive to antiplatelet treatment.[20] This results in the majority of benefit of potent antiplatelet therapy being observed early after an index stroke.[21] These stroke events clinically represent treatment failures for antiplatelet monotherapy and highlight the residual risk that patients with PAD have, and factors that need to be considered in optimizing clinical management, as well as identification of target populations in subsequent trial design. Surprisingly, some common risk factors generally associated with increased stroke risk such as body mass index >30 kg/m2, prior MI, prior carotid or coronary revascularization, and hyperlipidemia were not found to be significantly associated with stroke events in this PAD population, likely highlighting the burden of atherosclerosis in this group of patients.[3,22]

Our observations on risk variation by region are also intriguing. While there are many suggested factors to the regional and geographic differences in stroke prevalence, there has not been a clearly identified explanation.[23,24] The various studies are difficult to compare due to methodological differences and the heterogeneity of the prime risk factors including hypertension, diabetes mellitus, and dyslipidemia.[25] However, the relationship of these factors and additional factors such as patient and clinician awareness of stroke, access to care, and social determinants of health are also important to consider.[25] Data from EUCLID are insufficient to explore these regional differences in stroke risk and suggest that further work needs to be done to fully explore these observations.

Finally, we explored the effect of ticagrelor compared with clopidogrel to reduce the rate of stroke in patients with symptomatic PAD. We found that ticagrelor use was associated with a greater reduction in all-cause stroke and ischemic stroke when compared with clopidogrel without any associated increase in bleeding risk. This effect was observed despite the fact that no difference existed between therapies to reduce the composite of cardiovascular death, MI, or ischemic stroke in the overall EUCLID trial.[12] Similar results have been seen for ticagrelor in acute secondary prevention of ischemic stroke when compared with aspirin alone.[5] These results from the SOCRATES trial (Acute Stroke or Transient Ischaemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) suggest that more potent antiplatelet therapy may be particularly beneficial in patients with PAD acutely after a cardiovascular event. Indeed, studies in which combination antiplatelet therapy is given acutely, within 24 hours of an event, resulted in reduced rates of recurrent MI and stroke.[9,21]

This study has several limitations. EUCLID was not designed as a dedicated stroke prevention trial and, as a result, the patients who had a stroke experienced a combination of primary and secondary stroke events. In EUCLID, ≈8% of patients had prior stroke and are overrepresented in the group that had a subsequent stroke event during the trial. Indeed, patients with an established stroke mechanism are at very high risk for a subsequent stroke and dominated this stroke cohort (17.7% with prior stroke in stroke cohort versus 8% in the nonstroke cohort). The cohort also included patients with a history of AF, a key stroke risk factor, for which consensus guidelines would suggest therapeutic anticoagulation when possible. Since none of the patients in the trial were on anticoagulation (this was an exclusion for the parent trial), they remained at high risk and are thus also overrepresented in the stroke cohort (7.4% of stroke cohort versus 3.5% of nonstroke cohort). Finally, follow-up data were not available to assess the impact of stroke on functional status (eg, modified Rankin Scale) or major disability in EUCLID.

Implications for Future Trials

The current results, and results from other clinical trials, suggest that prevention of stroke as an end point may be different from other cardiovascular events (eg, nonfatal MI) within an at-risk population of patients with symptomatic PAD. Similar findings have been noted in other substudies that have looked at stroke in isolation from other cardiovascular events such as MI, cardiovascular death, or composite cardiovascular end points.[8,9] Furthermore, studies looking at early prevention after acute stroke or TIA found that dual antiplatelet therapy is generally better than monotherapy,[5,21] suggesting that long-term prevention differs from acute prevention and that strategies need to be adjusted based on when they are initiated relative to the initial vascular event. Future trials are needed to confirm this clinical approach and should aggressively address other stroke risk factors such as diabetes mellitus, hyperlipidemia, and hypertension in a standardized fashion, as these factors can result in high numbers of small vessel strokes that may not be as responsive to potent antiplatelet therapy over time.


We have demonstrated that all-cause stroke occurred in 2.4% of patients with symptomatic PAD in the EUCLID trial. Independent baseline factors associated with all-cause stroke included age, prior stroke, prior AF/flutter, diabetes mellitus, geographic region, baseline ABI <0.60, prior amputation, and baseline systolic blood pressure. Ticagrelor was also associated with a significantly lower incidence of ischemic stroke and all-cause stroke when compared with clopidogrel, but these results are limited by the overall absence of benefit for ticagrelor on the primary composite end point of the EUCLID trial. Further prospective study is needed to understand how to prevent all-cause stroke in high-risk populations such as patients with PAD.