Julie O. Denenberg

Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis

BACKGROUND Lower extremity peripheral artery disease is the third leading cause of atherosclerotic cardiovascular morbidity, following coronary artery disease and stroke. This study provides the first comparison of the prevalence of peripheral artery disease between high-income countries (HIC) and low-income or middle-income countries (LMIC), establishes the primary risk factors for peripheral artery disease in these settings, and estimates the number of people living with peripheral artery disease regionally and globally. METHODS We did a systematic review of the literature on the prevalence of peripheral artery disease in which we searched for community-based studies since 1997 that defined peripheral artery disease as an ankle brachial index (ABI) lower than or equal to 0·90. We used epidemiological modelling to define age-specific and sex-specific prevalence rates in HIC and in LMIC and combined them with UN population numbers for 2000 and 2010 to estimate the global prevalence of peripheral artery disease. Within a subset of studies, we did meta-analyses of odds ratios (ORs) associated with 15 putative risk factors for peripheral artery disease to estimate their effect size in HIC and LMIC. We then used the risk factors to predict peripheral artery disease numbers in eight WHO regions (three HIC and five LMIC). FINDINGS 34 studies satisfied the inclusion criteria, 22 from HIC and 12 from LMIC, including 112,027 participants, of which 9347 had peripheral artery disease. Sex-specific prevalence rates increased with age and were broadly similar in HIC and LMIC and in men and women. The prevalence in HIC at age 45-49 years was 5·28% (95% CI 3·38-8·17%) in women and 5·41% (3·41-8·49%) in men, and at age 85-89 years, it was 18·38% (11·16-28·76%) in women and 18·83% (12·03-28·25%) in men. Prevalence in men was lower in LMIC than in HIC (2·89% [2·04-4·07%] at 45-49 years and 14·94% [9·58-22·56%] at 85-89 years). In LMIC, rates were higher in women than in men, especially at younger ages (6·31% [4·86-8·15%] of women aged 45-49 years). Smoking was an important risk factor in both HIC and LMIC, with meta-OR for current smoking of 2·72 (95% CI 2·39-3·09) in HIC and 1·42 (1·25-1·62) in LMIC, followed by diabetes (1·88 [1·66-2·14] vs 1·47 [1·29-1·68]), hypertension (1·55 [1·42-1·71] vs 1·36 [1·24-1·50]), and hypercholesterolaemia (1·19 [1·07-1·33] vs 1·14 [1·03-1·25]). Globally, 202 million people were living with peripheral artery disease in 2010, 69·7% of them in LMIC, including 54·8 million in southeast Asia and 45·9 million in the western Pacific Region. During the preceding decade the number of individuals with peripheral artery disease increased by 28·7% in LMIC and 13·1% in HIC. INTERPRETATION In the 21st century, peripheral artery disease has become a global problem. Governments, non-governmental organisations, and the private sector in LMIC need to address the social and economic consequences, and assess the best strategies for optimum treatment and prevention of this disease. FUNDING Peripheral Arterial Disease Research Coalition (Europe).

The epidemiology of peripheral arterial disease: importance of identifying the population at risk

Data from the Framingham Study and other population studies indicate that intermittent claudication (IC) sharply increases in late middle age and is somewhat higher among men than women. Noninvasive testing in populations indicates that the true prevalence of peripheral arterial disease (PAD) is at least five times higher than would be expected based on the reported prevalence of IC. Peripheral arterial disease correlates most strongly with cigarette smoking and either diabetes or impaired glucose tolerance. Other risk factors for PAD include hypertension; low levels of high-density lipoprotein cholesterol; and high levels of triglycerides, apolipoprotein B, lipoprotein(a), homocysteine, fibrinogen and blood viscosity. Individuals with PAD are more likely to have coronary heart disease and cerebrovascular disease than those without PAD. Because of the high risk of both nonfatal and fatal cardiovascular disease (CVD) events in PAD patients, individuals with evidence of PAD should undergo both a careful examination of the entire cardiovascular system and aggressive modification of CVD risk factors.

The correlation between symptoms and non-invasive test results in patients referred for peripheral arterial disease testing.

The WHO/Rose questionnaire has served as the epidemiologic and clinical standard in the assessment of leg pain in patients with peripheral arterial disease (PAD) for over three decades. However, the structure of this questionnaire does not allow assessment of leg-specific (i.e. right versus left) symptoms. We studied 508 patients aged 39–95 years (mean 68 years), initially referred for PAD non-invasive testing. A revised questionnaire, the San Diego Claudication Questionnaire, was administered which allowed determination of leg-specific symptoms and evaluated thigh and buttock as well as calf pain. Leg-specific symptoms were categorized into no pain, pain at rest, non-calf claudication, non-Rose calf claudication, and Rose claudication. At the same visit, the ankle brachial index, the toe brachial index, and peak posterior tibial flow velocity were measured by Doppler ultrasound and five categories of non-invasive results by type and severity of PAD were defined. Legs with previous intervention (Rx), surgery or angioplasty, were evaluated separately. Claudication was reported in 42% of no Rx legs and 50% of Rx legs; 40% of claudication was atypical (not Rose); 64% of no Rx and 81% of Rx legs had PAD by non-invasive testing, and 27% of affected legs had severe PAD. The correlation between the severity of symptoms and the severity of ipsilateral PAD in no Rx legs was r=−0.40, p< 0.001. In Rx legs, this correlation was somewhat less (r=0.27, p< 0.001) due to more symptomatology at lesser degrees of PAD, suggesting reporting bias and/or more residual disease than evident from non-invasive testing. To our knowledge, these results provide the first comparison between a standardized assessment of leg pain and the severity of ipsilateral PAD by non-invasive testing.

Ethnicity and peripheral arterial disease: the San Diego Population Study.

Background— Previous studies have indicated higher rates of peripheral arterial disease (PAD) in blacks than in non-Hispanic whites (NHWs), with limited information available for Hispanics and Asians. The reason for the PAD excess in blacks is unclear. Methods and Results— Ethnic-specific PAD prevalence rates were determined in a randomly selected defined population that included 4 ethnic groups; NHWs, blacks, Hispanics, and Asians. A total of 2343 participants aged 29 to 91 years were evaluated. There were 104 cases of PAD (4.4%). In weighted logistic models with NHWs as the reference group and containing demographic factors only, blacks had a higher PAD prevalence than NHWs (OR=2.30, P<0.024), whereas PAD rates in Hispanics and Asians, although somewhat lower, were not significantly different from NHWs. Blacks had significantly more diabetes and hypertension than NHWs and a significantly higher body mass index. Inclusion of these variables and other PAD risk factors in the model did not change the effect size for black ethnicity (OR=2.34, P=0.048). A model containing interaction terms for black ethnicity and each of the other risk factors revealed no significant interaction terms, which indicates no evidence that blacks were more “susceptible” than NHWs to cardiovascular disease risk factors. Conclusions— Black ethnicity was a strong and independent risk factor for PAD, which was not explained by higher levels of diabetes, hypertension, and body mass index. There was no evidence of a greater susceptibility of blacks to cardiovascular disease risk factors as a reason for their higher PAD prevalence. Thus, the excess risk of PAD in blacks remains unexplained and requires further study.

Calcium Density of Coronary Artery Plaque and Risk of Incident Cardiovascular Events

IMPORTANCE Coronary artery calcium (CAC), measured by computed tomography (CT), has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is weighted upward for greater calcium density. However, some data suggest increased plaque calcium density may be protective for CVD. OBJECTIVE To determine the independent associations of CAC volume and CAC density with incident CVD events. DESIGN, SETTING, AND PARTICIPANTS Multicenter, prospective observational MESA study (Multi-Ethnic Study of Atherosclerosis), conducted at 6 US field centers of 3398 men and women from 4 race/ethnicity groups; non-Hispanic white, African American, Hispanic, and Chinese. Participants were aged 45-84 years, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010. MAIN OUTCOMES AND MEASURES Incident coronary heart disease (CHD) and all CVD events RESULTS During a median of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. With both lnCAC volume and CAC density scores in the same multivariable model, the lnCAC volume score showed an independent association with incident CHD, with a hazard ratio (HR) of 1.81 (95% CI, 1.47-2.23) per standard deviation (SD = 1.6) increase, absolute risk increase 6.1 per 1000 person-years, and for CVD an HR of 1.68 (95% CI, 1.42-1.98) per SD increase, absolute risk increase 7.9 per 1000 person-years. Conversely, the CAC density score showed an independent inverse association, with an HR of 0.73 (95% CI, 0.58-0.91) per SD (SD = 0.7) increase for CHD, absolute risk decrease 5.5 per 1000 person-years, and an HR of 0.71 (95% CI, 0.60-0.85) per SD increase for CVD, absolute risk decrease 8.2 per 1000 person years. Area under the receiver operating characteristic curve analyses showed significantly improved risk prediction with the addition of the density score to a model containing the volume score for both CHD and CVD. In the intermediate CVD risk group, the area under the curve for CVD increased from 0.53 (95% CI, 0.48-0.59) to 0.59 (95% CI, 0.54-0.64), P = .02. CONCLUSIONS AND RELEVANCE CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk. The role of CAC density should be considered when evaluating current CAC scoring systems.

Risk Factors for Progression of Peripheral Arterial Disease in Large and Small Vessels

Background— Data on the natural history of peripheral arterial disease (PAD) are scarce and are focused primarily on clinical symptoms. Using noninvasive tests, we assessed the role of traditional and novel risk factors on PAD progression. We hypothesized that the risk factors for large-vessel PAD (LV-PAD) progression might differ from small-vessel PAD (SV-PAD). Methods and Results— Between 1990 and 1994, patients seen during the prior 10 years in our vascular laboratories were invited for a new vascular examination. The first assessment provided baseline data, with follow-up data obtained at this study. The highest decile of decline was considered major progression, which was a −0.30 ankle brachial index decrease for LV-PAD and a −0.27 toe brachial index decrease for SV-PAD progression. In addition to traditional risk factors, the roles of high-sensitivity C-reactive protein, serum amyloid-A, lipoprotein(a), and homocysteine were assessed. Over the average follow-up interval of 4.6±2.5 years, the 403 patients showed a significant ankle brachial index and toe brachial index deterioration. In multivariable analysis, current smoking, ratio of total to HDL cholesterol, lipoprotein(a), and high-sensitivity C-reactive protein were related to LV-PAD progression, whereas only diabetes was associated with SV-PAD progression. Conclusions— Risk factors contribute differentially to the progression of LV-PAD and SV-PAD. Cigarette smoking, lipids, and inflammation contribute to LV-PAD progression, whereas diabetes was the only significant predictor of SV-PAD progression.

The association between elevated ankle systolic pressures and peripheral occlusive arterial disease in diabetic and nondiabetic subjects

OBJECTIVE The presence of a high ankle-brachial index (ABI) is related to stiff ankle arteries due to medial calcification. Recently, this condition has attracted new interest after reports of a worse cardiovascular prognosis, similar to a low ABI. We sought to compare risk factors contributing to a low (< or =0.90) and high (> or =1.40) ABI. Additionally, we hypothesized that in instances of high ABI, occlusive PAD may coexist. METHOD This cross-sectional study was conducted at vascular laboratories in a university medical center. The subjects were 510 ambulatory patients (37% had diabetes) previously examined at our vascular laboratories and who responded positively to our invitation. We collected data on smoking, diabetes, hypertension, dyslipidemia, and cardiovascular disease history. The noninvasive assessment of lower limb arteries consisted of the measurement of ABI, toe-brachial index (TBI), and posterior tibial artery peak flow velocity (Pk-PT). A TBI >0.7 and a Pk-PT >10 cm/s were considered normal. RESULTS High- and low-ABI were detected, respectively, in 2.1% and 57.8% of limbs. For a low ABI, age (odds ratio [OR], 1.29/10 y), pack-years (OR, 1.08/10 units), and hypertension (OR, 1.90) were independent significant (P < .001) factors. A strong association was found between diabetes and high ABI (OR, 16.0; P < .001). When ABI ranges were compared with TBI and Pk-PT results, those with ABI < or =0.90 and ABI > or =1.40 presented similar patterns of abnormalities. Pk-PT or TBI, or both, was abnormal in more than 80% of cases in both ABI < or =0.90 and > or =1.40 groups. The ABI vs TBI relationship appeared linear in nondiabetic patients, but had an inverted J-shape in diabetic patients, suggesting high ABI masked leg ischemia. CONCLUSIONS Diabetes is the dominant risk factor for a high (> or =1.40) ABI. Occlusive PAD is highly prevalent in subjects with high ABI, and these subjects should be considered as PAD-equivalent.

The generalized nature of atherosclerosis: how peripheral arterial disease may predict adverse events from coronary artery disease.

Non-invasive measurements, especially segmental pressure ratios and flow measurements, are useful for gauging the severity of peripheral arterial disease (PAD). Although the incidence of PAD is similar for men and women, men are more likely to have severe disease, while women usually have more moderate or asymptomatic disease. Published reports confirm the clinical impression that patients with PAD are more likely to have both coronary artery disease and cerebrovascular disease than those without PAD. However, the degree of overlap is a function of the sensitivity of the diagnostic assessments for the three conditions. A San Diego population study found that the incidence of PAD may be underestimated, with many patients being asymptomatic. Based on blood flow measurements, the study found that 11.9% of the study population had large vessel PAD. Morbidity from both coronary heart disease and stroke was increased in people with PAD, who were 2.5 times more likely to present with morbidity from cardiovascular disease (CVD) than those who did not have PAD. Several studies have now confirmed the strong predictive value of PAD for subsequent CVD mortality and that the risk of CVD mortality increases with the severity of PAD.

Exertional Leg Pain in Patients With and Without Peripheral Arterial Disease

Background— Although exertional leg pain is a hallmark of peripheral arterial disease (PAD) and can occur in persons without PAD, symptom variation has received inadequate attention. Methods and Results— Three cohort studies were combined for cross-sectional analysis. The San Diego Claudication Questionnaire assessed exertional leg pain. PAD was defined as ankle brachial index (ABI) ≤0.90 or history of lower-extremity revascularization. Of 3658 subjects, 3629 were analyzed after exclusions. Of these, 24.1% had PAD in 1 or both legs. There was a stepwise decrease in average ABI, from no pain to pain on exertion and rest, noncalf pain, atypical calf pain, and classic claudication (P=0.002). When stratified by PAD, this trend was no longer significant. Legs with ABIs >0.90 and revascularization had pain distributions intermediate between that of normal legs (ABI, 1.00 to 1.39) and legs with ABIs ≤0.90. Compared with normal legs, legs with low-normal (0.91 to 0.99) and high-normal (≥1.40) ABIs had higher pain rates, suggesting borderline disease and vascular stiffness, respectively. Multivariable logistic regression models showed that ABI was a strong correlate of pain category throughout the ABI range. Independently of ABI, age, male sex, diabetes, smoking history, high body mass index, myocardial infarction, and previous revascularization were all significant correlates of exertional leg pain. Conclusions— No category of exertional leg pain was sufficiently sensitive or specific for routine PAD diagnosis. Legs with low-normal and high-normal ABIs appeared to have ischemic leg pain; thus, a “normal ABI” is likely to range from 1.00 to 1.39. In addition to ABI, several risk variables were independent correlates of exertional leg pain.

Statin‐Associated Muscle‐Related Adverse Effects: A Case Series of 354 Patients

Study Objective. To characterize the properties and natural history of 3–hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor (statin)‐associated muscle‐related adverse effects (MAEs).