Consecutive diabetic patients referred to our vascular laboratory for suspected intermittent claudication were screened for enrollment in this study. Criteria for study entry were all of the following: 1) diagnosis of diabetes mellitus; 2) LE-PAD at stage II of Fontaine’s classification (intermittent claudication); 2) ABI ≤0.90; 3) one or more hemodynamically significant stenosis in at least one artery of the ileo-femoro-popliteal axis at B-mode ultrasound. Exclusion criteria were: 1) critical limb ischemia; 2) previous lower limb revascularization; 3) recent acute coronary or cerebrovascular ischemic events (6 months); 4) recent coronary or carotid revascularization procedures (6 months); 5) abnormal myocardial ischemia stress test at enrollment; 6) de-compensated heart failure; 7) malignant neoplasia or significant hepatic, renal, or inflammatory disease.
According to the inclusion/exclusion criteria, 252 consecutive diabetic patients affected by intermittent claudication were selected. All patients were treated with maximal medical therapy and encouraged to engage regular physical exercise for at least three months. After this time, patients complaining a severe disability caused by claudication, unable to perform normal work or with very serious impairment of daily life activities despite maximal medical therapy and regular physical exercise (n=139) were selected for angiography and eventually revascularization, while the remaining 113 patients were managed with medical therapy only (MT group). Among the patients initially selected for revascularization, 2 patients refused to undergo angiography, and were excluded from the study. Based on the angiograms, 12 patients displaying TASC D lesions were excluded from the study, while 125 underwent endovascular revascularization. Following PTA, only 123 patients displayed a successful angiographic result (2 patients showed a residual stenosis >30%), and therefore were included in the study (PTA group). All participants gave written informed consent to the study, which was approved by our institutional ethics committee.
In each patient, clinical history and risk factors were assessed at first visit. Smokers included current and former smokers. Hypertension was diagnosed if systolic arterial pressure exceeded 140 mmHg and/or diastolic arterial pressure exceeded 90 mmHg on repeated measurements, or if the patient used antihypertensive drugs. Hypercholesterolemia was diagnosed if plasma total cholesterol exceeded 200 mg/dl, plasma low-density lipoprotein cholesterol exceeded 130 mg/dl, or if the patient used lipid-lowering drugs because of a history of hypercholesterolemia. Hospital records documented previous cardiovascular events.
ABI and maximum walking distance assessment
ABI was measured at the first visit after participants had rested supine for 5 minutes. The systolic blood pressure in both brachial arteries and the ankle systolic blood pressure for the right and left posterior tibial and dorsalis pedis arteries were measured using a Doppler probe. The ABI for each leg was then determined using the higher of the two readings from either the posterior tibial or dorsalis pedis arteries, and the higher of the two brachial readings. The lower ABI of the two legs was used for diagnostic purposes and as predictor of future cardiovascular events. Maximum walking distance (MWD) was tested by treadmill (speed 3 km/h, inclination 10%) at the first visit.
Percutaneous Transluminal Angioplasty (PTA) was performed after diagnostic angiography and intra-venous injection of 70 U/kg of unfractionated heparin. Bailout nitinol self-expanding stent implantation was performed when a suboptimal angiographic result was obtained. Successful angioplasty was defined by a final angiogram with residual stenosis <30%.
Assessment of cardiovascular events
Patients underwent regular follow-up clinical examinations at our Institution at 3-month intervals. The occurrence of cardiovascular death, myocardial infarction, ischemic stroke and coronary or carotid revascularizations was prospectively assessed. Cardiovascular deaths comprised fatal myocardial infarction, fatal stroke, sudden death, and death secondary to arrhythmia or refractory heart failure. The minimum follow-up period was 6 months. Medical records and death certificates of all patients who had an event were obtained and validated by a physician unaware of patient’s peripheral treatment. For patients who had more than 1 event, only the first was considered in the analysis.
Statistical analyses were performed using SPSS 16.0 (SPSS, Inc., Chicago, IL, USA). Variables were expressed as absolute numbers and percentage or mean ± SD, with the exception of leukocyte count that was expressed as median and inter-quartile range because of its skewed distribution. Comparisons were made by t-test for unpaired samples, χ2 test, or Mann-Whitney U test, as appropriate. Cumulative event rates in the PTA vs. MT group were estimated by Kaplan-Meier curves and probability values by log-rank test.
Cox proportional hazard analyses were performed to verify if endovascular treatment was associated with a lower incidence of future cardiovascular events. The following covariates, known to be potential contributors of cardiovascular risk, were included in the adjusted model: age, sex, smoking, hypercholesterolemia, hypertension, baseline ABI, baseline maximum walking distance, and leukocyte count.
All statistical tests were two-sided. For all tests, a p-value <0.05 was considered statistically significant.