Prevalence of Peripheral Artery Disease by Abnormal Ankle-Brachial Index in Atrial Fibrillation: Implications for Risk and Therapy.

Non-valvular atrial fibrillation (NVAF) is the most common sustained arrhythmia encountered in clinical practice and is associated with a fivefold increased risk for stroke (1). Moreover, patients with NVAF often suffer from atherosclerotic complications such as acute myocardial infarction (AMI) (2). Peripheral artery disease (PAD) is an established marker of systemic atherosclerosis but its prevalence in NVAF is still unclear. We reasoned that inclusion of ankle/brachial index (ABI), which is an established tool for diagnosis of PAD (3), in the CHA2DS2-VASc (4) score would better define the prevalence of vascular disease. To address this issue, the Italian Society of Internal Medicine (SIMI) established an Italian registry documenting ABI in NVAF patients. The Atrial Fibrillation Registry for Ankle-brachial index Prevalence Assessment- Collaborative Italian Study (ARAPACIS) is an independent research project involving all Regional Councils of SIMI. The first objective of the study was to estimate prevalence of ABI ≤0.90 in NVAF patients. Consecutive patients with NVAF referred to internal medicine wards were eligible for the enrollment. Enrolment started on October 2010 and continued until 30 October 2012 (ClinicalTrials.gov Identifier: NCT01161251). Patients were enrolled if they were 18 years or older and had diagnosis of NVAF, recording during the qualifying admission/consultation or in the preceding 12 months, and if it was possible to obtain the ABI measurement. Exclusion criteria included the following: acquired or congenital valvular AF, active cancer, disease with life expectancy less than 3 years, hyperthyroidism and pregnancy. We initially planned to include 3,000 patients. The Data and Safety Monitoring Board (see appendix) decided to perform an interim analysis to assess the prevalence of ABI in the enrolled populations - as a higher than expected prevalence of low ABI was detected- and decided to interrupt the patients’ enrollment. The sample size was amended as follows: asample of 2,027 patients leads to the expected prevalence of 21% with a 95% confidence interval width of 3.5% (StataCorp LP, Texas, USA). Among the 2,027 NVAF patients included in the study, hypertension was detected in 83%, diabetes mellitus in 23%, dyslipidemia in 39%, metabolic syndrome in 29% and smoking in 15%. At least one atherosclerotic risk factor was detected in 90% of patients. The NVAF population was at high risk for stroke, with only 14% having a CHA2DS2-VASc score 0-1, while 86% had a risk ≥2. Despite this, 16% were untreated with any antithrombotic drug, 19% were treated with antiplatelet drugs (APs) APs and 61% with oral anticoagulants (OAC); 4% of patients were treated with both APs and OAC. Among AF population, 428 patients (21%) had ABI ≤0.90 compared to 1,381 patients, who had ABI 0.91-1.39 (69%); 204 patients (10%) had ABI≥1.40 (Figure 1). ABI recorded only in one leg was excluded from the analysis (n=14). ABI≤0.90 progressively increased from paroxysmal to permanent NVAF (18%, 21%, 24%;p=0.0315). NVAF patients with ABI≤0.90 were more likely to be hypertensive (88% vs. 82%;p=0.032), diabetic (34% vs. 20%;p<0.0001) or smokers (20% vs. 14%;p=0.0008), or to have experienced TIA or stroke (17% vs. 10%;p<0.001). NVAF patients with ABI≤0.90 had a higher percentage of CHA2DS2-VASc score≥2 compared to those with ABI>0.90 (93% vs. 82%;p<0.0001). Logistic regression analysis demonstrated that ABI ≤0.90 was significantly associated with smoking habit [OR; 95% CI): 1.99;1.48-2.66, p<0.0001], diabetes (1.93;1.51-2.46, p<0.0001), age class 65_74 yrs. (2.05;1.40-3.07, p<0.0001], age class≥75 yrs. (3.12;2.16- 4.61, p<0.0001), and history of previous TIA/stroke (1.64;1.20-2.24, p=0.002). Vascular disease, as assessed by the history elements of CHA2DS2VASc score was recorded in 17.3% of patients; inclusion of ABI≤0.90 in the definition of vascular disease yielded a total prevalence of 33%. A higher prevalence of vascular disease was detected if ABI≤0.90was included in the CHA2DS2VASc score (Figure 1). CHA2DS2VASc including ABI ≤0.90 was more associated with previous stroke [43%;OR (95% CL): 1.85 (1.41-2.44), P<0.0001] compared to CHA2DS2VASc with ABI 0.91-1.39 [23%; OR: 1.52 (1.10-2.11), P=0.0117]. To best of our knowledge, there is no large-scale study that specifically examined the prevalence of ABI≤0.90 in NVAF. In our population, 21% had ABI ≤0.90 indicating that NVAF is often associated with systemic atherosclerosis. The CHADS2, has been recently refined with the CHA2DS2-VASc score, which includes vascular disease as documented by a history of AMI, symptomatic PAD or detection of atherosclerotic plaque in the aortic arch (4). Comparison of vascular prevalence as assessed by CHA2DS2-VASc score and/or ABI ≤0.90 is of interest to define the potentially positive impact of measuring ABI in the management of NVAF patients. Inclusion of ABI≤0.90 in the definition of vascular disease greatly increased the prevalence of vascular disease, which increased from 17.3% (based on history alone) to 33% (based on ABI) in the entire population. If ABI ≤0.90 was encompassed in the definition of vascular disease of CHA2DS2-VASc score the prevalence of vascular disease increased in every risk class. Inclusion of ABI ≤0.90 in the CHA2DS2-VASc score allowed us better defining of the risk profile of NVAF patients with an up-grading of the risk score in each CHA2DS2-VASc score category. This may have important therapeutic implications if the new score could be tested prospectively, as a higher number of NVAF patients would be potentially candidates for an anticoagulant treatment by measuring ABI. A prospective study is, therefore, necessary to validate the risk score of this new definition of vascular disease. In conclusion, this study provides the first evidence that one fifth of NVAF patients had an ABI ≤0.90 indicating that it may represent a simple and cheap method to better define the prevalence of vascular disease in NVAF.