Outcome Differences Between Men and Women With PAD: EUCLID Insights

Compared with men, women with PAD are less likely to experience cardiovascular events or die despite having a higher burden of traditional CVD risk factors. However, both sexes have similar risk of major amputations and other limb events, a sex-based analysis of the EUCLID trial suggests.

Senior author William R. Hiatt, MD (University of Colorado School of Medicine, Aurora), said the historical underrepresentation of women in PAD trials has made it difficult to understand where the differences compared with men lie, and how they impact outcomes.

“It seems like we still have a harder time getting women in these trials, and people talk about them having less symptom burden, but that doesn't appear to be the case from the baseline characteristics. Once you get them in a trial like this and characterize them, then you see what I would say are some expected differences between the sexes,” he said in an interview with TCTMD.

EUCLID randomized 13,885 symptomatic PAD patients from 28 countries to receive either 90 mg of ticagrelor twice daily or 75 mg of clopidogrel once a day. At 3 years, there was no difference between the two drugs in the primary efficacy endpoint of cardiovascular death, MI, or ischemic stroke (HR 1.02; 95% CI 0.92-1.13). Hiatt noted that the ability to do subgroup analyses in a dedicated PAD population like EUCLID, beyond the main results, has proved important.

Another interesting difference that was born out in the analysis was that even when PAD severity was similar, women were less likely than men to have received lower-extremity revascularization prior to enrolling in the trial. After enrollment, revascularization rates were nearly identical at 12.6% for women and 12.5% for men (P = 0.797).

“It is encouraging that the environment of the clinical trial mitigated the biases, and this could potentially be implemented in daily patient care,” notes Naomi M. Hamburg, MD (Boston University School of Medicine, MA), in an accompanying editorial.

In addition to providing “a substantial next step in understanding sex-based differences in PAD outcomes,” Hamburg says the comparable limb outcomes and favorable overall outcomes seen in the study “belie the oft-cited concept that women with PAD who are older and sicker are poor candidates for intensive medical and procedural therapies.”

The study was published online February 10, 2020, ahead of print in the Journal of the American College of Cardiology.

Teasing Out Differences

Hiatt and colleagues led by Axel Haine, MD (University of Bern, Switzerland), compared CVD and limb event outcomes in the 3,888 women and 9,997 men enrolled in EUCLID. At baseline, prescribing of antiplatelet therapy, statins, ACE inhibitors and/or angiotensin receptor blockers for secondary prevention did not differ by sex. Compared with men, women were older and had a higher burden of diabetes, hypertension, hyperlipidemia, and chronic kidney disease. However, they were less likely than men to be current or former smokers or to have a history of cerebrovascular events/revascularizations, coronary events/revascularizations, or established polyvascular disease.

At a mean follow-up of 30 months, MACE rates were 9.5% in women versus 11.2% in men (P < 0.001). Similarly, all-cause mortality was 7.6% for women and 9.7% men (P < 0.001). Women also were less likely than men to die of cardiovascular causes or MI, but had a similar risk of ischemic stroke. There was no difference by sex in major adverse limb events (MALE; P = 0.369) or in hospitalization for acute limb ischemia (P = 0.536).

Commenting for TCTMD, Herbert Aronow, MD (Brown University, Providence, RI), said he is not convinced that the men and women in the study had similar degrees of PAD or atherosclerosis, however.

 “Although symptom status as reflected by the Rutherford classification was similar for both sexes, men were more likely to have had a prior revascularization (including below-the-knee) or an amputation,” he said in an email. “Furthermore, men were more likely to have atherosclerotic involvement of two or more vascular beds than women. Together, these observations suggest that men may have been at higher risk of MACE, despite statistical adjustment.”

To TCTMD, Hiatt said that may be a reasonable explanation. “It is hard to know if women have lower risk or men have higher risk when you're comparing across two different subgroups,” he said.

It is paramount that a greater percentage of women be included in future PAD trials and that sex-based differences in study endpoints be prespecified so that we may better understand how available treatments should be applied to the individual patient. Herbert Aronow

In her editorial, Hamburg notes that polyvascular disease is an important emerging risk factor for MACE. “There appears to be greater complexity to the biological processes leading to polyvascular disease than simply the cumulative effects of individual risk factors,” she writes.

Haine and colleagues conclude that more research is needed to define additional factors that may be responsible for sex-related disparities in PAD outcomes.

As for the similarities in limb events, Aronow said it’s not surprising since symptoms drive revascularization decisions and symptom status was similar between men and women at the time of enrollment.  “Interestingly, while MALE rates were statistically similar, the Kaplan-Meier curves may suggest a qualitative difference between the sexes, with men having higher numerical rates of MALE over time. It remains possible that were the study larger, or had more women been included, men would have suffered more MALE over time because of a greater overall atherosclerotic disease burden,” he noted.

Women made up only 28% of in EUCLID participants. “It is paramount,” Aronow said, “that a greater percentage of women be included in future PAD trials and that sex-based differences in study endpoints be prespecified so that we may better understand how available treatments should be applied to the individual patient.”