Mortality and Vascular Morbidity in Older Adults With Asymptomatic Versus Symptomatic Peripheral Artery Disease
Background— Our aim was to assess the mortality and vascular morbidity risk of elderly individuals with asymptomatic versus symptomatic peripheral artery disease (PAD) in the primary care setting.
Methods and Results— This prospective cohort study included 6880 representative unselected patients ≥65 years of age with monitored follow-up over 5 years. According to physician diagnosis, 5392 patients had no PAD, 836 had asymptomatic PAD (ankle brachial index <0.9 without symptoms), and 593 had symptomatic PAD (lower-extremity peripheral revascularization, amputation as a result of PAD, or intermittent claudication symptoms regardless of ankle brachial index). The risk of symptomatic compared with asymptomatic PAD patients was significantly increased for the composite of all-cause death or severe vascular event (myocardial infarction, coronary revascularization, stroke, carotid revascularization, or lower-extremity peripheral vascular events; hazard ratio, 1.48; 95% confidence interval, 1.21 to 1.80) but not for all-cause death alone (hazard ratio, 1.13; 95% confidence interval, 0.89 to 1.43), all-cause death/myocardial infarction/stroke (excluding lower-extremity peripheral vascular events and any revascularizations; hazard ratio, 1.18; 95% confidence interval, 0.92 to 1.52), cardiovascular events alone (hazard ratio, 1.20; 95% confidence interval, 0.89 to 1.60), or cerebrovascular events alone (hazard ratio, 1.33; 95% confidence interval, 0.80 to 2.20). Lower ankle brachial index categories were associated with increased risk. PAD was a strong factor for the prediction of the composite end point in an adjusted model.
Conclusions— Asymptomatic PAD diagnosed through routine screening in the offices of primary care physicians carries a high mortality and/or vascular event risk. Notably, the risk of mortality was similar in symptomatic and asymptomatic patients with PAD and was significantly higher than in those without PAD. In the primary care setting, the diagnosis of PAD has important prognostic value.
Received March 17, 2009; accepted September 9, 2009.
Atherosclerosis is a systemic disease that affects coronary, cerebral, and lower-extremity arteries and requires stringent secondary preventive measures to prevent premature mortality and morbidity.1 The manifestation of atherosclerosis in the legs, peripheral artery disease (PAD), has long been underestimated and underdiagnosed in the primary care setting.2,3 A series of large-scale epidemiological studies have shown that the disease is widespread, particularly in the elderly and in patients with diabetes mellitus or clusters of cardiovascular risk factors.4,5 Furthermore, PAD was shown to be associated with increased risk for premature mortality and cardiovascular and cerebrovascular events.6,7 Only a few studies have been stratified for asymptomatic and symptomatic PAD cases, but they did not provide consistent outcomes. Criqui et al8 described a progressive increase in patients with PAD who were asymptomatic, symptomatic, or severely symptomatic; Leng et al9 demonstrated that asymptomatic PAD patients had higher event rates than symptomatic patients. In addition, McDermott et al10 more recently reported that patients with asymptomatic PAD had poorer functional performance and quality of life than patients with intermittent claudication (IC). Overall, current data from the primary care setting on the prevalence and risk of premature mortality and of cardiovascular events associated with PAD are limited.
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Clinical Perspective on p 2061
Against this background, our objectives were to describe the prevalence of asymptomatic and symptomatic PAD in unselected elderly patients in a representative primary care setting in Germany, to investigate the long-term risk for total mortality or major vascular events in patients with PAD by clinical status (asymptomatic versus symptomatic) compared with individuals without PAD, and to quantify the association of PAD with outcomes compared with conventional cardiovascular risk factors.
The German Epidemiological Trial on Ankle Brachial Index (getABI) is an ongoing prospective observational cohort study initiated in October 2001. The methods and design of the study have been described elsewhere in greater detail.11,12 Briefly, 34 vascular physicians throughout Germany trained and supervised 344 general physicians (GPs) in their vicinity who were representative in terms of location (ZIP codes) and training (internists and general physicians) of the primary care setting in Germany. A prevalence assessment of primary care attendees, regardless of their reason for seeing the doctor, was then conducted in a prespecified week in October 2001. An average of 20 eligible patients per practice who fulfilled the inclusion criteria (age ≥65 years, legally competent, and able to cooperate appropriately and to provide written informed consent) were recruited evenly over this week to avoid selection bias. The only exclusion criterion was life expectancy ≤6 months as judged by the GP.
Medical History and Definitions at Baseline
A short physical examination was performed at baseline. Medical history assessment included the following conditions: cardiovascular events (myocardial infarction or coronary revascularization procedures); cerebrovascular events (stroke or revascularization procedures on the carotid arteries); lower-extremity peripheral vascular events (ie, a history of amputation [minor and major form] of the lower extremities because of PAD or revascularization procedures on the lower-extremity peripheral arteries); IC (ie, pain in the calf muscles while walking or during other exertion and disappearing within 10 minutes at rest); and risk factors such as arterial hypertension, diabetes mellitus, lipid disorders, or smoking. Subjects were defined as having diabetes mellitus if they had been assigned the clinical diagnosis by their physician, if their hemoglobin A1c was ≥6.5% (criterion used in 94 cases), and/or if they were receiving any oral antidiabetic drug and/or insulin at baseline. Subjects were defined as having hypertension if they had been assigned the clinical diagnosis by their physician and/or if they were receiving AT1 receptor antagonists, angiotensin-converting enzyme inhibitors, and/or diuretics at baseline. Subjects were defined as having lipid disorders if they had been assigned the clinical diagnosis by their physician, if they were receiving statins and/or fibrates, if their total cholesterol was ≥200 mg/dL at baseline, and/or if their triglyceride level was ≥150 mg/dL at baseline. All laboratory examinations were performed centrally. A cigarette smoking history was taken from all study subjects (never, current, past).
ABI at Rest
GPs were specifically trained to perform ABI measurements under standardized conditions. A standardized Doppler ultrasonic device was used in all centers (8-MHz Kranzbühler, General Electric, Solingen, Germany). Blood pressure measurements and ABI calculations were performed according to the recommendations of the American Heart Association.13
The ABI for each leg equals the ratio of the higher of the 2 systolic pressures (tibial posterior and anterior artery) above the ankle to the average of the right and left brachial artery pressures, unless there was a discrepancy ≥10 mm Hg in blood pressure values between the 2 arms. In such a case, the higher reading was used for the ABI. Pressures in each leg were measured, and the ABIs were calculated separately for each leg. The lower of the 2 ABI values was used for analyses.
Asymptomatic PAD was defined as resting ABI <0.9013 with an absence of prior lower-extremity peripheral vascular events or clinical symptoms indicative of IC. Symptomatic PAD was defined as IC, history of lower-extremity peripheral vascular revascularization, and/or limb amputation because of PAD regardless of ABI value. Total PAD was defined as either symptomatic or asymptomatic PAD. Fifty-nine patients with incompressible arteries (Mönckeberg sclerosis) as indicated by an ABI >1.5 were excluded, as in other studies, to avoid misclassification.14,15 Cases with missing ABI values (n=8) and no past peripheral events or IC were classified as patients without PAD.
Primary Study Outcomes and Identification of Cardiovascular Events During Follow-Up
Severe vascular events were defined as follows: cardiovascular, including myocardial infarction or coronary revascularization; cerebrovascular, including stroke or carotid revascularization; and lower-extremity peripheral vascular, including peripheral revascularization or amputation because of PAD during follow-up. Information on patients’ deaths and vascular events was obtained from the participating GPs, who were asked after 6 months and 1, 3, and 5 years to complete a case record form detailing the event. If possible, deaths resulting from cardiovascular or cerebrovascular causes were further investigated by verifying data from hospital or GP records to ensure that the protocol criteria were fulfilled. Deaths, coronary events, and peripheral events were not adjudicated. However, all strokes were further verified and adjudicated by 2 experienced neurologists independently who were unaware of the PAD status of patients.
Characteristics of subjects at baseline were illustrated descriptively for all 6821 patients and separately by PAD categories. In addition, the differences between symptomatic and asymptomatic PAD patients at baseline were investigated exploratively with χ2 tests and t tests. To assess associations between PAD, respective ABI categories (and conventional risk factors) and 5-year mortality/vascular morbidity incidence rates were calculated and Cox regression analyses were performed.
Incidence rates and their 95% confidence intervals (CIs) were calculated as events per 1000 person-years. Only the first event and time until first event were taken into account. The constant rate assumption was not met for the risks of interest. Therefore, the reported incidence rates have to be interpreted as a kind of average over the 5 years of the study.
Several unadjusted and adjusted Cox regression analyses were performed, and the corresponding hazard ratios (HRs) and their 95% CIs were calculated. When comparing PAD groups, we used 4 separate models: PAD no/unknown to PAD total (analysis includes all patients), PAD no/unknown to PAD asymptomatic (patients with symptomatic PAD were excluded), PAD no/unknown to PAD symptomatic (patients with asymptomatic PAD were excluded), and PAD asymptomatic to PAD symptomatic (patients without [or unknown] PAD were excluded).
To best illustrate the possible linear relations between low ABI values and the risk of death or vascular events, the ABI was categorized according to the cutoff points of 1.1, 0.9, 0.7, and 0.5 (the last category also includes history of peripheral revascularization or amputation resulting from PAD at baseline). When comparing ABI categories, we also used 4 separate models, with patients with an ABI ≥1.1 and ≤1.5 as the reference group in each case.
In addition to PAD groups, respectively ABI categories, the following variables were included in all adjusted statistical models: age (above/below median); gender; smoking status (never/ever); body mass index (≥/<30 kg/m2); history of severe cardiovascular or cerebrovascular events (yes/no or unknown); presence of diabetes mellitus, hypertension, and lipid disorders (each yes/no or unknown); and homocysteine (below/above the 4th quintile [19.1 μmol/L]). These results were also used to compare the relative prognostic importance of PAD and the other conventional risk factors.
Further, to visualize the findings, time-to-event distributions in the categories were summarized with Kaplan–Meier curves.
Statistical significance was accepted at the 2-sided 0.05 level, and all CIs were computed at the 95% level. Statistical analyses were performed with SAS version 9.1 (SAS Institute Inc, Cary, NC).
Characteristics of Subjects at Baseline
Of the 6880 patients included in this study, all but 59 (ABI >1.5, defined as patients with mediasclerosis) were analyzed. The survival status of all but 4 patients was known at the 5-year follow-up. According to physician diagnosis, 5392 patients had no PAD (79.0%), 836 had asymptomatic PAD (12.3%), and 593 had symptomatic PAD (8.7%; about one quarter had undergone peripheral artery revascularization or amputation). The Table displays the patient characteristics in the individual groups. Although there were no significant differences in age and most risk factors, in symptomatic PAD patients, the proportions of men, smokers, and patients with a history of cardiovascular or cerebrovascular events were higher. For mean body mass index, the opposite was true. Of note, the mean ABI was higher in symptomatic compared with asymptomatic PAD patients (0.85±0.23 versus 0.79±0.11).
Figure 1 provides an overview of mortality events in total and by cause. Of patients without PAD, with asymptomatic PAD, and with symptomatic PAD, 19.5, 41.7, and 53.0 patients per 1000 patient-years had died. Compared with patients without PAD, those with asymptomatic PAD (HR, 1.66; 95% CI, 1.38 to 2.00) or symptomatic PAD (HR, 1.89; 95% CI, 1.55 to 2.30) had a significantly increased risk of premature death. No significant differences between asymptomatic and symptomatic PAD groups were found for death regardless of reason (cardiovascular, cerebrovascular, other, unknown reason).
Composite Outcomes of All-Cause Mortality and Vascular Events
The composite end point of all-cause mortality or severe vascular events occurred in 27.2 (no PAD), 60.4 (asymptomatic PAD), and 104.7 (symptomatic PAD) cases per 1000 patient-years (Figure 2, top).
Compared with patients without PAD, those with asymptomatic PAD (HR, 1.81; 95% CI, 1.53 to 2.14) or symptomatic PAD (HR, 2.66; 95% CI, 2.25 to 3.15) had a significantly increased risk to experience the composite outcome, and the difference between the 2 PAD groups was significant (HR. 1.48; 95% CI, 1.21 to 1.80). Times to event for the composite outcomes by PAD status are also illustrated with Kaplan–Meier curves (Figure 3).
The breakdown for the various vascular event types is displayed by PAD status in Tables Ia through If of the online-only Data Supplement. Between symptomatic and asymptomatic PAD, no significant differences were found for myocardial infarction, stroke, peripheral amputation resulting from PAD, and carotid revascularization, whereas rates in the symptomatic PAD group were significantly increased for coronary revascularization and peripheral revascularization.
Figure 2 summarizes these findings and shows the patient-years and event rates for various individual and combined outcomes (all-cause death and/or severe vascular events) in the total PAD group and stratified for asymptomatic and symptomatic PAD, as well as the resulting adjusted risk increase compared with the group of patients without PAD. The relative number of events and the corresponding risk increase were consistently higher in symptomatic PAD patients.
Of note, the number of cerebrovascular events, including ischemic/hemorrhagic stroke, was substantially lower than the number of cardiovascular events. The adjusted HR for cerebrovascular events in the total PAD group was slightly lower than the risk for cardiovascular events (HR, 1.45; 95% CI, 1.06 to 1.98; versus HR, 1.89; 95% CI, 1.56 to 2.28).
Impact of Peripheral Events
The difference between total events in the symptomatic PAD group and the asymptomatic PAD group appeared to be driven by a greater number of peripheral revascularizations performed in the symptomatic group; perhaps these events were triggered by symptoms. Two separate analyses with group comparisons were performed to investigate this finding (Figure 2, middle, and Tables IIa and IIb of the online-only Data Supplement). In the first analysis, lower-extremity peripheral events (lower-extremity peripheral revascularization and amputation resulting from PAD) were excluded from the end point; in the second analysis, lower-extremity peripheral events and all revascularizations (coronary/carotid) were excluded from the end point (Figure 2). In the first analysis, the relative risk of symptomatic PAD patients compared with asymptomatic PAD patients was lower than in the overall end point of all-cause death or severe vascular event (1.32; 95% CI, 1.05 to 1.64; versus 1.48; 95% CI, 1.21 to 1.80), but the difference between symptomatic PAD patients and asymptomatic PAD patients was still significant. In the second analysis, the relative risk of PAD patients compared with non-PAD patients was similar (1.85; 95% CI, 1.57 to 2.17), but the difference between symptomatic PAD patients and asymptomatic PAD patients did not remain significant (1.18; 95% CI, 0.92 to 1.52).
In the analysis by ABI category, patients with an ABI of 1.1 to 1.5 had the lowest event rate per 1000 patient-years (24.3 events), whereas event rates increased substantially with decreasing ABI. In patients with an ABI <0.5, lower-extremity peripheral revascularization, or amputation resulting from PAD, event rates were increased 6-fold (146.3), and the corresponding adjusted risk was increased 4.65-fold (95% CI, 3.57 to 6.05). This finding is illustrated with event-free survival by ABI category in Figure 4, and further details are provided in the Table III of the online-only Data Supplement.
In a supplementary analysis, ABI was included as a continuous variable in the adjusted statistical model, along with the other risk factors. Patients with IC had lower ABI values than patients without IC, particularly among patients with an ABI <0.9 (Table IVa of the online-only Data Supplement). There was a significant independent prognostic effect of IC for death resulting from any cause in an adjusted model including ABI groups (<0.9/≥0.9); however, in the model with continuous ABI values, it was lower and did not remain significant (Table IVb of the online-only Data Supplement). The prognostic effect of IC for death resulting from any cause or severe vascular event was greater than that for death resulting from any cause alone and was significant in both models (Table IVc of the online-only Data Supplement).
Independent Association of PAD With Outcomes
After adjustment for known conventional risk factors in the adjusted model, PAD had the strongest independent association with death or severe vascular events (HR, 2.17; 95% CI, 1.90 to 2.48). Male gender, previous cardiovascular or cerebrovascular events, diabetes mellitus, high age, smoking, and high homocysteine levels were also significant factors in this model (Figure 5).
The present large-scale prospective study shows that 1 in 5 elderly patients visiting their primary care physician has PAD (12.2% asymptomatic, 8.7% symptomatic). With few exceptions, previous epidemiological studies have not differentiated between asymptomatic and symptomatic PAD but have focused on an ABI threshold (usually <0.9) for the diagnosis of PAD.16–20 In our study, regardless of the event type (death and/or severe vascular events), patients with PAD had a significantly increased risk compared with those without PAD. Within the PAD group, the risk of symptomatic PAD compared with asymptomatic PAD patients was significantly increased by ≈50% (HR, 1.48) for the composite end point of all-cause death or severe vascular event but not significantly for all-cause mortality alone (HR, 1.13), death/myocardial infarction/stroke (ie, excluding any peripheral events and any revascularizations; HR, 1.18), or cardiovascular or cerebrovascular events when assessed separately. Thus, asymptomatic PAD diagnosed through routine screening in the offices of primary care physicians carries a high 5-year mortality and cardiovascular or cerebrovascular event risk that is not substantially lower than that of symptomatic PAD. This early form of PAD has previously been underestimated, underdiagnosed, and undertreated because of a mistaken belief that it is relatively benign.2,3 The high mortality and vascular event rates, however, show the high risk that these patients face and the importance of treating the condition early.
The majority of earlier observational studies that investigated the risk of PAD patients were population based8,21–23 or done in high-risk patients.24 Cohorts in the primary care setting20,25 (particularly if source data are verified by monitoring as in our study) compared with population-based studies are likely to be characterized more thoroughly in terms of comorbidities and outcomes, and their results are more likely to be directly applicable to routine care. Generally, the risk increase associated with PAD observed in our study is on the same order as in previous population-based studies that used ABI cutoffs of 0.9 (in some studies, 0.85 or 0.5), as systematically reviewed by Doobay and Anand.6 They found, compared with individuals without PAD, a mean unadjusted relative risk of 3.2 (95% CI, 2.6 to 3.9) and adjusted risks between 1.6 and 3.1, depending on the individual study, for all-cause mortality. Moreover, they found an unadjusted relative risk of 2.3 (95% CI, 1.5 to 3.7) and adjusted risk between 1.4 and 2.7 for cardiovascular events.
Because rates for cerebrovascular events are substantially lower than those for cardiovascular events, large cohorts and/or long follow-up periods are necessary to address the question of whether the respective risk is increased in PAD patients. Thus, compared with coronary morbidity and mortality, cerebrovascular events have been infrequently reported with inconclusive results. The Edinburgh Artery Study25 and the Atherosclerosis Risk in Communities Study26 found a significant risk increase for stroke, whereas the Cardiovascular Health Study (after multivariable adjustment) did not.23 In our study, in the total PAD cohort, the adjusted HR of cerebrovascular events, if not differentiated between type of stroke, was significantly increased (HR, 1.5). Notably, in the group of asymptomatic PAD patients, the risk increase was not significant, which may be due to small power owing to low event numbers.
An important finding of the present study is that PAD (asymptomatic and symptomatic), after adjustment for multiple known cardiovascular risk factors, had a significant association with the composite outcome of death or vascular events. The association between PAD and the composite outcome was considerably stronger than with conventional risk factors, including diabetes mellitus or smoking. This result is in line with the majority of the older investigations focusing on low ABI,6 showing that PAD provides additional information on risk beyond the assessment of conventional risk factors. Hypertension and lipid disorders had no significant effect in the model, which may be due to pretreatment or the advanced age of the cohort.27
Certain types of vascular events are prompted by symptoms, namely revascularizations and amputations in the lower extremities (which are usually performed in patients with claudication), as well as most revascularizations of the carotid and coronary arteries. So, it could be expected that after the exclusion of all events that are influenced by symptoms and consequently physician decision, the risk difference between symptomatic and asymptomatic PAD decreases. Indeed, the difference between asymptomatic and symptomatic PAD patients was reduced somewhat after the exclusion of all lower-extremity peripheral vascular events from the analyses (HR, from 1.48 to 1.32) and to a greater extent after additional exclusion of revascularizations of the carotid and coronary arteries (HR, 1.18, no longer significant).
In our study, the ABI was measured by GPs or their staff. A recent validation study involving getABI investigators showed that between vascular experts, GPs, and nurses, no significant differences exist with respect to measurement variance.28 Therefore, the ABI measurement can be performed with reliable results after minimal training. It must be noted, however, that the intraobserver and interobserver variability of this investigation is 8% to 9%, which calls for confirmation measurements in patients near the 0.9 threshold to categorize them correctly.28 Furthermore, as shown in our analysis, the ABI value not only is of high interest for the PAD diagnosis but also conveys relevant information on the individual patient’s risk.
The prevalence of PAD in the primary care setting is alarmingly high, which supports the routine use of ABI measurements to identify patients who are at high risk for premature death and vascular events. Measurement of ABI at baseline provides prognostic information that cannot be derived from conventional risk factors alone. Patients with asymptomatic PAD have a significantly increased risk compared with patients without PAD, which calls for risk reduction measures such as stringent lipid-lowering and antiplatelet treatment. In terms of treatment (ie, secondary prevention), the current American Heart Association/American College of Cardiology guidelines or Transatlantic Inter-Society Consensus II guidelines do not differentiate between asymptomatic and symptomatic PAD patients,4,5 and our results corroborate this approach. The present study confirms the importance of PAD as an indicator disease for generalized atherosclerosis, and its high prognostic utility, in primary care.
Sources of Funding
This study was supported by an unrestricted educational grant from Sanofi-Aventis, Berlin, Germany (2001 to 2007), and the German Federal Ministry of Education and Research (since 2007).
Dr Mahn is a full-time employee of Sanofi-Aventis Pharma, which is one of the sponsors of the study. Dr Mahn had no voting rights. The sponsors have had no influence on the design of the study, research questions, and data interpretation. All analyses were performed by the University of Bochum. The authors report no conflicts of interest related to this study, which does not focus on drug-related research questions.
Belch JJF, Topol EJ, Agnelli G, Bertrand M, Califf RM, Clement DL, Creager MA, Easton JD, Gavin I, James R, 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.
Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation. 2006; 113: e463–654.
Doobay AV, Anand SS. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systematic review. Arterioscler Thromb Vasc Biol. 2005; 25: 1463–1469.
Golomb BA, Dang TT, Criqui MH. Peripheral arterial disease: morbidity and mortality implications. Circulation. 2006; 114: 688–699.
Leng GC, Lee AJ, Fowkes FG, Whiteman M, Dunbar J, Housley E, Ruckley CV. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol. 1996; 25: 1172–1181.
McDermott MM, Guralnik JM, Ferrucci L, Tian L, Liu K, Liao Y, Green D, Sufit R, Hoff F, Nishida T, Sharma L, Pearce WH, Schneider JR, Criqui MH. Asymptomatic peripheral arterial disease is associated with more adverse lower extremity characteristics than intermittent claudication. Circulation. 2008; 117: 2484–2491.
Greenland P, Abrams J, Aurigemma GP, Bond MG, Clark LT, Criqui MH, Crouse JR 3rd, Friedman L, Fuster V, Herrington DM, Kuller LH, Ridker PM, Roberts WC, Stanford W, Stone N, Swan HJ, Taubert KA, Wexler L. Prevention Conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: noninvasive tests of atherosclerotic burden. Circulation. 2000; 101: E16–E22.
Meijer WT, Hoes AW, Rutgers D, Bots ML, Hofman A, Grobbee DE. Peripheral arterial disease in the elderly: the Rotterdam Study. Arterioscler Thromb Vasc Biol. 1998; 18: 185–192.
McDermott MM, Greenland P, Liu K, Guralnik JM, Celic L, Criqui MH, Chan C, Martin GJ, Schneider J, Pearce WH, Taylor LM, Clark E. The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann Intern Med. 2002; 136: 873–883.
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.
Lee AJ, Price JF, Russell MJ, Smith FB, van Wijk MCW, Fowkes FGR. Improved prediction of fatal myocardial infarction using the ankle brachial index in addition to conventional risk factors: the Edinburgh Artery Study. Circulation. 2004; 110: 3075–3080.
Zheng Z, Sharrett A, Chambless L, Rosamond W, Nieto F, Sheps D, Dobs A, Evans G, 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.
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. Arterioscler Thromb Vasc Biol. 1999; 19: 538–545.
Leng GC, Fowkes FG, Lee AJ, Dunbar J, Housley E, Ruckley CV. Use of ankle brachial pressure index to predict cardiovascular events and death: a cohort study. BMJ. 1996; 313: 1440–1444.
Tsai AW, Folsom AR, Rosamond WD, Jones DW. Ankle-brachial index and 7-year ischemic stroke incidence: the ARIC study. Stroke. 2001; 32: 1721–1724.
Lange S, Trampisch H, Haberl R, Darius H, Pittrow D, Schuster A, von Stritzky B, Tepohl G, Allenberg H, Diehm C. Excess 1-year cardiovascular risk in elderly primary care patients with a low ankle-brachial index (ABI) and high homocysteine level: the getABI study. Atherosclerosis. 2005; 178: 351–357.
Holland-Letz T, Endres HG, Biedermann S, Mahn M, Kunert J, Groh S, Pittrow D, von Bilderling P, Sternitzky R, Diehm C. Reproducibility and reliability of the ankle-brachial index as assessed by vascular experts, family physicians and nurses. Vasc Med. 2007; 12: 105–112.
The clinical importance of the early identification and treatment of peripheral arterial disease (PAD) as a manifestation of generalized atherosclerosis is increasingly being acknowledged. However, differences in risk between the asymptomatic and symptomatic manifestations are less clear. Thus, the aim of this study was to compare the risk for all-cause death and vascular events in elderly individuals with asymptomatic PAD (evidenced by low ankle brachial index) and symptomatic PAD in the primary care setting. We found an alarmingly high prevalence of PAD in the primary care setting (12.2% asymptomatic, 8.7% symptomatic). The composite end point of all-cause mortality or severe cardiac, cerebral, or peripheral vascular events occurred in 27.2 (no PAD), 60.4 (asymptomatic PAD), and 104.7 (symptomatic PAD) cases per 1000 patient-years. Thus, asymptomatic PAD diagnosed through routine screening in the offices of primary care physicians carries a high mortality and vascular event risk, which, in cases of all-cause mortality, is not substantially lower than that of symptomatic PAD. This justifies the routine use of ankle brachial index measurements to identify patients who are at high risk for premature death and vascular events. Measurement of ankle brachial index at baseline provides prognostic information that cannot be derived from conventional risk factors alone. In terms of treatment (ie, secondary prevention), the current American Heart Association/American College of Cardiology guidelines or Transatlantic Inter-Society Consensus II guidelines on PAD do not differentiate between asymptomatic and symptomatic PAD patients, and our results corroborate this approach.
The main results of this study were presented at the Hotline Session of the Annual Meeting of the European Society of Cardiology; September 13, 2007; Vienna, Austria.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.865600/DC1.