Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial.

BACKGROUND: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER. METHODS: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee. RESULTS: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method (P-interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67-0.98]; P=0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding (P-interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding (P-interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; P=0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage (P=0.95) and postprocedural bleeding requiring intervention (P=0.93) was not significantly increased. CONCLUSIONS: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.

Comparison between activated clotting time and anti-activated factor X activity for the monitoring of unfractionated heparin therapy in patients with aortic aneurysm undergoing an endovascular procedure.

OBJECTIVE: Current guidelines recommend administration of unfractionated heparin (UFH) and measurement of activated clotting time (ACT) during endovascular procedures. The aim of this study was to compare ACT and anti-activated factor X (anti-Xa) measurements for monitoring of UFH therapy during an aortic endograft procedure and to assess the association of peak ACT and peak anti-Xa activity with periprocedural bleeding. METHODS: We retrospectively studied 104 patients with aortic aneurysm undergoing endovascular procedures with repeated coagulation measurements. After a UFH bolus, further UFH doses were given according to ACT (target range, ≥250 seconds) in clinical routine, and in parallel to each ACT (Hemochron; Accriva Diagnostics, Newport Beach, Calif) measurement, we determined anti-Xa activity (HemosIL Liquid anti-Xa; Instrumentation Laboratory, Bedford, Mass). UFH redosing was solely based on the ACT measurements. We defined periprocedural bleeding as a drop in hemoglobin level ≥3 g/dL or red blood cell transfusion within 24 hours. RESULTS: After the initial UFH bolus (median, 67 IU/kg body weight), ACT and anti-Xa measurements showed a weak correlation (rs, 0.46; P < .001). Median ACT was 233 seconds (range, 127-374 seconds; interquartile range [IQR], 204-257 seconds); median anti-Xa activity was 1.0 IU/mL (range, 0.5-2.0 IU/mL; IQR, 0.9-1.2 IU/mL). Only 31% of the patients had an ACT value ≥250 seconds, whereas all patients had an anti-Xa activity ≥0.5 IU/mL. Accordingly, ACT triggered redosing of UFH frequently. Consequently, we saw a median total UFH use of 90 IU/kg during the procedure, a median peak ACT of 255 seconds (IQR, 234-273 seconds), and a median peak anti-Xa activity of 1.2 IU/mL (IQR, 1.0-1.4 IU/mL). Periprocedural bleeding occurred in 40 (38%) patients. Peak ACT ≥250 seconds was not associated with bleeding (odds ratio, 1.05; 95% confidence interval, 0.41-2.70; P = .952), whereas peak anti-Xa activity ≥1.2 IU/mL was independently associated with bleeding (odds ratio, 4.95; 95% confidence interval, 1.82-13.48; P = .002). Moreover, no periprocedural thromboembolic event occurred. CONCLUSIONS: In this retrospective study of patients with aortic aneurysm undergoing an endovascular procedure, ACT and anti-Xa measurements showed poor correlation; only increased peak anti-Xa activity was independently associated with periprocedural bleeding, not increased ACT. Our findings also suggest that monitoring of UFH therapy with anti-Xa during aortic endograft procedures may reduce total UFH use. We further speculate that this approach could reduce periprocedural bleeding.

The heart matters in diabetes: 10-Year outcomes of peripheral artery disease.

OBJECTIVES: Mortality rates at 10 years are higher in diabetic patients with chronic lower extremity peripheral arterial disease than in non-diabetic peripheral arterial disease patients. We tested the hypothesis that the predictors of mortality differ between diabetic and non-diabetic peripheral arterial disease patients. METHODS: We studied 331 consecutive patients who were <75 years of age, symptomatic for peripheral arterial disease, and admitted to a tertiary care hospital. Our cohort included 216 patients without diabetes mellitus and 115 with diabetes mellitus. The outcome measure was all-cause mortality at 10 years post-admission. RESULTS: Mortality rates at 10 years were 29% among non-diabetic peripheral arterial disease patients and 58% among diabetic peripheral arterial disease patients. We identified the following independent predictors of death in the 216 peripheral arterial disease patients without diabetes: age ≥65 years (risk ratio: 2.15; 95% confidence interval: 1.28-3.59), ankle brachial index <0.60 mmHg/mmHg (risk ratio: 1.88; 95% confidence interval: 1.14-3.08), history of peripheral arterial disease-specific intervention (risk ratio: 1.81; 95% confidence interval: 1.10-2.97), and high-sensitivity C-reactive protein ≥5.0 mg/L (risk ratio: 2.11; 95% confidence interval: 1.28-3.47). For the 115 peripheral arterial disease patients with diabetes, independent predictors of mortality were as follows: age ≥65 years (risk ratio: 1.72; 95% confidence interval: 1.05-2.83) and amino-terminal pro-B-type natriuretic peptide ≥125 ng/L (risk ratio: 2.10; 95% confidence interval: 1.22-3.60). CONCLUSION: In this study, the predictors of death at 10 years differed between peripheral arterial disease patients with and without diabetes. Among the biomarkers tested, high-sensitivity C-reactive protein was independently associated with outcomes in non-diabetic patients, whereas amino-terminal pro-B-type natriuretic peptide was an independent predictor of death in patients with diabetes. Our findings suggest that in future studies, risk assessment and treatment strategies should be differentially applied to the two peripheral arterial disease subgroups.

Mortality rates at 10 years are higher in diabetic than in non-diabetic patients with chronic lower extremity peripheral arterial disease.

Patients with lower extremity peripheral artery disease (PAD) have a substantially increased risk for mortality as compared to healthy individuals. We aimed to evaluate the risk for all-cause mortality in PAD patients and in healthy controls during a 10-year follow-up period. Our hypothesis was that the mortality rates at 10 years would differ in diabetic and non-diabetic PAD patients. Our study group consisted of 331 consecutive patients with symptomatic PAD <75 years of age admitted to a tertiary care hospital, including 216 patients without diabetes and 115 with diabetes. Control subjects without atherosclerotic disease were matched to the patients in a 1:1 design by sex, age, and diabetes mellitus status. The outcome measure was all-cause mortality at 10 years. Mortality rates at 10 years were 29% in non-diabetic PAD patients versus 14% in age- and sex-matched non-diabetic controls (risk ratio (RR), 2.31; 95% confidence interval (CI), 1.54-3.47; p<0.001), and 58% in diabetic PAD patients versus 19% in age- and sex-matched diabetic controls (RR, 4.06; 95% CI, 2.67-6.18; p<0.001). Further, PAD patients with diabetes had a significantly increased risk for death within 10 years than did the non-diabetic PAD patients (RR, 2.51; 95% CI, 1.72-3.66; p<0.001). Diabetes was independently associated with outcome, and was the strongest predictor of death in multivariate Cox proportional hazards regression. We conclude that mortality rates at 10 years differ in PAD patients <75 years old with and without diabetes. Our findings suggest that future studies should apply distinct risk assessment strategies in the two PAD subgroups.

Mortality rates and mortality predictors in patients with symptomatic peripheral artery disease stratified according to age and diabetes.

OBJECTIVE: Atherosclerotic peripheral arterial disease (PAD) is one of the most prevalent, morbid, and mortal diseases. The aim of this study was to evaluate mortality rates of patients with atherosclerotic PAD stratified according to age and diabetes and to determine predictors of death. METHODS: We studied 487 patients with symptomatic PAD consecutively admitted to the hospital. This cohort included the following four patient subgroups: (1) 216 patients with PAD <75 years of age without diabetes mellitus; (2) 115 patients with PAD < 75 years of age with diabetes mellitus; (3) 102 patients with PAD ≥ 75 years of age without diabetes mellitus; and (4) 54 patients with PAD ≥ 75 years of age with diabetes mellitus. Control subjects without atherosclerotic disease were matched to the patients with PAD in a 1:1 design by sex, age (± 2 years), and diabetes mellitus status. Outcome measure was all-cause mortality at 5 years. RESULTS: Mortality rates at 5 years were 10% in nondiabetic patients with PAD < 75 years of age (vs 5% in control subjects; risk ratio [RR], 2.15; 95% confidence interval [CI], 1.60-4.34); 23% in diabetic patients with PAD < 75 years of age (vs 7% in control subjects; RR, 3.53; 95% CI, 1.80-6.91); 38% in nondiabetic patients with PAD ≥ 75 years of age (vs 22% in control subjects; RR, 2.08; 95% CI, 1.26-3.44); and 52% in diabetic patients with PAD ≥ 75 years of age. Applying multivariate Cox proportional hazards regression analyses (with cardiovascular risk factors, coexisting atherosclerotic disease, clinical stage of PAD, and several biochemical markers as predictor variables), we found the following independent predictors of outcome: in the 216 nondiabetic patients with PAD < 75 years of age, high-sensitivity C-reactive protein (hs-CRP) (RR, 3.04; 95% CI, 1.48-6.26); in the 115 diabetic patients with PAD < 75 years of age, amino-terminal pro-B-type natriuretic peptide (NT-proBNP) (RR, 2.63; 95% CI, 1.65-4.19); in the 102 nondiabetic patients with PAD ≥ 75 years of age, critical limb ischemia (RR, 3.70; 95% CI, 1.82-7.52) and NT-proBNP (RR, 1.93; 95% CI, 1.32-2.82); and in the 54 diabetic patients with PAD ≥ 75 years of age, hs-CRP (RR, 2.61; 95% CI, 1.45-4.67) and NT-proBNP (RR, 3.31; 95% CI, 1.96-5.60). CONCLUSIONS: Mortality rates at 5 years varied considerably among patients with PAD stratified according to age and diabetes. Predictors of death differed among the four patient subgroups in this study and included critical limb ischemia, hs-CRP, and NT-proBNP. Our results might help to develop future strategies for optimized treatment of hospitalized patients with symptomatic PAD.