What is the evidence for the efficacy and safety of dabigatran 110 mg twice daily, compared with warfarin, for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation?

Comment by InpharmD Researcher

There are limited data evaluating the safety and efficacy of dabigatran 110 mg twice daily in patients with atrial fibrillation (AF). The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial represents the largest available data set, in which dabigatran 110 mg was associated with rates of stroke and systemic embolism similar to warfarin, but with lower rates of major hemorrhage. Notably, findings from an age-stratified post hoc analysis of the RE-LY trial demonstrated that bleeding risk with dabigatran 150 mg twice daily was similar to, and potentially greater than, warfarin in patients ≥ 80 years of age, suggesting that the 110 mg twice daily dose may be preferred in elderly patients. In addition, a recent retrospective study found that, compared with the standard dose of dabigatran (150 mg twice daily), use of the reduced dose was not associated with an increased risk of stroke or systemic embolism but was associated with a lower risk of major bleeding. The European package insert for Pradaxa includes a dose adjustment for AF patients aged ≥80 years and for patients receiving concomitant verapamil. The European Society of Cardiology (ESC) AF guidelines likewise recommend dabigatran 110 mg twice daily for patients aged ≥80 years or those receiving concomitant verapamil, and advise consideration of this dose for patients aged 75–80 years, those with moderate renal impairment (CrCl 30–50 mL/min), patients with gastritis, esophagitis, or gastroesophageal reflux disease, and those at increased risk of bleeding. Overall, evidence supporting dabigatran 110 mg twice daily in AF remains limited, and its use may be considered on an individual basis in selected high-risk patient populations.

Background

According to the 2024 European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation, dabigatran 110 mg twice daily is recommended for patients aged ≥80 years and for those receiving concomitant verapamil. Dose reduction to 110 mg twice daily should also be considered on an individual basis for patients aged 75-80 years, those with moderate renal impairment (creatinine clearance [CrCl] 30-50 mL/min), patients with gastritis, esophagitis, or gastroesophageal reflux disease, and those at increased risk of bleeding. In patients with acute coronary syndromes or those undergoing percutaneous coronary intervention, dabigatran 110 mg twice daily should be considered in preference to dabigatran 150 mg twice daily when used in combination with antiplatelet therapy if concerns about bleeding risk outweigh concerns regarding stent thrombosis or ischemic stroke. [1]

A 2017 systematic review and meta-analysis conducted analyzed bleeding events associated with two different doses of dabigatran, specifically 110 mg and 150 mg, in patients treated for atrial fibrillation. This analysis included data from a large cohort of 29,264 patients, with 15,848 receiving the lower dose and 13,416 receiving the higher dose. The study aimed to address the comparative incidence of bleeding events, which had been insufficiently examined in prior research. By employing electronic searches across multiple medical databases, the authors identified relevant English-language publications that compared the two doses of dabigatran in the specified patient population. The results of this meta-analysis revealed that the 110 mg dose of dabigatran was associated with a significantly lower rate of minor bleeding compared to the 150 mg dose (OR: 1.19, 95% CI: 1.10-1.27; P<0.00001). However, both dosages yielded similar rates of major and fatal bleeding events, with no significant differences observed between the two groups (OR: 1.12, 95% CI: 0.69-1.82; P=0.65 for fatal bleeding and OR: 1.09, 95% CI: 0.86-1.37; P=0.49 for major bleeding). Additionally, while ischemic stroke outcomes showed a nonsignificant trend favoring the higher dose of dabigatran (OR: 0.77, 95% CI: 0.51-1.16; P=0.21), mortality rates significantly favored the 150 mg dose (OR: 0.41, 95% CI: 0.34-0.50; P<0.00001). These findings suggest that while the lower dose of dabigatran may reduce the risk of minor bleeding, the higher dose could be associated with improved mortality outcomes. The authors acknowledge the need for future trials to confirm these results. [2]

A 2011 analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial (Table 1) evaluated the risk of bleeding associated with dabigatran compared with warfarin in 18,113 patients with atrial fibrillation randomized to dabigatran 110 mg or 150 mg twice daily or warfarin (target INR 2.0-3.0), with a median follow-up of two years. Dabigatran 110 mg significantly reduced major bleeding compared with warfarin (2.87% vs. 3.57%; P=0.002), while dabigatran 150 mg had a similar overall bleeding risk (3.31% vs. 3.57%; P=0.32). Both doses were associated with lower rates of intracranial bleeding, although the 150 mg dose increased gastrointestinal bleeding (1.85% vs. 1.25%; P<0.001). Bleeding risk was lower with both doses in patients younger than 75 years, whereas patients aged 75 years or older receiving dabigatran 150 mg showed a trend toward higher extracranial bleeding. Separately, the RELY-ABLE trial was a long-term multicenter observational extension study of 5,851 patients who had previously participated in RE-LY and continued their originally assigned dabigatran dose for up to 28 additional months (median follow-up 2.3 years) across 35 countries. Annual rates of stroke or systemic embolism were 1.46% with dabigatran 150 mg and 1.60% with 110 mg, while major hemorrhage occurred more frequently with the higher dose (3.74% vs. 2.99%; hazard ratio 1.26; 95% CI, 1.04-1.53). Mortality rates were similar between groups, and hemorrhagic stroke remained rare with both doses. Overall, RELY-ABLE demonstrated that the efficacy and safety patterns observed in RE-LY persisted during extended follow-up, with higher major bleeding risk remaining the principal difference between dabigatran doses. [3], [4]

A 2017 age-stratified analysis of the RE-LY trial (Table 1) examined the effects of dabigatran versus warfarin on stroke, bleeding, and mortality in 18,113 patients with atrial fibrillation. Across age groups, both dabigatran 110 mg and 150 mg twice daily reduced stroke and intracranial bleeding compared with warfarin, while extracranial major bleeding risk varied by age. In patients younger than 75 years, dabigatran was associated with lower extracranial bleeding risk, whereas in patients aged 80 years or older, bleeding risk was similar to or greater than warfarin, particularly with the 150 mg dose, suggesting the lower dose may be preferable in elderly patients. Separately, a 2011 sub-analysis of the RE-LY trial evaluated outcomes in the Japanese cohort of 326 participants within the larger international study. Annual rates of stroke or systemic embolism among Japanese patients were 1.38% with dabigatran 110 mg, 0.67% with dabigatran 150 mg, and 2.65% with warfarin, findings consistent with the overall trial population. Bleeding risk with dabigatran 110 mg was slightly lower than warfarin (RR 0.79), while the 150 mg dose showed a similar bleeding risk (RR 1.06). Together, these analyses support dabigatran as an effective alternative to warfarin across diverse patient populations, while emphasizing the importance of dose selection based on age and patient-specific bleeding risk. [5], [6]

Relevant Prescribing Information

Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF) [7]

Dose recommendations for SPAF, DVT and PE
Dose reduction recommended: daily dose of 220 mg dabigatran etexilate taken as one 110 mg capsule twice daily
Patients aged ≥ 80 years
Patients who receive concomitant verapamil

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Dabigatran versus Warfarin in Patients with Atrial Fibrillation
Design	Noninferiority trial N= 18,113
Objective	To compare the efficacy and safety of dabigatran with warfarin in patients with atrial fibrillation at risk of stroke
Study Groups	Dabigatran 110 mg (n= 6015) Dabigatran 150 mg (n= 6076) Warfarin (n= 6022)
Inclusion Criteria	Patients with atrial fibrillation documented on ECG within 6 months and at least one of the following: previous stroke or TIA, LVEF <40%, NYHA class II or higher heart-failure symptoms within 6 months, age ≥75 years or age 65-74 with diabetes, hypertension, or CAD
Exclusion Criteria	Severe heart-valve disorder, stroke within 14 days or severe stroke within 6 months, condition increasing hemorrhage risk, creatinine clearance <30 ml/min, active liver disease, pregnancy
Methods	Randomized assignment to dabigatran 110 mg or 150 mg twice daily (blinded) or adjusted-dose warfarin (unblinded). Dabigatran administered in capsules, warfarin adjusted to INR 2.0-3.0. Follow-up visits at 14 days, 1 and 3 months, then every 3-4 months. Primary outcome: stroke or systemic embolism. Safety outcome: major hemorrhage
Duration	Median follow-up: 2.0 years
Outcome Measures	Primary: Stroke or systemic embolism Secondary: Major hemorrhage, death, myocardial infarction, pulmonary embolism, TIA, hospitalization
Baseline Characteristics		Dabigatran 110 mg (n= 6015)	Dabigatran 150 mg (n= 6076)	Warfarin (n= 6022)
	Age, years	71.4 ± 8.6	71.5 ± 8.8	71.6 ± 8.6
	Weight, kg	82.9 ± 19.9	82.5 ± 19.4	82.7 ± 19.7
	Systolic blood pressure, mm Hg	130.8 ± 17.5	131.0 ± 17.6	131.2 ± 17.4
	Diastolic blood pressure, mm Hg	77.0 ± 10.6	77.0 ± 10.6	77.1 ± 10.4
	Male	64.3%	63.2%	63.3%
	Type of atrial fibrillation Persistent Paroxysmal Permanent	32.4% 32.1% 35.4%	31.4% 32.6% 36.0%	32.0% 33.8% 34.1%
	CHADS₂ score	2.1 ± 1.1	2.2 ± 1.2	2.1 ± 1.1
	Previous stroke or transient ischemic attack	19.9%	20.3%	19.8%
Results		Dabigatran 110 mg (n= 6015)	Dabigatran 150 mg (n= 6076)	Warfarin (n= 6022)
	Stroke or systemic embolism, %/yr	1.53%	1.11%	1.69%
	Major bleeding, %/yr	2.71%	3.11%	3.36%
	Hemorrhagic stroke, %/yr	0.12%	0.10%	0.38%
	Death from any cause, %/yr	3.75%	3.64%	4.13%
Adverse Events	Dyspepsia was significantly more common with dabigatran (11.8% for 110 mg and 11.3% for 150 mg) compared to warfarin (5.8%). Higher rate of major gastrointestinal bleeding with 150 mg dabigatran compared to warfarin
Study Author Conclusions	Dabigatran at 110 mg is associated with similar rates of stroke and systemic embolism as warfarin but with lower rates of major hemorrhage. Dabigatran at 150 mg is associated with lower rates of stroke and systemic embolism compared to warfarin, with similar rates of major hemorrhage.
Critique	The study's strengths include a large sample size and rigorous design. However, the open-label administration of warfarin could introduce bias, and the higher rate of myocardial infarction with dabigatran requires further investigation. The study's findings may not be generalizable to all populations due to the specific inclusion criteria and the exclusion of patients with severe renal impairment or liver disease.

References:
[1] [1] Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. doi:10.1056/NEJMoa0905561

Effectiveness and Safety of Dabigatran 110 mg versus 150 mg for Stroke Prevention in Patients with Atrial Fibrillation at High Bleeding Risk
Design	Retrospective cohort study N= 7858
Objective	To evaluate the effectiveness and tolerability of a reduced dose (110 mg) of dabigatran versus the standard dose (150 mg) in subgroups of patients with atrial fibrillation (AF) at high bleeding risk.
Study Groups	Patients aged ≥ 80 years (n= 3472) Patients with moderate renal impairment (n= 1574) Patients with recent bleeding or HAS-BLED score ≥ 3 (n= 2812)
Inclusion Criteria	Adults with AF and a creatinine clearance rate ≥ 30 mL/min who were initiated on treatment with dabigatran between 2016 and 2018.
Exclusion Criteria	Patients who were pregnant, had a mechanical heart valve, mitral valve stenosis, severe liver disease, resided in a skilled nursing facility or hospice, had missing CrCl data or a CrCl of < 30 mL/min, and if the dose was switched during follow-up or if they were initiated on treatment with dabigatran between 2012 and 2015, given that dabigatran 110 mg was not available until 2016.
Methods	Kaiser Permanente Southern California health system initiated a pharmacist-led Safety Net program, whichis a computerized algorithm used for identifying patients with AF at high risk for bleeding, and recommend that primary care providers or cardiologists prescribe off-label reduced-dose dabigatran 110 mg bid instead of 150 mg bid. The interventions were conducted on three high–bleed-risk subgroups: (1) patients aged ≥80 years; (2) patients with moderate renal impairment (CrCl 30–<50 mL/min) regardless of age; and (3) patients with recent (preceding 12 months) bleeding or a HAS-BLED score ≥3. Patients were included in two or more subgroups if they qualified.
Duration	January 2012 to December 2018
Outcome Measures	Primary: Stroke or systemic embolism, major bleeding, all-cause mortality
Baseline Characteristics		Patients aged ≥80 y (n= 3472)*	Patients with moderate renal impairment (n= 1574)*	Patients with recent bleeding or HAS-BLED ≥3 (n= 2812)*
	Age, years	84.6 ± 3.8	84.2 ± 5.3	81.2 ± 6.6
	Female	52.1%	59.5%	44.6%
	Non-Hispanic White	62.3%	55.3%	55.7%
	Past medical history Hypertension Diabetes Heart failure	72.8% 28% 17.2%	74.4% 26.7% 20.9%	86% 38.3% 25.1%
	History of non-GI bleed	7.6%	7.6%	30.1%
	History of GI bleed	6.1%	6.1%	28%
	History of stroke/TIA	7.4%	7.7%	19.7%
	History of intracranial hemorrhage	0.4%	0.4%	2.2%
	Creatinine clearance rate 30 to < 60 mL/min	65.7%	100%	55.2%
	HAS-BLED score 0-1 2 3 4-6	44.7% 36.4% 15.1% 3.8%	42.5% 40.2% 13.6% 3.6%	0.9% 24.4% 58.5% 16.2%
	Abbreviations: TIA = transient ischemic attack * Only data for dabigatran 110 mg twice daily are presented
Results	Endpoint	Patients aged ≥80 y (n= 3472)*	Patients with moderate renal impairment (n= 1574)*	Patients with recent bleeding or HAS-BLED ≥3 (n= 2812)*
	Stroke or systemic embolism	1.08 (0.78–1.49)	0.82 (0.48–1.40)	0.94 (0.63–1.41)
	Major bleeding	0.65 (0.44–0.95)	0.54 (0.30–0.95)	0.84 (0.52–1.35)
	All-cause mortality	0.78 (0.65–0.92)	0.53 (0.40–0.71)	1.10 (0.89–1.36)
	* Data are presented as hazard ratio (95% confidence interval)
Adverse Events	Lower risk for major bleeding and all-cause mortality with reduced-dose dabigatran in patients aged ≥ 80 years and those with moderate renal impairment.
Study Author Conclusions	Reduced-dose dabigatran is associated with a lower risk for major bleeding and all-cause mortality in patients with AF aged ≥ 80 years or with moderate renal impairment, supporting its use in high bleeding risk patients.
Critique	The study's retrospective design and reliance on electronic health records may introduce bias and limit generalizability. The lack of validation for clinical outcomes and potential unmeasured confounding are limitations. However, the study's large sample size and focus on high-risk subgroups provide valuable insights into the safety and effectiveness of reduced-dose dabigatran.

References:
[1] [1] An J, Cheetham TC, Luong T, Lang DT, Lee MS, Reynolds K. Effectiveness and safety of dabigatran 110 mg versus 150 mg for stroke prevention in patients with atrial fibrillation at high bleeding risk. Clin Ther. 2023;45:e151-e158. doi:10.1016/j.clinthera.2023.05.007

Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation
Design	Multicenter, randomized trial N= 2725
Objective	To compare the safety and efficacy of dual antithrombotic therapy with dabigatran and a P2Y12 inhibitor versus triple therapy with warfarin, a P2Y12 inhibitor, and aspirin in patients with atrial fibrillation undergoing PCI
Study Groups	110-mg dual-therapy group (n= 981) 150-mg dual-therapy group (n= 763) Triple-therapy group (n= 981)
Inclusion Criteria	Patients aged ≥18 years with nonvalvular atrial fibrillation who had undergone PCI with a stent within the previous 120 hours
Exclusion Criteria	Presence of bioprosthetic or mechanical heart valves, severe renal insufficiency (creatinine clearance <30 ml/min), or other major coexisting conditions
Methods	Patients were randomly assigned to dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) or triple therapy with warfarin plus a P2Y12 inhibitor and aspirin. The primary endpoint was major or clinically relevant nonmajor bleeding. Follow-up was conducted every 3 months for a mean of 14 months.
Duration	Mean follow-up: 14 months
Outcome Measures	Primary: Major or clinically relevant nonmajor bleeding Secondary: Composite efficacy endpoint of thromboembolic events, death, or unplanned revascularization
Baseline Characteristics		Dual Therapy with Dabigatran, 110 mg (n= 981)	Triple Therapy with Warfarin (n= 981)		Dual Therapy with Dabigatran, 150 mg (n= 763)	Corresponding Triple Therapy with Warfarin† (n= 764)
	Age, years	71.5 ± 8.9	71.7 ± 8.9		68.6 ± 7.7	68.8 ± 7.7
	Elderly age group ‡	22.9%	22.9%		1.0%	1.0%
	Male	74.2%	76.5%		77.6%	77.7%
	Diabetes mellitus	36.9%	37.9%		34.1%	39.7%
	Previous stroke	7.5%	10.2%		6.8%	10.1%
	CHA₂DS₂-VASc score §	3.7 ± 1.6	3.8 ± 1.5		3.3 ± 1.5	3.6 ± 1.5
	HAS-BLED score ¶	2.7 ± 0.7	2.8 ± 0.8		2.6 ± 0.7	2.7 ± 0.8
	Creatinine clearance, mL/min ‖	76.3 ± 28.9	75.4 ± 29.1		83.7 ± 31.0	81.3 ± 29.6
	Previous myocardial infarction Previous PCI Previous CABG	24.2% 33.2% 9.9%	27.3% 35.4% 11.3%		25.4% 31.3% 10.4%	27.6% 35.6% 11.4%
	Type of atrial fibrillation Persistent Permanent Paroxysmal	17.7% 32.6% 49.6%	18.2% 32.4% 49.4%		17.3% 32.8% 49.8%	19.5% 31.2% 49.3%
	Indication for PCI Stable angina or positive stress test Acute coronary syndrome	44.1% 51.9%	43.7% 48.4%		41.9% 51.2%	44.4% 48.3%
	Type of stent Drug-eluting Bare-metal	82.1% 15.1%	84.6% 13.6%		81.5% 16.1%	84.1% 14.1%
	Abbreviations: CABG, coronary-artery bypass grafting; PCI, percutaneous coronary intervention. † The corresponding triple-therapy group included only patients who had been eligible to be assigned to the 150-mg dual-therapy group (i.e., did not include elderly patients outside the United States). ‡ Elderly was defined as 80 years of age or older (≥70 years of age in Japan). Stratification according to age group was performed with the use of an interactive voice-response system. § The CHA2DS2-VASc score reflects the risk of stroke, with values ranging from 0 to 9 and higher scores indicating greater risk. ¶ The HAS-BLED score reflects the risk of major bleeding among patients with atrial fibrillation who are receiving anticoagulant therapy, with values ranging from 0 to 9 and with higher scores indicating greater risk. ‖ Creatinine clearance was calculated with the use of the Cockcroft–Gault equation. Data are missing for 91 patients in the 110-mg dual-therapy group, 80 in the triple-therapy group, 61 in the 150-mg dual-therapy group, and 63 in the corresponding triple-therapy group.
Results		Dual Therapy with Dabigatran, 110 mg (n= 981)	Triple Therapy with Warfarin (n= 981)	p-value†	Dual Therapy with Dabigatran, 150 mg (n= 763)	Corresponding Triple Therapy with Warfarin (n= 764)	p-value†
	ISTH major or clinically relevant nonmajor bleeding	15.4%	26.9%	<0.001	20.2%	25.7%	0.002
	ISTH major bleeding	5.0%	9.2%	<0.001	5.6%	8.4%	0.02
	Total bleeding	27.1%	42.9%	<0.001	33.3%	41.4%	<0.001
	Intracranial hemorrhage	0.3%	1.0%	0.006	0.1%	1.0%	0.047
	TIMI major bleeding	1.4%	3.8%	0.002	2.1%	3.9%	0.03
	Thromboembolic events, death, or unplanned revascularization	13.7%	13.4%	<0.001	11.8%	12.8%	0.009
	Thromboembolic events or death	9.6%	8.5%	0.25	7.9%	7.9%	0.88
	Abbreviations: ISTH, International Society on Thrombosis and Hemostasis; TIMI, Thrombolysis in Myocardial Infarction † P values for noninferiority were calculated at a one-sided alpha level of 0.025 and are provided only if a noninferiority margin was prespecified. All other P values are for superiority and were calculated at a two-sided alpha level of 0.05; these P values are provided for descriptive purposes only.
Adverse Events	Serious adverse events occurred in 42.7% of the 110-mg dual-therapy group, 39.6% of the 150-mg dual-therapy group, and 41.8% of the triple-therapy group. Fatal serious adverse events occurred in 3.9% of the 110-mg dual-therapy group, 3.2% of the 150-mg dual-therapy group, and 4.3% of the triple-therapy group.
Study Author Conclusions	Dual therapy with dabigatran and a P2Y12 inhibitor resulted in a significantly lower risk of bleeding compared to triple therapy with warfarin, a P2Y12 inhibitor, and aspirin, while being noninferior in terms of thromboembolic events. This provides clinicians with additional treatment options based on patient risk profiles.
Critique	The study's strengths include its large sample size and rigorous design, providing robust evidence for the safety and efficacy of dual therapy with dabigatran. However, the trial's power was limited due to a smaller sample size than initially planned, and the open-label design may introduce bias. Additionally, the study did not fully explore the individual contributions of aspirin omission and the type of anticoagulant used, which could be addressed in future trials with a factorial design

References:
[1] [1] Cannon CP, Bhatt DL, Oldgren J, Lip GY, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017;377 (16):1513-1524. DOI: 10.1056/NEJMoa1708454