Elsevier

International Journal of Cardiology

Volume 362, 1 September 2022, Pages 76-82
International Journal of Cardiology

Review
Clinical effects of off-label reduced doses of Direct Oral Anticoagulants: A systematic review and meta-analysis

https://doi.org/10.1016/j.ijcard.2022.04.062Get rights and content

Highlights

  • Direct Oral Anticoagulants (DOAC) are the treatment of choice for most patients with Atrial Fibrillation (AF).

  • The use of DOACs on an off label dose is becoming a common clinical practice.

  • Off label underdose DOAC use is associated with a higher risk of all-cause mortality and composite cardiovascular outcomes.

  • The understanding of factors that influence decisions to prescribe different doses of DOAC is necessary to improve practice.

Abstract

Backgound

Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia among older patients, associated with thromboembolic events. Direct Oral Anticoagulants (DOAC) are the treatment of choice for most patients, but its use may have risks on standard dose. However, it is still unclear the effects related with the use of a lower dose off labelled DOAC.

Objectives

We conducted a systematic review and meta-analysis to assess the effects of off-label underdose use of DOAC in patients with AF.

Methods

MEDLINE, Cochrane Central Register of Controlled Trials, PsycINFO databases and EMBASE were searched for observational longitudinal studies evaluating the outcomes on off label underdosed patients compared with standard dosed patients with AF. We performed a random-effects meta-analysis to estimate the pooled Hazard Ratios (HR) with 95% Cis.

Results

Eighteen cohort studies evaluating 237,533 patients with AF were included. Off-label underdose DOAC use is associated with higher risk of all-cause mortality [HR = 1.27 (95%CI 1.09–1.48)] and cardiovascular composite outcomes [HR = 1.32 (95%CI 1.08–1.62)], when compared with standard dose DOAC use. The effects in thromboembolic events [HR = 1.14 (95%CI 1.00–1.31)], major bleeding [HR = 1.02 (95%CI 0.91–1.15)], and composite of ischemic and bleeding events [HR = 1.22 (95%CI 0.79–1.88)] were not statistically significant. The certainty in the evidence was low or very low.

Conclusions

Off label underdose DOAC use is associated with higher risk of all-cause mortality and cardiovascular composite outcomes, compared with standard dose.

Introduction

Atrial fibrillation (AF) is a cardiac arrythmia associated with an increased risk of stroke and death. In patients who are newly diagnosed with AF, the mortality risk is especially high during the first four months [1].

Direct Oral Anticoagulants (DOAC) are nowadays recommended as the treatment of choice for most patients with AF [2]. DOAC specific characteristics are the rapid onset of action, a short half-life, a predictable anticoagulant effect in standard conditions, not requiring prothrombin time monitoring, and a low level of food–drug interactions [[3], [4], [5]]. Due to their pharmacological profiles, this class of drugs is administered at a defined dose taking into account clinical indications, individual characteristics and renal function, without current indications for dose adjustment based on laboratory testing.

The use of DOACs on an off-label dose is becoming a common clinical practice [6], although data associated with its clinical consequences is still limited and clinical efficacy may be compromised. This can be explained by the fact that the fixed-dosing strategy is possibly at risk of confusion due to multiple dose regimens depending on indications and physiological and clinical parameters (age, body weight, renal insufficiency), and interacting drugs [7].

During the current days, the challenge faced by clinicians remains on selecting the optimal choice and dose of DOAC to maintain the delicate equilibrium between thrombosis and bleeding risk of patients, especially those with multiple medical co-morbidities or multiple co-medication [[8], [9], [10]]. The use of DOACs on standard dose may have risks, but the effects related with the use of a lower dose off labelled DOAC are still unclear [10].

Notably, there is a gap in knowledge about the efficacy and safety of reduced dose DOAC despite the disproportionately high usage of reduced dose DOAC, which is a cause of concern. Therefore, studies examining the effectiveness and safety of standard dose or reduced dose DOAC in direct comparisons are warranted [11,12].

The purpose of the study is to conduct a systematic review and meta-analysis on the impact, effects, and outcomes of the use of off-label dose-reduced direct anticoagulants in the referred population, patients with AF.

Section snippets

Methods

This systematic review follows the reporting principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13].

Study selection

The electronic database search yielded 444 references. After screening of title and abstract and evaluation for full-text eligibility, 18 studies remained for inclusion in the qualitative synthesis, and 18 studies in the meta-analysis (Supplementary Fig. 1) [[21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38]].

Study characteristics

All 18 studies included in the meta-analysis were cohort studies (thirteen retrospective and five prospective). There were no

Discussion

The main finding of this meta-analysis is that the best available evidence, based on low quality cumulative data, shows that the use of off label underdose DOAC on AF patients is associated with a significantly higher risk of all-cause mortality and cardiovascular composite outcomes, when compared with standard dose DOAC use. The effect in thromboembolic events (stroke/systemic embolism), major bleeding, and composite of ischemic and bleeding events was not statistically significant. However,

Conclusion

Our data supports the hypothesis that off label underdose DOAC use is associated with higher risk of all-cause mortality and cardiovascular composite outcome, when compared with standard dose DOAC use. We found no significant effect in thromboembolic events (stroke/systemic embolism), major bleeding and composite of ischemic and bleeding events.

Funding

This meta-analysis was an academic project and was not supported by any funding.

CRediT authorship contribution statement

Mariana Q. Pereira: Investigation, Data curation, Writing – original draft, Writing – review & editing. Cláudio David: Methodology, Writing – review & editing, Visualization. Ana G. Almeida: Writing – review & editing, Visualization. Dulce Brito: Writing – review & editing, Visualization. Fausto J. Pinto: Writing – review & editing, Visualization. Daniel Caldeira: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing – review & editing, Visualization,

Declaration of Competing Interest

DC has participated in educational meetings and/or attended a conferences or symposia (including travel, accommodation and/or hospitality) with Bial, Bristol-Myers Squibb, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck Serono, Ferrer, Pfizer, Novartis and Roche. FJP had consultant and speaker fees with Astra Zeneca, Bayer, BMS, Boehringer Ingelheim and Daiichi Sankyo. DB has received consultancy and/or lecture fees from Genzyme-Sanofi, Novartis, Orion, Pfizer, Roche, Servier, St. Jude,

Acknowledgments

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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