Antithrombotic Therapy for Symptomatic Peripheral Arterial Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND: High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD. METHODS: A systematic search was conducted to identify randomized controlled trials. The primary endpoints were major adverse cardiovascular events (MACE) and major bleedings. Secondary endpoints were major adverse limb events (MALE) and acute limb ischaemia (ALI). For each outcome, a frequentist network meta-analysis was used to compare relative risks (RRs) between medication and ASA. ASA was the universal comparator since a majority of studies used ASA as in the reference group. RESULTS: Twenty-four randomized controlled trials were identified including 48,759 patients. With regard to reducing MACE, clopidogrel [RR 0.78, 95% confidence interval (CI) 0.66-0.93], ticagrelor (RR 0.79, 95% CI 0.65-0.97), ASA plus ticagrelor (RR 0.79, 95% CI 0.64-0.97), and ASA plus low-dose rivaroxaban (RR 0.84, 95% CI 0.76-0.93) were more effective than ASA, and equally effective to one another. As compared to ASA, major bleedings occurred more frequently with vitamin K antagonists, rivaroxaban, ASA plus vitamin K antagonists, and ASA plus low-dose rivaroxaban. All regimens were similar to ASA concerning MALE, while ASA plus low-dose rivaroxaban was more effective in preventing ALI (RR 0.67, 95% CI 0.55-0.80). Subgroup analysis in patients undergoing peripheral revascularization revealed that ≥ 3 months after intervention, evidence of benefit regarding clopidogrel, ticagrelor, and ASA plus ticagrelor was lacking, while ASA plus low-dose rivaroxaban was more effective in preventing MACE (RR 0.87, 95% CI 0.78-0.97) and MALE (RR 0.89, 95% CI 0.81-0.97) compared to ASA. ASA plus clopidogrel was not superior to ASA in preventing MACE ≥ 3 months after revascularization. Evidence regarding antithrombotic treatment strategies within 3 months after a peripheral intervention was lacking. CONCLUSION: Clopidogrel, ticagrelor, ASA plus ticagrelor, and ASA plus low-dose rivaroxaban are superior to ASA monotherapy and equally effective to one another in preventing MACE in PAD. Of these four therapies, only ASA plus low-dose rivaroxaban provides a higher risk of major bleedings. More than 3 months after peripheral vascular intervention, ASA plus low-dose rivaroxaban is superior in preventing MACE and MALE compared to ASA but again at the cost of a higher risk of bleeding, while other treatment regimens show non-superiority. Based on the current evidence, clopidogrel may be considered the antithrombotic therapy of choice for most PAD patients, while in patients who underwent a peripheral vascular intervention, ASA plus low-dose rivaroxaban could be considered for the long-term (> 3 months) prevention of MACE and MALE.

Targeting Coagulation Factor Xa Promotes Regression of Advanced Atherosclerosis in Apolipoprotein-E Deficient Mice.

Atherosclerosis is a progressive inflammatory vascular disorder, complicated by plaque rupture and subsequently atherothrombosis. In vitro studies indicate that key clotting proteases, such as factor Xa (FXa), can promote atherosclerosis, presumably mediated through protease activated receptors (PARs). Although experimental studies showed reduced onset of atherosclerosis upon FXa inhibition, the effect on pre-existing plaques has never been studied. Therefore, we investigated effects of FXa inhibition by rivaroxaban on both newly-formed and pre-existing atherosclerotic plaques in apolipoprotein-e deficient (ApoE-/-) mice. Female ApoE-/- mice (age: 8-9 weeks, n = 10/group) received western type diet (WTD) or WTD supplemented with rivaroxaban (1.2 mg/g) for 14 weeks. In a second arm, mice received a WTD for 14 weeks, followed by continuation with either WTD or WTD supplemented with rivaroxaban (1.2 mg/g) for 6 weeks (total 20 weeks). Atherosclerotic burden in aortic arch was assessed by haematoxilin & eosin immunohistochemistry (IHC); plaque vulnerability was examined by IHC against macrophages, collagen, vascular smooth muscle cells (VSMC) and matrix metalloproteinases (MMPs). In addition, PAR1 and -2 expressions and their main activators thrombin and FXa in the plaque were determined in the plaque. Administration of rivaroxaban at human therapeutic concentrations reduced the onset of atherosclerosis (-46%, p < 0.05), and promoted a regression of pre-existing plaques in the carotids (-24%, p < 0.001). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (-39.03%, p < 0.05), enhanced collagen deposition (+38.47%, p < 0.05) and diminished necrotic core (-31.39%, p < 0.05). These findings were accompanied with elevated vascular smooth muscle cells and reduced MMPs. Furthermore, expression of PARs and their activators, thrombin and FXa was diminished after rivaroxaban treatment. Pharmacological inhibition of FXa promotes regression of advanced atherosclerotic plaques and enhances plaque stability. These data suggest that inhibition of FXa may be beneficial in prevention and regression of atherosclerosis, possibly mediated through reduced activation of PARs.

The prothrombin time does not predict the risk of recurrent venous thromboembolism or major bleeding in rivaroxaban-treated patients.

INTRODUCTION: For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), rivaroxaban is given in fixed doses without routine coagulation monitoring. PATIENTS AND METHODS: To determine whether monitoring would enhance its benefit-risk profile, we examined whether peak and trough prothrombin time (PT) values measured in 3797 rivaroxaban-treated patients included in the EINSTEIN DVT and PE studies correlated with subsequent recurrent VTE and major bleeding. In addition, we examined the stability of PT values over time and the impact of clinical variables on PT values. RESULTS: The mean peak PT values at months 3 and 6 or 12 were 21.9 ±â€¯5 and 21.7 ±â€¯6.0 s, respectively, while the mean trough PT values at months 2 and 6 were 15.1 ±â€¯5.1 and 15.3 ±â€¯2.9 s, respectively. Although peak and through PT values were higher in females, and with older age, frailty, active cancer, low body weight, impaired renal function and use of moderate to strong inhibitors of CYP3A4 and/or P-glycoprotein, and were lower in patients taking strong CYP 3A4 inducers, the differences were small and results were overlapping. Neither peak nor trough PT values correlated with recurrent VTE or major bleeding. CONCLUSIONS: PT monitoring is unlikely to improve the benefit-risk profile of rivaroxaban in patients with DVT or PE. The study was registered at www.clinicaltrials.gov as #NCT00440193 (EINSTEIN-DVT) and #NCT00439777 (EINSTEIN-PE).

Comparison of EQ-5D and SF-36 in untreated patients with symptoms of intermittent claudication.

AIM: To compare health-related quality of life (HRQoL) descriptions and utility scores in newly diagnosed peripheral arterial disease (PAD) patients, using two most widely used instruments, EuroQol 5D (EQ-5D) and Medical Outcome Study 36-item Short-Form Health Status Survey (SF-36). METHODS: Patients' self-assessment of HRQoL was measured by the Dutch versions of the EQ-5D and SF-36 in the 204 patients. RESULTS: Mean utility scores ranged from 0.675 for Short-Form Six-Dimension, 0.648 for the EQ-5D UK tariff and 0.715 for the Dutch EQ-5D tariff. A moderate correlation between the utility scores was found due to different valuation techniques of these instruments. CONCLUSION: Both instruments have clinical validity for use in the PAD and can be used alongside each other to provide a holistic assessment of the HRQoL. Before using these two instruments interchangeably for utility score calculations and healthcare resource allocation, a thorough sensitivity analysis is necessary to explore the robustness of the value argument based on these utility scores.

Assessment of bleeding risk in patients with coronary artery disease on dual antiplatelet therapy. A systematic review.

Patients with coronary artery disease are usually treated with dual antiplatelet therapy (DAPT) after percutaneous coronary intervention. Patients on DAPT are at risk of both ischaemic and bleeding events. Although side-lined for a long time, real-life studies have shown that both the incidence and the associated morbidity and mortality of out-of-hospital bleeding are high. This indicates that prevention of (post-interventional) bleeding is as important as prevention of ischaemia. For this purpose it is crucial to reliably identify patients with a high bleeding risk. In order to postulate an algorithm, which could help identifying these patients, we performed a systematic review to determine the value of previously proposed prognostic modalities for bleeding. We searched and appraised the following tools: platelet function tests, genetic tests, bleeding scores and questionnaires and haemostatic tests. Most studies indicated that low on-treatment platelet reactivity (LTPR), as measured by several platelet function tests, and the carriage of CYP2C19*17 allele were independent risk factors for bleeding. A bleeding score also proved to be helpful in identifying patients at risk. No studies on haemostatic tests were retrieved. Several patient characteristics were also identified as independent predictors of bleeding, such as older age, female sex and renal failure. Combining these risk factors we propose an algorithm that would hypothetically facilitate identification of those patients at highest risk, warranting prevention measures for bleeding. This could be a starting point for further research concerning the topic.