Uncertainty on the effectiveness and safety of rivaroxaban in premenopausal women with atrial fibrillation: empirical evidence needed

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Abstract

Background

Novel anticoagulations (NOACs) are increasingly prescribed for the prevention of stroke in premenopausal women with atrial fibrillation. Small studies suggest NOACs are associated with a higher risk of abnormal uterine bleeds than vitamin K antagonists (VKAs). Because there is no direct empirical evidence on the benefit/risk profile of rivaroxaban compared to VKAs in this subgroup, we synthesize available indirect evidence, estimate decision uncertainty on the treatments, and assess whether further research in premenopausal women is warranted.

Methods

A Markov model with annual cycles and a lifetime horizon was developed comparing rivaroxaban (the most frequently prescribed NOAC in this population) and VKAs. Clinical event rates, associated quality adjusted life years, and health care costs were obtained from different sources and adjusted for gender, age, and history of stroke. A Monte Carlo simulation with 10,000 iterations was then performed for a hypothetical cohort of premenopausal women, estimated to be reflective of the population of premenopausal women with AF in The Netherlands.

Results

In the simulation, rivaroxaban is the better treatment option for the prevention of ischemic strokes in premenopausal women in 61% of the iterations. Similarly, this is 98% for intracranial hemorrhages, 24% for major abnormal uterine bleeds, 1% for minor abnormal uterine bleeds, 9% for other major extracranial hemorrhages, and 23% for other minor extracranial hemorrhages. There is a 78% chance that rivaroxaban offers the most quality-adjusted life years. The expected value of perfect information in The Netherlands equals 122 quality-adjusted life years and 22 million Euros.

Conclusions

There is a 22% risk that rivaroxaban offers a worse rather than a better benefit/risk profile than vitamin K antagonists in premenopausal women. Although rivaroxaban is preferred over VKAs in this population, further research is warranted, and should preferably take the shape of an internationally coordinated registry study including other NOACs.

Electronic supplementary material

The online version of this article (10.1186/s12872-017-0692-1) contains supplementary material, which is available to authorized users.

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Most cited references 27

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Decision Modelling for Health Economic Evaluation

Andrew H Briggs, Karl Claxton, Mark J Sculpher (2006)

In financially constrained health systems across the world, increasing emphasis is being placed on the ability to demonstrate that health care interventions are not only effective, but also cost-effective. This book deals with decision modelling techniques that can be used to estimate the value for money of various interventions including medical devices, surgical procedures, diagnostic technologies, and pharmaceuticals. Particular emphasis is placed on the importance of the appropriate representation of uncertainty in the evaluative process and the implication this uncertainty has for decision making and the need for future research. This highly practical guide takes the reader through the key principles and approaches of modelling techniques. It begins with the basics of constructing different forms of the model, the population of the model with input parameter estimates, analysis of the results, and progression to the holistic view of models as a valuable tool for informing future research exercises. Case studies and exercises are supported with online templates and solutions. This book will help analysts understand the contribution of decision-analytic modelling to the evaluation of health care programmes. [Ed.]

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Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.

Harriette Van Spall, Andrew Toren, Alex Kiss … (2007)

Selective eligibility criteria of randomized controlled trials (RCTs) are vital to trial feasibility and internal validity. However, the exclusion of certain patient populations may lead to impaired generalizability of results. To determine the nature and extent of exclusion criteria among RCTs published in major medical journals and the contribution of exclusion criteria to the representation of certain patient populations. The MEDLINE database was searched for RCTs published between 1994 and 2006 in certain general medical journals with a high impact factor. Of 4827 articles, 283 were selected using a series technique. Trial characteristics and the details regarding exclusions were extracted independently. All exclusion criteria were graded independently and in duplicate as either strongly justified, potentially justified, or poorly justified according to previously developed and pilot-tested guidelines. Common medical conditions formed the basis for exclusion in 81.3% of trials. Patients were excluded due to age in 72.1% of all trials (60.1% in pediatric populations and 38.5% in older adults). Individuals receiving commonly prescribed medications were excluded in 54.1% of trials. Conditions related to female sex were grounds for exclusion in 39.2% of trials. Of all exclusion criteria, only 47.2% were graded as strongly justified in the context of the specific RCT. Exclusion criteria were not reported in 12.0% of trials. Multivariable analyses revealed independent associations between the total number of exclusion criteria and drug intervention trials (risk ratio, 1.35; 95% confidence interval, 1.11-1.65; P = .003) and between the total number of exclusion criteria and multicenter trials (risk ratio, 1.26; 95% confidence interval, 1.06-1.52; P = .009). Industry-sponsored trials were more likely to exclude individuals due to concomitant medication use, medical comorbidities, and age. Drug intervention trials were more likely to exclude individuals due to concomitant medication use, medical comorbidities, female sex, and socioeconomic status. Among such trials, justification for exclusions related to concomitant medication use and comorbidities were more likely to be poorly justified. The RCTs published in major medical journals do not always clearly report exclusion criteria. Women, children, the elderly, and those with common medical conditions are frequently excluded from RCTs. Trials with multiple centers and those involving drug interventions are most likely to have extensive exclusions. Such exclusions may impair the generalizability of RCT results. These findings highlight a need for careful consideration and transparent reporting and justification of exclusion criteria in clinical trials.

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Atrial fibrillation prevalence revisited.

L E Friberg, L Bergfeldt (2013)

The estimate of 0.4-1.0% prevalence of atrial fibrillation in the most recent American guidelines is based mainly on studies including patients with permanent atrial fibrillation (AF), although recent evidence shows that the stroke risk is similar with paroxysmal and persistent AF. Our objective was to determine the prevalence of AF in Sweden, irrespective of type and to what extent patients with AF receive adequate stroke prophylaxis. Retrospective study of patients with a clinical diagnosis of atrial fibrillation between 2005 and 2010 in the national Swedish Patient Register matched with data from the National Prescribed Drugs Register. We identified 307 476 individuals with a diagnosis of atrial fibrillation. Of these, 209 141 were still alive on the last day of the inclusion period, signifying a prevalence of clinically diagnosed AF in Sweden of 2.9% of the total adult (≥20 years) population. Only 42% of them had purchased an oral anticoagulant within 6 months of the first presentation with AF during the study period. Those at the highest risk of stroke were those least likely to receive anticoagulant treatment. Undertreatment was common amongst women and individuals >80 years, whilst overtreatment was common amongst young men without risk factors. The prevalence of atrial fibrillation is at least 2.9% of the Swedish adult population, not counting 'silent atrial fibrillation'. The official US figures probably underestimate the magnitude of the problem by a factor of 3-5. More than 80% had risk factors motivating anticoagulation therapy. © 2013 The Association for the Publication of the Journal of Internal Medicine.

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Author and article information

Contributors

Herbert J. A. Rolden: herbert.rolden@gmail.com

Angela H. E. M. Maas: angela.maas@radboudumc.nl

Gert Jan van der Wilt: gertjan.vanderwilt@radboudumc.nl

Janneke P. C. Grutters: janneke.grutters@radboudumc.nl

Journal

Journal ID (nlm-ta): BMC Cardiovasc Disord

Journal ID (iso-abbrev): BMC Cardiovasc Disord

Title: BMC Cardiovascular Disorders

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2261

Publication date (Electronic): 13 October 2017

Publication date PMC-release: 13 October 2017

Publication date Collection: 2017

Volume: 17

Electronic Location Identifier: 260

Affiliations

[1 ]Council for Public Health and Society, The Hague, The Netherlands

[2 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department for Health Evidence, , Radboud University Medical Center, ; Nijmegen, The Netherlands

[3 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Cardiology, , Radboud University Medical Center, ; Nijmegen, The Netherlands

Article

Publisher ID: 692

DOI: 10.1186/s12872-017-0692-1

PMC ID: 5640919

PubMed ID: 29029621

SO-VID: 949a0427-ab16-4b29-a7e8-7e994a056586

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 18 January 2017

Date accepted : 3 October 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001826, ZonMw;

Award ID: 113105004

Award Recipient : Janneke P. C. Grutters

Custom metadata

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: abnormal uterine bleeding,atrial fibrillation,premenopausal women,rivaroxaban,value of information,vitamin k antagonists

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ScienceOpen disciplines: Cardiovascular Medicine

Keywords: abnormal uterine bleeding, atrial fibrillation, premenopausal women, rivaroxaban, value of information, vitamin k antagonists

Uncertainty on the effectiveness and safety of rivaroxaban in premenopausal women with atrial fibrillation: empirical evidence needed

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Karger: Cardiovascular System

Most cited references 27

Decision Modelling for Health Economic Evaluation

Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.

Atrial fibrillation prevalence revisited.

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