doi: 10.1161/CIRCULATIONAHA.105.593442
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(Circulation. 2006;114:688-699.)
© 2006 American Heart Association, Inc.
Contemporary Reviews in Cardiovascular Medicine |
Peripheral Arterial Disease
Morbidity and Mortality Implications
From the Department of Medicine (B.A.G., T.T.D., M.H.C.), Department of Family and Preventive Medicine (B.A.G., M.H.C.), and Department of Physics (T.T.D.), University of California at San Diego, San Diego, Calif.
Correspondence to Beatrice A. Golomb, MD, PhD, Department of Medicine 0995, University of California, San Diego School of Medicine, 9500 Gilman Dr, La Jolla, CA 92093-0995. E-mail bgolomb{at}ucsd.edu
Key Words: peripheral arterial disease • peripheral vascular disease • coronary artery disease • cerebrovascular disorders • risk factors
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Introduction |
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Peripheral arterial disease (PAD) has been estimated to reduce quality of life in approximately 2 million symptomatic Americans,1 and millions more Americans without claudication are likely to suffer PAD-associated impairment.2 PAD is a strongly age-dependent condition that contributes significantly to morbidity and healthcare expenditures in the elderly: There are 413 000 discharges per year with chronic PAD, 88 000 hospitalizations involving lower-extremity arteriography, and 28 000 discharges citing embolectomy or thrombectomy of lower-limb arteries.3 Figures for prevalence of asymptomatic PAD are several-fold higher. These figures were based on National Hospital Discharge Survey and National Vital Statistics System 1985 to 1987 US data; numbers of procedures had increased in the prior decade3 and are likely to have increased in the intervening years as the population continues to age. Even though few deaths were directly attributed to PAD, PAD has potent mortality implications. Although symptomatic disease directly affects functional capacity and quality of life by restricting ambulation, asymptomatic disease is also important, not only because it may augur risk of future compromised ambulation, lower-extremity ulcers, or need for vascular surgery or amputation, but perhaps most importantly because asymptomatic and symptomatic PAD are consistent and powerful independent predictors of coronary artery disease (CAD) and cerebrovascular disease (CBVD) events and mortality. The evidence relating PAD to prevalent and incident cardiac and cerebrovascular disease (CCVD) forms the focus of the present report.
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Methods |
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A PubMed search (updated June 2005) covering years 1966 to 2005 yielded all abstracts with title words "peripheral artery disease," "peripheral arterial disease," or "peripheral vascular disease." These were reviewed for content pertaining to co-occurrence with or prediction by PAD of atherosclerotic disease and total mortality. Additional citations were identified from bibliographies of culled articles and consultation with experts. Identified citations with original epidemiological data pertaining to the relation of lower-extremity PAD to cardiovascular and overall morbidity and mortality were reviewed. Data were stratified into cross-sectional or retrospective studies versus prospective studies, to distinguish the cross-sectional association of PAD with prevalent CCVD from the prognostic significance of PAD for incident CCVD and mortality. All studies with defined populations, PAD assessment, and outcome assessment for CCVD morbidity and mortality (or total mortality) were considered. Population characteristics, criteria for PAD and for CCVD outcomes, coprevalence of CCVD with PAD (cross-sectional data), and risk ratios and confidence intervals relating PAD to incident CCVD and mortality outcomes (prospective data) were extracted. Covariates adjusted in the studies’ multivariable models examining PAD as a risk marker for incident cardiovascular and mortality outcomes were annotated. Findings relating PAD to atherosclerosis-relevant outcomes were tabulated by vascular bed.
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Results |
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Cross-Sectional Data: Coprevalence
CAD in PAD
The prevalence of CAD in PAD patients ranged from 14% to 90%, which clearly reflects differences in sensitivity of the detection technique for CAD.4,5 CAD was present in 19% to 47% of PAD patients in studies using clinical history plus ECG; in 62% to 63% using stress tests (modified stress ECG or dipyridamole-stress thallium); and in 90% of subjects when angiography was used. Data are shown in Figure 1.6–26
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CBVD in PAD
PAD may be a particularly potent predictor of comorbid CBVD, with evidence of significant concurrent CBVD defined by carotid stenosis on Doppler imaging or by cerebrovascular events (Figure 2).7,8,10,11,16,19,20,26–30 As in Figure 1 for CAD in PAD, the prevalence of CBVD in PAD is a direct function of the sensitivity of CBVD assessment. Thus, comorbid carotid stenosis >30% was cited in &51% to 72% of subjects and stenosis >70% in 25%, and a history of clinical disease generally was seen in fewer subjects (although 1 study cited clinical disease in 35%). Notably, in a study of Chinese subjects with PAD, CAD, abdominal aortic aneurysm, CBVD symptoms, or asymptomatic carotid bruits in whom routine screening carotid duplex scans were performed, PAD subjects had the highest prevalence of significant (>70%) carotid stenosis, at 25%.30 This compared with lower rates of significant carotid stenosis in patients with CAD (11%), carotid bruits (10%), and abdominal aortic aneurysm (9%), each of whom, in turn, had rates of significant stenosis greater than those of normal controls (0%; P<0.001).30 This suggests that PAD may be a stronger predictor of concurrent CBVD risk than is CAD. In an evaluation of subjects aged 60 to 80 years from the Edinburgh Artery Study, carotid artery intimal-medial thickness by ultrasound, sometimes used as a gauge of subclinical CBVD, was significantly associated with PAD assessed by ankle-brachial index (ABI) <0.9 (P<0.05).31
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CCVD in PAD
Perhaps more direct evidence of CCVD prevalence in PAD derives from comparisons of rates of CCVD in those with versus without PAD drawn from the same population. In a San Diego, Calif, population study of subjects aged 38 to 82 years, clinical CCVD was present in 29% of men with PAD (defined by noninvasive tests) versus 12% of men without PAD and 21% of women with and 9% of women without PAD.5 Thus, CCVD was 2 to 3 times more common in persons with than without PAD. Similarly, in a cross-sectional evaluation of a stratified sample of patients from 18 general practice clinics, in whom prevalence of PAD was 7% (95% confidence interval [CI] 5.2% to 7.9%), asymptomatic PAD (ABI <0.95) conferred a 3- to 4-fold excess risk of CAD and CBVD.32
PAD in CCVD
Just as CCVD may be more common in those with PAD, so PAD may be more common in those with CCVD. In a San Diego cohort, PAD was present in 32% of men with clinical CCVD compared with 13% of men without and in 25% of women with CCVD versus 11% of women without.5 Thus, PAD was 2 to 3 times more common among those with than without CCVD. Hospital prevalence rates for Saudi Arabian patients aged 50 to 80 years (mean 59 years) for ABI <0.9 were 21% in those with CAD compared with 4% in controls without CAD, renal disease, or diabetes mellitus, which suggests a 5-fold increase in prevalence.33
Prospective Data: PAD Prediction of Future CCVD Morbidity and Mortality and All-Cause Mortality
Because PAD shares many identified risk factors in common with CAD and CBVD, it is axiomatic that concomitant disease should be observed. Specifically, because traditional risk factors for CCVD are commonly present, those with PAD may be at heightened risk not only for coprevalent but also for future CAD and CBVD morbidity and mortality.
PAD Predicts CAD
Presence of PAD, by any of various criteria, is associated with increased risk of CAD and sequelae that may arise from CAD, including new angina, coronary artery bypass graft, nonfatal or total myocardial infarction (MI), congestive heart failure, and fatal MI and CAD death (Table 1).34–47 Comparison of findings according to PAD criteria suggests that symptomatic PAD (ie, intermittent claudication) is more strongly associated with subsequent symptomatic angina (risk ratio 2.3) than is asymptomatic PAD; indeed, major asymptomatic PAD was associated with no trend toward an increase in new angina, although minor asymptomatic disease showed a trend (41% increase).35
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PAD is associated with increases in risk for nonfatal MI across PAD categories (symptomatic, major asymptomatic, and minor asymptomatic), with risk ratios ranging from 1.2 to 1.4. (PAD in patients without prior CCVD is also associated with a significant 60% increase in progression to congestive heart failure after multivariate adjustment.34) PAD by noninvasive criteria is more persuasively and significantly associated with fatal MI and CAD death, after univariate and multivariate adjustment; risk ratios range from a low of 1.9 in an Edinburgh, Scotland, medical population sample43 to 3.2,38 5.0,45 and 6.646 in other samples. A population-based study with 10-year follow-up and slightly more severe disease (ABI cutoff <0.8) showed the highest of these risks. Indeed, although this study entailed full multivariable adjustment, data from the study suggest that limited adjustment (eg, for age and sex) yields risk ratios similar to those obtained with full adjustment.
PAD Predicts CBVD
Table 2 shows increased relative risks for CBVD outcomes in those with versus without PAD.35,37,39,40,43,48,49 ABI <0.9 was clearly and significantly associated with increased nonfatal (but not fatal) stroke in 1 study43; in another analysis, severity of PAD was monotonically correlated with combined definite and possible stroke or transient ischemic attack.35 A Spanish study found that PAD was associated with increased risk not only of ischemic stroke but also of hemorrhagic stroke (indeed, a somewhat higher risk ratio for hemorrhagic than ischemic stroke was observed).48 Of note, PAD has also been associated with worse outcome in patients with stroke.50
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PAD Predicts CCVD Mortality
Because CAD and CBVD outcomes are increased in those with PAD, an increase in combined CCVD outcomes would be anticipated. Indeed, as Table 3 shows, both combined CCVD morbidity and mortality and CCVD mortality are increased in those with PAD, by all PAD definitions employed, with risk ratios ranging from approximately 2 to 6.34,35,37–39,43,45–47,51,52 Again, stringency of PAD criteria may influence the increase in risk for CCVD outcomes; thus, risk ratios for CCVD outcomes calculated from the San Diego population study, employing ABI <0.8 as a PAD criterion (more significant PAD),46 are higher than those of studies using a threshold of ABI <0.9.
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Another study, not represented in Table 3, is of interest with regard to the predictive power of PAD for CCVD outcomes. In a cohort of 1672 men and 2264 women aged 47 to 99 years participating in the Framingham Study, either absent pedal pulses (considered an indicator of PAD, although with imperfect sensitivity and specificity53) or femoral and carotid bruits were associated with greater increased risk of CAD, congestive heart failure, and CBVD than was glucose intolerance (itself a powerful risk factor), and the combination was a still more potent predictor of CCVD-defining conditions.54
PAD Predicts Overall Mortality
Some major risk factors predict CCVD mortality but not overall mortality in key target populations.55 In contrast, PAD powerfully predicts overall mortality (Table 4
).9,34,35,37–39,41,43,45,46,51,56–66 This is true in men and in women, in community cohorts, in medical-based cohorts, and in populations at heightened CCVD risk, such as elderly with systolic hypertension, with risk increases ranging from 50% to 400%. A mortality gradient with increased PAD severity has been shown. In a San Diego population-based study, 10-year mortality progressively increased from normal subjects to those with asymptomatic PAD, to those with severe symptomatic PAD.46 The corresponding mortality figures were 15%, 45%, and 75%, respectively, even after adjustment for major CCVD risk factors and baseline CCVD. Similarly, in another study, a marked mortality gradient over 10 years was seen based on noninvasive testing, which progressed from ABI >0.85 (&20% mortality), to ABI of 0.4 to 0.85 (&50%), to ABI <0.4 (&70%).60 In a historical cohort study of persons over the age of 40 years with PAD who had undergone previous ABI testing (PAD defined as ABI <0.9) for whom data on mortality or occurrence of a vascular event were available (average 6 years of follow-up), the relative risk for mortality was 3.1 per 0.50 decrease of the ABI at rest.67 Data from the Edinburgh Artery Study population also suggest a survival gradient with PAD severity, whether measured by ABI35 or by "severity" gradient from minor asymptomatic disease through major asymptomatic disease to intermittent claudication.35
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As Table 4
also illustrates, PAD predicts increased mortality not only in general or medical populations but also in specialized populations defined by cardiovascular events or surgery,56,57,59,61,63,65 such as patients with acute MI56,59 or those undergoing coronary artery bypass grafting65 (including both in-hospital mortality, after multivariate adjustment,61 and long-term mortality among that subset discharged alive63). Associations of PAD with mortality and events have also been reported in subjects enrolled in randomized trials of drug treatment.68 Notably, among PAD patients, lower ABI predicts greater mortality and cardiovascular morbidity.37 Increased total mortality with PAD has been further shown in association with noncardiovascular events and surgery (not shown in Table 4). Thus, among patients undergoing renal transplant, low toe blood pressure or "toe brachial index," present in 32% of diabetics and 16% of nondiabetics, was associated with reduced survival.69 In addition, peripheral atherosclerosis may be associated with increased complications and death in trauma patients. It has been theorized that even if the trauma does not directly affect diseased vessels, hypotension resulting from major trauma may lead to increased risk of thrombosis in vessels that have critical stenosis; moreover, if a diseased vessel is itself injured, bypass may be difficult, and amputation may be required.70
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Discussion |
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Data across many studies robustly support the finding that PAD cross-sectionally relates to CCVD morbidity and mortality, and more importantly, that PAD is a strong prospective predictor of CCVD morbidity and mortality and total mortality, independent of other adjusted risk factors. More stringent criteria for PAD increase the strength of association, compatible with a biological gradient.
Additional observations substantiate the importance of these findings. PAD in the absence of known CAD predicted cardiovascular events more strongly than did CAD in the absence of PAD in the Heart Protection Study (30.5% versus 22.5% event rate, placebo group).71 Elsewhere, in CAD patients, PAD was found to be a stronger risk factor for CCVD death and total mortality than prior MI.57
The basis of the "independent" association of PAD to CCVD remains incompletely characterized. PAD may be a proxy for generalized atherosclerotic disease burden and shared unmeasured risk factors, and/or it may itself causally induce increased risk. Because PAD shares with CAD and CBVD a number of CCVD risk factors, heightened risk of cardiovascular morbidity and mortality would be anticipated due to shared risk factors. The relation of PAD to future outcomes is preserved after adjustment for other recognized risk markers, which suggests that PAD confers independent risk for CAD and total mortality beyond that attributable to shared risk factors. Nonetheless, the prognostic significance of PAD could derive purely from its role as a proxy for generalized atherosclerotic disease burden and unmeasured common risk factors: Most studies do not adjust for all recognized risk factors, and even after adjustment, the possibility of residual confounding remains. Moreover, emerging risk factors for CCVD have been identified that are not adjusted in existing analyses, and new risk factors for CCVD continue to be defined. If PAD serves exclusively as a proxy for a cadre of potent and less potent CCVD risk factors and generalized atherosclerotic disease burden, its importance as a risk marker is not diminished; rather, the determination that increased risk is present dictates a need for more aggressive risk factor reduction.
Nonetheless, if PAD is in addition causally involved in promoting CCVD events or death, this may influence the approach to PAD and CCVD management. Two mechanisms were identified by which PAD may causally promote CCVD events and death. First and most obviously, clinical PAD reduces the ability to ambulate, and exercise is protective against CAD and CBVD, in part through its beneficial effects on prominent risk factors, including insulin resistance, hypertension, and dyslipidemia. This consideration is not limited to patients with classic intermittent claudication. Many persons with PAD reported atypical, vague, or nonspecific symptoms, including fatigue and numbness. Although atypical, such symptoms also limit ambulation.
Second, PAD may directly promote myocardial and cerebral ischemia. PAD is linked to impaired peripheral endothelial function, with impaired vasodilation (or even vasoconstriction) in response to certain challenges such as stress. This appears responsible for the fall in left ventricular ejection fraction with stress seen in some CAD patients: Only those whose peripheral vascular resistance increased experienced this left ventricular ejection fraction reduction, which reduced stroke volume and cardiac output.72 CAD patients show abnormal coronary vasoconstriction (or loss of vasodilation) in response to endogenous stimuli such as acetylcholine, an effect that can be reproduced in animals by inducing coronary occlusion.73 Analogously, peripheral ischemia—and PAD patients—may show abnormal peripheral vasoconstriction in response to stress and other stimuli. The loss of normal vasodilation, or paradoxical vasoconstriction, may provoke a relative drop in ejection fraction and cardiac output, reducing oxygen delivery to vital organs during stress. PAD may thereby increase events in patients with otherwise comparable CAD or CBVD. Consistent with this possibility, PAD patients with worse peripheral endothelial dysfunction experience more major cardiovascular events.74
Although asymptomatic PAD strongly predicted most CCVD outcomes, major asymptomatic PAD was, strikingly, not associated with an increase in new angina, in contrast to findings for symptomatic PAD. This finding could have a foundation in pathways involved in pain perception. Patients who are free of pain despite major disease in 1 site (as with major asymptomatic PAD) may more likely be free of pain when disease arises in another vascular bed, as suggested by an increase in total MI but no trend toward increased angina. In contrast, symptomatic PAD (intermittent claudication) was associated with a strong and significant increase in symptomatic disease in the other site (angina). Individual differences in endogenous pain-signaling systems (including but not confined to opioid, substance P, serotonin, and nicotinic and muscarinic cholinergic signaling systems) and exogenous influences on pain (eg, caffeine, nicotine, antidepressants, corticosteroids, aspirin, and nonsteroidal antiinflammatory drugs) may modify perception of pain in both sites in parallel. Additionally, some factors, such as proinflammatory cytokines, conjointly dispose to cardiovascular disease and increased pain,75–77 whereas others, like hyperglycemia and glycation end products, dispose both to cardiovascular disease and impaired pain perception.78 Thus, different profiles of cardiovascular disease–related mediators could typify persons who have and those who do not have pain, an avenue that can be explored in future research.
The data presented have several limitations. First, study populations and criteria for PAD and for CCVD outcomes varied across studies, which precludes pooled analysis; however, preservation of the qualitative finding despite this heterogeneity underscores the robustness of the association. Second, many studies did not control for all recognized and potential cardiovascular risk factors. The role of PAD as an independent predictor will merit ongoing reappraisal as CCVD risk factors emerge. Finally, the data are observational; however, randomized trial data would not strengthen the character of inference with regard to risk prediction by PAD, which is not predicated on causality. Moreover, interventions targeted to reduce PAD may reduce CCVD in parallel, rather than through their impact on PAD, so such data would do little to address the issue of a causal role for PAD in elevating CCVD risk.
The findings presented have important implications. Although PAD is linked strongly and apparently independently with CCVD morbidity and mortality, perhaps more strongly than prior MI, PAD is less emphasized and less systematically evaluated than other atherosclerotic conditions or risk factors such as hyperlipidemia and hypertension.2 Moreover, once PAD is detected, treatment of atherosclerotic risk factors and prevention of atherothrombotic events is less reliably undertaken than in patients with CAD,2,79 although the future risk of atherosclerotic events and deaths is equivalent or greater. Although it has been known for many years that even mild, asymptomatic PAD increases the risk of cardiovascular disease events,46 which impels (high) risk stratification based on the presence of PAD, recent clinical trial data showing the benefits of both lipid therapy71 and antiplatelet therapy71 in PAD patients in preventing cardiovascular disease events provide a strong evidence base for aggressive medical therapy in these patients. Given the strong prognostic significance of PAD, ABI assessment may merit a more central role in CCVD risk assessment and in dictating receipt of cardiovascular protective treatments. Of note, in light of the escalating prevalence of PAD with advancing age, the role of PAD in adjudicating risk can be expected to assume mounting importance as the population ages.
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Acknowledgments |
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We thank Janis Richie and Marcella Evans for excellent administrative assistance.
Sources of Funding
This work was supported in part by a grant from Bristol-Myers Squibb/Sanofi to Dr Criqui.
Disclosures
None.
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