Nabila Ferahta1, Lukshe Kanagaratnam2, Moustapha Dramé2,3 Thomas Vogel4, Pierre-Jacques Ambrosi5 and Pierre-Olivier Lang11,6*
1Geriatric and rehabilitation geriatric division, University hospital of Lausanne, Lausanne, Switzerland
2Department of Research and Public Health, University hospitals of Reims, Reims, France
3EA-3797, Faculty of Medicine, University of Reims-Champagne-Ardenne, Reims, France
4Geriatric Department, University Hospital of Strasbourg, Strasbourg, France
5Department of Cardiology, La Timone Hospital, Aix-Marseille University, Marseille, France
6Health and Wellbeing academy, Anglia Ruskin University, Cambridge, United Kingdom
Received: 09 June, 2017; Accepted: 08 July, 2017; Published: 10 July, 2017
Pierre Olivier Lang, Geriatric and Geriatric rehabilitation division, University Hospital of Lausanne (CHUV), Chemin de Mont Paisible 16, CH-1011 Lausanne, Switzerland, Tel: +41.(0)21.314.37.04; Fax: +41.(0)21.314.17.20; E-mail:
Ferahta N, Kanagaratnam L, Dramé M, Vogel T, Ambrosi PJ, et al. (2017) Bleeding Risk under Oral Factor Xa Inhibitors: Meta-analysis of the randomized comparison with Vitamin K Antagonists and Meta-Regression analysis. J Cardiovasc Med Cardiol 4(3): 038-048. 10.17352/2455-2976.000048
© 2017 Ferahta N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Oral Anticoagulants; Factor Xa Inhibitor; Antivitamin K; Bleeding Events; Major Bleeding; Gastrointestinal Bleeding; Intracranial Haemorrhage; Atrial Fibrillation; Meta-Analysis
Background: Randomized trials have shown that oral direct factor Xa inhibitors (ODIXa) offer potential advantages over vitamin K antagonists (VKAs). It is however unclear whether the magnitude of their benefit is similar at the current recommended doses.
Objective: We assessed bleeding risks and total mortality associated with ODIXa therapy compared to VKAs among patients with non-valvular atrial fibrillation or acute venous thromboembolic disease.
Methods: Medline, Embase and Cochrane library databases were searched to identify all randomized controlled trials comparing ODIXa to VKAs. The main outcomes were major bleeding, major and clinically relevant non-major (CRNM) bleeding, intracranial haemorrhage, gastrointestinal bleeding, total bleeding events and overall mortality. Pooled odds ratios were calculated with random effect model. Meta-regression was performed.
Results: The use of ODIXa was associated with a significant reduced-risk of major bleeding (OR, 0.72; 95% CI, 0.60-0.87), major and CNRM bleeding (OR, 0.72; 95% CI, 0.54-0.96), intracranial bleeding (OR, 0.48; 95% CI, 0.39-0.59) and total bleeding events (OR, 0.69; 95% CI, 0.60-0.80). No difference in risk of gastrointestinal bleeding was observed in NVAF. A linear association was found between a higher CHADS2 and risk of major bleeding; increasing age and a high quality of warfarin monitoring (TTR) were also correlated with a higher risk of gastrointestinal bleeding on ODIXa.
Conclusion: ODIXa therapy was associated with a lower rate of bleedings complications and overall mortality. The gastrointestinal bleeding risk, which was globally similar, was however increasing in ODIXa groups with advancing age and greater quality of VKAs management.
Adequate antithrombotic therapy with vitamin K antagonists (VKAs) significantly reduces the risk of stroke in patients with atrial fibrillation (AF) which were until recently the cornerstone of treatment in patients with an increased risk of thromboembolic complications. VKAs were thus our standard for oral anticoagulation for more than 50 years, with about 30 million prescriptions annually in the USA .
The increased bleeding risk common to anticoagulants ranges in severity from clinically manageable epistaxis to life-threatening intracranial hemorrhage. All those bleeding events are also one of the leading causes for emergency department (ED) visits and preventable costs . In the USA, warfarin was incriminated in 17.3% of ED visits for adverse drug events in older adults, and about 90% of warfarin-related hospitalizations were attributed to unintentional overdose . VKAs management was inappropriate in 48.7% (31% were not or under treated and 17.7% over treated) among hospitalized patients with AF .
The development of oral direct thrombin (DTI) and factor Xa inhibitors (ODIXa) have streamlined clinical care and evidence-based guidelines contributed to their rapid adoption . Based on data from the IMS Health National Disease and Therapeutic Index, the prescription of direct oral anticoagulants (DOACs) was dramatically extended but matching the use of VKAs and was associated with increased number AF patients receiving oral anticoagulants . DOACs have more favorable pharmacological profile compared with VKAs (i.e. predictable effect, lack of frequent monitoring or re-dosing, fewer drug-drug and drug-food interaction) , and are therapeutically at least as effective [7-21]. When there is probably no doubt that DOACs represent a major step forward in the management of patients needing oral antithrombotic, better knowledge about risk of bleeding complications would certainly provide relevant insights into treatment outcomes. Despite the availability of predictive tools and evidence-based guidelines, many patients are still inappropriately treated for conditions that predispose to thromboembolic complications and debilitating strokes. Indeed, the fear of bleeding commonly leads physician to estimate systematically the risk of bleeding greater than the risk of stroke .
Meta-analyses have already attempted to assess the exact benefit and safety of DOACs [7-12,14-16,18,20,21,23-26]. Globally they all reported a lower risk of intracranial and major bleeding compared to warfarin or aspirin [7,8,10,11,14-16,19-21,26,27]. However, either they considered phase III studies only [7,10,13-16,19,21,24], or combined data from heterogeneous pharmacological classes (ODIXa and DTI) [7-14,16-21,25,28], leading to sub-group comparisons or sensitivity analyses [13,15,18,20,27]. Meta-analyses have also considered a limited number of ODIXa [7,9,12,14,17,19,24,26,29], in comparison with the current number of available molecules that would also have different safety profiles. Previous reports have also mixed different therapeutic indications .
The aim of the present meta-analysis was to estimate the safety profile of the five currently available ODIXa in terms of bleeding risk in patients with non-valvular (NV) AF, acute DVT, or PE compared to VKAs. The primary objective was to assess the risk of major bleeding when ODIXa was prescribed at recommended dose. Secondary objectives were composite outcomes of major bleeding and clinically relevant non-major bleeding (CRNM), intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), all bleeding events, and all-cause mortality. We also assessed the influence of potential modulators for all these outcomes through meta-regression analyses.
Materials and Methods
This meta-analysis was conducted and reported in accordance with the PRISMA statement .
Design: Randomized controlled trials (RCTs) comparing the effect of one of the five currently available ODIXa (rivaroxaban, apixaban, edoxaban, betrixaban and darexaban) to VKAs in patients with NVAF, DVT, or PE were identified. Phase III and II dose-ranging clinical trials were considered. For the latter, only trials or trial arms testing doses that were finally approved, recommended, or considered for phase III studies were included. Double blind and open-label trials were included because dose monitoring of VKAs makes blind design very challenging.
Treatment: For ODIXa, standard daily dose (approved or recommended doses) were considered: apixaban 10 mg, betrixaban 80 mg, darexaban 120 mg, edoxaban 60 mg and rivaroxaban 20 mg or 15 mg twice day. Low-dose ODIXa were considered in case of renal insufficiency according to guidelines. For VKAs, all molecules were considered and therapeutic dosing was adjusted to a target international normalized ratio (INR) range of 1.5 to 3.0 according to study protocols (Table 1).
Search strategy, data extraction and quality assessment
A comprehensive systematic database search for manuscripts was conducted using MEDLINE, Embase, and Cochrane Central Register of controlled Trials via OVID from 1990 to January 2016. The search was subsequently updated to April 15, 2017. In order to identify unpublished data, abstract books from the congresses of the International Society of Thrombosis and Hemostasis, the European Society of Cardiology, the American Heart Association, the American Society of Hematology, and the American College of Cardiology were scrutinized as well as www.clinicaltrial.gov and ,www.strokecenter.org. Electronic databases were consulted with search keywords: « apixaban » [MeSH Terms] OR « edoxaban » [MeSH Terms] OR « rivaroxaban » [MeSH Terms] OR « betrixaban » [MeSH Terms] OR « darexaban » [MeSH Terms]. Articles were searched manually for potential inclusion; duplicates were immediately removed (Figure 1). Reference lists of articles retrieved, reviews articles, and position stands were reviewed for further references.
Two reviewers (NF and TV) independently assessed manuscripts for potential inclusion. Disagreements were first resolved through discussion and, when necessary, the opinion of a third reviewer (POL) was considered. Briefly, data were extracted according to study design, population’s characteristics (total number, mean or median age, gender), treatment type (pharmaceutical component, clinical indication, dose, treatment duration, and follow-up), and the report of adverse events. The latter was defined as follows: “major bleeding”, the combination of “major and clinically relevant non-major (CRNM) bleeding”, “intracranial hemorrhage”, “gastrointestinal bleeding”, “total bleeding”, and “all-cause mortality”.
Once studies were collected based on a minimum quality threshold, defined as having met all inclusion criteria, a more detailed assessment was conducted according to the Cochrane Collaboration risk of bias assessment for potential bias .
Analyses were computed using R (version 3.1.2; R Foundation for Statistical Computing, Vienna, Austria). The significant threshold was set at P=0.05. Data from ODIXa were pooled to perform a comparison in a random effect model (Mantel-Haenszel method) for primary (major bleeding) and secondary objectives (major bleeding and CRNM, ICH, GIB, total bleeding events, and all-cause mortality). Results were expressed as Mantel–Haenszel pooled odds ratio (OR) and 95% confidence interval (CI). Heterogeneity between trials was assessed using the χ2 (Chi2) test and I² statistic. The random effect model was considered independently of the existence of heterogeneity because we used pooled results of studies with different designs and patient’s characteristics. Analyses were also stratified according to therapeutic indication and study phase. In addition, sensitivity analysis including meta-analysis of only phase III RCTs was performed.
Finally, meta-regressions by a random effect model were computed; the log OR for primary and secondary objectives were predicted according to the age, patient’s time in therapeutic range (TTR) on VKAs, sex-ratio, heparin therapy duration when applied, CHADS2 score, and the combined use of aspirin. Funnel plots asymmetries were considered (showing the standard errors and the effect size) to investigate publication bias.
The process of study inclusion/exclusion is detailed in (Figure 1). Briefly, 20 RCTs were eligible for final inclusion; two were secondarily excluded because the dose of ODIXa was not the one recommended for the therapeutic indications [32,33]. The 18 remaining [34-51] consisted of 5 RCTs reporting the effect of apixaban [34,36,43,45,46,52], 1 trial for betrixaban , 2 for darexaban [44,48], 5 for edoxaban [37,40,42,49,51], and 5 for rivaroxaban [35, 38, 39, 47, 50]. Fourteen RCTs have considered warfarin as VKA in control group and 4 studies authorized warfarin or another VKA [35, 36, 38, 39]. NVAF was the therapeutic indication in 10 RCTs [40-44, 46-49, 51], and DVT and PE in 8 [34-36, 38, 39, 45, 50]. Major and CRNM bleedings were defined according to the definition of the ISTH  in most RCTs (Table 1). No publication bias was detected according to funnel plot analysis. All studies were funded and/or supported by pharmaceutical companies.