Prevalence of and Risk Factors for Peripheral Arterial Disease in the United States
Results From the National Health and Nutrition Examination Survey, 1999–2000
Background— Peripheral arterial disease (PAD) is associated with significant morbidity and mortality and is an important marker of subclinical coronary heart disease. However, estimates of PAD prevalence in the general US population have varied widely.
Methods and Results— We analyzed data from 2174 participants aged 40 years and older from the 1999–2000 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial index <0.90 in either leg. The prevalence of PAD among adults aged 40 years and over in the United States was 4.3% (95% CI 3.1% to 5.5%), which corresponds to ≈5 million individuals (95% CI 4 to 7 million). Among those aged 70 years or over, the prevalence was 14.5% (95% CI 10.8% to 18.2%). In age- and gender-adjusted logistic regression analyses, black race/ethnicity (OR 2.83, 95% CI 1.48 to 5.42) current smoking (OR 4.46, 95% CI 2.25 to 8.84), diabetes (OR 2.71, 95% CI 1.03 to 7.12), hypertension (OR 1.75, 95% CI 0.97 to 3.13), hypercholesterolemia (OR 1.68, 95% CI 1.09 to 2.57), and low kidney function (OR 2.00, 95% CI 1.08 to 3.70) were positively associated with prevalent PAD. More than 95% of persons with PAD had 1 or more cardiovascular disease risk factors. Elevated fibrinogen and C-reactive protein levels were also associated with PAD.
Conclusions— This study provides nationally representative prevalence estimates of PAD in the United States, revealing that PAD affects more than 5 million adults. PAD prevalence increases dramatically with age and disproportionately affects blacks. The vast majority of individuals with PAD have 1 or more cardiovascular disease risk factors that should be targeted for therapy.
Received March 15, 2004; revision received May 4, 2004; accepted May 5, 2004.
Peripheral arterial disease (PAD) commonly results from progressive narrowing of arteries in the lower extremities, due to atherosclerosis. Previous studies have shown that PAD is associated with a significantly elevated risk of cardiovascular disease morbidity and mortality.1–3 However, estimates of PAD prevalence in the general US population have varied widely. Despite using similar diagnostic criteria, prior estimates of PAD prevalence in the United States have ranged from 3% to 30% in US adult populations.4–10
The risk for short-term cardiovascular ischemic events is a major concern for persons with PAD. Indeed, major risk factors for PAD include hypertension, hypercholesterolemia, diabetes, and smoking. In addition, limb amputation, a frequent clinical complication of PAD, is common among individuals with kidney disease11,12 and diabetes.13 Recent studies have also shown positive associations between PAD and inflammatory markers, including C-reactive protein (CRP) and fibrinogen.14,15
The present study was undertaken (1) to assess the prevalence of PAD among the general US adult population, (2) to assess the prevalence of cardiovascular risk factors among individuals with PAD, and (3) to determine the associations between hypothesized PAD risk factors and the prevalence of PAD in the US adult population. Prevalence estimates from this study are nationally representative of the noninstitutionalized population of adults aged 40 years and over in the United States.
This study was based on data from the 1999–2000 National Health and Nutrition Examination Survey (NHANES), an ongoing cross-sectional survey of the civilian, noninstitutionalized population of the United States. Detailed in-person interviews, physical examinations, and serum samples were obtained from more than 9000 persons in the 1999–2000 survey. Valid information on mean ankle-brachial blood pressure index (ABI) was available for 2381 individuals aged ≥40 years (83% of eligible persons). We excluded 6 participants with ABI values >1.5, values usually related to noncompressible vessels in the legs,16 and 228 participants (<10%) with missing variables of interest, which left 2174 individuals in the present study.
PAD can be determined with high sensitivity and specificity using the ABI, a simple, noninvasive procedure.17–19 We defined PAD on the basis of ABI measurements obtained from NHANES 1999–2000 participants aged ≥40 years during the examination component of the survey. Systolic blood pressure was measured on the right arm (brachial artery) and both ankles (posterior tibial arteries). If the participant had a condition associated with the right arm that would interfere with measurement, the left arm was used for brachial pressure measurement. Systolic blood pressure was measured twice at each site for participants aged 40 to 59 years and once at each site for participants aged ≥60 years. Left and right ABI measurements were obtained by dividing mean systolic blood pressure in the right and left ankle by mean blood pressure in the arm. PAD was defined as an ABI <0.90 in either leg.
Other Variables of Interest
Hypertension was defined as mean systolic blood pressure of 140 mm Hg or greater, mean diastolic blood pressure of 90 mm Hg or greater, physician diagnosis, or medication use. Mean blood pressure was composed of up to 4 readings on 2 separate occasions. Total cholesterol was measured enzymatically.20 Hypercholesterolemia was defined as a total cholesterol level 240 mg/dL or higher, physician diagnosis, or medication use. Diabetes was defined as self-reported physician diagnosis, use of diabetes medication, fasting glucose of ≥126 mg/dL, or nonfasting glucose of ≥200 mg/dL. Persons reporting “borderline diabetes” or solely reporting a diabetes diagnosis during pregnancy were considered nondiabetic.
Glomerular filtration rate (GFR), a measure of kidney function, was estimated by the Modification of Diet in Renal Disease (MDRD) Study formula21 based on serum creatinine, age, gender, and race. To appropriately estimate GFR, serum creatinine was calibrated to account for laboratory differences between NHANES III and NHANES 1999–2000.22 Failure to account for laboratory differences would lead to an overestimate of the prevalence of PAD among persons with low GFR. Kidney function was categorized on the basis of the classification system established by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative.21 Normal kidney function was defined as a GFR >90 mL · min−1 · 1.73 m−2; a GFR of 60 to 90 mL · min−1 · 1.73 m−2 was considered mildly decreased kidney function, and a GFR <60 mL · min−1 · 1.73 m−2 was considered low kidney function. There were too few individuals in the severely decreased GFR group (GFR <30 mL · min−1 · 1.73 m−2) to include these persons in a separate category.
Fibrinogen was measured quantitatively by the Clauss clotting method.20 High-sensitivity CRP was measured with a Behring Nephelometer II Analyzer.20 In analyses, both fibrinogen and CRP were categorized into quartiles. Body mass index (BMI) was estimated by dividing kilograms of weight by height in meters squared and was categorized according to the classification system established by the National Institutes of Health (<25, 25.0 to 30, and >30.0 kg/m2).23
Information on age, gender, race/ethnicity, and smoking was based on self-report during the questionnaire portion of the survey. Smoking status was determined using answers to the questions, “Have you smoked at least 100 cigarettes in your life?” and “Do you now smoke cigarettes?” During the interview, participants were also asked questions about their history of cardiovascular disease. For the purposes of the present study, prevalent coronary heart disease was defined as self-reported coronary heart disease or previous heart attack. Congestive heart failure and stroke were also defined on the basis of self-report.
Detailed information about data collection in NHANES 1999–2000 is available elsewhere.20
The NHANES surveys are ongoing complex, multistage probability samples of the civilian, noninstitutionalized population of the United States. The NHANES 1999–2000 survey oversampled the elderly, low-income persons, adolescents, Mexican Americans, and non-Hispanic blacks to provide more reliable estimates for these population subgroups.
Analyses were performed with SAS version 8.0 (SAS Institute Inc) and SUDAAN software (Research Triangle Institute) to obtain unbiased estimates from the complex NHANES sampling design. Standard errors for all estimates were obtained by the jackknife “leave-one-out” method. Adjusted ORs and their 95% CIs were estimated with logistic regression models.
Prevalence of PAD
The prevalence of PAD among individuals aged ≥40 years was 4.3% (95% CI 3.1% to 5.5%). Thus, in 2000, there were ≈5 million adults (95% CI 4 to 7 million) aged ≥40 years who would be classified as having PAD on the basis of an ABI <0.90. The Figure shows the prevalence of PAD by gender and age groups. The prevalence of PAD dramatically increased with advancing age in both sexes. The overall prevalence of PAD among individuals aged ≥70 years was 14.5% (95% CI 10.8% to 18.2%), which corresponds to ≈4 million individuals (95% CI 3 to 5 million). Table 1 shows the prevalence of PAD by selected population characteristics. No clear gender differences in PAD prevalence were observed.
The prevalence of PAD among non-Hispanic blacks was 7.9% (95% CI 5.2% to 10.6%), the highest among all race/ethnic groups. Prevalent PAD was associated with smoking status, with a prevalence of 6.8% (95% CI 3.7% to 9.9%) among current smokers compared with 4.4% (95% CI 2.8% to 6.0%) among former smokers and only 3.1% (95% CI 1.7% to 4.5%) in never-smokers. Among individuals with diabetes, 10.8% (95% CI 3.2% to 18.4%) had PAD compared with 3.6% (95% CI 2.2% to 5.0%) of individuals without diabetes. The prevalence of PAD among persons with low kidney function (GFR <60 mL · min−1 · 1.73 m−2) was 18.2% (95% CI 9.2% to 27.2%). The prevalence of PAD among individuals self-reporting a history of cardiovascular disease (coronary heart disease, congestive heart failure, or stroke) was 12.9% (95% CI 7.6% to 18.2%).
Cardiovascular Disease Risk Factors and PAD
Table 2 shows the distribution of cardiovascular disease risk factors among those individuals with and without PAD. The prevalence of “traditional” cardiovascular disease risk factors such as hypertension, high cholesterol, diabetes, and smoking was high among persons with PAD. More than 60% (95% CI 52% to 70%) of individuals with PAD had hypercholesterolemia, 74% (95% CI 64% to 83%) were hypertensive, 26% (95% CI 10% to 43%) had diabetes, and 33% (95% CI 22% to 44%) were current smokers. Approximately 95% (95% CI 90% to 100%) had at least 1 of these cardiovascular disease risk factors, and 72% (95% CI 63% to 80%) had 2 or more risk factors (analysis not shown). The overall prevalence of self-reported cardiovascular disease (coronary heart disease, congestive heart failure, and/or stroke) was 33% (95% CI 24% to 43%) among persons with PAD.
Risk Factors for PAD
The adjusted and unadjusted ORs of prevalent PAD according to selected risk factors are presented in Table 3. In age- and gender-adjusted analysis, individuals of non-Hispanic black race/ethnicity were ≈3 times as likely as their non-Hispanic white counterparts to have prevalent PAD (OR 2.83, 95% CI 1.48 to 5.42). The OR remained significant even after further adjustment for smoking status, BMI, hypertension, hypercholesterolemia, diabetes, and GFR (OR 2.39, 95% CI 1.11 to 5.12).
In age- and gender-adjusted analyses, traditional risk factors for cardiovascular disease were associated with PAD. Current smoking (OR 4.46, 95% CI 2.25 to 8.84), diabetes (OR 2.71, 95% CI 1.03 to 7.12), and self-reported cardiovascular disease (OR 2.69, 95% CI 1.63 to 4.42) were highly associated with prevalent PAD. Hypertension and hypercholesterolemia were positively associated with PAD, with ORs of 1.75 (95% CI, 0.97 to 3.15) and 1.68 (95% CI 1.09 to 2.57), respectively. These ORs were only slightly attenuated after multivariable adjustment (Table 3).
Low kidney function was highly associated with PAD. After multivariable adjustment, individuals with low kidney function were twice as likely to have prevalent PAD (OR 2.17, 95% CI 1.10 to 4.30). These data provided no evidence that BMI was associated with prevalent PAD.
Inflammation and PAD
In gender- and age-adjusted analyses (not shown), both CRP (P for trend <0.01) and fibrinogen (P for trend <0.01) were associated with prevalent PAD. After adjustment for age, gender, race/ethnicity, smoking status, and BMI, the ORs of PAD comparing quartiles 2 through 4 of CRP with the lowest quartiles were 0.81 (95% CI 0.33 to 2.02), 1.26 (95% CI 0.49 to 3.25), and 1.72 (95% CI 0.74 to 3.99), respectively (P for trend <0.05). In a model adjusted for the same risk factors, the ORs of PAD comparing quartiles 2 through 4 of fibrinogen with the lowest quartiles were 0.46 (95% CI 0.26 to 1.90), 1.48 (95% CI 0.54 to 4.01), and 1.68 (95% CI 0.67 to 4.23), respectively (P for trend <0.05).
This study reports nationally representative estimates of PAD in the US adult population. These results show that PAD affects ≈5 million US adults. As the US population ages, PAD is likely to become an increasing problem. If risk factors remain stable, we expect an estimated 7 million individuals aged 40 years and over will have PAD by the year 2020, according to census population projections.24
Previous prevalence estimates for PAD have largely derived from studies of subjects from clinical settings, which would be expected to overestimate the burden of disease in the general population. Compared with the prevalence estimates from NHANES 1999–2000 presented here, recent reports have overstated the prevalence of PAD in the United States by a factor of 2 to 3,4–6,9,10,25 despite using similar diagnostic criteria. The prevalence estimates and risk factor associations in the present study are consistent with those observed among middle-aged adults in US community-based studies, such as the Framingham Offspring Study7 and the Atherosclerosis Risk in Communities Study,8 and among elderly individuals in the Honolulu Heart Program26 and the Cardiovascular Health Study.2 The prevalence of PAD in these other studies, which used similar diagnostic criteria, ranged from 3% to 4% among middle-aged adults and between 13% and 14% in the elderly.
The results of the present study show that PAD disproportionately affects older individuals and non-Hispanic blacks. The excess PAD prevalence among blacks was not explained by known risk factors for PAD. This is consistent with previous studies that have shown a higher prevalence of PAD in non-Hispanic blacks.27 We also demonstrate that there is a particularly high prevalence of PAD among current smokers, diabetics, and persons with low kidney function.
PAD is also highly associated with traditional cardiovascular disease risk factors such as current smoking, diabetes, hypertension, and hypercholesterolemia, with 95% of persons with prevalent PAD having at least 1 of these risk factors. Nontraditional risk factors were also associated with prevalent PAD. Both fibrinogen and CRP were positively associated with prevalent PAD after adjustment for potential confounders. Although these findings might suggest a causal role for inflammation in the pathogenesis of PAD, they may also reflect a high burden of atherosclerosis in individuals with PAD.
The rigorous methodology used in NHANES provides nationally representative estimates of the prevalence of PAD and its risk factors. Moreover, NHANES 1999–2000 was the first NHANES survey to perform ankle-brachial blood pressure measurements on participants and hence allows for direct comparison with prior prevalence studies in adult populations. Despite these strengths, several limitations deserve consideration. It is possible that the prevalence of PAD in the present study underestimates the true prevalence in the population. The use of a different cutpoint for ABI and/or the inclusion of measurements from the anterior tibial arteries might have resulted in a greater sensitivity. However, the magnitude of this problem is likely to be small because the sensitivity of our definition has been shown to be >90% in other studies.17–19 Additionally, the cross-sectional nature of NHANES limits conclusions about direction or causality of associations observed in the present study. The use of self-reported data for some risk factors could underestimate prevalence, especially for health conditions such as coronary heart disease. Furthermore, this study may be subject to “survival bias,” in that individuals with chronic disease or severe risk factors may be less likely to participate in NHANES. However, this form of selection bias is likely to underestimate observed associations between risk factors and PAD, especially for conditions associated with poor physical functioning and comorbidities such as kidney disease.
In summary, these results demonstrate that ≈5 million adults aged ≥40 years have PAD and that PAD disproportionately affects older age individuals, non-Hispanic blacks, current smokers, diabetics, and persons with reduced kidney function. In addition, there is a high prevalence of traditional and nontraditional cardiovascular risk factors among persons with PAD. More than 95% of individuals with PAD have at least 1 traditional cardiovascular risk factor, and the majority have multiple risk factors. These findings highlight the importance of aggressive risk factor management in persons with PAD and in those at increased risk for PAD.
E. Selvin was supported by NHLBI grant T32HL07024.
Newman AB, Shemanski L, Manolio TA, Cushman M, Mittelmark M, Polak JF, Powe NR, Siscovick D. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study: the Cardiovascular Health Study Group. Arterioscler Thromb Vasc Biol. 1999; 19: 538–545.
Braunwald E, Zipes DP, Libby P. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, Pa: Saunders; 2001.
Zheng ZJ, Sharrett AR, Chambless LE, Rosamond WD, Nieto FJ, Sheps DS, Dobs A, Evans GW, Heiss G. Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. 1997; 131: 115–125.
Belch JJF, Topol EJ, Agnelli G, Bertrand M, Califf RM, Clement DL, Creager MA, Easton JD, Gavin JR III, Greenland P, Hankey G, Hanrath P, Hirsch AT, Meyer J, Smith SC, Sullivan F, Weber MA. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med. 2003; 163: 884–892.
O’Hare A, Johansen K. Lower-extremity peripheral arterial disease among patients with end-stage renal disease. J Am Soc Nephrol. 2001; 12: 2838–2847.
Luscher TF, Creager MA, Beckman JA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. Circulation. 2003; 108: 1655–1661.
Newman AB, Siscovick DS, Manolio TA, Polak J, Fried LP, Borhani NO, Wolfson SK. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study: Cardiovascular Heart Study (CHS) Collaborative Research Group. Circulation. 1993; 88: 837–845.
Feigelson HS, Criqui MH, Fronek A, Langer RD, Molgaard CA. Screening for peripheral arterial disease: the sensitivity, specificity, and predictive value of noninvasive tests in a defined population. Am J Epidemiol. 1994; 140: 526–534.
National Center for Health Statistics. National Health and Nutrition Examination Survey, 1999–2000. Available at: http://www.cdc.gov/nchs/about/major/nhanes/NHANES99_00.htm. Accessed July 8, 2004.
Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, Perrone RD, Lau J, Eknoyan G. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification [published erratum appears in Ann Intern Med 2003;139:605]. Ann Intern Med. 2003; 139: 137–147.
US Census Bureau, Population Division, Population Projections Branch. National Population Projections. Available at: http://www.census.gov/population/www/projections/natproj.html. Accessed July 8, 2004.
American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003; 26: 3333–3341.
Curb JD, Masaki K, Rodriguez BL, Abbott RD, Burchfiel CM, Chen R, Petrovitch H, Sharp D, Yano K. Peripheral artery disease and cardiovascular risk factors in the elderly: the Honolulu Heart Program. Arterioscler Thromb Vasc Biol. 1996; 16: 1495–1500.