Bhatt, Shubhang K.

Introduction: Peripheral artery disease impacts 202 million patients worldwide and is commonly diagnosed via ankle-brachial index. PAD is associated with endothelial dysfunction, which is also common to venous thromboembolism formation. Despite the suspected overlap in pathogenesis, few studies exist investigating the association between these pathologies. We investigated whether PAD with low or elevated ABI is an independent risk factor for VTE. Methods: We reviewed medical records of patients ≥18 years old undergoing ABI measurement with or without PAD symptoms from 01/01/1996 to 08/31/2018 and classified patients by ABI: severely low (ABI 0.00-0.39), moderately low (0.40-0.69), mildly low (0.70-0.90), borderline (0.91-0.99), normal (1.00-1.40), and elevated (>1.40). The primary outcome was incident VTE event after ABI measurement, defined as deep vein thrombosis or pulmonary embolism. Multivariable Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals after adjusting for age, sex, active smoking, cancer or VTE history, thrombophilia, anticoagulation, and revascularization within 14 days of VTE. Results: In 39,384 unique patients (mean age 66.3±14.2 years, median follow-up 34 months), 5,141 VTE events were observed. Increased VTE risk was observed in PAD patients with severely low ABI (HR 1.26, 95%CI [1.02, 1.29]) compared to patients with normal ABI after multivariable regression. Patients with elevated ABI did not demonstrate an increased risk of VTE. Conclusions: Patients with severe PAD are at higher risk for VTE than patients with normal ABI, which may be due to a multifactorial pathophysiology of profound endothelial injury as well as immobility due to claudication. Further exploration of VTE incidence in patients with severe PAD stratified by functional status is warranted to determine the optimal strategy to minimize thromboembolic morbidity and mortality in this population.

Summary: Background: Peripheral artery disease (PAD) impacts 3–12% of patients worldwide and is characterized by endothelial dysfunction and inflammatory pathways which are also common to venous thromboembolism (VTE), but there is a paucity of evidence regarding VTE risk in PAD patients. We investigated whether PAD is an independent risk factor for VTE. Patients and methods: We reviewed medical records of patients undergoing ABI studies at Mayo Clinic from 01/1996-02/2020. We classified patients by ABI (low [<1.0], normal [1.0–1.4], or elevated [>1.4]), as well as by specific low ABI subgroup: severely reduced (ABI: 0.00–0.39), moderately reduced (0.40–0.69), mildly reduced (0.70–0.90), and borderline reduced (0.91–0.99). The primary outcome was incident VTE event (acute lower extremity deep vein thrombosis or pulmonary embolism) after ABI measurement. Multivariable Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, active smoking, cancer, previous VTE, thrombophilia, anticoagulation, and revascularization. Results: 39,834 unique patients (mean age 66.3±14.3 years, median follow-up 34 months) were identified. 2,305 VTE events occurred in patients without PAD (13.0%), 2,218 in low ABI patients (13.0%), and 751 in elevated ABI patients (14.8%). After risk factor adjustment, VTE risk was modestly increased for PAD overall (HR: 1.12, 95% CI [1.06, 1.18]), including low ABI (HR: 1.11, 95% CI [1.04, 1.18]) and elevated ABI groups (HR: 1.15, 95% CI [1.04, 1.26]), compared to patients without PAD. The greatest VTE risk was in severely low ABI patients (HR: 1.46, 95% CI [1.31, 1.64]). Conclusions: In a large longitudinal cohort, we present strong clinical evidence of PAD, with low and elevated ABI, as an independent VTE risk factor, with the highest risk seen in patients with severely low ABI. Continued research is required to further investigate this relationship and its intersection with functional performance status to optimize VTE risk reduction or anticoagulation strategies in the PAD population.

Introduction: Patients with concomitant peripheral artery disease (PAD) and heart failure (HF) are known to have increased morbidity and mortality. Though they share common risk factors, the utility of HF screening in patients with PAD remains controversial and without international consensus. We sought to clarify whether PAD is an independent risk factor for HF. Methods: We performed a retrospective analysis of adult patients without a history of heart failure who underwent ankle brachial index (ABI) measurement for any indication between 1995-2020. Patients were then stratified by ABI: PAD with low ABI (<1.10), healthy (ABI= 1.10-1.39), and PAD with elevated ABI (>1.39). The associations between PAD and incident diagnosis of heart failure, systolic dysfunction (HF with reduced ejection fraction, HFrEF), and diastolic dysfunction (HF with preserved ejection fraction, HFpEF) were assessed. All patient and outcomes variables were obtained using the institutional electronic health record. Multivariable Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, hypertension, diabetes, and active tobacco use. Results: The cohort included 36,816 patients (median follow-up 4.21 years), of whom 2,116 (5.7%) were diagnosed with HF. Among HF patients, 1,110 (3.0%) had HFrEF and 1,006 (2.7%) had HFpEF. Both low and elevated ABI groups were associated with an increased risk of HF, both HFrEF, and HFpEF. After multivariable analysis, PAD with elevated ABI was associated with higher overall HF risk (HR, 2.36 [95% CI, 2.03, 2.73]) than low ABI (HR, 1.56 [95% CI, 1.40, 1.74]) when compared to normal ABI. Similarly, PAD with elevated ABI was associated with greater risk of HFrEF (HR, 2.37 [95% CI, 1.93, 2.92]) and HFpEF (HR, 1.82 [95% CI, 1.48, 2.25]) than PAD with low ABI (HFrEF: HR 1.77 [95% CI, 1.52, 2.07], HFpEF: HR 1.31 [95% CI, 1.12, 1.52]). Conclusions: PAD, especially with elevated ABI, is an independent risk factor for heart failure even after adjusting for common HF risk factors. Our findings support HF screening in PAD patients, but longitudinal data on HF morbidity and mortality is necessary to evaluate the value of this practice.

Abstract Context Peripheral artery disease (PAD) is highly prevalent in the general population, affecting up to 25% of patients 55 years of age or older. There is a known association with acute ischemic stroke, but limited large cohort studies exist pertaining to the relationship between PAD severity and incident ischemic stroke. Objectives To evaluate the risk of incident ischemic stroke and mortality along the spectrum of low and elevated ankle brachial index (ABI) measurement. Methods We performed a retrospective extraction of ABI data of all adult patients who underwent lower extremity physiology study for any indication from January 1, 1996 to June 30, 2018 in the Mayo Clinic health system. PAD was categorized into severe, moderate, mild, and borderline based on ABI measurements and poorly compressible arteries (PCA). These were compared with normal ABI measurements. Associations of PAD/PCA with new ischemic stroke events and all cause mortality were analyzed. Hazard ratios (HR) were calculated using multivariable Cox proportional regression with 95% confidence intervals. Results A total of 39,834 unique patients were included with a median follow up duration of 4.59 years. All abnormal ABI groups, except borderline PAD, were associated with increased risk of incident ischemic stroke after multivariate regression compared to normal ABI. A severity-dependent association was observed between PAD and ischemic stroke with moderate (HR, 1.22 [95% CI, 1.10–1.35]) and severe (HR, 1.19 [95% CI, 1.02–1.40]) categories conferring similar risk in comparison to normal ABI. Patients with PCA carried the greatest ischemic stroke risk (HR, 1.30 [95% CI, 1.15–1.46]). Similarly, abnormal ABI groups were associated with a significant risk for all cause mortality in a severity-dependent manner, with severe PAD conferring the greatest risk (HR, 3.07 [95% CI, 2.88–3.27]). Conclusions This study adds to the growing body of evidence that both PAD and PCA are independent risk factors for incident ischemic stroke and all cause mortality. The association of PAD severity and PCA with risk of ischemic stroke may help clinicians with risk stratification and determining treatment intensity.

Abstract Introduction Antiplatelet therapy is the cornerstone of treatment for many atherosclerotic vascular pathologies including peripheral arterial disease (PAD). Patients with PAD often have comorbid conditions that require complex antithrombotic therapy, i.e. combined antiplatelet and anticoagulation. Methods All adult patients undergoing ankle brachial index (ABI) measurements were included in the study. ABI values between 1.00 and 1.40 were considered normal, and values below 1.00 or above 1.40 were considered PAD. Demographic, comorbidity and outcome data were obtained using diagnostic codes from the electronic health record. Three medication classes were analyzed: aspirin, non-aspirin oral antiplatelets (e.g. P2Y12 inhibitors) and oral anticoagulants (warfarin and the direct oral anticoagulants). Medication use was determined for patients who had been on a medication for at least one year. Cox proportional hazard analysis for the time to first bleeding event was analyzed. Bleeding was defined as any bleeding requiring medical evaluation (including clinically-relevant non-major bleeding and major bleeding). Results In all, 40,144 patients were included in the analysis (mean age 66±15, 43% female). Patients with PAD were more likely to be on double therapy (one antiplatelet with anticoagulation) (28% vs 19%) and triple therapy (dual antiplatelet with anticoagulation) (10% vs 4%). Unadjusted hazard ratios for bleeding risk showed increased risk of bleeding for patients with PAD (1.18, 95% confidence interval [CI]: 1.08–1.29), though the association is no longer present after adjustment for antithrombotic therapy. Adjusting for age, sex and PAD class, compared to no antithrombotic therapy, there was increased risk of bleeding for monotherapy (1.91, 95% CI: 1.61–2.26), double therapy (3.40, 95% CI: 2.89–4.00) and triple therapy (5.00, 95% CI: 4.21–5.96). Among medications, aspirin and anticoagulant use was independently associated with the greatest increase in risk of bleeding. Conclusion Patients in PAD are at increased risk of bleeding secondary to antithrombotic therapy. Complex antithrombotic therapy with double or triple therapy confer additional bleeding risk, particularly regimens containing aspirin and oral anticoagulants. Funding Acknowledgement Type of funding source: None

Abstract Introduction Given the potential side effects and the lack of data on its efficacy, the role of statins in the very elderly (age 75+) with peripheral arterial disease (PAD) is uncertain. Previous studies have shown significant mortality benefit in very elderly patients with coronary artery disease, but the effect in PAD has not been evaluated. Methods Very elderly patients aged 75 to 80 with at least five years of follow-up who underwent ankle-brachial index (ABI) measurement were included. PAD was defined as either low ABI &lt;0.90 or high ABI &gt;1.40. Demographic, medication use, comorbidity and mortality data was obtained using the electronic medical record. Univariate and multivariate Cox proportional hazard analyses were performed. Results In total, 4,560 very elderly subjects with PAD were included in the analysis. The median age was 77 (interquartile range 76–79) and 39% were female. 3,462 (76%) had low ABI while 1098 (24%) had high ABI. Univariate analysis showed that patients on statins were more likely to be male, have diabetes, have coronary artery disease, and have hyperlipidemia. Overall, 1,355 (30%) patients died in the five-year period. Unadjusted all-cause mortality hazard ratios for patients with low or high ABI with statin use was 0.66 (95% confidence interval [CI]: 0.57–0.75) and 0.80 (95% CI: 0.66–0.97), respectively. After adjusting for age, sex, coronary artery disease and diabetes, statin use in low and high ABI was still associated with significant reductions in risk of all-cause mortality of 0.59 (95% CI: 0.51–0.67) and 0.66 (95% CI: 0.54–0.80), respectively. The survival curve for very elderly patients with PAD by statin use is shown in Figure 1. Conclusion Statin use in the very elderly was associated with lower risk of all-cause mortality in the five-year period after diagnosis of PAD. There appears to be a mortality benefit with statin use in the very elderly with PAD, though careful consideration of benefits and side effects should be individualized in this age group. Figure 1 Funding Acknowledgement Type of funding source: None