Arnost Fronek

Ankle brachial index combined with Framingham risk score to predict cardiovascular events and mortality - A meta-analysis

CONTEXT Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

The prevalence of peripheral arterial disease in a defined population.

Because patients with peripheral arterial disease (PAD) may be asymptomatic or may present with atypical symptoms or findings, the true population prevalence of PAD is essentially unknown. We used four highly reliable, sophisticated noninvasive tests (segmental blood pressure, flow velocity by Doppler ultrasound, postocclusive reactive hyperemia, and pulse reappearance half-time) to assess the prevalence of large-vessel PAD and small-vessel PAD in an older (average age 66 years) defined population of 613 men and women. A total of 11.7% of the population had large-vessel PAD on noninvasive testing, and nearly half of those with large-vessel PAD also had small-vessel PAD (5.2%). An additional 16.0% of the population had isolated small-vessel PAD. Large-vessel PAD increased dramatically with age and was slightly more common in men and in subjects with hyperlipidemia. Isolated small-vessel PAD, by contrast, was essentially unrelated to sex, hyperlipidemia, or age, although it was somewhat less common before age 60. Intermittent claudication rates in this population were 2.2% in men and 1.7% in women, and abnormalities in femoral or posterior tibial pulse were present in 20.3% of men and 22.1% of women compared with the noninvasively assessed large-vessel PAD rate of 11.7%. Thus assessment of large-vessel PAD prevalence by intermittent claudication dramatically underestimated the true large-vessel PAD prevalence and assessment by peripheral pulse examination dramatically overestimated the true prevalence.

The sensitivity, specificity, and predictive value of traditional clinical evaluation of peripheral arterial disease: results from noninvasive testing in a defined population.

In a companion article we have reported the prevalence, in an older, defined population, of traditional assessments (intermittent claudication and abnormal pulse examination) of peripheral arterial disease (PAD) as compared with the results of highly accurate noninvasive testing. In this article we report the sensitivity, specificity, and positive and negative predictive values for claudication and abnormal pulses for the diagnosis of large-vessel and small-vessel PAD as determined by noninvasive testing. Claudication and abnormal pulses were completely unrelated to isolated small-vessel PAD. In contrast, both claudication and abnormal pulses were significantly correlated with large-vessel PAD. Claudication and an abnormal femoral pulse showed a high specificity and positive predictive value but a low sensitivity for large-vessel PAD. Conversely, an abnormal dorsalis pedis pulse showed a good sensitivity but low specificity and positive predictive value. The best single discriminator was an abnormal posterior tibial pulse, which had high sensitivity, specificity, and positive predictive value. Various combinations of claudication and pulse abnormalities revealed a good sensitivity for broader criteria but at the expense of specificity, whereas stricter criteria had a good specificity and positive predictive value but a poor sensitivity. No combination was superior to an abnormal posterior tibial pulse alone.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Progression of Peripheral Arterial Disease Predicts Cardiovascular Disease Morbidity and Mortality

OBJECTIVES The purpose of this study was to examine the association of progressive versus stable peripheral arterial disease (PAD) with the risk of future cardiovascular disease (CVD) events. BACKGROUND An independent association between PAD, defined by low values of the ankle-brachial index (ABI), and future CVD risk has been demonstrated. However, the prognostic significance of declining versus stable ABI has not been studied. METHODS We recruited 508 subjects (59 women, 449 men) from 2 hospital vascular laboratories in San Diego, California. ABI and CVD risk factors were measured at Visit 2 (1990 to 1994). ABI values from each subjects earliest vascular laboratory examination (Visit 1) were abstracted from medical records. Mortality and morbidity were tracked for 6 years after Visit 2 using vital statistics and hospitalization data. RESULTS In multivariate models adjusted for CVD risk factors, very low (<0.70) and, in some cases, low (0.70 < or = ABI <0.90) Visit 2 ABIs were associated with significantly elevated all-cause mortality, CVD mortality, and combined CVD morbidity/mortality at 3 and 6 years. Decreases in ABI of more than 0.15 between Visit 1 and Visit 2 were significantly associated with an increased risk of all-cause mortality (risk ratio [RR]: 2.4) and CVD mortality (RR: 2.8) at 3 years, and CVD morbidity/mortality (RR: 1.9) at 6 years, independent of Visit 2 ABI and other risk factors. CONCLUSIONS Progressive PAD (ABI decline >0.15) was significantly and independently associated with increased CVD risk. Patients with decreasing ABI may be candidates for more intensive cardiovascular risk factor management.

Current status of noninvasive tests in the diagnosis of peripheral arterial disease.

In this review of the current status of the vascular laboratory, the major emphasis has been upon those tests that have become well-established and documented, including resting pressure, pulse volume measurements, velocity studies, and three stress measurements--exercise ankle pressure, postocclusive reactive hyperemia, and the toe pulse reappearance time. Additional technology that may have application to peripheral arterial disease includes photoplethysmography, transcutaneous oxygen tension, laser-Doppler velocimetry, fluorescein angiography, infrared thermography, and transcutaneous electromagnetic flowmetry. These techniques, which are currently in development and experimental trial, were not discussed but are likely to provide significant additional information. The future role of the vascular diagnostic laboratory in the area of peripheral arterial occlusive disease appears clear. It has already become a standard resource of the community hospital and tertiary referral center. Its functions will become more and more generally accepted with time as newly graduating physicians who have been exposed to this technology enter the practice of medicine. It should permit obtaining an evaluation of all patients at the expert level, aid in the education of all physicians concerned with peripheral arterial disease, and play an important part in guaranteeing a higher level of patient care than has heretofore been available.

Noninvasively diagnosed peripheral arterial disease as a predictor of mortality: results from a prospective study.

Intermittent claudication has been reported in previous studies to approximately double the risk of subsequent mortality. However, a history of claudication is often present in the absence of significant peripheral arterial disease (PAD) and absent in the presence of PAD. For this reason we evaluated the association between large-vessel and small-vessel PAD, measured by highly reliable and valid noninvasive tests, and mortality in 567 older subjects from a defined population followed-up for an average of 4 years. Large-vessel PAD was strongly and significantly predictive of all-cause mortality in both men and women with a relative risk of 4 to 5, and this finding was independent of other cardiovascular disease risk factors in multivariable analysis. In addition, this finding persisted after exclusion of subjects with extant cardiovascular disease at baseline. The associations of both claudication and abnormal peripheral pulses with mortality were weaker than the large-vessel PAD association. Isolated small-vessel PAD was unrelated to subsequent mortality. These findings suggest older subjects of both sexes at a high risk of impending mortality can be identified through noninvasive testing for large-vessel PAD.