Prognostic value of ankle-brachial index and dobutamine stress echocardiography for cardiovascular morbidity and all-cause mortality in patients with peripheral arterial disease

Article Outline

• Abstract
• Methods
  • Study population
  • Ankle-brachial measurement
  • Dobutamine stress echocardiography
  • Study end points, major event definition
  • Statistical methods
• Results
  • Demographic and clinical characteristics
  • Ankle-brachial index
  • Dobutamine stress echo
  • Cardiovascular morbidity and all-cause mortality
  • Predictors of cardiovascular morbidity and all-cause mortality
  • Effect of peripheral artery disease severity on study end points
  • Correlation between ankle-brachial index and dobutamine stress echocardiography
• Discussion
  • Study limitations
• Conclusion
• Author contributions
• References
• Copyright

Background

Peripheral arterial disease (PAD) is associated with an excessive risk for cardiovascular events and mortality. To determine measures prognostic of adverse events, ankle-brachial index (ABI) was compared with dobutamine stress echocardiography (DSE) in patients referred to our vascular center for the evaluation of PAD.

Methods

The medical records of consecutive patients referred for the concurrent evaluation of PAD and coronary artery disease (CAD) between 1992 and 1995 were reviewed for subsequent cardiovascular events and death.

Results

Among 395 patients (mean age, 69.7 ± 9.6 years; 40% women), 341 had abnormal ABI and 268 had abnormal DSE (95 fixed and 173 stress-induced wall motion abnormalities). During a mean follow-up of 4.7 years, 27.3% of patients experienced a cardiovascular event, and 39.4% died. By multivariate analysis, ABI provided the strongest prediction of all-cause mortality (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.36 to 4.05; P = .002). Conversely, DSE with inducible or fixed wall motion abnormalities showed no association with cardiovascular events or increased mortality in multivariate analysis. The only DSE variable independently predictive of mortality was decreased left ventricular ejection fraction (<50%) at peak stress (HR, 1.70; 95% CI, 1.22 to 2.36; P = .002). Statin and aspirin therapy, but not β-blockers, were protective. There was no relation between ABI and wall motion index score at rest or after stress.

Conclusions

In high-risk patients referred to our vascular center for the evaluation of PAD, the assessment of ABI provided a strong independent prediction of all-cause mortality. Therefore, proper interpretation of this simple, affordable, and reproducible measure extends beyond the assessment of PAD severity. Although a poor left ventricular response to dobutamine was also predictive, other echo variables were not.

Peripheral arterial occlusive disease (PAD) is prevalent in Western societies.¹ PAD manifested as claudication is found in 3.7% of people aged between 60 and 70 years old and in 5.2% of those >70 years old,² but the incidence of asymptomatic disease is approximately five times higher.³ Atherosclerosis is a generalized process involving different arterial territories, therefore it is not surprising that the presence of flow-limiting lesions in a peripheral artery indicates disease in coronary, renal, and carotid arteries.⁴ PAD is an independent predictor of early⁵ and late⁶ cardiovascular complications and death. Consequently, individuals with PAD are among the highest-risk vascular patients, and a cost-effective strategy is required for their evaluation and treatment.

Ankle-brachial index (ABI) is not only widely used as a noninvasive test for PAD⁷ but is also an independent predictor of cardiovascular risk.⁸, ⁹, ¹⁰ However, the utility of this measure as a predictor of cardiovascular event and mortality has recently been questioned, particularly among patients with multiple atherosclerotic risk factors or established vascular disease.¹¹ Furthermore, in patients with PAD, it is unclear whether more extensive and sophisticated cardiac testing adds useful prognostic information once the ABI is known.

Dobutamine stress echocardiography (DSE) detects coronary artery disease (CAD) without walking exercise and is therefore very useful in patients with PAD.¹², ¹³, ¹⁴, ¹⁵ DSE is used to define preoperative cardiovascular risk in patients undergoing noncardiac surgery¹⁶, ¹⁷ and is also an independent predictor of late coronary events.¹⁸, ¹⁹

Our first objective was to determine if ABI predicts cardiovascular morbidity and all-cause mortality in a selected, comprehensively evaluated group of high-risk patients. Our second objective was to compare the predictive value of low ABI with positive DSE and other clinical and therapeutic variables for cardiovascular morbidity and all-cause mortality. Finally, by determining if lower ABI predicts positive DSE, we wanted to challenge the general opinion that low ABI predicts cardiovascular morbidity and mortality because it selects patients with particularly severe coronary disease.

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Methods 

Study population 

All patients undergoing assessment of PAD by ABI measurement between November 1, 1992, and May 31, 1995 at the Vascular Laboratory of Gonda Vascular Center and who also had DSE testing ≤6 months of their vascular evaluation were included. The study was approved by the Mayo Clinic Institutional Review Board. Data were collected from a centralized system that contains records of all patients treated and followed up at Mayo Medical Center. It includes the details for every inpatient hospitalization, outpatient visit, radiology examination, all laboratory and pathology results, death certificates, and relevant correspondence.

The follow-up period began at the time of the initial patient encounter and ended with the most recent medical evaluation or time of death. Causes of death were determined by a review of medical records, death certificate or United States Social Security Death Index, and autopsy results, when available.

Diabetes mellitus was diagnosed from the criteria recommended by the American Diabetes Association,²⁰ and dyslipidemia according to recommendations of the National Cholesterol Education Program expert panel and the American College of Physicians.²¹ Prior CAD was recognized when a patient had clinical symptoms of angina and a confirmatory test result (abnormal electrocardiogram, positive cardiac stress test, abnormal coronary angiogram), or had had a previous myocardial infarction (MI), percutaneous coronary intervention, or coronary artery bypass graft.

We used a control group constructed on the basis of age-specific and sex-specific mortality rates in the United States white population for the period of this study.²² We assumed that the expected survival rate accounts for the effects of other medical conditions according to their known prevalence in this reference population.

Ankle-brachial measurement 

The ABI was measured according to a standard protocol used at the Gonda Vascular Center, Mayo Clinic, as previously described.²³ Briefly, blood pressures were measured with the patient in the supine position by using a 8.3-MHz continuous wave Doppler probe over each ankle from both dorsalis pedis and posterior tibial arteries and in the brachial artery of each arm. The greater of ankle systolic to the greater of brachial systolic pressures were used to calculate the ratio. If bilateral disease was present, the lower ratio was taken for study analysis.

All the test results were interpreted by physician from the Mayo Clinic Vascular Laboratory and subsequently reviewed by the study vascular physician (W. E. W.). An ABI <0.9 was defined as abnormal.⁸ For the purpose of data analysis, the abnormal ABI group was further divided into mild PAD (ABI, 0.8 to 0.9), moderate PAD (ABI, 0.5 to 0.8), and severe PAD (ABI <0.5).

Dobutamine stress echocardiography 

DSE was performed according to a previously described protocol.²⁴ The left ventricular ejection fraction was evaluated by a modified method of Quinones et al²⁵ or by visual estimation. Wall motion was assessed at rest and with stress in each of 16 segments by using a scale of 1 through 5, in which 1= normal, 2 = hypokinesis, 3 = akinesis, 4 = dyskinesis, and 5 = aneurysm. The wall motion score index was calculated at rest and during stress by dividing the total wall motion severity score by the number of measured segments.²⁶

For the purpose of this study, the rest and stress images were analyzed for inducible myocardial ischemia and the presence of fixed abnormalities. Ischemia was diagnosed when new or worsening wall motion abnormalities were observed with stress, and defined as positive DSE for myocardial ischemia or simply positive DSE. Fixed wall motion abnormalities were those present at rest and unchanged with stress. DSE was considered abnormal in the presence of ischemia or fixed wall motion abnormalities. Results were interpreted by a cardiologist from the Mayo Clinic Echocardiography Laboratory and subsequently analyzed by the study cardiologist (P. A. P.).

Study end points, major event definition 

Study end points incorporated cardiovascular events and death. Cardiovascular events included stroke, transient ischemic attack (TIA), unstable angina, and MI. Criteria to define MI, unstable angina, stroke, and TIA were adapted from those proposed by the American Heart Association.²⁷

Statistical methods 

Continuous variables were reported as mean ± SD and categoric variables as percentages. Univariate and multivariate associations of clinical and echocardiographic variables were assessed with Cox proportional hazards models for the two end points of first cardiovascular adverse event and all-cause mortality. In the multivariate models, variables were chosen in a forward selection manner, with entry and retention in the model set at a significance level of 0.15 and 0.05, respectively.

The multivariate models were constructed in two steps: (1) fitting a multivariate model of only clinical and echocardiographic data and (2) evaluating the association of the variables of interest and their interaction. In the second, step three variables were added to the constructed model, one for abnormal ABI, one for positive DSE, and one for their interaction. The interaction term was not significant in any of the two multivariate models, thus it was removed from the final models.

The results of these analyses were summarized as hazard ratios (HR) with 95% confidence intervals (CI). End point-free survivals were estimated by use of the Kaplan-Meier method. Expected survival was compared with observed using the one-sample log-rank test. Two-sided values of P < .05 were considered statistically significant. All analyses were done using SAS 8 software (SAS Institute, Cary, NC).

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Results 

Demographic and clinical characteristics 

Between November 1, 1992, and May 31, 1995, 437 patients underwent ABI measurement and DSE testing ≤6 months of their vascular evaluation for various clinical indications, including preoperative evaluation for major noncardiac surgery (71%), risk stratification for known CAD (11%), evaluation of chest pain (11%), or other (7%). Of these, 42 patients were excluded because of noncompressible arteries (n = 23), incomplete vascular laboratory evaluation (n = 5), or poor-quality baseline echocardiographic images (n = 14). Therefore, 395 patients were included into the analysis.

Demographic and clinical data of this group are summarized in Table I. Cardiovascular risk factors were prevalent in this cohort, with 83.3% having more than three atherosclerotic risk factors. The two most common risk factors were tobacco use and hypertension. One third of patients received statin therapy, and nearly 75% received antiplatelet therapy, principally aspirin. No relationship was found between DSE results (positive, negative, abnormal, normal) and therapy with β-blockers, statins, or antiplatelet agents by statistical modeling. Those individuals with both an abnormal ABI and a positive DSE more often had diabetes, history of MI, and documented carotid artery disease relative to those with a negative DSE (P < .05 for each comparison).

Table I. Demographic and clinical characteristics

ABI, Ankle-brachial index; DSE, dobutamine stress echocardiography; CAD, coronary artery disease; MI, myocardial infarction; ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker.

Ankle-brachial index 

Abnormal ABI was found in 341of patients (86%), and the mean ABI value for the whole study group was 0.5 ± 0.3. Within the abnormal ABI group, 23 (6%) had mild PAD (ABI, 0.8 to 0.9), 123 (31%) had moderate PAD (ABI, 0.5 to 0.8), and 195 (49%) had severe PAD (ABI <0.5) The Rutherford classification, which combines clinical features and ABI values,²⁸ was calculable for 305 symptomatic patients. Ulceration/tissue loss (classes V and VI) was present in 88 patients, rest pain (class IV) in 29, severe claudication (class III) in 177, but only 11 had mild-to-moderate claudication (classes I and II).

Dobutamine stress echo 

Among the 395 patients, mean left ventricular ejection fraction at rest was 53.7% ± 12% (range, 13% to 75%), and the mean wall motion score at rest was 1.36 ± 0.48 (range, 1.00 to 3.00). Wall motion abnormalities were present in 24.8% ± 30.9% of segments (median, 12.5%) during the resting study. DSE was normal in 127 and abnormal in 268 patients (68%). Of the 268 patients with abnormal studies, 173 had dobutamine-induced ischemia. Among those with inducible ischemia, resting wall motion abnormalities were present in 131 (76%), and the remaining 95 patients had fixed wall motion abnormalities with no inducible ischemia.

Cardiovascular morbidity and all-cause mortality 

The mean duration of follow up was 4.7 ± 4 years (median, 4.1 years; range, 0.0 to 11.8 years). The predicted 5-year rates were 27.3% for a cardiovascular event and 39.4% for mortality (Table II). Patients with an abnormal ABI experienced nearly twice as many cardiovascular events than did individuals with normal ABI. Furthermore, cerebral ischemic events were 3.75-fold more common in those patients with an abnormal ABI. All cause mortality was twofold higher in this group. In those patients with abnormal DSE (both inducible and fixed wall motion abnormalities), cardiovascular events and all cause mortality were increased by 1.6-fold. Cerebral ischemic events were not predicted by DSE results.

Table II. Predicted percent of patients with cardiovascular morbidity and all-cause mortality at 5 years

ABI, Ankle-brachial index; DSE, dobutamine stress echocardiography; MI, myocardial infarction; TIA, transient ischemic attack; CV, cardiovascular accident.

Predictors of cardiovascular morbidity and all-cause mortality 

Log-rank test analysis demonstrated that abnormal ABI was associated with significantly higher rate of cardiovascular events (P = .02) and all-cause mortality (P < .001) vs normal ABI (Fig 1). Positive DSE (inducible wall motion abnormalities) was not associated with a significantly increased rate of mortality or cardiovascular events compared with negative DSE (Fig 2, A and B). DSE with fixed wall motion abnormalities showed no association with increased rate of cardiovascular events or mortality (data not shown). However, when the combined group of inducible and fixed wall motion abnormalities (abnormal DSE) was compared with normal DSE, a borderline higher cardiovascular event rate (P = .052), and significantly worse survival (P = .02) was found (Fig 2, C and D).

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• Fig 1. 

  Kaplan-Meier analysis of (A) survival free from the first cardiovascular event and (B) overall survival, for normal ankle-brachial index (ABI, solid line), abnormal ABI (dashed line), and control group (dotted line). The control group (expected) was constructed on the basis of age-specific and sex-specific mortality rates in the United States white population for the period of this study.

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• Fig 2. 

  Kaplan-Meier analysis of (A and C) survival free from the first cardiovascular event and (B and D) overall survival . A and B, Positive dobutamine stress echocardiography (DSE, dashed line) and negative DSE (solid line). C and D, Abnormal DSE (dashed line), normal DSE (solid line), and control group (dotted line). The control group (expected) was constructed on the basis of age-specific and sex-specific mortality rates in the United States white population for the period of this study.

When our study patients were compared with the data from our population-based cohort matched for age and gender, an abnormal ABI was associated with worse survival (P < .001). Our study patients with normal ABI had a nonstatistically significant trend toward worse survival (P = .069), and this trend might have reached significance if our group had included more patients with normal ABI. In addition, both abnormal and normal DSE were associated with worse than expected survival (P < .001).

Univariate regression analysis showed that ABI, diabetes mellitus, presence of ≥3 cardiovascular risk factors, history of CAD, previous MI, carotid disease, therapy with β-blockers, angiotensin-converting enzyme inhibitors (ACE)/angiotensin receptor-blockers (ARB) therapy, and abnormal wall-motion score index at stress were all predictors of cardiovascular event (data not shown). However, after adjustment for other clinical variables, only carotid disease, diabetes mellitus, ≥3 cardiovascular risk factors, and unexpectedly, also treatment with β-blockers, were found to be statistically significant predictors of a cardiovascular event (Table III). Abnormal ABI did not predict a cardiovascular event. Neither inducible wall motion abnormalities (positive DSE) nor inducible and fixed wall motion abnormalities jointly (abnormal DSE) predicted cardiovascular event by multivariate analysis (Table III).

Table III. Multivariate analysis of demographic, clinical, and echocardiographic variables for prediction of first cardiovascular event and all-cause mortality

Variable	HR	95% CI	P
Cardiovascular event
Diabetes	1.55	1.02-2.35	.04
Carotid bruit	2.01	1.32-3.05	.001
CV risk factors >3	1.93	0.90-4.17	.09
β-Blockers therapy	1.77	1.17-2.67	.006
Abnormal ABI⁎	1.69	0.81-3.55	.17
Positive DSE†	1.13	0.76-1.68	.56
Abnormal DSE‡	1.33	0.86-2.08	.20
All-cause mortality
Age	1.04	1.03-1.06	<.001
Diabetes	1.84	1.37-2.48	<.001
Previous CAD	1.43	1.04-1.98	.028
Antiplatelet therapy	0.64	0.46-0.90	.009
Statin therapy	0.28	0.20-0.39	<.001
LVEF < 50 at peak stress	1.7	1.22-2.36	.002
Abnormal ABI⁎	2.34	1.36-4.05	.002
Positive DSE†	1.16	0.86-1.57	.32
Abnormal DSE‡	1.11	0.79-1.57	.55

HR, Hazard ratio; CI, confidence interval; CV, cardiovascular; ABI, ankle-brachial index; DSE, dobutamine stress echocardiography; CAD, coronary artery disease; LVEF, left ventricular ejection fraction.

Treatment with β-blockers, antiplatelet agents, and statins was associated with improved survival by univariate analysis (data not shown). ABI, age, diabetes mellitus, dyslipidemia, history of CAD, left ventricular end-systolic volume at rest or peak stress, left ventricular ejection fraction at rest or peak stress, wall-motion score indices at rest or peak stress, and presence of left ventricular ejection fraction <50% at rest or peak stress, were all predictive of all-cause mortality by univariate analysis (data not shown). By multivariate analysis (Table III), ABI was the strongest predictor of all-cause mortality (HR, 2.34; 95% CI, 1.36 to 4.05; P = .002). Statin therapy was the most protective variable (HR, 0.28; 95% CI, 0.20 to 0.39; P < .001), and treatment with antiplatelet agents also appeared to be protective. Age, diabetes mellitus, history of CAD, and left ventricular ejection fraction <50% at peak stress predicted mortality after adjustment for other clinical variables. In multivariate analysis, neither positive nor abnormal DSE predicted all-cause mortality (Table III).

DSE test results were abnormal in 286 patients (95 fixed and 173 stress-induced wall motion abnormalities), and 69 (26%) underwent catheter-based or surgical coronary revascularization. Cardiovascular event rates and mortality, however, were similar for those patients undergoing coronary revascularization compared with those treated conservatively (data not shown). Of the 61 patients who underwent vascular surgical intervention, 20 (15.7%) of 127 had a normal and 41 (15.2%) of 268 had abnormal preoperative DSE results. The cardiovascular morbidity and all cause mortality were similar in both groups.

Effect of peripheral artery disease severity on study end points 

To assess the effect of PAD severity on outcomes, we analyzed predictive power of ABI along the whole spectrum of its value. Significant worsening of all-cause mortality (P < .001) and trend towards worse survival free from cardiovascular event (P = .07) were observed with decrease of ABI by log-rank test analysis (Fig 3, A and B).

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• Fig 3. 

  Kaplan-Meier analysis of (A) survival free from the first cardiovascular event and (B) overall survival for normal vascular studies (ankle-brachial index [ABI] ≥0.9), and mild (ABI 0.8 to 0.9), moderate (ABI 0.5 to 0.8), and severe (ABI < 0.5) peripheral arterial disease. *Only 23 (6%) patients had mild peripheral arterial disease.

Correlation between ankle-brachial index and dobutamine stress echocardiography 

To determine the association between flow-limiting lesions in peripheral and coronary circulation, we compared ABI value with DSE wall motion score index at stress. A complete lack of correlation between these measures is readily apparent (Fig 4). Indeed, no correlation was found between ABI and any of the echocardiographic variables assessed, including presence of ischemia, abnormal study, or change in wall motion score index with stress (data not shown).

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• Fig 4. 

  Linear regression analysis of the correlation between wall motion score index at stress and ankle-brachial index values.

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Discussion 

This present study confirms the poor prognosis for patients with PAD who have undergone objective testing of both the coronary (DSE) and peripheral circulation (ABI): nearly 67% experienced a cardiovascular event or died ≤5 years. Multiple cohort studies⁷, ⁹, ¹⁰, ¹¹, ¹² and subanalyses of coronary trials⁵, ²⁹, ³⁰, ³¹, ³² have shown that the presence of PAD predicts cardiovascular morbidity and mortality, but all these studies had incomplete assessment of either coronary or peripheral circulations. Moreover, PAD was defined in coronary trials⁵, ²⁹, ³⁰, ³¹, ³² as “extracardiac vascular disease” and therein had combined cerebral atherosclerosis, aortic aneurysmal disease, and PAD into one category. This mixture conveys different clinical meaning, because the potential direct cardiovascular complications of carotid disease or abdominal aortic aneurysm are quite different than leg ischemia. Also, the lack of ABI evaluation in “coronary” series makes it very likely that about 25% of “cardiac cases without PAD” had indeed either nondiagnosed or asymptomatic PAD.², ³, ⁴, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹

ABI was the strongest independent predictor of all-cause mortality in patients with extensive PAD. Previous studies have had conflicting results: some reported a lack of predictive power for ABI¹¹, ³³ and others found a significant association between abnormal ABI and cardiovascular events and mortality.⁶, ⁷, ⁸, ⁹, ¹⁰ This study also demonstrated that PAD severity correlates with an unfavorable outcome. The log-rank test illustrated a definite trend of increasing risk of death with decreasing values of ABI. This observation of inverse relation of ABI values and adjusted risk of mortality is in agreement with previous reports.⁸, ⁹, ¹⁰

We now show that beyond defining the location and severity of PAD, ABI provides important prognostic information in high-risk patients. This is important clinically because the ABI is a well-established, reproducible, and inexpensive test that requires little training and few resources to perform.⁷ Although ABI was designed for both disease identification and quantitative severity staging, its apparent association with cardiovascular events and mortality may be of additional benefit. The prognostic strength of ABI assessment is evident in this data set, despite the inclusion of a relatively small number of subjects with normal ABI.

To our knowledge, this is the first study to assess the prognostic value of DSE in patients referred for ABI. DSE is an established method for evaluation of myocardial ischemia,¹², ¹³, ¹⁴, ¹⁵ with published diagnostic sensitivities (74% to 89%) and specificities (82% to 88%) similar to other methods of stress imaging. A meta-analysis of 28 separate studies¹² showed that the mean sensitivities of DSE for single-vessel, double-vessel, and triple-vessel obstructive coronary disease were 74%, 86%, and 92%, respectively. Moreover, DSE has shown prognostic value in predicting cardiac events extending out to 5 years in prior studies of patients undergoing elective noncardiac surgery.¹⁶, ¹⁷, ¹⁸, ¹⁹

In this high-risk patient population with PAD, DSE positive for myocardial ischemia or DSE that demonstrated fixed wall motion abnormalities did not predict cardiovascular events or all-cause mortality when analyzed separately. When inducible ischemia and fixed wall motion abnormalities were analyzed together by log-rank test, abnormal DSE showed association with increased mortality (P = .02) and a borderline association (P = .052) with cardiovascular events. However, abnormal DSE lost its predictive power after adjustment for other clinical variables. The only DSE variable that independently predicted all-cause mortality was a reduced ejection fraction at peak stress.

In a previous large study of patients with PAD,¹⁹ DSE provided incremental prognostic information beyond that provided by clinical and echocardiographic data for predicting mortality and cardiac morbidity, including MI and coronary revascularization. In contrast to the current study, this previous report did not include stroke, TIA, or unstable angina among cardiac events; these events may be better predicted by ABI (see also Table II).

The last but also very important finding of this study was the lack of correlation between ABI and DSE results. This showed that the presence of more severe PAD did not predict the presence of more severe CAD. Previously, Papamichael et al³³ reported a relationship between ABI and the extension of CAD measured by the number of diseased coronary arteries and Gensini angiographic score, but the mean ABI value for this study group was normal (0.93): only 27 patients (16%) had an ABI <0.9. In fact, this study established a connection between the severity of CAD and the presence (ABI <0.9) or absence (ABI >0.9) of PAD, but not its gravity. A number of coronary trials⁵, ²⁹, ³³ showed that patients with CAD and PAD disease had more advanced CAD disease than CAD patients without PAD, but some also reported an identical³⁰, ³¹ or nearly the same³² angiographic picture of coronary circulation in both groups. It is well established that PAD patients die primarily from cardiac causes.³, ⁴, ⁵, ⁶, ⁸, ⁹, ¹⁰, ¹¹, ²⁹, ³⁰, ³¹, ³², ³³

The fact that DSE measures predicting poor outcome were those indicating the presence of CAD, but not those associated with its acute pathophysiologic significance, and the fact that coronary interventions had no impact on long-term outcomes in our patients implies that factors other than current myocardial ischemia predict future atherothrombotic events in these patients.

The presence of PAD detected by an abnormal ABI indicates the presence of enormous plaque burden with large areas of atherosclerotic vessel wall in continuity with flowing blood. The iliofemoral and femoropopliteal arterial segments have surface areas that are orders of magnitude larger than that of the coronary arteries; therefore, atherosclerosis in these segments may be associated with much greater activation of the coagulation system. Indeed, previous studies reported positive correlation between increasing burden of atherosclerotic disease and the rate of cardiovascular complications.³⁴

Increased platelet and coagulation cascade activation were also found in patients with PAD.³⁵ Shankar et al³⁶ showed that blood coagulability increased as it flowed through an atherosclerotic iliac artery, and the magnitude of that change was related to the severity of stenosis. It therefore seems likely that a significant cause of the morbidity and mortality associated with PAD could be related to thrombosis. Our analysis showed that antiplatelet therapy significantly improved survival in PAD patients.

The Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study³⁷ and, more recently, the Clopidogrel for the Reduction of Events During Observation (CREDO) trial³⁸ showed that intensive antiplatelet therapy is associated with a significantly greater reduction in cardiovascular events and mortality in patients with PAD compared with all cardiovascular disease patients. The Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) trial³⁹ revealed no advantage of combined clopidogrel and aspirin versus aspirin alone therapy in cardiovascular patients, but there was no separate analysis for PAD patients.

In our study, statin therapy also showed profound impact on mortality, which may not only reflect prevention of burden growth but also the antithrombotic potential of these medications.⁴⁰

If proven in a well-designed prospective trial, our hypothesis that the mere presence of a critical atherosclerotic burden is sufficient to enhance coagulation and effect survival would lead to a significant modification in the treatment of atherosclerosis and in secondary prophylaxis after cardiovascular events. In fact, we plan to initiate a prospective trial in which we would use computed tomography angiography to measure the total atherosclerotic burden and associated laminated thrombus in PAD patients and correlate these measurements with platelet and coagulation system activation as well as morbidity and mortality.

Study limitations 

This study has several important limitations that should be highlighted. First, this study was neither prospective nor population-based and was conducted on a selected group of high-risk patients with known or suspected CAD referred to a tertiary care center for evaluation of PAD, and thus, our results may not be directly extrapolated to the population in general. However, the intent of this study was to provide information relevant to risk stratification for patients with PAD. With the aging of our population and the growing epidemic of atherosclerosis, the relevance of this data is anticipated to increase. Diabetic patients with noncompressible arteries or those patients for whom ABI assessment cannot be performed owing to painful limb ulceration represent unique circumstances for which this data may further not apply.

Second, death certificates and autopsy reports were not universally available, so our analysis was restricted to all-cause mortality, which limited our ability to parse cardiovascular and noncardiovascular causes of death.

Third, the retrospective nature of this study will only permit speculation about how the clinician altered the medical management of these patients based on results of DSE. We could not establish a relationship between DSE results (positive, negative, abnormal, normal) and therapy with β-blockers, statins, or antiplatelet agents by statistical modeling. Nonetheless, the beneficial impact of both statin and antiplatelet therapy must be underscored for these patients with peripheral arterial occlusive disease, regardless of severity.

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Conclusion 

The present study confirms a poor prognosis in PAD, shows that in this selected group of high-risk patients ABI is an independent predictor of all-cause mortality, and demonstrates a correlation between the severity of PAD and survival. Conversely, DSE with inducible or fixed wall motion abnormalities showed no association with cardiovascular events or increased mortality in multivariate analysis. The lack of correlation between the severity of PAD (as measured by ABI) and CAD (as measured by DSE) suggests that in high-risk patients, low ABI may not predict more advanced CAD.

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Author contributions 

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References 

1. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation. 2001;104:2746–2753
   • View In Article
   • CrossRef
2. Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71:510–515
   • View In Article
   • MEDLINE
   • CrossRef
3. Stoffers HE, Rinkens PE, Kester AD, Kaiser V, Knottnerus JA. The prevalence of asymptomatic and unrecognized peripheral arterial occlusive disease. Int J Epidemiol. 1996;25:282–290
   • View In Article
   • MEDLINE
   • CrossRef
4. Hertzer NR, Beven EG, Young JR, O’Hara PJ, Ruschhaupt WF, Graor RA, et al. Coronary artery disease in peripheral vascular patients (A classification of 1000 coronary angiograms and results of surgical management). Ann Surg. 1984;199:223–233
   • View In Article
   • MEDLINE
   • CrossRef
5. Mukherjee D, Eagle KA, Smith DE. Impact of extracardiac vascular disease on acute prognosis in patients who undergo percutaneous coronary interventions. Am J Cardiol. 2003;92:972–974
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (60 KB)
   • CrossRef
6. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381–386
   • View In Article
   • MEDLINE
   • CrossRef
7. Caruana MF, Bradbury AW, Adam DJ. The validity, reliability, reproducibility and extended utility of ankle to brachial pressure index in current vascular surgical practice. Eur J Vasc Endovasc Surg. 2005;29:443–451
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (160 KB)
   • CrossRef
8. McKenna M, Wolfson S, Kuller L. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis. 1991;87:119–128
   • View In Article
   • Abstract
   • Full-Text PDF (999 KB)
   • CrossRef
9. Vogt MT, McKenna M, Wolfson SK, Kuller LH. The relationship between ankle brachial index, other atherosclerotic disease, diabetes, smoking and mortality in older men and women. Atherosclerosis. 1993;101:191–202
   • View In Article
   • Abstract
   • Full-Text PDF (1021 KB)
   • CrossRef
10. Newman AB, Shemanski L, Manolio TA, Cushman M, Mittelmark M, Polak JF, et al. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 1999;19:538–545
    • View In Article
    • MEDLINE
    • CrossRef
11. 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
    • View In Article
    • CrossRef
12. Geleijnse ML, Fioretti PM, Roelandt JRTC. Methodology, feasibility, safety and diagnostic accuracy of dobutamine stress echocardiography. J Am Coll Cardiol. 1997;30:595–606
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (682 KB)
    • CrossRef
13. Anthopoulos LP, Bonou MS, Kardaras FG, Sioras EP, Kardara DN, Sideris AM, et al. Stress echocardiography in elderly patients with coronary artery disease. J Am Coll Cardiol. 1996;28:52–59
    • View In Article
    • Abstract
    • Full-Text PDF (950 KB)
    • CrossRef
14. Marwick T, Willemart B, D’Hondt AM, Baudhuin T, Wijns W, Detry JM, et al. Selection of the optimal nonexercise stress for the evaluation of ischemic regional myocardial dysfunction and malperfusion (Comparison of dobutamine and adenosine using echocardiography and 99mTc-MIBI single photon emission computed tomography). Circulation. 1993;87:345–354
    • View In Article
    • MEDLINE
15. Sawada SG, Seger DS, Ryan T, Brown SE, Dohan AM, Williams R, et al. Echocardiographic detection of coronary artery disease during dobutamine infusion. Circulation. 1991;83:1605–1614
    • View In Article
    • MEDLINE
16. Poldermans D, Fioretti PM, Forster T, Thomson IR, Boersma E, el-Said EM, et al. Dobutamine stress echocardiography for assessment of perioperative cardiac risk in patients undergoing major vascular surgery. Circulation. 1993;87:1506–1512
    • View In Article
    • MEDLINE
17. Lane RT, Sawada SG, Segar DS, Ryan T, Lalka SG, Williams R, et al. Dobutamine stress echocardiography for assessment of cardiac risk before noncardiac surgery. Am J Cardiol. 1991;68:976–977
    • View In Article
    • MEDLINE
    • CrossRef
18. Chuah SC, Pellikka PA, Roger VL, McCully RB, Seward JB. Role of dobutamine stress echocardiography in predicting outcome in 860 patients with known or suspected coronary artery disease. Circulation. 1998;97:1474–1480
    • View In Article
    • MEDLINE
19. Chaowalit N, Maalouf JF, Rooke TW, Barnes ME, Bailey KR, Pellikka PA. Prognostic significance of chronotropic response to dobutamine stress echocardiography in patients with peripheral arterial disease. Am J Cardiol. 2004;94:1523–1528
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (134 KB)
    • CrossRef
20. Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26:3160–3167
    • View In Article
    • MEDLINE
    • CrossRef
21. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497
    • View In Article
    • MEDLINE
    • CrossRef
22. Therneau T, Sicks J, Bergstralh E, Offord J. Expected survival based on hazard rates. Section of biostatistics. Rochester, Minn: Mayo Clinic; 1994;Technical report series. No. 52. March
    • View In Article
23. Wysokinski WE, Spittell PC, Pellikka PA, Miller WL, Seward JB. Dobutamine effect on ankle-brachial pressure index in patients with peripheral arterial occlusive disease (New noninvasive test for evaluation of peripheral circulation?). Intern Angiology. 1998;17:201–207
    • View In Article
24. Pellikka PA, Roger VL, Oh JK, Miller FA, Seward JB, Tajik AJ. Stress echocardiography. Part II. Dobutamine stress echocardiography: techniques, implementation, clinical applications, and correlations. Mayo Clin Proc. 1995;70:16–27
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (11731 KB)
    • CrossRef
25. Quinones M, Wagoner A, Reduto L, Nelson JG, Young JB, Winters WL, et al. A new, simplified and accurate method for determining ejection fraction with 2-dimentional echocardiography. Circulation. 1981;64:744–753
    • View In Article
    • MEDLINE
    • CrossRef
26. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr. 1989;2:358–367
    • View In Article
    • MEDLINE
27. Gillum RF, Fortmann SP, Prineas RJ, Kottke TE. International diagnostic criteria for acute myocardial infarction and acute stroke. Am Heart J. 1984;108:150–158
    • View In Article
    • MEDLINE
    • CrossRef
28. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg. 1997;26:517–538
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1996 KB)
    • CrossRef
29. Cotter G, Cannon CP, McCabe CH. OPUS-TIMI 16 Investigators. Prior peripheral arterial disease and cerebrovascular disease are independent predictors of adverse outcome in patients with acute coronary syndromes: are we doing enough? Results from the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis In Myocardial Infarction (OPUS-TIMI) 16 study. Am Heart J. 2003;145:622–627
    • View In Article
    • Abstract
    • Full-Text PDF (92 KB)
    • CrossRef
30. Sutton-Tyrrell K, Rihal C, Sellers MA, Burek K, Trudel J, Roubin G, et al. Long-term prognostic value of clinically evident noncoronary vascular disease in patients undergoing coronary revascularization in the Bypass Angioplasty Revascularization Investigation (BARI). Am J Cardiol. 1998;81:375–381
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (194 KB)
    • CrossRef
31. Rihal CS, Sutton-Tyrrell K, Guo P, Keller NM, Jandova R, Sellers MA, et al. Increased incidence of periprocedural complications among patients with peripheral vascular disease undergoing myocardial revascularization in the bypass angioplasty revascularization investigation. Circulation. 1999;100:171–177
    • View In Article
32. Eagle KA, Rihal CS, Foster ED the Coronary Artery Surgery Study (CASS) Investigators. Long-term survival in patients with coronary artery disease: importance of peripheral vascular disease. J Am Coll Cardiol. 1994;23:1091–1095
    • View In Article
    • Abstract
    • Full-Text PDF (247 KB)
    • CrossRef
33. Papamichael CM, Lekakis JP, Stamatelopoulos KS, Papaioannou TG, Alevizaki MK, Cimponeriu AT, et al. Ankle-brachial index as a predictor of the extent of coronary atherosclerosis and cardiovascular events in patients with coronary artery disease. Am J Cardiol. 2000;86:615–618
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (67 KB)
    • CrossRef
34. van der Meer IM, Bots ML, Hofman A, del Sol AI, van der Kuip DA, Witteman JC. Predictive value of noninvasive measures of atherosclerosis for incident myocardial infarction (The Rotterdam Study). Circulation. 2004;109:1089–1094
    • View In Article
    • CrossRef
35. Boneu B, Leger P, Arnaud C. Haemostatic system activation and prediction of vascular events in patients presenting with stable peripheral arterial disease of moderate severity. Blood Coagul Fibrinolysis. 1998;9:129–135
    • View In Article
    • MEDLINE
    • CrossRef
36. Shankar VK, Chaudhury S, Ray S, Uthappa MC, Handa A, Hands LJ. Changes in blood coagulability as it traverses the ischemic limb. J Vasc Surg. 2004;39:1033–1042
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (518 KB)
    • CrossRef
37. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329–1339
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (88 KB)
    • CrossRef
38. Mukherjee D, Topol EJ, Moliterno DJ, Brennan DM, Ziada K, Cho L CREDO Investigators. Extracardiac vascular disease and effectiveness of sustained clopidogrel treatment. Heart. 2006;92:49–51
    • View In Article
39. CHARISMA Investigators. Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events. N Engl J Med. 2006;354:1706–1717
    • View In Article
    • CrossRef
40. Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol. 2005;25:287–294
    • View In Article
    • CrossRef