Comparison of dabigatran versus warfarin in diabetic patients with atrial fibrillation: Results from the RE-LY trial

doi:10.1016/j.ijcard.2015.05.141

International Journal of Cardiology

Volume 196, 1 October 2015, Pages 127-131

https://doi.org/10.1016/j.ijcard.2015.05.141 Get rights and content

Abstract

Objective

Diabetes mellitus (DM) is frequent among patients with atrial fibrillation (AF). The RE-LY trial permits evaluation of patient characteristics, outcomes and the effectiveness of dabigatran etexilate among diabetic individuals.

Methods

Patient characteristics and outcomes were compared between diabetic and non-diabetic patients and the relative efficacy of each dose of dabigatran (150 mg bid and 110 mg bid) versus warfarin was evaluated.

Results

Of 18,113 patients in RE-LY, 4221 patients (23.3%) had DM. Patients with DM were younger (70.9 vs. 71.7 years), more likely to have hypertension (86.6% vs. 76.5%), coronary artery disease (37.4% vs. 24.9%) and peripheral vascular disease (5.6% vs. 3.2%); (all p < 0.01). Time in therapeutic range for warfarin-treated patients was 65% for diabetic versus 68% for non-diabetic patients (p < 0.001). Regardless of assigned treatment, stroke or systemic embolism was more common among patients with DM (1.9% per year vs. 1.3% per year, p < 0.001). DM was also associated with an increased risk of death (5.1% per year vs. 3.5% per year, p < 0.001) and major bleeding (4.2% per year vs. 3.0% per year, p < 0.001). The absolute reduction in stroke or systemic embolism with dabigatran compared to warfarin was greater among patients with DM than those without DM (dabigatran 110 mg: 0.59% per year vs. 0.05% per year; dabigatran 150 mg: 0.89% per year vs. 0.51% per year).

Conclusions

Compared to non-DM patients, AF patients with DM derive a greater absolute risk reduction in embolic events when treated with dabigatran. ClinicalTrials.gov Identifier: NCT00262600.

Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia and a major risk factor for stroke [1]. Patients with AF have a five-fold increased risk of stroke compared to patients without AF [1]; however, patients' absolute risk is modulated by age and the presence of cardiovascular conditions. DM is one of the most frequent comorbidities among patients with AF [2], [3] and cohort studies demonstrate that the presence of DM is associated with an increased risk of developing AF [4], [5]. Multiple studies have identified DM as a strong independent predictor for stroke among AF patients [6] and as a result, DM is an important component of all major AF-stroke risk stratification schemes, such as CHA₂DS₂-VASC [7], [8]. Using these schemes, current guidelines recommend the use of oral anticoagulation therapy for all AF patients with DM [9], [10]. DM is not only an independent risk factor for stroke [11], but diabetics who suffer stroke have more severe residual disability [12] and an increased long-term mortality compared to non-diabetic patients [11]. The risk of death following stroke is two-fold higher in patients with DM within the first year and only 20% of these patients survive beyond 5 years [13].

Oral anticoagulation is highly effective at preventing stroke due to AF. Compared to no therapy, adjusted-dose warfarin reduces stroke by 64% [14] and novel oral anticoagulants (NOACs), including dabigatran, reduce stroke or systemic embolism risk by an additional 20% compared to warfarin [15], [16]. The aim of this subgroup analysis of RE-LY trial [17], [18] is to investigate the efficacy and safety of dabigatran among patients with DM and to describe the characteristics and outcomes of AF patients with DM.

Section snippets

Study participants

The detailed methods and results of the RE-LY have been published previously [17], [18], [19]. The main efficacy outcome was stroke or systemic embolism after a mean follow-up duration of 2 years. Patients were eligible if they had documented non-valvular AF and at least one of the following risk factor for stroke: previous ischemic stroke or transient ischemic attack (TIA); a left ventricular dysfunction; New York Heart Association class II or higher within 6 months before screening; or age ≥ 75

Results

Among 18,113 patients enrolled in the RELY trial, 4221 patients (23.3%) had DM. Patients with DM were younger with a greater body mass index (BMI), and more likely to have hypertension, coronary artery disease and peripheral vascular disease (p < 0.01) (Table 1). The mean CHADS₂ and CHA₂DS₂VASc scores were 3.0 and 4.4 for diabetic patients and 1.9 and 3.3 for non-diabetic patients, respectively (p < 0.01) (Table 1). Among patients receiving warfarin, the median time in INR range 2.0–3.0 was 65% for

Discussion

This analysis from RE-LY [17], [18] demonstrates that among patients with AF, DM is common and is associated with an increased risk of thromboembolic events and death, independent of the choice of oral anticoagulation in all patients. Although similar relative benefits are seen with dabigatran compared to warfarin among diabetic patients, patients with diabetes had a greater absolute risk reduction of thromboembolic events. Thus, this data suggests that dabigatran is effective even in a

Conclusions

Although warfarin is considered the standard therapy for the prevention of stroke AF related stroke, its management appears to be more difficult among patients with DM. The present sub-analysis of the RE-LY suggests that among diabetic patients, the use of dabigatran provides similar relative benefits compared to the non-diabetic population; however, the absolute benefits among diabetic patients are greater.

Potential conflicts of interest

Dr Darius has received consulting fees, lecture fees, and grant support from Boehringer Ingelheim, consulting fees from Sanofi-Aventis and Bayer Schering Pharma, and lecture fees from the Medicines Company and Eli Lill. Dr Oldgren has received institutional grant support from Boehringer Ingelheim and consulting fees and lecture fees from Bayer, Boehringer Ingelheim, and BMS. Dr Wallentin has received consulting fees, lecture fees, and grant support from Boehringer Ingelheim; consulting fees

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Cited by (75)

ORal anticoaGulants in diAbetic and Nondiabetic patients with nOn-valvular atrial fibrillatioN (ORGANON)
2023, Journal of Diabetes and its Complications
Diabetes represents a pro-thrombotic condition.
The primary objective was to evaluate the effects of Vitamin K Antagonist (VKA) compared to direct oral anticoagulants (DOACs) in diabetic and nondiabetic patients with non-valvular atrial fibrillation, newly diagnosed. The secondary objective was to evaluate the effects on the risk of bleeding.
We enrolled 300 patients with newly diagnosed atrial fibrillation. One hundred and sixteen patients were taking warfarin, 31 acenocumarol, 22 dabigatran, 80 rivaroxaban, 34 apixaban, and 17 edoxaban. We evaluated: anthropometric parameters, glycated hemoglobin (HbA_1c), fasting and post-prandial glucose (FPG, and PPG), lipid profile, Lp(a), small and dense low-density lipoprotein (SD-LDL), oxidized LDL (Ox-LDL), I-troponin (I-Tn), creatinine, transaminases, iron, red blood cells (RBC); hemoglobin (Hb), platelets (PLT), fibrinogen, D-dimer, anti-thrombin III, C-reactive protein (Hs-CRP), Metalloproteinases-2 (MMP-2), Metalloproteinases-9 (MMP-9), and incidence of bleeding.
We did not record any differences among nondiabetic patients between VKA and DOACs. However, when we considered diabetic patients, we found a slight, but significant improvement of triglycerides and SD-LDL. As regards incidence of bleeding, minor bleeding was more frequent in VKA diabetic group compared to DOACs diabetic group; furthermore, the incidence of major bleeding was higher with VKA in nondiabetic and diabetic group, compared to patients with DOACs. Among DOACs, we recorded a higher incidence of bleeding (minor and major) with dabigatran compared to rivaroxaban, apixaban and edoxaban in nondiabetic and diabetic patients.
DOACs seem to be metabolically favourable in diabetic patients. Regarding incidence of bleeding, DOACs with the exception of dabigatran, seem better than VKA in diabetic patients.
Clinical evolution of patients with AF and diabetes mellitus in the COVID-19 pandemic. REFADI Registry
2023, REC: CardioClinics
Analizar la evolución de los pacientes que padecen fibrilación auricular (FA) y diabetes a medio plazo en una situación de pandemia de la COVID-19 y describir su influencia en esta población.
Registro multicéntrico y prospectivo que incluyó a pacientes con FA y diabetes atendidos en consultas de cardiología. Se realizó un análisis multivariante para determinar las variables asociadas a la aparición de eventos clínicos y mortalidad. La inclusión se realizó en febrero-diciembre de 2019.
Se analizó la evolución de 633 pacientes, 96,2% de los incluidos en el registro REFADI durante un seguimiento medio de 835 días (edad media 73,8 ± 8,5 años, 54,3% varones, CHA₂DS₂-VASc 4,34 ± 1,4, HAS-BLED 2,47 ± 0,96). La proporción de pacientes anticoagulados se mantuvo constante (95,6 frente a 94,5%; p = 0,24). Hubo un descenso de antagonistas de la vitamina K (del 31,4 al 19,7%; p < 0,01), y un aumento de los anticoagulantes directos (del 62,0 al 70,3%; p < 0,01). Durante el seguimiento hubo un aumento en la prescripción de inhibidores SGLT2 (del 20,0 al 25,5%; p < 0,01) y agonistas GLP1 (del 4,2 al 9,1%; p < 0,01). Falleció el 17,2% de los pacientes, la mayoría de causa cardiovascular, 6,4% por COVID-19, 2,8% por ictus y 1,8% por hemorragia. La mayor edad, la menor fracción de eyección, los niveles más bajos de hemoglobina y especialmente la menor prescripción de anticoagulantes directos se asociaron con la mortalidad.
Los pacientes con FA y diabetes tienen un elevado riesgo tromboembólico y de sufrir complicaciones, sobre todo de origen cardiovascular.
To analyze the evolution of patients with atrial fibrillation (AF) and diabetes in the mid-term follow-up during the COVID-19 pandemic and to describe its impact on this population.
Multicenter and prospective registry that included patients with AF and diabetes attended in cardiology clinics. A multivariate analysis was performed to determine the variables associated with the occurrence of clinical events and mortality. Recruitment was performed in February-December 2019.
The evolution of 633 patients, 96,2% of those included in the REFADI registry with a median follow-up of 835 days was analyzed (mean age 73.8 ± 8.5 years, 54.3% male, CHA₂DS₂-VASc 4,34 ± 1,4, HAS-BLED 2,47 ± 0,96) were analyzed. The proportion of anticoagulated patients remained constant (95.6% vs 94.5%; P = .24). There was a decrease in the prescription of vitamin K antagonists (from 31.4% to 19.7%; P < .01), and an increase in the use of direct anticoagulants (from 62.0% to 70.3%; P < .01). During the follow-up there was an increase in the prescription of SGLT2 inhibitors (from 20.0% to 25.5%; P < .01) and GLP1 agonists (from 4.2% to 9.1%; P < .01). During this period, 17.2% of patients died, the majority from cardiovascular causes, 6.4% from COVID-19, 2.8% from stroke, and 1.8% from hemorrhage. Older age, lower ejection fraction, lower hemoglobin levels, and especially lower direct anticoagulants prescription were associated with mortality.
Patients with AF and diabetes have a high thromboembolic risk and a high risk of developing complications, especially of cardiovascular origin.
Gender difference in association between diabetes mellitus and all-cause mortality in atrial fibrillation patients
2022, Journal of Diabetes and its Complications
There may be gender difference in correlation of diabetes mellitus (DM) and cardiovascular events. We attempt to investigate whether there is gender-heterogeneity in one-year outcomes of atrial fibrillation (AF) patients with DM or not.
Patients who were diagnosed with AF admitted to the emergency departments in the Chinese AF Multicenter Registry study were enrolled. Basic demographics information, initial Blood Pressure and heart rate, medical histories, and treatments of each patient were collected. Follow-up was carried out with a mean duration of one year. The primary endpoint was all-cause mortality and systemic embolism.
A total of 2016 patients were selected from September 2008 and April 2011. All-cause mortality was significantly higher in male AF patients with DM than those without (21.8 % & 13.6 %, P = 0.014). Cox regression analysis showed that there was an interaction between gender and DM for one-year all-cause mortality (P = 0.049). DM was significantly associated with one-year all-cause mortality regardless of univariate analysis (HR = 1.436, 95%CI:1.079–1.911, P = 0.013) or multivariate analysis (HR = 1.418, 95%CI: 1.059–1.899, P = 0.019). For male patients with AF, DM was significantly associated with one-year all-cause mortality (P = 0.048), but not for female patients with AF (P = 0.362).
DM was independently associated with one-year all-cause mortality in the entire cohort of AF patients. This association was found mainly in male patients with AF, but not in female patients. DM management programs may need to reflect gender difference.
The safety and efficacy of the use of oral anticoagulant medications in patients with diabetes mellitus: A systematic review
2021, Saudi Pharmaceutical Journal
Citation Excerpt :
DOACs are characterised by better and safer pharmacokinetic and pharmacodynamic profiles. In previous randomised controlled trials, patients who were using DOACs had a 14% reduction in the incidence of bleeding compared to patients who were on warfarin therapy (Giugliano et al., 2013, Ruff et al., 2014, Brambatti et al., 2015, Ezekowitz et al., 2015). Atrial fibrillation is an independent risk factor for diabetes (Dublin et al., 2010).
Diabetes mellitus (DM) and atrial fibrillation (AF) commonly co-exist. Oral anticoagulants (OACs) are widely used in patients with DM. This review aims to summarise the available literature on the safety (hypoglycaemia or bleeding) and efficacy (stroke or systemic embolism) of the use of OACs in patients with DM.
We searched the Medline, the Excerpta Medica dataBASE (Embase) and Cochrane databases up to the 10th of December 2020. The search strategy was conducted using both keywords and MeSH terms. We included randomised controlled trials (RCTs) and observational studies that reported on the safety and efficacy of the use of OACs in patients with diabetes from all age groups. Study selection, data extraction and quality assessment were conducted independently by two reviewers.
A total of 3,976 articles were identified through the search process, of which seven studies met the inclusion criteria of the systematic review: four observational studies and three studies that were randomised controlled trials, with a total of 703,855 patients. Two observational studies reported that the use of warfarin was associated with a higher risk of hypoglycaemic events, specifically with sulfonylurea. One observational study and three randomised controlled trials reported that the use of warfarin compared to other oral anticoagulants was associated with a higher risk of bleeding. In addition, three randomised controlled trials reported that the use of warfarin compared to other oral anticoagulants was associated with a lower risk of stroke or systemic embolism.
This systematic review found that DOACs had a better efficacy outcome and safer clinical outcomes in comparison to warfarin in patients with diabetes.
Net clinical benefit of direct oral anticoagulants in atrial fibrillation patients with or without diabetes mellitus: A meta-analysis of outcome trials
2021, Diabetes Research and Clinical Practice
To evaluate the net clinical benefit following direct oral anticoagulants (DOACs) vs warfarin by diabetes status in patients with non-valvular atrial fibrillation.
We searched 3 electronic databases through end-February 2021 to identify relevant outcome trials in patients with and without diabetes mellitus (DM). All-cause death, non-fatal stroke/systemic embolism and major bleedings defined net clinical benefit. Outcome risk ratios and 95% confidence interval (CI), and absolute risk outcome reduction per 1000 treated patients were assessed.
Four trials of DOACs vs warfarin compared 22,087 patients with DM to 49,592 patients without DM. CHADS2 and 10-year fatal cardiovascular risk were higher in patients with vs those without DM (3.7 vs 2.5 and 28.4% vs 23.4%, respectively). DOACs were associated with more favorable net clinical benefit compared to warfarin in patients with and without DM (relative risk reduction, 0.85 [95% CI, 0.81–0.89] and 0.87 [95% CI, 0.79–0.96]; absolute risk reduction per 1000 patients treated, −33 [95% CI, −45, −21]) and −24 [95% CI, −43, −5]), but interaction test was not significant by relative and absolute numbers (P = 0.68 and P = 0.44, respectively).
Net clinical benefit following DOACs was not different between patients with and without DM over a period of 2.2 years.
Anticoagulation status and adherence in patients with atrial fibrillation hospitalized for ACS and the impact on 1‑year prognosis: a multicenter cohort study
2023, Chinese Journal of Cardiology

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^☆: All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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Comparison of dabigatran versus warfarin in diabetic patients with atrial fibrillation: Results from the RE-LY trial☆

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Study participants

Results

Discussion

Conclusions

Potential conflicts of interest

Am. J. Cardiol.

Am. J. Cardiol.

Chest

Can. J. Cardiol.

J. Am. Coll. Cardiol.

Lancet

J. Diabetes Complicat.

Am. J. Med.

Chest

J. Am. Coll. Cardiol.

Blood

Can. J. Cardiol.

Am. J. Kidney Dis.

Atrial fibrillation as an independent risk factor for stroke: the Framingham Study

Stroke

Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on atrial fibrillation

Eur. Heart J.

Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: the Atherosclerosis Risk in Communities (ARIC) Study

Circulation

Independent predictors of stroke in patients with atrial fibrillation: a systematic review

Neurology

Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation

Stroke

Diabetes mellitus as a risk factor for death from stroke. Prospective study of the middle-aged Finnish population

Stroke