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. Author manuscript; available in PMC: 2022 May 1.
Published in final edited form as: Atherosclerosis. 2021 Mar 29;324:52–57. doi: 10.1016/j.atherosclerosis.2021.03.031

Risk of peripheral artery disease according to race and sex: The Atherosclerosis Risk in Communities (ARIC) Study

Caitlin W Hicks 1, Ning Ding 2, Lucia Kwak 2, Shoshana H Ballew 2, Corey A Kalbaugh 3, Aaron R Folsom 4, Gerardo Heiss 5, Josef Coresh 2, James H Black III 1, Elizabeth Selvin 2, Kunihiro Matsushita 2
PMCID: PMC8096721  NIHMSID: NIHMS1690971  PMID: 33823370

Abstract

Background and aims

Previous community-based studies have demonstrated sex and race-based disparities in the risk of cardiovascular disease. We sought to examine the association of sex and race with incident peripheral artery disease (PAD) and critical limb ischemia (CLI) related hospitalizations.

Methods

In 13,451 Black and White ARIC participants without prevalent PAD at baseline (1987–89), we estimated the cumulative incidence of PAD- and CLI-related hospitalization over a median follow-up of 26 years. We quantified hazard ratios (HRs) using Cox models across four sex- and race-groups. PAD and CLI were defined by hospitalization discharge codes.

Results

The cumulative incidence of PAD-related hospitalization was higher in males than females in Whites (5.1% vs. 2.7%; p<0.001) but not in Blacks (5.7% vs. 5.0%; p=0.39). The cumulative incidence of CLI-related hospitalization differed significantly by race more than sex, occurring in 3.1% Black males, 3.1% Black females, 1.4% White males, and 0.8% White females (p<0.001). After risk factor adjustment, the risk of incident PAD-related hospitalization was similar for White males vs. White females [HR 1.14, 95%CI 0.90–1.45], and slightly higher for Black males [HR 1.26, 95%CI 0.92–1.72] and Black females [HR 1.39, 95%CI 1.03–1.87] compared to White females. The adjusted risk of incident CLI-related hospitalization was similar for White males vs. White females [HR 1.15, 95%CI 0.75–1.76], and significantly higher for Black males [HR 1.96, 95%CI 1.22–3.16] and Black females [HR 2.06, 95%CI 1.31–3.24] compared to White females.

Conclusions

These data suggest that there are both sex- and race-specific patterns of PAD-related hospitalization that lead to differences in clinical disease risk and presentation.

Graphical Abstract

graphic file with name nihms-1690971-f0001.jpg

1. Introduction

Women have a lower cumulative lifetime risk of atherosclerotic cardiovascular disease than men1–3. However, several epidemiologic studies based on ankle-brachial index (ABI) have demonstrated a similar or higher prevalence of peripheral artery disease (PAD) in women compared to men4–6. Although the higher prevalence in women may be partially due to lower ABI in persons with shorter height7, women also tend to have more advanced disease upon presentation with PAD than men8. To our knowledge, there are no prospective studies that have evaluated the association of sex with incident PAD, including its severe form, critical limb ischemia (CLI).

There have also been a number of studies describing racial disparities in PAD. In a recent meta-analysis comparing PAD prevalence in different ethnic groups, Blacks were found to have the highest prevalence of disease, followed by Whites and south Asians, respectively9. Black patients have been shown to have a higher likelihood of lower extremity amputation compared to White patients10, 11, suggesting a higher prevalence of CLI in Blacks.

The aim of this study was to quantify the risk of PAD- and CLI-related hospitalizations according to sex and race using data from the Atherosclerosis Risk in Communities (ARIC) Study. We hypothesize that incident PAD- and CLI-related hospitalizations will be similar between men and women, and higher in Black participants compared to White participants.

2. Materials and methods

2.1. Study cohort

The ARIC Study is a prospective community-based cohort study that enrolled 15,792 adults between 1987 and 1989 from four U.S. communities, including Washington County, Maryland, suburban Minneapolis, Minnesota, Jackson, Mississippi, and Forsyth County, North Carolina. Participants were between 45 and 64 years of age at baseline, and have been followed with serial in-person assessments and hospitalization surveillance. For this analysis, we excluded participants with races other than Black or White (N=48), Black participants from Minneapolis and Washington County (N=55), participants missing covariates of interest (N=1348), and participants with prevalent PAD (defined as ABI ≤0.9, self-reported intermittent claudication based on Rose questionnaire12, or a history of leg artery revascularization) at baseline (N=673), resulting in a study population of 13,668 participants.

2.2. Baseline variables

Sex, race, age, education level, income, frequency of visits for health care, and health insurance status were based on self-report. Smoking pack-years and alcohol status were also based on self-report. Total cholesterol and HDL cholesterol were determined by enzymatic methods. Diabetes was defined as fasting glucose ≥126 mg/dL, non-fasting glucose ≥200 mg/dL, use of antidiabetic medications, or self‐reported physician diagnosis of diabetes mellitus. Blood pressure (mmHg) was measured three times at baseline, and the average of the last two measurements were used for the analysis. Anti-hypertensive medication use and stroke were based on self-report. Prevalent coronary heart disease was defined as electrocardiogram evidence of myocardial infarction at visit 1, self-reported physician-diagnosed myocardial infarction, or history of coronary revascularization procedure. Prevalent heart failure was defined as self-reported taking of any medication for heart failure, or a Gothenburg score12 of 3 that incorporated cardiac and pulmonary factors and treatment with digitalis or loop diuretics. Estimated glomerular filtration rate (eGFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using age, sex, race and serum creatinine13.

2.3. Outcomes

The primary outcomes of the study were incident PAD-related hospitalizations and incident CLI-related hospitalizations, which were identified according to International Classification of Diseases, Ninth Revision (ICD-9) discharge codes. PAD-related hospitalizations were identified according to the following ICD-9 codes based on previous literature14, 15: atherosclerosis of native arteries of the extremities, unspecified (440.20); atherosclerosis of native arteries of the extremities with intermittent claudication (440.21); atherosclerosis of native arteries of the extremities with rest pain (440.22); atherosclerosis of native arteries of the extremities with ulceration (440.23); atherosclerosis of native arteries of the extremities with gangrene (440.24); other atherosclerosis of native arteries of the extremities (440.29); atherosclerosis of bypass graft of the extremities (440.3); atherosclerosis of other specified arteries (440.8); peripheral vascular disease, unspecified (443.9); and leg artery revascularization (38.18, 39.25, 39.29, 39.50). Of these, 440.22, 440.23, and 440.24 were considered to be CLI. We also considered any cases including PAD and an ICD-9 code for leg amputation (84.1x), lower extremity ulcer (707.1x), or gangrene (785.4) to be CLI. Participants were followed until incident PAD/CLI, date of death or last contact, or September 30, 2015, whichever came first. September 2015 was chosen as the last point of follow-up to maintain diagnostic consistency since ICD codes switched from ICD-9 to ICD-10 in October 2015.

2.4. Statistical analysis

Baseline data for all patients in each sex-race group were described as means (standard deviation, SD) or counts (percent) as appropriate. We estimated the cumulative incidence of PAD- and CLI-related hospitalizations across the four sex- and race-groups (White female; White male; Black female; Black male), using the Fine and Grey method accounting for competing risk of mortality16.

Cox proportional hazards models (hazard ratios [HR] with 95% confidence intervals [CI]) were then used to quantify the association between sex-race and incident PAD- and CLI-related hospitalizations. We constructed three different models to address potential mechanisms behind the sex/race-based difference in PAD- or CLI-related hospitalizations. Model 1 adjusted for age. Model 2 adjusted for age and sociodemographic factors, including education level, income, frequency of visits for health care, and health insurance. Model 3 adjusted for all variables in Model 2 as well as clinical risk factors, including pack-years of smoking, current drinking status, total cholesterol, HDL cholesterol, diabetes, systolic blood pressure, anti-hypertensive medication use, eGFR, prevalent heart failure, prevalent coronary heart disease, and prevalent stroke. In order to assess whether any sex-race differences found on our initial analysis persisted after accounting for mortality as a competing event, we also ran Fine and Gray’s proportional subhazards models16.

Stata version 14.2 (StataCorp LP, TX) was used for all analyses. All p-values were two-sided and significance was set at p < 0.05.

3. Results

3.1. Baseline characteristics

Among the 13,451 ARIC participants analyzed, 45.7% (N = 6,143) were male and 24.0% (N = 3,221) were Black. Within the White cohort, 48.1% (N = 4920) were male. Within the Black cohort, 38.0% (N = 1,223) were male. Participant socioeconomic factors, comorbidities, blood pressure, and plasma cholesterol levels differed across sex-race categories (Table 1). In both the White and Black race groups, females tended to have a higher prevalence of anti-hypertensive use and heart failure but a lower prevalence of coronary heart disease compared to men. Females also had lower annual incomes but a higher frequency of health care visits compared to men. Mean number of smoking pack-years was higher for males compared to females. Diabetes was most prevalent among Black females and Black males.

Table 1.

Baseline characteristics of ARIC participants by sex-race category (1987–1989) (N= 13,451)

White Black
Female Male Female Male
N 5310 4920 1998 1223
Age, years (SD) 54.4 (5.7) 55.2 (5.7) 53.7 (5.7) 54.2 (5.9)
Pack-years of smoking, mean (SE) 11.2 (17.0) 23.2 (24.5) 7.3 (14.0) 19.3 (24.5)
Current drinking status, % 3230 (60.8%) 3410 (69.3%) 409 (20.5%) 596 (48.7%)
Anti-hypertensive use, % 1406 (26.5%) 1176 (23.9%) 958 (47.9%) 440 (36.0%)
Diabetes, % 429 (8.1%) 489 (9.9%) 407 (20.4%) 210 (17.2%)
Prevalent stroke, % 86 (1.6%) 74 (1.5%) 40 (2.0%) 27 (2.2%)
Prevalent heart failure, % 253 (4.8%) 127 (2.6%) 169 (8.5%) 47 (3.8%)
Prevalent coronary heart disease, % 85 (1.6%) 402 (8.2%) 50 (2.5%) 65 (5.3%)
Systolic blood pressure, mmHg (SD) 116.8 (17.5) 120.0 (16.1) 127.9 (20.9) 130.3 (21.2)
Diastolic blood pressure, mmHg (SD) 69.8 (9.7) 73.6 (9.9) 77.9 (11.5) 82.6 (12.9)
HDL cholesterol, mmol/L (SD) 5.6 (1.1) 5.4 (1.0) 5.6 (1.2) 5.4 (1.2)
Total cholesterol, mmol/L (SD) 1.5 (0.4) 1.1 (0.3) 1.5 (0.4) 1.3 (0.4)
eGFR, ml/min 101.3 (12.1) 97.5 (12.4) 113.3 (20.2) 107.9 (18.8)
Health insurance, % 5056 (95.2%) 4709 (95.7%) 1527 (76.4%) 946 (77.4%)
Education level, %
 <High school 838 (15.8%) 858 (17.4%) 790 (39.5%) 533 (43.6%)
 <College 2700 (50.8%) 1927 (39.2%) 596 (29.8%) 321 (26.2%)
 College 1772 (33.4%) 2135 (43.4%) 612 (30.6%) 369 (30.2%)
Income, %
 <12,000/yr 468 (8.8%) 201 (4.1%) 918 (45.9%) 359 (29.4%)
 $12,000/yr to 24999/yr 1184 (22.3%) 792 (16.1%) 594 (29.7%) 392 (32.1%)
 ≥$25000/yr 3658 (68.9%) 3927 (79.8%) 486 (24.3%) 472 (38.6%)
Frequency of health care visit, %
 None 1398 (26.3%) 1647 (33.5%) 337 (16.9%) 397 (32.5%)
 Less than once per year 1422 (26.8%) 1835 (37.3%) 357 (17.9%) 280 (22.9%)
 Once or more per year 2490 (46.9%) 1438 (29.2%) 1304 (65.3%) 546 (44.6%)
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3.2. Incidence of PAD- and CLI-related hospitalizations by sex and race

After a median of 26 years of follow-up, there were 566 incident PAD-related hospitalizations (including 323 cases with revascularization procedure codes) and 212 incident CLI-related hospitalizations. Adjusting for competing risk of death, the cumulative incidence of PAD-related hospitalization was higher in males than in females in Whites (5.1% vs. 2.7%; p <0.001) but not in Blacks (5.7% vs. 5.0%; p = 0.39) (Figure 1A). The 26-year cumulative incidence of CLI-related hospitalization differed significantly by race more than sex, occurring in 3.1% of Black males, 3.1% of Black females, 1.4% of White males, and 0.8% of White females (p < 0.001; Figure 1B).

Figure 1.

Figure 1.

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Cumulative incidence of incident (A) PAD and (B) CLI related hospitalization stratified by race and sex after accounting for competing risk of death (ARIC, 1987 to 2015).

3.3. Associations of sex and race with incident PAD-related hospitalization

The age-adjusted risk of incident PAD-related hospitalization was higher in Black males, Black females, and White males compared to White females (Model 1, Table 2). After adjusting for socioeconomic factors (Model 2), the risk of incident PAD-related hospitalization was higher in White males [HR 2.00 (95% CI 1.62–2.46)] compared to White females. The risk of PAD-related hospitalization was attenuated but also significantly higher for Black males [HR 1.65 (95% CI 1.21–2.24)] and Black females [HR 1.44 (95% CI 1.08–1.91)] compared to White females. Further adjusting for clinical risk factors (Model 3, Table 2) attenuated the results such that risk of PAD-related hospitalization for White males vs. White females was no longer significant. Adjusting for competing risk of death did not substantially change our results (Supplementary Table 1).

Table 2.

Hazard ratios (95% CI) for the association of sex and race with incident PAD and CLI related hospitalizations in ARIC (1987–2015)

Outcome Model White-Female White-Male Black-Female Black-Male
PAD Model 1a Reference 2.00 (1.63–2.46) 2.12 (1.65–2.74) 2.64 (1.98–3.53)
Model 2b Reference 2.30 (1.86–2.84) 1.42 (1.07–1.89) 2.02 (1.49–2.74)
Model 3c Reference 1.14 (0.90–1.45) 1.39 (1.03–1.87) 1.26 (0.92–1.72)
CLI Model 1a Reference 1.75 (1.20–2.55) 4.37 (2.98–6.40) 4.70 (3.03–7.30)
Model 2b Reference 2.19 (1.49–3.23) 2.39 (1.55–3.70) 3.25 (2.04–5.17)
Model 3c Reference 1.15 (0.75–1.76) 2.06 (1.31–3.24) 1.96 (1.22–3.16)
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a

Model 1: Adjusted for age.

b

Model 2: Further adjusted for education level, income, frequency of visits for health care, health insurance.

c

Model 3: Adjusted for variables in Model 2 plus pack-years of smoking, current drinking status, total cholesterol, HDL cholesterol, eGFR, diabetes, systolic blood pressure, anti-hypertensive medication use, prevalent heart failure, prevalent coronary heart disease, and prevalent stroke.

PAD: peripheral artery disease; CLI: critical limb ischemia.

3.4. Associations of sex and race with incident CLI-related hospitalizations

The age-adjusted risk of incident CLI-related hospitalization was much higher in Black males and Black females compared to White females, with age-adjusted HR exceeding 4 in both groups (Model 1, Table 2). White males also had a higher risk of CLI-related hospitalization (although lesser magnitude than Blacks) compared to White females in Model 1. Adjusting for socioeconomic and atherosclerotic factors attenuated the association of White males with CLI-related hospitalization, but the risk of CLI-related hospitalization remained significantly higher in Blacks regardless of sex, with HR around 2 in both groups (Model 3, Table 2). The elevated risk of incident CLI-related hospitalization for Black females [sub-HR 1.93 (95% CI 1.22–3.08)] and Black males [sub-HR 1.68 (95% CI 1.03–2.75)] vs. White females remained significant after additionally accounting for competing risk of death (Supplementary Table 1). In contrast, the risk of CLI-related hospitalization was not significant for White males [sub-HR 1.33 (0.88–2.01)] in competing risk analysis.

4. Discussion

Based on 26 years of follow-up in Black and White participants in the ARIC study, we found that the crude cumulative incidence of PAD-related hospitalization was higher for males than females in Whites but not in Blacks. The crude cumulative incidence of CLI was largely similar for males and females within race groups. After adjusting for covariates, Blacks had the highest risk of incident CLI-related hospitalization regardless of sex. The elevated risk of PAD and CLI in White males compared to White females was no longer significant after accounting for covariates and competing risk of mortality.

Overall, we observed a similar risk of PAD- and CLI-related hospitalizations between men and women in our study. These findings are consistent with epidemiologic studies of PAD in the general population17, 18. For example, data from the Cardiovascular Health Study demonstrated that the risk of ABI decline to a value ≤ 0.90 was not significantly different in women compared to men over 6 years of follow-up18. In contrast, there are a few studies that suggest a higher prevalence of PAD in women compared to men based on cross-sectional analyses19, 20. The Chronic Renal Insufficiency Cohort (CRIC), which reported the incidence of a more broad definition of PAD (either ABI <0.90 or an adjudicated lower extremity revascularization or major amputation), found even a higher risk of incident PAD in women compared to men for persons with chronic kidney disease21. Our study confirms a similar risk of PAD- and CLI-related hospitalizations in males and females in the general population over nearly 30 years of follow-up.

There are well described sex differences in the risk of atherosclerotic disease in other vascular beds. The prevalence and incidence of both coronary heart disease and stroke are consistently higher in males compared to females, regardless of race22, 23. It is postulated that exposure to endogenous estrogens prior to menopause delays the manifestation of coronary heart disease in women by regulating lipids, inflammatory markers, and the coagulation cascade, and promoting vasodilation24, 25. As a result, females tend to present with coronary syndromes at an older age than men26, which may reduce their overall cumulative lifetime risk. We did not find a similar difference in the risk of PAD- or CLI-related hospitalizations for women vs. men. The mechanisms behind this discrepancy are unclear17, 18, 27 but suggest there may be differences in the pathophysiology of atherosclerosis in different vascular beds26, 28.

Our observation that White males had a higher crude cumulative risk of PAD-related hospitalization compared to White females was somewhat of an exception to our overall findings. The higher risk of incident PAD-related hospitalization for White males compared to White females may occur because this race-sex group tends to undergo more lower extremity revascularization procedures than the others, especially for claudication (i.e. mild or moderate PAD)15, 29, 30. Women tend to present with PAD at older ages than men, and are more frequently asymptomatic or present with atypical symptoms31. As a result, the lower risk of incident PAD-related hospitalizations (without CLI) in White women may represent under-diagnosis rather a lower risk of disease32. Notably, the risk of PAD-related hospitalization was similar for White men and White women after adjusting for socioeconomic and atherosclerotic risk factors. The attenuation of PAD-related hospitalization risk after adjustment confirms that men have a higher prevalence of atherosclerotic risk factors than women33.

The higher risk of CLI-related hospitalization in Blacks compared to Whites deserves attention. Race-based differences in the prevalence and incidence of PAD have been previously described34. The prevalence of PAD as defined by ABI < 0.9 has been shown to be higher in Blacks compared to Whites in both prospective34,17,35 and cross-sectional studies36,37. The lifetime risk estimate of PAD is approximately 30% for Blacks compared to 20% for Whites, although the absolute risk varies according to clinical risk factors35. A recent study demonstrated that among PAD patients, Blacks are more likely to require major amputations than Whites38. Our study extends these findings to CLI-related hospitalization risk in the general population. It is noteworthy that this racial difference remains significant after accounting for several socioeconomic and clinical factors in our study as well as others27, 38, 39, indicating that there may be other social determinants of health that our study could not account for40,38,41,42.

The findings of our study have important clinical and research implications. Clinically, our data highlight the notion that physicians should maintain a high index of suspicion for PAD regardless of sex and race. Traditionally, PAD was considered a disease that primarily affected White males32. We provide contemporary evidence to suggest that the risk of PAD is more similar by sex and race than previously thought, at least regarding PAD-related hospitalization17, 18, 27. As a result, early and aggressive risk factor modification is equally important for both men and women regardless of race43. Despite this, women are less likely to receive antiplatelet, lipid-lowering, and β-blocker therapy in the presence of either peripheral or cardiovascular disease44, 45. Similarly, Black adults are less likely to receive cardiovascular preventive therapy and adequate risk factor control than While adults46, 47. By raising awareness that PAD and CLI are not limited to White males, we hope that risk factor management will be applied more broadly in the clinical setting. From a research standpoint, there is a critical need for additional epidemiologic studies evaluating the sex- and race-specific incidence and risk factors for the full spectrum of PAD including asymptomatic cases, PAD with claudication, and CLI. There is also a need for the development of focused disease prevention and early diagnosis strategies that may help reduce the economic burden and adverse outcomes associated with PAD in Blacks and in women14, 48–50.

The limitations of our study include our use of diagnostic codes to define PAD and CLI, self-reporting of several study variables (e.g. prevalent heart failure), and the restricted sampling of Black participants in the ARIC study. As noted above, we chose to define PAD and CLI based on hospitalization codes in an effort to capture clinical PAD diagnoses uniformly over the follow-up time in ARIC. However, these data likely underestimate the true prevalence of PAD, particularly among asymptomatic patients. Also, we do not have information on exact criteria of admissions for PAD across hospitals. Nonetheless, the investigation of PAD-related hospitalization is of value given its impact on patient prognosis and medical expenditure51. Black participants were only enrolled at two ARIC sites due to community demographics, and findings may not necessarily generalize to the US population. Nonetheless, surveillance data from the ARIC communities have been informing national guidelines and reports52, 53. The strengths of our study include the long follow-up time over >25 years, total capture of all hospitalizations and associated PAD and CLI events in the ARIC cohort, and the prospective nature of the study design.

In conclusion, males have a higher risk of incident PAD-related hospitalization than females in Whites, but not in Blacks. After adjusting for covariates, Blacks had the highest risk of incident CLI-related hospitalization regardless of sex. These findings suggest that there are both sex- and race-specific patterns of peripheral atherosclerotic disease that lead to differences in clinical disease risk and presentation.

Supplementary Material

1

Highlights.

  • Males have a higher risk of incident clinical PAD than females in Whites, but not in Blacks

  • The risk of incident CLI differs significantly by race more than sex

  • The elevated risk of incident CLI was similar between Black males and females

  • There are both sex- and race-specific patterns of peripheral atherosclerotic disease that lead to differences in clinical disease risk and presentation

Acknowledgements

The authors thank the staff and participants of the ARIC study for their important contributions.

Financial support

The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). Dr. Hicks was supported by NIH/NIDDK grant K23DK124515. Dr. Selvin was supported by NIH/NIDDK grants K24DK106414 and R01DK089174. Dr. Matsushita was supported by NIH/NHLBI grant R21HL133694.

Footnotes

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Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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