Bleeding in patients receiving non-vitamin K oral anticoagulants: clinical trial evidence

In optimizing anticoagulation therapy, it is essential to balance treatment efficacy with the major adverse effect of anticoagulant treatment, bleeding risk. This narrative review examines the efficacy and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban compared with standard anticoagulation or placebo. NOAC therapies provide equivalent to superior protection versus standard therapy, with similar or superior safety, and potential benefits in convenience. We will review the phase III evidence for each of the available NOACs in different antithrombotic indications, including atrial fibrillation (in the absence of significant mitral stenosis or mechanical heart valves); prophylaxis of venous thromboembolism (VTE) in patients undergoing orthopedic surgery; and acute and long-term treatment of VTE. Further, we will illustrate scenarios in which the evidence is stronger for a particular agent in the context of the overall positive safety and efficacy profile of NOACs in general. Limitations of the factor Xa inhibitors include the lack of a specific antidote in case of a bleeding emergency (an approved agent is available for reversing the effect of the direct thrombin inhibitor). We discuss the options for mitigating bleeding and describe the ongoing developments towards specific reversal agents. In conclusion, the available data for efficacy and safety, together with reliable pharmacokinetics obviating the need for regular monitoring, indicate that NOACs may offer substantial benefits for patients with nonvalvular atrial fibrillation or VTE.

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Letter by Tong et al Regarding Article, “Efficacy and Safety of the Use of Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation and Concomitant Aspirin Therapy: A Meta-Analysis of Randomized Trials”

Circulation ◽

10.1161/circulationaha.118.035321 ◽

2018 ◽

Vol 138 (12) ◽

pp. 1277-1278

Author(s):

Suiyang Tong ◽

Liangliang Zhang ◽

Jacob Joseph

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Randomized Trials ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Aspirin Therapy ◽

Vitamin K Antagonist ◽

Efficacy And Safety ◽

Nonvalvular Atrial Fibrillation

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Comparative Efficacy and Safety of the Non–Vitamin K Antagonist Oral Anticoagulants for Patients with Nonvalvular Atrial Fibrillation

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0035-1544156 ◽

2015 ◽

Vol 41 (02) ◽

pp. 146-153 ◽

Cited By ~ 8

Author(s):

Keitaro Senoo ◽

Gregory Lip

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Efficacy And Safety ◽

Comparative Efficacy ◽

Nonvalvular Atrial Fibrillation

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Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants After Cardioversion for Nonvalvular Atrial Fibrillation

The American Journal of Medicine ◽

10.1016/j.amjmed.2016.05.007 ◽

2016 ◽

Vol 129 (10) ◽

pp. 1117-1123.e2 ◽

Cited By ~ 10

Author(s):

Giulia Renda ◽

Marco Zimarino ◽

Fabrizio Ricci ◽

Jonathan P. Piccini ◽

Michael D. Ezekowitz ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Efficacy And Safety ◽

Nonvalvular Atrial Fibrillation

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Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Asians With Nonvalvular Atrial Fibrillation: A Network Meta-Analysis

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029619885188 ◽

2019 ◽

Vol 25 ◽

pp. 107602961988518

Author(s):

Qinmei Xiong ◽

Cen Wang ◽

Hualong Liu ◽

Zhaochong Tan ◽

Chen Chen ◽

...

Keyword(s):

Myocardial Infarction ◽

Atrial Fibrillation ◽

Vitamin K ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Efficacy And Safety ◽

Systemic Embolism ◽

Nonvalvular Atrial Fibrillation ◽

End Points

There are few head-to-head trials directly comparing non-vitamin K antagonist oral anticoagulants (NOACs) against one other. A network meta-analysis (NMA) was performed to examine the indirect comparisons among NOACs in Asians with nonvalvular atrial fibrillation (NVAF). STATA 15.0 and ADDIS 1.16.8 softwares were used to perform the statistical analysis. Odds ratios with 95% credible intervals were applied to evaluate the end points. The probabilities of treatment rank were used to understand which interventions are more effective and safe, and the total rank probability was 1. In our NMA, the rank probabilities of apixaban in the case of stroke or systemic embolism, death from any cause, major bleeding, and intracranial hemorrhage (ICH) were 0.47, 0.49, 0.42, and 0.51, respectively. For cases of myocardial infarction, the rank probabilities of rivaroxaban were 0.40. This NMA indirectly compares the main efficacy and safety end points among NOACs in Asians with NVAF, and the rank probability analysis showed that apixaban likely performs best in cases of stroke or systemic embolism, death from any cause, and ICH; rivaroxaban may have the best performance for myocardial infarction.

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Drug Adherence in Patients With Nonvalvular Atrial Fibrillation Taking Non-Vitamin K Antagonist Oral Anticoagulants in Turkey: NOAC-TR

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029617693940 ◽

2017 ◽

Vol 24 (3) ◽

pp. 525-531 ◽

Cited By ~ 9

Author(s):

Sadık Volkan Emren ◽

Oktay Şenöz ◽

Murat Bilgin ◽

Osman Beton ◽

Abdullah Aslan ◽

...

Keyword(s):

Atrial Fibrillation ◽

Medication Adherence ◽

Vitamin K ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Self Report ◽

Efficacy And Safety ◽

Adherence Level ◽

Nonvalvular Atrial Fibrillation ◽

Factors Affecting

Adherence to non-vitamin K antagonist oral anticoagulants (NOACs) is an important factor for ensuring efficacy and safety in nonvalvular atrial fibrillation (NVAF). There are controversial results regarding NOAC adherence in real-world data and there are no data about NOAC adherence in Turkish population. This study investigated the NOAC adherence based on self-report, factors affecting nonadherence, and the relation of the adherence level with efficacy and safety outcomes. This multicenter cross-sectional study included 2738 patients (59% female) using NOAC (dabigatran, apixaban, and rivaroxaban) due to NVAF for more than 3 months with >30 days of supply between September 1, 2015, and February 28, 2016. To measure the adherence level, an 8-item Morisky Medication Adherence Scale was used. The mean age of the patients was 70 ± 10 years. Of the 2738 patients, 44% were receiving dabigatran, 38% rivaroxaban, and 18% apixaban. A total of 630 (23%) patients had high medication adherence, 712 (26%) moderate adherence, and 1396 (51%) low adherence. Nonadherence had related to stroke (5.6% vs 2.5%, P < .001) and minor (21.2% vs 11.1%, P < .001) and major (6.1% vs 3.7%, P = .004) bleeding rates. The adherence to NOAC was found to be quite low in Turkey. Nonadherence is associated with bleeding and thromboembolic cardiovascular events. Age, taking NOAC twice a day, and the additional noncardiac diseases, depression, and dementia were the independent factors affecting poor medication adherence.

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Direct Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation: Update and Periprocedural Management

Critical Care Nurse ◽

10.4037/ccn2019292 ◽

2019 ◽

Vol 39 (2) ◽

pp. 54-67 ◽

Cited By ~ 1

Author(s):

Joya D. Pickett

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Fixed Dose ◽

Thrombin Inhibitor ◽

National Guidelines ◽

Nonvalvular Atrial Fibrillation ◽

Periprocedural Management

Vitamin K antagonists (eg, warfarin) have been the standard of care for stroke prophylaxis in atrial fibrillation. The direct oral anticoagulants dabigatran (direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (direct factor Xa inhibitors) are as efficacious as and in some instances superior to vitamin K antagonists in the prevention of stroke, systemic embolism, and major bleeding compared with warfarin for nonvalvular atrial fibrillation. Benefits of direct oral anticoagulants include a rapid onset of therapeutic effect, fixed dose-response relationships without the need for routine monitoring, a short half-life, and infrequent need for periprocedural bridging with a parenteral agent. However, direct oral anticoagulants differ in subsets of patients. Critical care and advanced practice nurses must understand these differences, prescribing considerations, drug aherence interventions, drug-drug interactions, and periprocedural management. This article presents an update and review of direct oral antigcoagulants based on the latest national guidelines.

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Direct Oral Anticoagulants in Nonvalvular Atrial Fibrillation: Practical Considerations on the Choice of Agent and Dosing

Cardiology ◽

10.1159/000489922 ◽

2018 ◽

Vol 140 (2) ◽

pp. 126-132 ◽

Cited By ~ 9

Author(s):

Dimitrios Farmakis ◽

Periklis Davlouros ◽

Gregory Giamouzis ◽

George Giannakoulas ◽

Athanasios Pipilis ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Comparable Efficacy ◽

Thrombin Inhibitor ◽

Systemic Embolism ◽

Nonvalvular Atrial Fibrillation ◽

Clinical Scenarios

Direct or new oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, have recently revolutionized the field of antithrombotic therapy for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (NVAF). Randomized controlled trials have shown that these agents have at least comparable efficacy with vitamin K antagonists along with superior safety, at least in what concerns intracranial hemorrhage. As a result, NOACs are indicated as first-line anticoagulation therapy for NVAF patients with at least one risk factor for stroke or systemic embolism. The rapid introduction, however, of NOACs in a field dominated for decades by vitamin antagonists and the variety of agents and dosing schemes may create difficulties in decision making. In the present article, we attempt to determine a practical approach to the choice of agent and dose in different clinical scenarios by considering not only the results of seminal randomized trials and post hoc analyses but also data from real-world patient populations as well as the recently available possibility of rapid NOAC reversal.

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