Dabigatran and Warfarin for Secondary Prevention of Stroke in Atrial Fibrillation Patients: A Nationwide Cohort Study

doi:10.1016/j.amjmed.2014.07.023

The American Journal of Medicine

Volume 127, Issue 12, December 2014, Pages 1172-1178.e5

https://doi.org/10.1016/j.amjmed.2014.07.023 Get rights and content

Abstract

Background

This register-based observational study compares dabigatran to warfarin for secondary stroke prevention in atrial fibrillation patients among both “new starters” on dabigatran and “switchers” to dabigatran from warfarin.

Methods

We identified, in nationwide Danish registries, 2398 patients with atrial fibrillation and a history of stroke/transient ischemic attack, making a first-time purchase of dabigatran 110 mg twice a day (bid; D110) and 150 mg bid (D150). Patients were categorized as either vitamin K antagonist (VKA) naive or experienced. Warfarin controls were identified using a complete (for VKA-naive dabigatran patients) or matched sampling approach (for VKA-experienced dabigatran patients). Subjects were followed for an average of 12.6 months for stroke and transient ischemic attacks. Confounder-adjusted Cox regression models were used to compare event rates between treatments.

Results

Among patients with a history of stroke/transient ischemic attack and prior VKA experience, switching to dabigatran was associated with an increased stroke/transient ischemic attack rate for both dabigatran doses compared with continuing on warfarin (D110 hazard ratio [HR] 1.99; 95% confidence interval [CI], 1.42-2.78; D150 HR 2.34; 95% CI, 1.60-3.41). Among prior stroke/transient ischemic attack patients who were new starters on dabigatran or warfarin, the rate of stroke/transient ischemic attack for both doses of dabigatran was similar to or lower than warfarin (D110 HR 0.64; 95% CI, 0.50-0.80; D150 HR 0.92l; 95% CI, 0.73-1.15).

Conclusions

In this register-based study, VKA-experienced patients with a history of stroke or transient ischemic attack who switched to dabigatran therapy had an increased rate of stroke compared with patients persisting with warfarin therapy.

Section snippets

Methods

We used the civil registration number assigned to all Danish residents to link 3 nationwide databases: 1) the Danish National Prescription Registry,¹² which holds information on purchase date, Anatomical Therapeutic Chemical (ATC) classification code, and package size for every prescription purchase in Denmark since 1994; 2) the Danish National Patient Register¹³ established in 1977, which includes admission/discharge date and discharge International Classification of Diseases (ICD) diagnoses

Study Population Characteristics

A flow chart of the study population is shown in Figure 1. In the VKA-naive stratum, we included 1439 patients with atrial fibrillation and a history of stroke/transient ischemic attack making a first-time dabigatran purchase, alongside 1825 patients making a first-time warfarin purchase (controls). In the VKA-experienced stratum, 959 dabigatran switchers were matched to 1918 warfarin controls (selected among 11,159 unique subjects with a total of 76,553 purchases).

Baseline information is shown

Discussion

In this large register-based observational study of secondary stroke prevention among atrial fibrillation patients, we found similar effectiveness of dabigatran relative to warfarin for secondary prevention of stroke/transient ischemic attack among “new starters” on anticoagulant therapy. In contrast, we found a doubling of the stroke/transient ischemic attack rate among “switchers” to both dabigatran doses compared with persisters on warfarin. The overall stroke risk was generally higher in

Conclusion

In this nationwide cohort study, we found that for patients with a history of stroke/transient ischemic attack who are VKA-naive, both dabigatran doses provided similar protection to warfarin against recurrent stroke/TIA. Among VKA-experienced patients, the risk of recurrent stroke/transient ischemic attack was significantly increased compared with continued warfarin usage. Although clinical implications from observational data must be drawn carefully, our findings stress the importance of

References (22)

T.B. Larsen et al.
Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study
J Am Coll Cardiol
(2013)
H.-C. Diener et al.
Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial
Lancet Neurol
(2010)
T.B. Larsen et al.
Myocardial ischemic events in “real world” patients with atrial fibrillation treated with dabigatran or warfarin
Am J Med
(2014)
D.A. Lane et al.
Dabigatran in atrial fibrillation: balancing secondary stroke prevention against bleeding risk
Lancet Neurol
(2010)
I.E. Albertsen et al.
Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: a systematic review and meta-analysis
Stroke
(2013)
A. Banerjee et al.
A new landscape for stroke prevention in atrial fibrillation: focus on new anticoagulants, antiarrhythmic drugs, and devices
Stroke
(2011)
S.J. Connolly et al.
Dabigatran versus warfarin in patients with atrial fibrillation
N Engl J Med
(2009)
R. Sørensen et al.
Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study
BMJ Open
(2013)
L.H. Rasmussen et al.
Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis
BMJ
(2012)
T.B. Larsen et al.
Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation
Am J Med
(2014)

M.D. Ezekowitz et al.

Dabigatran and warfarin in vitamin K antagonist-naive and -experienced cohorts with atrial fibrillation

Circulation

(2010)

Cited by (40)

Risk of Major Gastrointestinal Bleeding With New vs Conventional Oral Anticoagulants: A Systematic Review and Meta-analysis
2020, Clinical Gastroenterology and Hepatology
There is controversy over whether use of non-vitamin K antagonist oral anticoagulants (NOACs) associates with increased risk of major gastrointestinal bleeding (GIB) compared with conventional therapies (such as vitamin K antagonists or anti-platelet agents). We performed a systematic review and meta-analysis of data from randomized controlled trials and high-quality real-world studies.
We performed a systematic search of the MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov Website databases (through Oct 12, 2018) for randomized controlled trials and high-quality real-world studies that reported major GIB events in patients given NOACs or conventional therapy. Relative risks (RRs) for randomized controlled trials and adjusted hazard ratios (aHRs) for real-world studies were calculated separately using random-effects models.
We analyzed data from 43 randomized controlled trials (183,752 patients) and 41 real-world studies (1,879,428 patients). The pooled major rates of GIB for patients on NOACs (1.19%) vs conventional treatment (0.92%) did not differ significantly (RR from randomized controlled trials, 1.09; 95% CI, 0.91–1.31 and aHR from real-world studies, 1.02; 95% CI, 0.94–1.10; P_interaction=.52). Rivaroxaban, but not other NOACs, was associated with an increased risk for major GIB (RR from randomized controlled trials, 1.39; 95% CI, 1.17–1.65 and aHR from real-world studies, 1.14; 95% CI, 1.04–1.23; P_interaction = .06). Analyses of subgroups, such as patients with different indications, dosage, or follow-up time, did not significantly affect results. Meta-regression analysis failed to detect any potential confounding to impact the primacy outcome.
In a systematic review and meta-analysis of data from randomized controlled trials and real-world studies, we confirmed that there is no significant difference in risk of major GIB between patients receiving NOACs vs conventional treatment. Rivaroxaban users had a 39% increase in risk for major GIB.
Direct Oral Anticoagulants Versus Vitamin K Antagonists in Real-life Patients With Atrial Fibrillation. A Systematic Review and Meta-analysis
2019, Revista Espanola de Cardiologia
Determinar la efectividad de los anticoagulantes orales directos frente a los antagonistas de la vitamina K en pacientes con fibrilación auricular de la práctica clínica.
Se realizó una revisión sistemática acorde con los estándares metodológicos de Cochrane. Los resultados de la revisión se publicaron según la declaración PRISMA. Se empleó la herramienta ROBINS-I para determinar el riesgo de sesgos.
Se incluyeron datos de 27 estudios diferentes provenientes de 30 publicaciones. En los estudios con seguimiento hasta 1 año, el apixabán (HR = 0,93; IC95%, 0,71-1,20) y dabigatrán (HR = 0,95; IC95%, 0,80-1,13) no se redujo significativamente el riesgo de ictus isquémico frente a la warfarina, pero sí el rivaroxabán (HR = 0,83; IC95%, 0,73-0,94). Con respecto al riesgo de hemorragias mayores, el apixabán (HR = 0,66; IC95%, 0,55-0,80) y el dabigatrán (HR = 0,83; IC95%, 0,70-0,97) lo redujeron significativamente frente a la warfarina, pero no el rivaroxabán (HR = 1,02, IC95%, 0,95-1,10), aunque con heterogeneidad entre los estudios. El apixabán (HR = 0,56; IC95%, 0,42-0,73), el dabigatrán (HR = 0,45; IC95%, 0,39-0,51) y el rivaroxabán (HR = 0,66; IC95%, 0,49-0,88) redujeron significativamente el riesgo de hemorragia intracraneal frente a la warfarina. El empleo de dosis bajas de anticoagulantes orales directos se asoció con una ligera mejoría del perfil de seguridad, pero con una marcada reducción de la efectividad en la prevención de ictus.
Los resultados de este metanálisis indican que, en comparación con la warfarina, la efectividad para prevenir el riesgo de ictus y de hemorragias de los anticoagulantes orales directos en los pacientes con fibrilación auricular de la práctica clínica real puede ser diferente.
To assess the effectiveness of direct oral anticoagulants vs vitamin K antagonists in real-life patients with atrial fibrillation.
A systematic review was performed according to Cochrane methodological standards. The results were reported according to the PRISMA statement. The ROBINS-I tool was used to assess risk of bias.
A total of 27 different studies publishing data in 30 publications were included. In the studies with a follow-up up to 1 year, apixaban (HR, 0.93; 95%CI, 0.71-1.20) and dabigatran (HR, 0.95; 95%CI, 0.80-1.13) did not significantly reduce the risk of ischemic stroke vs warfarin, whereas rivaroxaban significantly reduced this risk (HR, 0.83; 95%CI, 0.73-0.94). Apixaban (HR, 0.66; 95%CI, 0.55-0.80) and dabigatran (HR, 0.83; 95%CI, 0.70-0.97) significantly reduced the major bleeding risk vs warfarin, but not rivaroxaban (HR, 1.02; 95%CI, 0.95-1.10), although with a high statistical heterogeneity among studies. Apixaban (HR, 0.56; 95%CI, 0.42-0.73), dabigatran (HR, 0.45; 95%CI, 0.39-0.51), and rivaroxaban (HR, 0.66; 95%CI, 0.49-0.88) significantly reduced the risk of intracranial bleeding vs warfarin. Reduced doses of direct oral anticoagulants were associated with a slightly better safety profile, but with a marked reduction in stroke prevention effectiveness.
Data from this meta-analysis suggest that, vs warfarin, the stroke prevention effectiveness and bleeding risk of direct oral anticoagulants may differ in real-life patients with atrial fibrillation.
Full English text available from: www.revespcardiol.org/en
Indications for suboptimal low-dose direct oral anticoagulants for non-valvular atrial fibrillation patients
2017, Journal of Arrhythmia
Citation Excerpt :
Minor bleedings, such as subcutaneous hemorrhage, were also collected from the medical records because even slight bleeding can lead to a low adherence to medication. Only 6 out of 670 patients had major bleeding events, which is more or less similar to the proportion reported in other large clinical trials [10–12]. Interestingly, the neurological prognosis following intracranial bleeding was comparatively good; 2 patients had only slight symptoms, including higher brain dysfunction, 1 patient had a trivial ataxic gait, and 1 had a reduced level of consciousness (Japan coma scale, 100).
Direct oral anticoagulants (DOACs) have been developed for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). We conducted a retrospective cohort study of patients with NVAF who were newly treated with DOACs in a real-world clinical setting.
We retrospectively analyzed patients with NVAF newly treated with one of three DOACs—dabigatran, rivaroxaban, or apixaban—between January 1, 2013, and December 31, 2015.
A total of 670 patients with NVAF who were newly prescribed one of the three DOACs were analyzed; 74 patients (10.9%) received dabigatran, 290 (43.3%) received rivaroxaban, and 306 (45.8%) received apixaban. Fifteen patients had thromboembolic events, almost half of which were due to discontinuation of DOACs. Six patients had major bleeding, although almost all were discharged with good neurological prognoses. A total of 129 patients were treated with a suboptimal low-dose DOAC; none experienced a thromboembolic event as long as the DOAC was taken regularly, and none of the patients in any of the three DOAC groups had major bleeding events.
With good adherence, the clinical course associated with DOACs is comparatively good. In the future, suboptimal low-dose DOAC therapy may serve as an appropriate choice for some patients with a high risk of stroke and bleeding.
Effectiveness and Safety of Non–vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillation and Venous Thromboembolism: A Systematic Review and Meta-analyses
2017, Clinical Therapeutics
Citation Excerpt :
Furthermore, the effectiveness and safety of NOACs may be influenced by actual adherence patterns, patient baseline risks, and other real-world differences that may not be predicted by RCT results. Given these concerns about RCTs and inconsistent findings from observational studies of NOACs,26–52 rigorous meta-analyses of both RCTs and observational studies may offer a good basis for evidence-based decision-making in clinical care. In the present study, we performed a systematic review and separate meta-analyses to examine the efficacy/effectiveness and safety of NOACs compared with VKAs according to condition (AF vs VTE), study design (RCTs vs observational studies), and each NOAC (dabigatran, rivaroxaban, apixaban, and edoxaban).
The findings from the observational studies comparing the effectiveness and safety of non–vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) for atrial fibrillation (AF) and venous thromboembolism (VTE) are inconsistent. We conducted separate meta-analyses examining the efficacy/effectiveness and safety of NOACs versus VKAs by disease (AF vs VTE), study design (randomized controlled trials [RCTs] vs observational studies), and NOAC (dabigatran, rivaroxaban, apixaban, and edoxaban).
The main data sources included PubMed/MEDLINE, EMBASE, Web of Science, CINAHL, and Scopus from January 1, 2005, to February 15, 2016. We searched for Phase III RCTs and observational studies comparing NOACs versus VKAs. The primary outcomes were stroke/systemic embolism (SE) for AF; recurrent VTE/fatal pulmonary embolism (PE) for VTE; and major bleeding for both conditions. Secondary outcomes included stroke and myocardial infarction (MI) for AF, recurrent deep vein thrombosis (DVT)/PE for VTE, and mortality, intracranial hemorrhage (ICH), and gastrointestinal bleeding for both conditions. Pooled hazard ratios (HRs) were reported by using inverse variance–weighted random effects models.
A total of 13 RCTs and 27 observational studies (AF, n = 32; VTE, n = 8) were included. For AF, dabigatran and VKAs were comparable for stroke/SE risk in 1 RCT (HR, 0.77 [95% CI, 0.57–1.03]) and 6 observational studies (HR, 1.03 [95% CI, 0.83–1.27]). Rivaroxaban had a 20% decreased risk of stroke/SE in 3 RCTs (HR, 0.80 [95% CI, 0.67–0.95]) compared with VKA, but the effect was nonsignificant in 3 observational studies (HR, 0.78 [95% CI, 0.59–1.04]). Apixaban decreased stroke/systemic embolism risk (HR, 0.79 [95% CI, 0.66–0.95]) compared with VKA in 1 RCT, but edoxaban was comparable to VKA (HR, 0.99 [95% CI, 0.77–1.28]) in 1 RCT (no observational studies available for apixaban/edoxaban). Dabigatran, apixaban, and edoxaban decreased the risk of hemorrhagic stroke, mortality, major bleeding, and ICH by 10% to 71% compared with VKAs but not rivaroxaban. For VTE, NOACs and VKAs were comparable for recurrent VTE/fatal PE/DVT/PE risk in 7 RCTs and 1 observational study. The 7 RCTs demonstrated a 32% to 69% decreased risk of major bleeding for dabigatran, rivaroxaban, and apixaban compared with VKAs. No difference was shown in 1 rivaroxaban observational study (HR, 0.77 [95% CI, 0.40–1.49]) and 1 edoxaban RCT (HR, 0.84 [95% CI, 0.59–1.20]). Except for dabigatran, the NOACs had a 61% to 86% decreased risk of ICH and gastrointestinal bleeding.
Overall, NOACs were comparable or superior to VKAs. Although no observational studies are currently available for apixaban/edoxaban, a few notable inconsistencies exist for dabigatran (ischemic stroke, MI) and rivaroxaban (stroke/SE, major bleeding in VTE) between RCTs and observational studies. Individualizing NOAC/VKA therapy based on benefit/safety profiles and patient characteristics is suggested.
Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation at high risk of bleeding and normal kidney function
2017, Thrombosis Research
The comparative cost-effectiveness of all oral anticoagulants approved up to date has not been evaluated from the US perspective. The objective of this study was to compare the cost-effectiveness of edoxaban 60 mg, apixaban 5 mg, dabigatran 150 mg, dabigatran 110 mg, rivaroxaban 20 mg and warfarin in stroke prevention in atrial fibrillation patients at high-risk of bleeding (defined as HAS-BLED score ≥ 3).
We constructed a Markov state-transition model to evaluate lifetime costs and quality-adjusted life years (QALYs) with each of the six treatments from the perspective of US third-party payers. Probabilities of clinical events were obtained from the RE-LY, ROCKET-AF, ARISTOTLE and ENGAGE AF-TIMI trials; costs were derived from the Healthcare Cost and Utilization Project, and other studies. Because edoxaban is only indicated in patients with creatinine clearance ≤ 95 ml/min, we re-ran our analyses after excluding edoxaban from the analysis.
Treatment with edoxaban 60 mg cost $77,565/QALY gained compared to warfarin, and apixaban 5 mg cost $108,631/QALY gained compared to edoxaban 60 mg. When edoxaban was not included in the analysis, treatment with apixaban 5 mg cost $84,128/QALY gained, compared to warfarin. Dabigatran 150 mg, dabigatran 110 mg and rivaroxaban 20 mg were dominated strategies.
For patients with creatinine clearance between 50 and 95 ml/min, apixaban 5 mg was the most cost-effective treatment for willingness-to-pay thresholds (WTP) above $115,000/QALY gained, and edoxaban 60 mg was cost-effective when the WTP was between $75,000 and $115,000/QALY gained. For patients with creatinine clearance > 95 ml/min, apixaban 5 mg was the most cost-effective treatment for WTP thresholds above $80,000/QALY gained.
Effectiveness and Safety of Non-Vitamin K Oral Anticoagulants versus Warfarin in Patients with Atrial Fibrillation and Previous Stroke: A Systematic Review and Meta-Analysis
2024, Neuroepidemiology

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: Funding: None.

: Conflicts of Interest: GYHL has served as a consultant for Bayer, Astellas, Merck, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Portola, and Boehringer Ingelheim, and has served as a speaker for Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo and Sanofi Aventis. DAL has received investigator-initiated educational grants from Bayer Healthcare and Boehringer Ingelheim and served as a speaker for Boehringer Ingelheim, Bayer Healthcare, and BMS/Pfizer. In addition, DAL is on the Steering Committee of a Phase IV apixaban study (AEGEAN). Both GYHL and DAL have participated in various clinical trials of stroke prevention in atrial fibrillation. Associate Professor TBL has served as an investigator for Janssen Scientific Affairs, LLC and Boehringer Ingelheim. Associate Professor TBL and Professor AGR have been on the speaker bureaus for Bayer, BMS/Pfizer, Janssen Pharmaceuticals, Takeda, Roche Diagnostics and Boehringer Ingelheim. Other authors – none declared.

: Authorship: TBL provided the idea for the article and contributed to drafting and subsequent revisions. LHR, AGR, DAL, and GYHL contributed to manuscript drafts and revisions. FS and AGR did the analyses and contributed to manuscript revisions. TBL and GYHL are the guarantors.

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Clinical research studyDabigatran and Warfarin for Secondary Prevention of Stroke in Atrial Fibrillation Patients: A Nationwide Cohort Study

Abstract

Background

Methods

Results

Conclusions

Section snippets

Methods

Study Population Characteristics

Discussion

Conclusion

J Am Coll Cardiol

Lancet Neurol

Am J Med

Lancet Neurol

Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: a systematic review and meta-analysis

Stroke

A new landscape for stroke prevention in atrial fibrillation: focus on new anticoagulants, antiarrhythmic drugs, and devices

Stroke

Dabigatran versus warfarin in patients with atrial fibrillation

N Engl J Med

Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study

BMJ Open

Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis

BMJ

Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation

Am J Med

Dabigatran and warfarin in vitamin K antagonist-naive and -experienced cohorts with atrial fibrillation

Circulation

Clinical research study
Dabigatran and Warfarin for Secondary Prevention of Stroke in Atrial Fibrillation Patients: A Nationwide Cohort Study