An abnormal ankle-brachial index (ABI) is associated with higher risk for future cardiovascular (CV) events; however, it is unknown whether this association is true in patients with established coronary artery disease (CAD) and associated diabetes mellitus (DM). We evaluated 679 patients with stable CAD enrolled in the Excellence in Peripheral Arterial Disease and Veterans Affairs North Texas Healthcare System peripheral arterial disease databases. ABI and 12-month major adverse CV events (MACEs, a composite of all-cause death, nonfatal myocardial infarction, need for repeat coronary revascularization, and ischemic stroke) were assessed. Cox proportional hazard models were used to assess the association of ABI and DM with subsequent CV events. An abnormal ABI (<0.9 or >1.4) was present in 72% of patients with stable CAD and 68% had DM. Using patients without DM and normal ABI as reference, the adjusted hazard ratio for 12-month MACE was 1.7 (95% confidence interval [CI] 0.71 to 4.06) for patients with DM and normal ABI; 2.03 (95% CI 0.83 to 4.9) for patients without DM with abnormal ABI; and 4.85 (95% CI 2.22 to 10.61) for patients with DM and abnormal ABI. In conclusion, in patients with stable CAD, an abnormal ABI confers an incremental risk of MACE in addition to DM and traditional CV risk factors.
Routine assessment of peripheral arterial disease (PAD) in patients with established coronary artery disease (CAD) is performed in a minority of patients. Ankle-brachial index (ABI) is a noninvasive, easy to perform, and cost-effective method of evaluation for PAD. PAD, identified by an abnormal ABI, is present in 16% of outpatients with low-to-moderate risk for cardiovascular (CV) disease and in about 40% of hospitalized high-risk patients with CAD. Presence of PAD and diabetes mellitus (DM) in patients with established CAD is associated with worse outcomes. Although routine assessment for DM is performed in patients with CAD, assessment for PAD is not. This is often attributed to the presence of overlapping risk factors, especially in diabetic patients, and to the lack of dedicated strategies to mitigate the additional risk conferred by the presence of PAD in patients with established CAD. Also, the predictive value of an abnormal ABI in patients with CAD above and beyond the presence of DM is not clear and often contested. We sought to evaluate the association between CV outcomes and the presence of an abnormal ABI and/or DM in patients with stable CAD and asked the question whether an ABI assessment provided prognostic information in addition to the presence of DM in patients with stable ischemic heart disease.
Methods
We evaluated 679 patients from the Excellence in PAD and Veterans Affairs North Texas Healthcare System PAD databases from 2002 to 2012 with stable CAD who also underwent an inpatient ABI evaluation for evaluation symptoms consistent with lower extremity claudication.
CAD was defined as follows: history of nonfatal myocardial infarction, angiographic evidence of ≥50% epicardial coronary artery stenosis, history of prior (≥1 year) coronary revascularization, or evidence of at least moderate stress-induced ischemia by any clinical stress testing modality. DM was defined by either hemoglobin A1C >6.5 or use of hypoglycemic medications. Demographic information, risk factors, physical examination findings, medication use, laboratory and imaging data, and clinical outcomes were obtained from the Excellence in PAD and Veterans Affairs North Texas Healthcare System databases. Clinical variables and outcome analysis were based on discharge diagnoses and procedure codes associated with each patient encounter. Dual antiplatelet therapy was defined as use of aspirin and a P2Y 12 inhibitor.
ABI assessment and coronary angiographic analysis were performed using standard methodology by Veterans Affairs North Texas Healthcare System vascular and VA North Texas angiographic and ultrasound core laboratory, respectively. An ABI value of <0.9 or >1.4 was defined as abnormal, and 0.9 to 1.4 was considered normal. All ABI assessments were performed on bilateral lower extremities, and the lower of the 2 limb values was assigned to a patient in the study cohort. However, in the presence of a normal ABI in one leg and an ABI >1.4 in the contralateral extremity, the patient was assigned an abnormal ABI >1.4.
The prespecified primary outcome was the 12-month incidence of major adverse CV events (MACEs), defined as a composite of all-cause death, nonfatal myocardial infarction, need for repeat coronary revascularization, and ischemic stroke. We also recorded and analyzed individual components of MACE. The institutional review boards of each site and all data were analyzed in aggregate without patient identifiers.
Continuous variables are reported as mean ± SD, and discrete variables are reported as a percentage value. Continuous variables were compared with a one-way analysis of variance or the Wilcoxon rank-sum test, and discrete variables were compared with the Pearson’s chi-square or the Fisher’s exact test, as appropriate. Twelve-month MACE and its individual components were analyzed in patients with or without DM and/or an abnormal ABI, categorized into 4 groups: no DM with normal ABI, DM with normal ABI, no DM with abnormal ABI, and DM with abnormal ABI. We used Cox proportional hazard models to assess the association of ABI and DM with subsequent CV events. The variables were treated as time-dependent covariates. We ran the model for each of the CV end points adjusted for age, sex, hypertension, tobacco use, estimated glomerular filtration rate, low-density lipoprotein cholesterol level, high-density lipoprotein cholesterol level, lipid lowering, and antiplatelet therapy use. All analyses were performed using SAS 9.1 or SPSS 14.0 for Windows.
Results
The baseline characteristics of the study patients are listed in Table 1 . Mean age was 65 ± 4.2 years, and most patients had angiography defined, epicardial CAD (68%), and DM (68%). The diagnosis of PAD was established by an abnormal ABI in 72% of patients with known CAD (abnormal ABI group, n = 333), and the rest was categorized into a normal ABI group (n = 129). Most patients with abnormal ABI were diabetic (71%), and abnormal ABI values <0.9 or >1.4 were present in 95% and 4.7%, respectively ( Figure 1 ). History of tobacco use was greater in the abnormal ABI group compared with normal ABI (80% vs 64%, respectively, p = 0.0001). More patients with abnormal ABI had lower serum high-density lipoprotein levels (42 ± 11 vs 44 ± 14, respectively, p = 0.008) and were treated with antiplatelet therapy (93% vs 83%, respectively, p = 0.0001) and lipid-lowering therapies (91% vs 80%, respectively, p = 0.0001).
| Variable | Normal ABI (n = 217) | Abnormal ABI (n = 462) | p Value |
|---|---|---|---|
| Age (yrs) | 64.1 ± 9.4 | 66.2 ± 8.5 | 0.002 |
| Men | 211 (97.2) | 462 (100) | 0.11 |
| Hypertension | 192 (88.5) | 443 (95.9) | 0.0003 |
| Smoker | 139 (64.1) | 366 (79.2) | 0.0001 |
| Diabetes mellitus | 132 (60.8) | 328 (71.0) | 0.008 |
| Coronary narrowing ≥50% severity | 129 (59.5) | 333 (72.1) | 0.001 |
| Cerebrovascular disease | 39 (18.0) | 117 (25.3) | 0.03 |
| Body mass index (kg/m 2 ) | 30.5 ± 6.6 | 29.0 ± 6.1 | 0.003 |
| Systolic blood pressure (mm Hg) | 132.2 ± 17.4 | 133.1 ± 17.1 | 0.42 |
| Diastolic blood pressure (mm Hg) | 75.9 ± 10.6 | 74.5 ± 10.5 | 0.09 |
| Total cholesterol (mg/dl) | 166.3 ± 47.8 | 162.4 ± 65.1 | 0.54 |
| Triglycerides (mg/dl) | 155.0 ± 96.4 | 154.3 ± 83.4 | 0.47 |
| Low-density cholesterol (mg/dl) | 93.6 ± 34.8 | 87.7 ± 33.3 | 0.15 |
| High-density cholesterol (mg/dl) | 44.1 ± 13.8 | 41.5 ± 11.4 | 0.008 |
| Serum glucose (mg/dl) | 128.4 ± 58.0 | 126.9 ± 49.7 | 0.75 |
| Glomerular filtration rate (ml/min) | 76.7 ± 26.0 | 81.2 ± 40.9 | 0.01 |
| Lipid-lowering therapy | 174 (80.2) | 421 (91.1) | 0.0001 |
| Antihypertensive therapy | 181 (83.4) | 423 (91.6) | 0.002 |
| Dual antiplatelet therapy | 18 (8.3) | 110 (23.8) | 0.0001 |
| β blockers | 142 (73.4) | 339 (65.4) | 0.03 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker | 156 (71.9) | 381 (82.5) | 0.002 |
Overall 12-month MACE and its individual components in patients with or without DM and/or an abnormal ABI are shown in Figure 2 , categorized into 4 patient groups: no DM with normal ABI, DM with normal ABI, no DM with abnormal ABI, and DM with abnormal ABI. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for MACE and all-cause death are listed in Tables 2 and 3 and Figure 3 , respectively. After adjustment for age and sex, presence of an abnormal ABI was associated with higher risk of MACE among patients both without DM (HR 3.44, 95% CI 2.04 to 5.79) and with DM (HR 5.97, 95% CI 3.68 to 9.68) compared with no DM and normal ABI (p = 0.0001 for both comparisons). After adjusting for age, sex, hypertension, tobacco use, estimated glomerular filtration rate, low-density lipoprotein level, high-density lipoprotein level, use of lipid lowering, and antiplatelet therapies, the associated HRs were 2.56 (95% CI 1.52 to 4.34) and 3.99 (95% CI 2.43 to 6.55), respectively, for the above comparisons (p = 0.0001 for both comparisons). MACE-free survival was lowest in the group with DM and abnormal ABI ( Figure 4 ). Hazard rate for MACE in patients with DM and normal ABI was 1.7, 95% CI 0.71 to 4.06, in patients with no DM and an abnormal ABI was 2.03, 95% CI 0.83 to 4.98, and in those with DM and an abnormal ABI was 4.85, 95% CI 2.22 to 10.61, compared with the reference group (no DM and normal ABI).
| HR ∗ | 95% CI ∗ | p Value ∗ | HR † | 95% CI † | p Value † | |
|---|---|---|---|---|---|---|
| No DM, normal ABI | Reference group | |||||
| DM, normal ABI | 1.65 | 0.95–2.85 | 0.08 | 1.29 | 0.74–2.25 | 0.37 |
| No DM, abnormal ABI | 3.44 | 2.04–5.79 | 0.0001 | 2.56 | 1.52–4.34 | 0.0001 |
| DM, abnormal ABI | 5.97 | 3.68–9.68 | 0.0001 | 3.99 | 2.43–6.55 | 0.0001 |
† Adjusted for age, sex, hypertension, tobacco use, eGFR, LDL level, HDL level, use of lipid lowering, and antiplatelet therapy use. See Figure 3 .
| HR ∗ | 95% CI ∗ | p Value ∗ | HR † | 95% CI † | p Value † | |
|---|---|---|---|---|---|---|
| No DM, normal ABI | Reference group | |||||
| DM, normal ABI | 3.13 | 0.38–26.08 | 0.22 | 2.47 | 0.28–22.02 | 0.42 |
| No DM, abnormal ABI | 3.73 | 0.45–36.08 | 0.11 | 3.65 | 0.41–32.23 | 0.24 |
| DM, abnormal ABI | 4.16 | 0.55–31.41 | 0.01 | 3.48 | 0.42–29.19 | 0.25 |
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