Abstract
AimsThe well-known limitations of vitamin K antagonists (VKA) led to development of new oral anticoagulants (NOAC) in non-valvular atrial fibrillation (NVAF). The aim of this meta-analysis was to determine the consistency of treatment effects of NOAC irrespective of age, comorbidities, or prior VKA exposure.Methods and ResultsAll randomized, controlled phase III trials comparing NOAC to VKA up to October 2012 were eligible provided their results (stroke/systemic embolism (SSE) and major bleeding (MB)) were reported according to age (≤ or >75 years), renal function, CHADS2 score, presence of diabetes mellitus or heart failure, prior VKA use or previous cerebrovascular events. Interactions were considered significant at p <0.05. Three studies (50,578 patients) were included, respectively evaluating apixaban, rivaroxaban, and dabigatran versus warfarin. A trend towards interaction with heart failure (p = 0.08) was observed with respect to SSE reduction, this being greater in patients not presenting heart failure (RR = 0.76 [0.67–0.86]) than in those with heart failure (RR = 0.90 [0.78–1.04]); Significant interaction (p = 0.01) with CHADS2 score was observed, NOAC achieving a greater reduction in bleeding risk in patients with a score of 0–1 (RR 0.67 CI 0.57–0.79) than in those with a score ≥2 (RR 0.85 CI 0.74–0.98). Comparison of MB in patients with (RR 0.97 CI 0.79–1.18) and without (RR 0.76 CI 0.65–0.88) diabetes mellitus showed a similar trend (p = 0.06). No other interactions were found. All subgroups derived benefit from NOA in terms of SSE or MB reduction.ConclusionsNOAC appeared to be more effective and safer than VKA in reducing SSE or MB irrespective of patient comorbidities. Thromboembolism risk, evaluated by CHADS2 score and, to a lesser extent, diabetes mellitus modified the treatment effects of NOAC without complete loss of benefit with respect to MB reduction.
Highlights
Non-valvular atrial fibrillation (NVAF) is a major cause of ischemic stroke and systemic embolism and is characterized by increased mortality and morbidity and higher costs of medical care [1,2]
In 29 randomized trials involving more than 28,000 patients, pooled according to metaanalytic methods, adjusted-dose warfarin reduced the risk of stroke by 64% compared to the control and by 37% compared to aspirin, but at the cost of an increased risk of bleeding [3]
New oral anticoagulants (NOAC), directly inhibiting thrombin or factor Xa, have recently been developed. Their wide therapeutic windows allow the use of fixed doses without any need for laboratory monitoring [4,5]. These new drugs could potentially overcome the well-known limitations of Vitamin K antagonists (VKA), such as slow onset of action, need for regular blood sampling to monitor the international normalized ratio (INR), narrow therapeutic windows, marked inter-individual variations in drug metabolism, and multiple drug-drug and drug-food interactions, all of which lead to an increased risk of bleeding [6,7,8]
Summary
Non-valvular atrial fibrillation (NVAF) is a major cause of ischemic stroke and systemic embolism and is characterized by increased mortality and morbidity and higher costs of medical care [1,2]. Warfarin was associated with a 26% reduction in all-cause mortality, compared to no anticoagulation therapy, in randomized, controlled trials in patients with NVAF [3]. New oral anticoagulants (NOAC), directly inhibiting thrombin or factor Xa, have recently been developed. Their wide therapeutic windows allow the use of fixed doses without any need for laboratory monitoring [4,5]. These new drugs could potentially overcome the well-known limitations of VKA, such as slow onset of action, need for regular blood sampling to monitor the international normalized ratio (INR), narrow therapeutic windows, marked inter-individual variations in drug metabolism, and multiple drug-drug and drug-food interactions, all of which lead to an increased risk of bleeding [6,7,8]. NOAC are associated with a reduced risk of stroke and systemic embolism as well as major bleeding, especially intracranial bleeding [9,10,11]
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