- Split View
-
Views
-
Cite
Cite
Ki Hong Lee, Hyung Wook Park, Nuri Lee, Dae Young Hyun, Jumin Won, Sung Sik Oh, Hyuk Jin Park, Yongcheol Kim, Jae Yeong Cho, Min Chul Kim, Doo Sun Sim, Hyun Joo Yoon, Nam Sik Yoon, Kye Hun Kim, Young Joon Hong, Ju Han Kim, Youngkeun Ahn, Myung Ho Jeong, Jong Chun Park, Jeong Gwan Cho, Optimal dose of dabigatran for the prevention of thromboembolism with minimal bleeding risk in Korean patients with atrial fibrillation, EP Europace, Volume 19, Issue suppl_4, December 2017, Pages iv1–iv9, https://doi.org/10.1093/europace/eux247
- Share Icon Share
Abstract
We aim to determine the optimal dose of dabigatran in Korean patients with atrial fibrillation (AF).
We analysed 1834 patients with non-valvular AF, classified into a warfarin group (n = 990), dabigatran 150 mg group (D150, n = 294), and 110 mg group (D110, n = 550). The D110 group was further classified into patients concordant (co-D110, n = 367) and patients discordant (di-D110, n = 183) with guidelines to dose reduction. Propensity-matched 1-year clinical outcomes were then compared. Efficacy outcomes were defined as thromboembolism composed of new-onset stroke or systemic embolism. Safety outcomes were major bleeding. Both D150 and D110 had comparable efficacies as warfarin. However, only D110 significantly lowered the risk of major bleeding [hazard ratio (HR) 0.19, 95% confidence interval (CI) 0.07–0.55, P = 0.002]. In a subgroup analysis according to guideline-concordant indications for dose reduction, both co-D110 and di-D110 displayed a comparable efficacy as warfarin. Both co-D110 (HR 0.22, 95% CI 0.06–0.76, P = 0.017) and di-D110 (HR 0.11, 95% CI 0.02–0.81, P = 0.030) significantly lowered incidences of major bleeding. There were no differences in the efficacy and safety between di-D110 and D150, and net clinical outcomes were similar.
Although D150 and D110 had a comparable efficacy, only D110 lowered the risk of major bleeding in Korean AF patients compared with warfarin. Even the guideline-discordant use of dabigatran 110 mg demonstrated a similar efficacy and safety compared with D150. However, further prospective randomized trials are needed in order to comprehensively evaluate whether D150 or D110 is the optimal dosage in Asian patients with AF.
Dabigatran 150 and 110 mg displayed comparable efficacies for reducing the risk of thromboembolism compared with warfarin in real world Korean AF patients.
Major bleeding events were significantly lower in patients treated with dabigatran 110 mg than patients with warfarin in Korean AF patients.
Guideline-discordant use of dabigatran 110 mg displayed comparable efficacy and safety as dabigatran 150 mg in Korean AF patients.
Introduction
Non-vitamin K antagonist oral anticoagulants (NOACs) including dabigatran have emerged as potential alternatives to warfarin for the prevention of thromboembolisms (TEs), with reduced bleeding risk in patients with atrial fibrillation (AF). However, even though NOACs have reduced the adverse events compared with warfarin in many randomized controlled trials and registry data, bleeding complications remain in real-world applications.
The optimal dose of dabigatran has been recommended according to current guidelines, based on the results of global trials.1–3 However, there have only been a few studies investigating the optimal dabigatran dosage for Asian patients, because of the limited number of Asians enrolled in current studies.
A comparison between Asians and non-Asians using dabigatran revealed the superiority for risk reduction of TE and major bleeding in Asian patients than for non-Asians.4,5 Real-world evidence for dabigatran in Asia revealed that 88% patients took dabigatran 110 mg, whereas only 12% patients took dabigatran 150 mg.6 These results suggest that optimal dose of dabigatran may be different between the two groups, and that a lower dose is sufficient and safe for the Asian population.
We aim here to compare the efficacy and safety between dabigatran and warfarin and to verify the optimal dose of dabigatran for Korean patients with AF. Furthermore, to confirm whether dabigatran 110 mg is the optimal dose for Korean patients with AF, we compared the efficacy and safety between patients being treated with guideline-concordant dabigatran 110 mg and dabigatran 150 mg.
Methods
Study population
A total of 3613 patients with AF that were taking warfarin or dabigatran from January 2012 to December 2013 were initially included in a cross-sectional analysis at the Department of Neurology and Cardiology, Chonnam National University Hospital, Gwangju, South Korea. A total of 1834 patients (70.6 ± 10.6 years old; 1177 males) comprised the study population that met both the inclusion and exclusion criteria. The criteria for inclusion included taking OACs such as warfarin or dabigatran, and having a CHA2DS2-VASc score ≥ 2. The criteria for exclusion included valvular AF (rheumatic mitral stenosis, prosthetic mitral valve replacement or repair), any OAC class change (from warfarin to NOACs, from NOACs to warfarin), and a dabigatran dose change during 1 year of follow-up. Follow-up for all selected patients was 1 year, or until the first occurrence of any study outcome from the date of enrolment.
Warfarin was used in 990 patients (54.0%), and dabigatran in 844 patients (46.0%). Patients treated with dabigatran were divided into the dabigatran 150 mg group (D150, n = 294, 16.0%) and the dabigatran 110 mg group (D110, n = 550, 30.0%). The D110 group was further subdivided into guideline-concordant (co-D110, n = 367) and guideline-discordant (di-D110, n = 183) groups with dose reduction.1,2 Guideline-concordant dabigatran dose reduction (co-D110) was defined as when dabigatran 110 mg was used according to guidelines based on at least one criteria: old age (≥ 75 years old), renal dysfunction [glomerular filtration rate (GFR) < 50 mL/min], or low body weight (<50 kg). Guideline-discordant dabigatran dose reduction (di-D110) was defined as dabigatran 110 mg use with none of the above criteria.
Definition
The primary endpoints were efficacy and safety outcomes. Primary efficacy outcomes included TE composed of new-onset stroke, or systemic embolism. The primary safety outcome was major bleeding. Secondary endpoints were death, hospitalization, myocardial infarction (MI), and any major or minor bleeding. Primary net clinical outcomes were defined as the composite of new-onset stroke, systemic embolism, major bleeding, and all-cause death. Secondary net clinical outcomes were defined as the composite of new-onset stroke, systemic embolism, and major bleeding.
New-onset stroke was defined as the sudden onset of a focal neurologic deficit in a location consistent with the territory of a major cerebral artery and categorized as an ischaemic, haemorrhagic, or transient ischaemic attack (TIA). Transient ischaemic attack was defined as the sudden onset of a focal neurologic deficit without evidence of a newly developed cerebral lesion. A systemic embolism was defined as an acute vascular occlusion of an extremity or organ, documented via imaging or surgery. Major bleeding was defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria, as clinically overt bleeding accompanied by a 2 g/dL decrease in the haemoglobin level or transfusion of at least two units of packed red cells, occurring at a critical site, or resulting in death. Minor bleeding was defined as clinically overt bleeding that did not meet major bleeding criteria.
Statistical analysis
For continuous variables, differences between groups were evaluated using an unpaired t-test or Mann–Whitney rank-sum test. For discrete variables, differences were expressed as counts and percentages, and were analysed using a χ2 test or Fisher’s exact test between groups, as appropriate.
To minimize the effect of selection bias in comparisons between warfarin and dabigatran, equal numbers of patients having similar baseline characteristics among D150, co-D110, and di-D110 (1:1:1) were paired using propensity scores; equal numbers of patients having similar baseline characteristics between warfarin and dabigatran (1:1) were then paired. The propensity scores were estimated based on the likelihood of selection of OACs, using a multiple logistic regression model that was comprised of the patient’s age, sex, hypertension, diabetes mellitus, previous history of MI, previous history of heart failure, and previous history of stroke or TIA. Matching was performed using a greedy matching protocol (1:1 nearest neighbour matching without replacement).
We subsequently constructed Kaplan–Meier curves for clinical outcomes, and differences among the groups were assessed using a log-rank test. A Cox proportional hazards regression was used to analyse the hazard ratios (HRs) as estimates for clinical outcomes. The HRs were adjusted for propensity scores and important risk co-variables that displayed a significant effect (P < 0.1), using a univariate analysis. All statistical analyses were performed using SPSS 21.0 (SPSS-PC Inc., Chicago, IL, USA) and R version 2.14.2 (R foundation for Statistical Computing, Vienna, Austria). All analyses were two-tailed, with clinical significance defined as values of P < 0.05.
Results
Baseline clinical characteristics
Before propensity score matching, the dabigatran treatment group was older, and had a higher prevalence of hypertension and previous history of stroke/TIA. The CHA2DS2-VASc score was higher in patients treated with dabigatran (3.8 ± 1.6 vs. 3.1 ± 1.8, P < 0.001). However, there was no difference in gender, prevalence of diabetes mellitus, smoking, previous history of MI, and previous history of heart failure. After propensity score matching, there was no difference in gender, age, hypertension, diabetes mellitus, smoking, previous history of MI, previous history of heart failure, previous history of TIA/stroke, and CHA2DS2-VASc score (Table 1).
. | Before PS matching . | After PS matching . | ||||
---|---|---|---|---|---|---|
. | Patients with warfarin (n = 990) . | Patients with Dabigatran (n = 844) . | P-value . | Patients with warfarin (n = 549) . | Patients with dabigatran (n = 549) . | P-value . |
Female gender, n (%)a | 338 (34.1) | 319 (37.8) | 0.104 | 207 (37.7) | 213 (38.8) | 0.709 |
Age, yearsb | 71.0 (63.0–77.0) | 74.0 (67.0–79.0) | <0.001 | 72.0 (64.0–78.0) | 72.0 (65.0–77.0) | 0.936 |
≥65 years old | 710 (71.7) | 693 (82.1) | <0.001 | 410 (74.7) | 426 (77.6) | 0.257 |
≥75 years old | 356 (36.0) | 384 (45.5) | <0.001 | 212 (38.6) | 189 (34.4) | 0.149 |
Medical history, n (%)a | ||||||
Hypertension | 517 (52.2) | 550 (65.2) | <0.001 | 334 (60.8) | 332 (60.5) | 0.902 |
Diabetes mellitus | 213 (21.5) | 196 (22.2) | 0.381 | 138 (25.1) | 134 (24.4) | 0.780 |
Smoking | 265 (26.8) | 207 (24.5) | 0.274 | 157 (29.7) | 139 (26.3) | 0.217 |
Previous history of MI | 57 (5.8) | 49 (5.8) | 0.965 | 24 (4.4) | 24 (4.4) | 1.000 |
Previous history of HF | 77 (7.8) | 77 (9.1) | 0.396 | 41 (7.5) | 44 (8.0) | 0.731 |
Previous history of TIA, stroke | 378 (38.2) | 420 (49.8) | <0.001 | 249 (45.4) | 247 (45.0) | 0.903 |
CHA2DS2-VASc score | 3.1 ± 1.8 | 3.8 ± 1.6 | <0.001 | 3.3 ± 1.7 | 3.3 ± 1.6 | 0.821 |
Laboratory findings | ||||||
Hs-CRP, mg/dLb | 0.2 (0.1–0.5) | 0.3 (0.1–0.7) | <0.001 | 0.2 (0.1–0.6) | 0.3 (0.1–0.7) | <0.001 |
NT-proBNP, pg/mLb | 783.0 (283.9–1913.3) | 1112.0 (472.3–2677.0) | <0.001 | 895.7 (285.5–2334.0) | 1061.0 (456.8–2484.0) | 0.220 |
Creatinine, mg/dLb | 0.9 (0.7–1.0) | 0.9 (0.7–1.0) | 0.203 | 0.9 (0.7–1.0) | 0.9 (0.7–1.0) | 0.638 |
CCl, mL/minb | 83.8 (67.3–93.9) | 66.1 (52.8–83.0) | <0.001 | 83.1 (64.2–93.1) | 69.5 (56.6–85.4) | <0.001 |
. | Before PS matching . | After PS matching . | ||||
---|---|---|---|---|---|---|
. | Patients with warfarin (n = 990) . | Patients with Dabigatran (n = 844) . | P-value . | Patients with warfarin (n = 549) . | Patients with dabigatran (n = 549) . | P-value . |
Female gender, n (%)a | 338 (34.1) | 319 (37.8) | 0.104 | 207 (37.7) | 213 (38.8) | 0.709 |
Age, yearsb | 71.0 (63.0–77.0) | 74.0 (67.0–79.0) | <0.001 | 72.0 (64.0–78.0) | 72.0 (65.0–77.0) | 0.936 |
≥65 years old | 710 (71.7) | 693 (82.1) | <0.001 | 410 (74.7) | 426 (77.6) | 0.257 |
≥75 years old | 356 (36.0) | 384 (45.5) | <0.001 | 212 (38.6) | 189 (34.4) | 0.149 |
Medical history, n (%)a | ||||||
Hypertension | 517 (52.2) | 550 (65.2) | <0.001 | 334 (60.8) | 332 (60.5) | 0.902 |
Diabetes mellitus | 213 (21.5) | 196 (22.2) | 0.381 | 138 (25.1) | 134 (24.4) | 0.780 |
Smoking | 265 (26.8) | 207 (24.5) | 0.274 | 157 (29.7) | 139 (26.3) | 0.217 |
Previous history of MI | 57 (5.8) | 49 (5.8) | 0.965 | 24 (4.4) | 24 (4.4) | 1.000 |
Previous history of HF | 77 (7.8) | 77 (9.1) | 0.396 | 41 (7.5) | 44 (8.0) | 0.731 |
Previous history of TIA, stroke | 378 (38.2) | 420 (49.8) | <0.001 | 249 (45.4) | 247 (45.0) | 0.903 |
CHA2DS2-VASc score | 3.1 ± 1.8 | 3.8 ± 1.6 | <0.001 | 3.3 ± 1.7 | 3.3 ± 1.6 | 0.821 |
Laboratory findings | ||||||
Hs-CRP, mg/dLb | 0.2 (0.1–0.5) | 0.3 (0.1–0.7) | <0.001 | 0.2 (0.1–0.6) | 0.3 (0.1–0.7) | <0.001 |
NT-proBNP, pg/mLb | 783.0 (283.9–1913.3) | 1112.0 (472.3–2677.0) | <0.001 | 895.7 (285.5–2334.0) | 1061.0 (456.8–2484.0) | 0.220 |
Creatinine, mg/dLb | 0.9 (0.7–1.0) | 0.9 (0.7–1.0) | 0.203 | 0.9 (0.7–1.0) | 0.9 (0.7–1.0) | 0.638 |
CCl, mL/minb | 83.8 (67.3–93.9) | 66.1 (52.8–83.0) | <0.001 | 83.1 (64.2–93.1) | 69.5 (56.6–85.4) | <0.001 |
CCl, creatinine clearance; EF, left ventricular ejection fraction; HF, heart failure; Hs-CRP, high sensitivity C-reactive protein; MI, myocardial infarction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PS, propensity scores; TIA, transient ischaemic attack.
Comparison made using χ2 test.
Median (25–75% percentiles); comparison made using Mann–Whitney test.
. | Before PS matching . | After PS matching . | ||||
---|---|---|---|---|---|---|
. | Patients with warfarin (n = 990) . | Patients with Dabigatran (n = 844) . | P-value . | Patients with warfarin (n = 549) . | Patients with dabigatran (n = 549) . | P-value . |
Female gender, n (%)a | 338 (34.1) | 319 (37.8) | 0.104 | 207 (37.7) | 213 (38.8) | 0.709 |
Age, yearsb | 71.0 (63.0–77.0) | 74.0 (67.0–79.0) | <0.001 | 72.0 (64.0–78.0) | 72.0 (65.0–77.0) | 0.936 |
≥65 years old | 710 (71.7) | 693 (82.1) | <0.001 | 410 (74.7) | 426 (77.6) | 0.257 |
≥75 years old | 356 (36.0) | 384 (45.5) | <0.001 | 212 (38.6) | 189 (34.4) | 0.149 |
Medical history, n (%)a | ||||||
Hypertension | 517 (52.2) | 550 (65.2) | <0.001 | 334 (60.8) | 332 (60.5) | 0.902 |
Diabetes mellitus | 213 (21.5) | 196 (22.2) | 0.381 | 138 (25.1) | 134 (24.4) | 0.780 |
Smoking | 265 (26.8) | 207 (24.5) | 0.274 | 157 (29.7) | 139 (26.3) | 0.217 |
Previous history of MI | 57 (5.8) | 49 (5.8) | 0.965 | 24 (4.4) | 24 (4.4) | 1.000 |
Previous history of HF | 77 (7.8) | 77 (9.1) | 0.396 | 41 (7.5) | 44 (8.0) | 0.731 |
Previous history of TIA, stroke | 378 (38.2) | 420 (49.8) | <0.001 | 249 (45.4) | 247 (45.0) | 0.903 |
CHA2DS2-VASc score | 3.1 ± 1.8 | 3.8 ± 1.6 | <0.001 | 3.3 ± 1.7 | 3.3 ± 1.6 | 0.821 |
Laboratory findings | ||||||
Hs-CRP, mg/dLb | 0.2 (0.1–0.5) | 0.3 (0.1–0.7) | <0.001 | 0.2 (0.1–0.6) | 0.3 (0.1–0.7) | <0.001 |
NT-proBNP, pg/mLb | 783.0 (283.9–1913.3) | 1112.0 (472.3–2677.0) | <0.001 | 895.7 (285.5–2334.0) | 1061.0 (456.8–2484.0) | 0.220 |
Creatinine, mg/dLb | 0.9 (0.7–1.0) | 0.9 (0.7–1.0) | 0.203 | 0.9 (0.7–1.0) | 0.9 (0.7–1.0) | 0.638 |
CCl, mL/minb | 83.8 (67.3–93.9) | 66.1 (52.8–83.0) | <0.001 | 83.1 (64.2–93.1) | 69.5 (56.6–85.4) | <0.001 |
. | Before PS matching . | After PS matching . | ||||
---|---|---|---|---|---|---|
. | Patients with warfarin (n = 990) . | Patients with Dabigatran (n = 844) . | P-value . | Patients with warfarin (n = 549) . | Patients with dabigatran (n = 549) . | P-value . |
Female gender, n (%)a | 338 (34.1) | 319 (37.8) | 0.104 | 207 (37.7) | 213 (38.8) | 0.709 |
Age, yearsb | 71.0 (63.0–77.0) | 74.0 (67.0–79.0) | <0.001 | 72.0 (64.0–78.0) | 72.0 (65.0–77.0) | 0.936 |
≥65 years old | 710 (71.7) | 693 (82.1) | <0.001 | 410 (74.7) | 426 (77.6) | 0.257 |
≥75 years old | 356 (36.0) | 384 (45.5) | <0.001 | 212 (38.6) | 189 (34.4) | 0.149 |
Medical history, n (%)a | ||||||
Hypertension | 517 (52.2) | 550 (65.2) | <0.001 | 334 (60.8) | 332 (60.5) | 0.902 |
Diabetes mellitus | 213 (21.5) | 196 (22.2) | 0.381 | 138 (25.1) | 134 (24.4) | 0.780 |
Smoking | 265 (26.8) | 207 (24.5) | 0.274 | 157 (29.7) | 139 (26.3) | 0.217 |
Previous history of MI | 57 (5.8) | 49 (5.8) | 0.965 | 24 (4.4) | 24 (4.4) | 1.000 |
Previous history of HF | 77 (7.8) | 77 (9.1) | 0.396 | 41 (7.5) | 44 (8.0) | 0.731 |
Previous history of TIA, stroke | 378 (38.2) | 420 (49.8) | <0.001 | 249 (45.4) | 247 (45.0) | 0.903 |
CHA2DS2-VASc score | 3.1 ± 1.8 | 3.8 ± 1.6 | <0.001 | 3.3 ± 1.7 | 3.3 ± 1.6 | 0.821 |
Laboratory findings | ||||||
Hs-CRP, mg/dLb | 0.2 (0.1–0.5) | 0.3 (0.1–0.7) | <0.001 | 0.2 (0.1–0.6) | 0.3 (0.1–0.7) | <0.001 |
NT-proBNP, pg/mLb | 783.0 (283.9–1913.3) | 1112.0 (472.3–2677.0) | <0.001 | 895.7 (285.5–2334.0) | 1061.0 (456.8–2484.0) | 0.220 |
Creatinine, mg/dLb | 0.9 (0.7–1.0) | 0.9 (0.7–1.0) | 0.203 | 0.9 (0.7–1.0) | 0.9 (0.7–1.0) | 0.638 |
CCl, mL/minb | 83.8 (67.3–93.9) | 66.1 (52.8–83.0) | <0.001 | 83.1 (64.2–93.1) | 69.5 (56.6–85.4) | <0.001 |
CCl, creatinine clearance; EF, left ventricular ejection fraction; HF, heart failure; Hs-CRP, high sensitivity C-reactive protein; MI, myocardial infarction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PS, propensity scores; TIA, transient ischaemic attack.
Comparison made using χ2 test.
Median (25–75% percentiles); comparison made using Mann–Whitney test.
Clinical outcomes in warfarin vs. dabigatran treatment groups
There was no difference in the risk of TE between D150 vs. warfarin, D110 vs. warfarin, and D110 vs. D150 (Table 2, Figure 1A, log-rank P = 0.927). There were no differences in the risk of new-onset stroke, embolic stroke, and haemorrhagic stroke between D150 vs. warfarin, D110 vs. warfarin, and D110 vs. D150 (Table 2).
. | Before PS matching . | After PS matching . | . | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
. | Warfarin . | Dabigatran . | Warfarin . | Dabigatran . | D150 vs. warfarin . | D110 vs. warfarin . | D110 vs. D150 . | |||||
. | (n = 990) . | (n = 844) . | (n=549) . | (n = 549) . | ||||||||
. | Warfarin (n = 990) . | D150 (n = 294) . | D110 (n = 550) . | Warfarin (n = 549) . | D150 (n = 183) . | D110 (n = 366) . | ||||||
. | n (%) . | n (%) . | n (%) . | n (%) . | n (%) . | n (%) . | HR (95% CI) . | P-value . | HR (95% CI) . | P-value . | HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||||
Thromboembolism | 33 (3.3) | 9 (3.1) | 18 (3.3) | 19 (3.5) | 5 (2.7) | 7 (1.9) | 0.81 (0.29–2.21) | 0.675 | 0.46 (0.19–1.12) | 0.086 | 0.98 (0.93–1.03) | 0.440 |
Systemic embolism | 2 (0.2) | 0 | 1 (0.2) | 0 | 0 | 1 (0.3) | ||||||
New-onset stroke | 31 (3.1) | 9 (3.1) | 17 (3.1) | 19 (3.5) | 5 (2.7) | 6 (1.6) | 0.81 (0.29–2.22) | 0.675 | 0.40 (0.16–1.01) | 0.051 | 0.71 (0.21–2.46) | 0.591 |
Embolic stroke | 20 (2.0) | 8 (2.7) | 13 (2.4) | 12 (2.2) | 4 (2.2) | 5 (1.4) | 1.00 (0.32–3.14) | 0.996 | 0.58 (0.20–1.67) | 0.312 | 0.75 (0.19–2.93) | 0.676 |
Haemorrhagic stroke | 11 (1.1) | 1 (0.3) | 2 (0.4) | 7 (1.3) | 0 | 0 | ||||||
TIA | 0 | 1 (0.3) | 3 (0.5) | 0 | 1 (0.5) | 1 (0.3) | 0.99 (0.03–1.07) | 0.696 | ||||
Major bleeding | 39 (3.9) | 6 (2.0) | 8 (1.5) | 26 (4.7) | 4 (2.2) | 4 (1.1) | 0.54 (0.18–1.59) | 0.264 | 0.19 (0.07–0.55) | 0.002 | 0.24 (0.05–1.15) | 0.075 |
GI bleeding | 21 (2.1) | 3 (1.0) | 5 (0.9) | 15 (2.7) | 2 (1.1) | 3 (0.8) | 0.54 (0.12–2.46) | 0.426 | 0.25 (0.07–0.88) | 0.030 | 0.18 (0.02–1.37) | 0.097 |
Mucosal bleeding | 27 (2.7) | 4 (1.4) | 5 (0.9) | 19 (3.5) | 3 (1.6) | 3 (0.8) | 0.55 (0.16–1.93) | 0.353 | 0.20 (0.06–0.69) | 0.011 | 0.24 (0.04–1.44) | 0.118 |
Intracranial bleeding | 9 (0.9) | 0 | 0 | 6 (1.1) | 0 | 0 | – | |||||
Secondary endpoints | ||||||||||||
Cardiac death | 12 (1.2) | 1 (0.3) | 3 (0.5) | 6 (1.1) | 1 (0.5) | 2 (0.5) | 0.43 (0.05–3.67) | 0.439 | 0.54 (0.11–2.74) | 0.458 | 1.30 (0.11–15.39) | 0.836 |
All-cause death | 36 (3.6) | 6 (2.0) | 13 (2.4) | 20 (3.6) | 3 (1.6) | 7 (1.9) | 0.47 (0.14–1.63) | 0.236 | 0.46 (0.19–1.10) | 0.081 | 1.10 (0.26–4.66) | 0.888 |
Hospitalization | 35 (3.5) | 7 (2.4) | 9 (1.6) | 23 (4.2) | 4 (2.2) | 6 (1.6) | 0.95 (0.31–2.88) | 0.929 | 0.65 (0.26–1.66) | 0.370 | 1.00 (0.27–3.70) | 0.999 |
Myocardial infarction | 5 (0.5) | 1 (0.3) | 2 (0.4) | 1 (0.2) | 1 (0.5) | 2 (0.5) | 2.03 (0.21–18.22) | 0.466 | 3.16 (0.26–38.74) | 0.368 | 0.52 (0.05–5.77) | 0.597 |
Any bleeding | 151 (15.3) | 17 (5.8) | 31 (5.6) | 83 (15.1) | 12 (6.6) | 15 (4.1) | 0.65 (0.35–1.20) | 0.168 | 0.35 (0.20–0.62) | <0.001 | 0.52 (0.23–1.18) | 0.115 |
Minor bleeding | 111 (11.2) | 11 (3.7) | 23 (4.2) | 57 (10.4) | 8 (4.4) | 11 (3.0) | 0.77 (0.36–1.65) | 0.505 | 0.48 (0.25–0.93) | 0.030 | 0.66 (0.25–1.74) | 0.401 |
Net clinical outcomesa | ||||||||||||
Primary | 84 (8.5) | 16 (5.4) | 34 (6.2) | 51 (9.3) | 10 (5.5) | 16 (4.4) | 0.63 (0.31–1.26) | 0.187 | 0.40 (0.22–0.70) | 0.001 | 0.66 (0.28–1.55) | 0.660 |
Secondary | 60 (6.1) | 14 (4.8) | 25 (4.5) | 37 (6.7) | 9 (4.9) | 11 (3.0) | 0.78 (0.37–1.64) | 0.508 | 0.37 (0.19–0.74) | 0.005 | 0.55 (0.21–1.42) | 0.218 |
. | Before PS matching . | After PS matching . | . | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
. | Warfarin . | Dabigatran . | Warfarin . | Dabigatran . | D150 vs. warfarin . | D110 vs. warfarin . | D110 vs. D150 . | |||||
. | (n = 990) . | (n = 844) . | (n=549) . | (n = 549) . | ||||||||
. | Warfarin (n = 990) . | D150 (n = 294) . | D110 (n = 550) . | Warfarin (n = 549) . | D150 (n = 183) . | D110 (n = 366) . | ||||||
. | n (%) . | n (%) . | n (%) . | n (%) . | n (%) . | n (%) . | HR (95% CI) . | P-value . | HR (95% CI) . | P-value . | HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||||
Thromboembolism | 33 (3.3) | 9 (3.1) | 18 (3.3) | 19 (3.5) | 5 (2.7) | 7 (1.9) | 0.81 (0.29–2.21) | 0.675 | 0.46 (0.19–1.12) | 0.086 | 0.98 (0.93–1.03) | 0.440 |
Systemic embolism | 2 (0.2) | 0 | 1 (0.2) | 0 | 0 | 1 (0.3) | ||||||
New-onset stroke | 31 (3.1) | 9 (3.1) | 17 (3.1) | 19 (3.5) | 5 (2.7) | 6 (1.6) | 0.81 (0.29–2.22) | 0.675 | 0.40 (0.16–1.01) | 0.051 | 0.71 (0.21–2.46) | 0.591 |
Embolic stroke | 20 (2.0) | 8 (2.7) | 13 (2.4) | 12 (2.2) | 4 (2.2) | 5 (1.4) | 1.00 (0.32–3.14) | 0.996 | 0.58 (0.20–1.67) | 0.312 | 0.75 (0.19–2.93) | 0.676 |
Haemorrhagic stroke | 11 (1.1) | 1 (0.3) | 2 (0.4) | 7 (1.3) | 0 | 0 | ||||||
TIA | 0 | 1 (0.3) | 3 (0.5) | 0 | 1 (0.5) | 1 (0.3) | 0.99 (0.03–1.07) | 0.696 | ||||
Major bleeding | 39 (3.9) | 6 (2.0) | 8 (1.5) | 26 (4.7) | 4 (2.2) | 4 (1.1) | 0.54 (0.18–1.59) | 0.264 | 0.19 (0.07–0.55) | 0.002 | 0.24 (0.05–1.15) | 0.075 |
GI bleeding | 21 (2.1) | 3 (1.0) | 5 (0.9) | 15 (2.7) | 2 (1.1) | 3 (0.8) | 0.54 (0.12–2.46) | 0.426 | 0.25 (0.07–0.88) | 0.030 | 0.18 (0.02–1.37) | 0.097 |
Mucosal bleeding | 27 (2.7) | 4 (1.4) | 5 (0.9) | 19 (3.5) | 3 (1.6) | 3 (0.8) | 0.55 (0.16–1.93) | 0.353 | 0.20 (0.06–0.69) | 0.011 | 0.24 (0.04–1.44) | 0.118 |
Intracranial bleeding | 9 (0.9) | 0 | 0 | 6 (1.1) | 0 | 0 | – | |||||
Secondary endpoints | ||||||||||||
Cardiac death | 12 (1.2) | 1 (0.3) | 3 (0.5) | 6 (1.1) | 1 (0.5) | 2 (0.5) | 0.43 (0.05–3.67) | 0.439 | 0.54 (0.11–2.74) | 0.458 | 1.30 (0.11–15.39) | 0.836 |
All-cause death | 36 (3.6) | 6 (2.0) | 13 (2.4) | 20 (3.6) | 3 (1.6) | 7 (1.9) | 0.47 (0.14–1.63) | 0.236 | 0.46 (0.19–1.10) | 0.081 | 1.10 (0.26–4.66) | 0.888 |
Hospitalization | 35 (3.5) | 7 (2.4) | 9 (1.6) | 23 (4.2) | 4 (2.2) | 6 (1.6) | 0.95 (0.31–2.88) | 0.929 | 0.65 (0.26–1.66) | 0.370 | 1.00 (0.27–3.70) | 0.999 |
Myocardial infarction | 5 (0.5) | 1 (0.3) | 2 (0.4) | 1 (0.2) | 1 (0.5) | 2 (0.5) | 2.03 (0.21–18.22) | 0.466 | 3.16 (0.26–38.74) | 0.368 | 0.52 (0.05–5.77) | 0.597 |
Any bleeding | 151 (15.3) | 17 (5.8) | 31 (5.6) | 83 (15.1) | 12 (6.6) | 15 (4.1) | 0.65 (0.35–1.20) | 0.168 | 0.35 (0.20–0.62) | <0.001 | 0.52 (0.23–1.18) | 0.115 |
Minor bleeding | 111 (11.2) | 11 (3.7) | 23 (4.2) | 57 (10.4) | 8 (4.4) | 11 (3.0) | 0.77 (0.36–1.65) | 0.505 | 0.48 (0.25–0.93) | 0.030 | 0.66 (0.25–1.74) | 0.401 |
Net clinical outcomesa | ||||||||||||
Primary | 84 (8.5) | 16 (5.4) | 34 (6.2) | 51 (9.3) | 10 (5.5) | 16 (4.4) | 0.63 (0.31–1.26) | 0.187 | 0.40 (0.22–0.70) | 0.001 | 0.66 (0.28–1.55) | 0.660 |
Secondary | 60 (6.1) | 14 (4.8) | 25 (4.5) | 37 (6.7) | 9 (4.9) | 11 (3.0) | 0.78 (0.37–1.64) | 0.508 | 0.37 (0.19–0.74) | 0.005 | 0.55 (0.21–1.42) | 0.218 |
GI, gastrointestinal; PS, propensity scores; TIA, transient ischaemic attack; HR, hazard ratio; CI, confidence interval.
Primary net clinical outcomes = the composite of new-onset stroke, systemic embolism, major bleeding and all-cause death; secondary net clinical outcomes = the composite of new-onset stroke, systemic embolism and major bleeding; D150 = patients with dabigatran 150 mg; D110 = patients with dabigatran 110 mg.
. | Before PS matching . | After PS matching . | . | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
. | Warfarin . | Dabigatran . | Warfarin . | Dabigatran . | D150 vs. warfarin . | D110 vs. warfarin . | D110 vs. D150 . | |||||
. | (n = 990) . | (n = 844) . | (n=549) . | (n = 549) . | ||||||||
. | Warfarin (n = 990) . | D150 (n = 294) . | D110 (n = 550) . | Warfarin (n = 549) . | D150 (n = 183) . | D110 (n = 366) . | ||||||
. | n (%) . | n (%) . | n (%) . | n (%) . | n (%) . | n (%) . | HR (95% CI) . | P-value . | HR (95% CI) . | P-value . | HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||||
Thromboembolism | 33 (3.3) | 9 (3.1) | 18 (3.3) | 19 (3.5) | 5 (2.7) | 7 (1.9) | 0.81 (0.29–2.21) | 0.675 | 0.46 (0.19–1.12) | 0.086 | 0.98 (0.93–1.03) | 0.440 |
Systemic embolism | 2 (0.2) | 0 | 1 (0.2) | 0 | 0 | 1 (0.3) | ||||||
New-onset stroke | 31 (3.1) | 9 (3.1) | 17 (3.1) | 19 (3.5) | 5 (2.7) | 6 (1.6) | 0.81 (0.29–2.22) | 0.675 | 0.40 (0.16–1.01) | 0.051 | 0.71 (0.21–2.46) | 0.591 |
Embolic stroke | 20 (2.0) | 8 (2.7) | 13 (2.4) | 12 (2.2) | 4 (2.2) | 5 (1.4) | 1.00 (0.32–3.14) | 0.996 | 0.58 (0.20–1.67) | 0.312 | 0.75 (0.19–2.93) | 0.676 |
Haemorrhagic stroke | 11 (1.1) | 1 (0.3) | 2 (0.4) | 7 (1.3) | 0 | 0 | ||||||
TIA | 0 | 1 (0.3) | 3 (0.5) | 0 | 1 (0.5) | 1 (0.3) | 0.99 (0.03–1.07) | 0.696 | ||||
Major bleeding | 39 (3.9) | 6 (2.0) | 8 (1.5) | 26 (4.7) | 4 (2.2) | 4 (1.1) | 0.54 (0.18–1.59) | 0.264 | 0.19 (0.07–0.55) | 0.002 | 0.24 (0.05–1.15) | 0.075 |
GI bleeding | 21 (2.1) | 3 (1.0) | 5 (0.9) | 15 (2.7) | 2 (1.1) | 3 (0.8) | 0.54 (0.12–2.46) | 0.426 | 0.25 (0.07–0.88) | 0.030 | 0.18 (0.02–1.37) | 0.097 |
Mucosal bleeding | 27 (2.7) | 4 (1.4) | 5 (0.9) | 19 (3.5) | 3 (1.6) | 3 (0.8) | 0.55 (0.16–1.93) | 0.353 | 0.20 (0.06–0.69) | 0.011 | 0.24 (0.04–1.44) | 0.118 |
Intracranial bleeding | 9 (0.9) | 0 | 0 | 6 (1.1) | 0 | 0 | – | |||||
Secondary endpoints | ||||||||||||
Cardiac death | 12 (1.2) | 1 (0.3) | 3 (0.5) | 6 (1.1) | 1 (0.5) | 2 (0.5) | 0.43 (0.05–3.67) | 0.439 | 0.54 (0.11–2.74) | 0.458 | 1.30 (0.11–15.39) | 0.836 |
All-cause death | 36 (3.6) | 6 (2.0) | 13 (2.4) | 20 (3.6) | 3 (1.6) | 7 (1.9) | 0.47 (0.14–1.63) | 0.236 | 0.46 (0.19–1.10) | 0.081 | 1.10 (0.26–4.66) | 0.888 |
Hospitalization | 35 (3.5) | 7 (2.4) | 9 (1.6) | 23 (4.2) | 4 (2.2) | 6 (1.6) | 0.95 (0.31–2.88) | 0.929 | 0.65 (0.26–1.66) | 0.370 | 1.00 (0.27–3.70) | 0.999 |
Myocardial infarction | 5 (0.5) | 1 (0.3) | 2 (0.4) | 1 (0.2) | 1 (0.5) | 2 (0.5) | 2.03 (0.21–18.22) | 0.466 | 3.16 (0.26–38.74) | 0.368 | 0.52 (0.05–5.77) | 0.597 |
Any bleeding | 151 (15.3) | 17 (5.8) | 31 (5.6) | 83 (15.1) | 12 (6.6) | 15 (4.1) | 0.65 (0.35–1.20) | 0.168 | 0.35 (0.20–0.62) | <0.001 | 0.52 (0.23–1.18) | 0.115 |
Minor bleeding | 111 (11.2) | 11 (3.7) | 23 (4.2) | 57 (10.4) | 8 (4.4) | 11 (3.0) | 0.77 (0.36–1.65) | 0.505 | 0.48 (0.25–0.93) | 0.030 | 0.66 (0.25–1.74) | 0.401 |
Net clinical outcomesa | ||||||||||||
Primary | 84 (8.5) | 16 (5.4) | 34 (6.2) | 51 (9.3) | 10 (5.5) | 16 (4.4) | 0.63 (0.31–1.26) | 0.187 | 0.40 (0.22–0.70) | 0.001 | 0.66 (0.28–1.55) | 0.660 |
Secondary | 60 (6.1) | 14 (4.8) | 25 (4.5) | 37 (6.7) | 9 (4.9) | 11 (3.0) | 0.78 (0.37–1.64) | 0.508 | 0.37 (0.19–0.74) | 0.005 | 0.55 (0.21–1.42) | 0.218 |
. | Before PS matching . | After PS matching . | . | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
. | Warfarin . | Dabigatran . | Warfarin . | Dabigatran . | D150 vs. warfarin . | D110 vs. warfarin . | D110 vs. D150 . | |||||
. | (n = 990) . | (n = 844) . | (n=549) . | (n = 549) . | ||||||||
. | Warfarin (n = 990) . | D150 (n = 294) . | D110 (n = 550) . | Warfarin (n = 549) . | D150 (n = 183) . | D110 (n = 366) . | ||||||
. | n (%) . | n (%) . | n (%) . | n (%) . | n (%) . | n (%) . | HR (95% CI) . | P-value . | HR (95% CI) . | P-value . | HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||||
Thromboembolism | 33 (3.3) | 9 (3.1) | 18 (3.3) | 19 (3.5) | 5 (2.7) | 7 (1.9) | 0.81 (0.29–2.21) | 0.675 | 0.46 (0.19–1.12) | 0.086 | 0.98 (0.93–1.03) | 0.440 |
Systemic embolism | 2 (0.2) | 0 | 1 (0.2) | 0 | 0 | 1 (0.3) | ||||||
New-onset stroke | 31 (3.1) | 9 (3.1) | 17 (3.1) | 19 (3.5) | 5 (2.7) | 6 (1.6) | 0.81 (0.29–2.22) | 0.675 | 0.40 (0.16–1.01) | 0.051 | 0.71 (0.21–2.46) | 0.591 |
Embolic stroke | 20 (2.0) | 8 (2.7) | 13 (2.4) | 12 (2.2) | 4 (2.2) | 5 (1.4) | 1.00 (0.32–3.14) | 0.996 | 0.58 (0.20–1.67) | 0.312 | 0.75 (0.19–2.93) | 0.676 |
Haemorrhagic stroke | 11 (1.1) | 1 (0.3) | 2 (0.4) | 7 (1.3) | 0 | 0 | ||||||
TIA | 0 | 1 (0.3) | 3 (0.5) | 0 | 1 (0.5) | 1 (0.3) | 0.99 (0.03–1.07) | 0.696 | ||||
Major bleeding | 39 (3.9) | 6 (2.0) | 8 (1.5) | 26 (4.7) | 4 (2.2) | 4 (1.1) | 0.54 (0.18–1.59) | 0.264 | 0.19 (0.07–0.55) | 0.002 | 0.24 (0.05–1.15) | 0.075 |
GI bleeding | 21 (2.1) | 3 (1.0) | 5 (0.9) | 15 (2.7) | 2 (1.1) | 3 (0.8) | 0.54 (0.12–2.46) | 0.426 | 0.25 (0.07–0.88) | 0.030 | 0.18 (0.02–1.37) | 0.097 |
Mucosal bleeding | 27 (2.7) | 4 (1.4) | 5 (0.9) | 19 (3.5) | 3 (1.6) | 3 (0.8) | 0.55 (0.16–1.93) | 0.353 | 0.20 (0.06–0.69) | 0.011 | 0.24 (0.04–1.44) | 0.118 |
Intracranial bleeding | 9 (0.9) | 0 | 0 | 6 (1.1) | 0 | 0 | – | |||||
Secondary endpoints | ||||||||||||
Cardiac death | 12 (1.2) | 1 (0.3) | 3 (0.5) | 6 (1.1) | 1 (0.5) | 2 (0.5) | 0.43 (0.05–3.67) | 0.439 | 0.54 (0.11–2.74) | 0.458 | 1.30 (0.11–15.39) | 0.836 |
All-cause death | 36 (3.6) | 6 (2.0) | 13 (2.4) | 20 (3.6) | 3 (1.6) | 7 (1.9) | 0.47 (0.14–1.63) | 0.236 | 0.46 (0.19–1.10) | 0.081 | 1.10 (0.26–4.66) | 0.888 |
Hospitalization | 35 (3.5) | 7 (2.4) | 9 (1.6) | 23 (4.2) | 4 (2.2) | 6 (1.6) | 0.95 (0.31–2.88) | 0.929 | 0.65 (0.26–1.66) | 0.370 | 1.00 (0.27–3.70) | 0.999 |
Myocardial infarction | 5 (0.5) | 1 (0.3) | 2 (0.4) | 1 (0.2) | 1 (0.5) | 2 (0.5) | 2.03 (0.21–18.22) | 0.466 | 3.16 (0.26–38.74) | 0.368 | 0.52 (0.05–5.77) | 0.597 |
Any bleeding | 151 (15.3) | 17 (5.8) | 31 (5.6) | 83 (15.1) | 12 (6.6) | 15 (4.1) | 0.65 (0.35–1.20) | 0.168 | 0.35 (0.20–0.62) | <0.001 | 0.52 (0.23–1.18) | 0.115 |
Minor bleeding | 111 (11.2) | 11 (3.7) | 23 (4.2) | 57 (10.4) | 8 (4.4) | 11 (3.0) | 0.77 (0.36–1.65) | 0.505 | 0.48 (0.25–0.93) | 0.030 | 0.66 (0.25–1.74) | 0.401 |
Net clinical outcomesa | ||||||||||||
Primary | 84 (8.5) | 16 (5.4) | 34 (6.2) | 51 (9.3) | 10 (5.5) | 16 (4.4) | 0.63 (0.31–1.26) | 0.187 | 0.40 (0.22–0.70) | 0.001 | 0.66 (0.28–1.55) | 0.660 |
Secondary | 60 (6.1) | 14 (4.8) | 25 (4.5) | 37 (6.7) | 9 (4.9) | 11 (3.0) | 0.78 (0.37–1.64) | 0.508 | 0.37 (0.19–0.74) | 0.005 | 0.55 (0.21–1.42) | 0.218 |
GI, gastrointestinal; PS, propensity scores; TIA, transient ischaemic attack; HR, hazard ratio; CI, confidence interval.
Primary net clinical outcomes = the composite of new-onset stroke, systemic embolism, major bleeding and all-cause death; secondary net clinical outcomes = the composite of new-onset stroke, systemic embolism and major bleeding; D150 = patients with dabigatran 150 mg; D110 = patients with dabigatran 110 mg.
There were no differences in major bleeding events between D150 and warfarin, though bleeding was significantly lower in D110 compared with warfarin (1.1% vs. 4.7%, adjusted HR 0.19, 95% confidence interval (CI) 0.07–0.55, Table 2, Figure 1B, log-rank P = 0.007). The risk of gastrointestinal (0.8% vs. 2.7%, adjusted HR 0.25, 95% CI 0.07–0.88, P = 0.030) and mucosal bleeding (0.8% vs. 3.5%, adjusted HR 0.20, 95% CI 0.06–0.69, P = 0.011) was lower in D110 compared with warfarin. There was no difference in the risk of major bleeding between D110 and D150 (Table 2).
Cardiac death, all-cause death, hospitalization, and MI event rates were not different between D150 vs. warfarin, D110 vs. warfarin, and D110 vs. D150. Any bleeding events were lower in D110 compared with warfarin (4.1% vs. 15.1%, adjusted HR 0.35, 95% CI 0.20–0.62, P < 0.001). There was no difference in the incidence of any bleeding events between D150 vs. warfarin, and D110 vs. D150 (Table 2).
Primary (4.4% vs. 9.3%, adjusted HR 0.40, 95% CI 0.22–0.70, P = 0.001) and secondary (3.0% vs. 6.7%, adjusted HR 0.37, 95% CI 0.19–0.74, P = 0.005) net clinical outcomes were lower in D110 compared with warfarin. There were no differences in the risk of primary and secondary net clinical outcomes between D150 vs. warfarin, and D110 vs. D150 (Table 2).
Comparison of outcomes in warfarin and dabigatran groups according to guideline-concordant dose reduction
There were no differences in the risk of TE, new-onset stroke, and embolic stroke between co-D110 vs. warfarin, di-D110 vs. warfarin and di-D110 vs. D150 (Table 3, Figure 2A, log-rank P = 0.906).
. | Warfarin (n = 549) . | co-D110 (n = 183) . | di-D110 (n = 183) . | D150 (n = 183) . | co-D110 vs. warfarin . | . | di-D110 vs. warfarin . | . | di-D110 vs. D150 . | . |
---|---|---|---|---|---|---|---|---|---|---|
. | n (%) . | n (%) . | n (%) . | n (%) . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||
Thromboembolism | 19 (3.5) | 2 (1.1) | 5 (2.7) | 5 (2.7) | 0.28 (0.07–1.22) | 0.091 | 0.96 (0.60–1.62) | 0.872 | 1.03 (0.30–3.56) | 0.965 |
Systemic embolism | 0 | 0 | 1 (0.5) | 0 | ||||||
New-onset stroke | 19 (3.5) | 2 (1.1) | 4 (2.2) | 5 (2.7) | 0.28 (0.07–1.22) | 0.091 | 0.81 (0.22–3.02) | 0.752 | 0.81 (0.22–3.02) | 0.752 |
Embolic stroke | 12 (2.2) | 1 (0.5) | 4 (2.2) | 4 (2.2) | 0.24 (0.03–1.87) | 0.999 | 0.85 (0.27–2.62) | 0.770 | 1.00 (0.25–4.01) | 0.999 |
Haemorrhagic stroke | 7 (1.3) | 0 | 0 | 0 | ||||||
TIA | 0 | 1 (0.5) | 0 | 1 (0.5) | ||||||
Major bleeding | 26 (4.7) | 3 (1.6) | 1 (0.5) | 4 (2.2) | 0.22 (0.06–0.76) | 0.017 | 0.11 (0.02–0.81) | 0.030 | 0.36 (0.04–3.49) | 0.376 |
GI bleeding | 15 (2.7) | 2 (1.1) | 1 (0.5) | 2 (1.1) | 0.26 (0.06–1.20) | 0.085 | 0.20 (0.03–1.50) | 0.117 | 0.54 (0.05–5.96) | 0.616 |
Mucosal bleeding | 19 (3.5) | 2 (1.1) | 1 (0.5) | 3 (1.6) | 0.21 (0.05–0.97) | 0.045 | 0.16 (0.02–1.17) | 0.071 | 0.50 (0.05–5.47) | 0.570 |
Intracranial bleeding | 6 (1.1) | 0 | 0 | 0 | ||||||
Secondary endpoints | ||||||||||
Cardiac death | 6 (1.1) | 2 (1.1) | 0 | 1 (0.5) | 0.91 (0.18–4.60) | 0.912 | ||||
All-cause death | 20 (3.6) | 4 (2.2) | 3 (1.6) | 3 (1.6) | 0.55 (0.19–1.61) | 0.275 | 0.45 (0.13–1.53) | 0.202 | 0.99 (0.20–4.92) | 0.991 |
Hospitalization | 23 (4.2) | 1 (0.5) | 5 (2.7) | 4 (2.2) | 0.23 (0.03–1.70) | 0.148 | 1.07 (0.39–2.89) | 0.899 | 1.33 (0.36–4.96) | 0.672 |
Myocardial infarction | 1 (0.2) | 2 (1.1) | 0 | 1 (0.5) | 7.32 (0.41–133.12) | 0.179 | ||||
Any bleeding | 83 (15.1) | 8 (4.4) | 7 (3.8) | 12 (6.6) | 0.32 (0.15–0.68) | 0.003 | 0.35 (0.16–0.76) | 0.008 | 0.58 (0.23–1.47) | 0.251 |
Minor bleeding | 57 (10.4) | 5 (2.7) | 6 (3.3) | 8 (4.4) | 0.40 (0.15–1.04) | 0.060 | 0.55 (0.24–1.28) | 0.166 | 0.71 (0.25–2.05) | 0.526 |
Net clinical outcomesa | ||||||||||
Primary | 51 (9.3) | 9 (4.9) | 7 (3.8) | 10 (5.5) | 0.35 (0.17–0.74) | 0.006 | 0.40 (0.18–0.88) | 0.024 | 0.74 (0.28–1.93) | 0.532 |
Secondary | 37 (6.7) | 5 (2.7) | 6 (3.3) | 9 (4.9) | 0.26 (0.10–0.68) | 0.006 | 0.47 (0.20–1.12) | 0.090 | 0.70 (0.25–1.96) | 0.492 |
. | Warfarin (n = 549) . | co-D110 (n = 183) . | di-D110 (n = 183) . | D150 (n = 183) . | co-D110 vs. warfarin . | . | di-D110 vs. warfarin . | . | di-D110 vs. D150 . | . |
---|---|---|---|---|---|---|---|---|---|---|
. | n (%) . | n (%) . | n (%) . | n (%) . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||
Thromboembolism | 19 (3.5) | 2 (1.1) | 5 (2.7) | 5 (2.7) | 0.28 (0.07–1.22) | 0.091 | 0.96 (0.60–1.62) | 0.872 | 1.03 (0.30–3.56) | 0.965 |
Systemic embolism | 0 | 0 | 1 (0.5) | 0 | ||||||
New-onset stroke | 19 (3.5) | 2 (1.1) | 4 (2.2) | 5 (2.7) | 0.28 (0.07–1.22) | 0.091 | 0.81 (0.22–3.02) | 0.752 | 0.81 (0.22–3.02) | 0.752 |
Embolic stroke | 12 (2.2) | 1 (0.5) | 4 (2.2) | 4 (2.2) | 0.24 (0.03–1.87) | 0.999 | 0.85 (0.27–2.62) | 0.770 | 1.00 (0.25–4.01) | 0.999 |
Haemorrhagic stroke | 7 (1.3) | 0 | 0 | 0 | ||||||
TIA | 0 | 1 (0.5) | 0 | 1 (0.5) | ||||||
Major bleeding | 26 (4.7) | 3 (1.6) | 1 (0.5) | 4 (2.2) | 0.22 (0.06–0.76) | 0.017 | 0.11 (0.02–0.81) | 0.030 | 0.36 (0.04–3.49) | 0.376 |
GI bleeding | 15 (2.7) | 2 (1.1) | 1 (0.5) | 2 (1.1) | 0.26 (0.06–1.20) | 0.085 | 0.20 (0.03–1.50) | 0.117 | 0.54 (0.05–5.96) | 0.616 |
Mucosal bleeding | 19 (3.5) | 2 (1.1) | 1 (0.5) | 3 (1.6) | 0.21 (0.05–0.97) | 0.045 | 0.16 (0.02–1.17) | 0.071 | 0.50 (0.05–5.47) | 0.570 |
Intracranial bleeding | 6 (1.1) | 0 | 0 | 0 | ||||||
Secondary endpoints | ||||||||||
Cardiac death | 6 (1.1) | 2 (1.1) | 0 | 1 (0.5) | 0.91 (0.18–4.60) | 0.912 | ||||
All-cause death | 20 (3.6) | 4 (2.2) | 3 (1.6) | 3 (1.6) | 0.55 (0.19–1.61) | 0.275 | 0.45 (0.13–1.53) | 0.202 | 0.99 (0.20–4.92) | 0.991 |
Hospitalization | 23 (4.2) | 1 (0.5) | 5 (2.7) | 4 (2.2) | 0.23 (0.03–1.70) | 0.148 | 1.07 (0.39–2.89) | 0.899 | 1.33 (0.36–4.96) | 0.672 |
Myocardial infarction | 1 (0.2) | 2 (1.1) | 0 | 1 (0.5) | 7.32 (0.41–133.12) | 0.179 | ||||
Any bleeding | 83 (15.1) | 8 (4.4) | 7 (3.8) | 12 (6.6) | 0.32 (0.15–0.68) | 0.003 | 0.35 (0.16–0.76) | 0.008 | 0.58 (0.23–1.47) | 0.251 |
Minor bleeding | 57 (10.4) | 5 (2.7) | 6 (3.3) | 8 (4.4) | 0.40 (0.15–1.04) | 0.060 | 0.55 (0.24–1.28) | 0.166 | 0.71 (0.25–2.05) | 0.526 |
Net clinical outcomesa | ||||||||||
Primary | 51 (9.3) | 9 (4.9) | 7 (3.8) | 10 (5.5) | 0.35 (0.17–0.74) | 0.006 | 0.40 (0.18–0.88) | 0.024 | 0.74 (0.28–1.93) | 0.532 |
Secondary | 37 (6.7) | 5 (2.7) | 6 (3.3) | 9 (4.9) | 0.26 (0.10–0.68) | 0.006 | 0.47 (0.20–1.12) | 0.090 | 0.70 (0.25–1.96) | 0.492 |
GI, gastrointestinal; PS, propensity scores; TIA, transient ischaemic attack; HR, hazard ratio; CI, confidence interval.
Primary net clinical outcomes = the composite of new-onset stroke, systemic embolism, major bleeding and all-cause death; secondary net clinical outcomes = the composite of new-onset stroke, systemic embolism and major bleeding; D150 = patients with dabigatran 150mg; D110 = patients with dabigatran 110mg; co-D110 = patients with guideline-concordant dabigatran dose reduction; di-D110 = patients with guideline-discordant dabigatran dose reduction.
. | Warfarin (n = 549) . | co-D110 (n = 183) . | di-D110 (n = 183) . | D150 (n = 183) . | co-D110 vs. warfarin . | . | di-D110 vs. warfarin . | . | di-D110 vs. D150 . | . |
---|---|---|---|---|---|---|---|---|---|---|
. | n (%) . | n (%) . | n (%) . | n (%) . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||
Thromboembolism | 19 (3.5) | 2 (1.1) | 5 (2.7) | 5 (2.7) | 0.28 (0.07–1.22) | 0.091 | 0.96 (0.60–1.62) | 0.872 | 1.03 (0.30–3.56) | 0.965 |
Systemic embolism | 0 | 0 | 1 (0.5) | 0 | ||||||
New-onset stroke | 19 (3.5) | 2 (1.1) | 4 (2.2) | 5 (2.7) | 0.28 (0.07–1.22) | 0.091 | 0.81 (0.22–3.02) | 0.752 | 0.81 (0.22–3.02) | 0.752 |
Embolic stroke | 12 (2.2) | 1 (0.5) | 4 (2.2) | 4 (2.2) | 0.24 (0.03–1.87) | 0.999 | 0.85 (0.27–2.62) | 0.770 | 1.00 (0.25–4.01) | 0.999 |
Haemorrhagic stroke | 7 (1.3) | 0 | 0 | 0 | ||||||
TIA | 0 | 1 (0.5) | 0 | 1 (0.5) | ||||||
Major bleeding | 26 (4.7) | 3 (1.6) | 1 (0.5) | 4 (2.2) | 0.22 (0.06–0.76) | 0.017 | 0.11 (0.02–0.81) | 0.030 | 0.36 (0.04–3.49) | 0.376 |
GI bleeding | 15 (2.7) | 2 (1.1) | 1 (0.5) | 2 (1.1) | 0.26 (0.06–1.20) | 0.085 | 0.20 (0.03–1.50) | 0.117 | 0.54 (0.05–5.96) | 0.616 |
Mucosal bleeding | 19 (3.5) | 2 (1.1) | 1 (0.5) | 3 (1.6) | 0.21 (0.05–0.97) | 0.045 | 0.16 (0.02–1.17) | 0.071 | 0.50 (0.05–5.47) | 0.570 |
Intracranial bleeding | 6 (1.1) | 0 | 0 | 0 | ||||||
Secondary endpoints | ||||||||||
Cardiac death | 6 (1.1) | 2 (1.1) | 0 | 1 (0.5) | 0.91 (0.18–4.60) | 0.912 | ||||
All-cause death | 20 (3.6) | 4 (2.2) | 3 (1.6) | 3 (1.6) | 0.55 (0.19–1.61) | 0.275 | 0.45 (0.13–1.53) | 0.202 | 0.99 (0.20–4.92) | 0.991 |
Hospitalization | 23 (4.2) | 1 (0.5) | 5 (2.7) | 4 (2.2) | 0.23 (0.03–1.70) | 0.148 | 1.07 (0.39–2.89) | 0.899 | 1.33 (0.36–4.96) | 0.672 |
Myocardial infarction | 1 (0.2) | 2 (1.1) | 0 | 1 (0.5) | 7.32 (0.41–133.12) | 0.179 | ||||
Any bleeding | 83 (15.1) | 8 (4.4) | 7 (3.8) | 12 (6.6) | 0.32 (0.15–0.68) | 0.003 | 0.35 (0.16–0.76) | 0.008 | 0.58 (0.23–1.47) | 0.251 |
Minor bleeding | 57 (10.4) | 5 (2.7) | 6 (3.3) | 8 (4.4) | 0.40 (0.15–1.04) | 0.060 | 0.55 (0.24–1.28) | 0.166 | 0.71 (0.25–2.05) | 0.526 |
Net clinical outcomesa | ||||||||||
Primary | 51 (9.3) | 9 (4.9) | 7 (3.8) | 10 (5.5) | 0.35 (0.17–0.74) | 0.006 | 0.40 (0.18–0.88) | 0.024 | 0.74 (0.28–1.93) | 0.532 |
Secondary | 37 (6.7) | 5 (2.7) | 6 (3.3) | 9 (4.9) | 0.26 (0.10–0.68) | 0.006 | 0.47 (0.20–1.12) | 0.090 | 0.70 (0.25–1.96) | 0.492 |
. | Warfarin (n = 549) . | co-D110 (n = 183) . | di-D110 (n = 183) . | D150 (n = 183) . | co-D110 vs. warfarin . | . | di-D110 vs. warfarin . | . | di-D110 vs. D150 . | . |
---|---|---|---|---|---|---|---|---|---|---|
. | n (%) . | n (%) . | n (%) . | n (%) . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||
Thromboembolism | 19 (3.5) | 2 (1.1) | 5 (2.7) | 5 (2.7) | 0.28 (0.07–1.22) | 0.091 | 0.96 (0.60–1.62) | 0.872 | 1.03 (0.30–3.56) | 0.965 |
Systemic embolism | 0 | 0 | 1 (0.5) | 0 | ||||||
New-onset stroke | 19 (3.5) | 2 (1.1) | 4 (2.2) | 5 (2.7) | 0.28 (0.07–1.22) | 0.091 | 0.81 (0.22–3.02) | 0.752 | 0.81 (0.22–3.02) | 0.752 |
Embolic stroke | 12 (2.2) | 1 (0.5) | 4 (2.2) | 4 (2.2) | 0.24 (0.03–1.87) | 0.999 | 0.85 (0.27–2.62) | 0.770 | 1.00 (0.25–4.01) | 0.999 |
Haemorrhagic stroke | 7 (1.3) | 0 | 0 | 0 | ||||||
TIA | 0 | 1 (0.5) | 0 | 1 (0.5) | ||||||
Major bleeding | 26 (4.7) | 3 (1.6) | 1 (0.5) | 4 (2.2) | 0.22 (0.06–0.76) | 0.017 | 0.11 (0.02–0.81) | 0.030 | 0.36 (0.04–3.49) | 0.376 |
GI bleeding | 15 (2.7) | 2 (1.1) | 1 (0.5) | 2 (1.1) | 0.26 (0.06–1.20) | 0.085 | 0.20 (0.03–1.50) | 0.117 | 0.54 (0.05–5.96) | 0.616 |
Mucosal bleeding | 19 (3.5) | 2 (1.1) | 1 (0.5) | 3 (1.6) | 0.21 (0.05–0.97) | 0.045 | 0.16 (0.02–1.17) | 0.071 | 0.50 (0.05–5.47) | 0.570 |
Intracranial bleeding | 6 (1.1) | 0 | 0 | 0 | ||||||
Secondary endpoints | ||||||||||
Cardiac death | 6 (1.1) | 2 (1.1) | 0 | 1 (0.5) | 0.91 (0.18–4.60) | 0.912 | ||||
All-cause death | 20 (3.6) | 4 (2.2) | 3 (1.6) | 3 (1.6) | 0.55 (0.19–1.61) | 0.275 | 0.45 (0.13–1.53) | 0.202 | 0.99 (0.20–4.92) | 0.991 |
Hospitalization | 23 (4.2) | 1 (0.5) | 5 (2.7) | 4 (2.2) | 0.23 (0.03–1.70) | 0.148 | 1.07 (0.39–2.89) | 0.899 | 1.33 (0.36–4.96) | 0.672 |
Myocardial infarction | 1 (0.2) | 2 (1.1) | 0 | 1 (0.5) | 7.32 (0.41–133.12) | 0.179 | ||||
Any bleeding | 83 (15.1) | 8 (4.4) | 7 (3.8) | 12 (6.6) | 0.32 (0.15–0.68) | 0.003 | 0.35 (0.16–0.76) | 0.008 | 0.58 (0.23–1.47) | 0.251 |
Minor bleeding | 57 (10.4) | 5 (2.7) | 6 (3.3) | 8 (4.4) | 0.40 (0.15–1.04) | 0.060 | 0.55 (0.24–1.28) | 0.166 | 0.71 (0.25–2.05) | 0.526 |
Net clinical outcomesa | ||||||||||
Primary | 51 (9.3) | 9 (4.9) | 7 (3.8) | 10 (5.5) | 0.35 (0.17–0.74) | 0.006 | 0.40 (0.18–0.88) | 0.024 | 0.74 (0.28–1.93) | 0.532 |
Secondary | 37 (6.7) | 5 (2.7) | 6 (3.3) | 9 (4.9) | 0.26 (0.10–0.68) | 0.006 | 0.47 (0.20–1.12) | 0.090 | 0.70 (0.25–1.96) | 0.492 |
GI, gastrointestinal; PS, propensity scores; TIA, transient ischaemic attack; HR, hazard ratio; CI, confidence interval.
Primary net clinical outcomes = the composite of new-onset stroke, systemic embolism, major bleeding and all-cause death; secondary net clinical outcomes = the composite of new-onset stroke, systemic embolism and major bleeding; D150 = patients with dabigatran 150mg; D110 = patients with dabigatran 110mg; co-D110 = patients with guideline-concordant dabigatran dose reduction; di-D110 = patients with guideline-discordant dabigatran dose reduction.
Major bleeding event was significantly lower in both co-D110 (1.6% vs. 4.7%, adjusted HR 0.22, 95% CI 0.06–0.76, P = 0.017) and di-D110 (0.5% vs. 4.7%, adjusted HR 0.11, 95% CI 0.02–0.81, P = 0.030) than warfarin (Table 3, Figure 2B, log-rank P = 0.014). There was no difference in the risk of major bleeding between di-D110 and D150.
There were no differences in all-cause death, hospitalization, and stroke between co-D110 vs. warfarin, di-D110 vs. warfarin, and di-D110 vs. D150. Any bleeding events were lower in both co-D110 (4.4% vs. 15.1%, adjusted HR 0.32, 95% CI 0.15–0.68, P = 0.003) and di-D110 (3.8% vs. 15.1%, adjusted HR 0.35, 95% CI 0.16–0.76, P = 0.008) compared with warfarin. There were no differences in the incidences of bleeding events between di-D110 vs. D150 (Table 3).
Primary (4.9% vs. 9.3%, adjusted HR 0.35, 95% CI 0.17–0.74, P = 0.006) and secondary (2.7% vs. 6.7%, adjusted HR 0.26, 95% CI 0.10–0.68, P = 0.006) net clinical outcomes were lower in co-D110 compared with warfarin. Primary net clinical outcomes were lower in di-D110 than warfarin (3.8% vs. 9.3%, adjusted HR 0.40, 95% CI 0.18–0.88, P = 0.024). There were no differences in the risk of primary and secondary net clinical outcomes between di-D110 and D150 (Table 3).
Comparison of outcomes in warfarin and dabigatran groups in patients with a previous history of stroke/transient ischaemic attack
A subgroup analysis was performed to evaluate whether similar effects of dabigatran vs. warfarin on clinical outcomes could persist only in patients with a previous history of stroke/TIA. Overall, the risk of TE, new-onset stroke, and embolic stroke were similar between D150 vs. warfarin, di-D110 vs. warfarin, and di-D110 vs. D150 (Table 3). Although major bleeding events were lower in D150 vs. warfarin and di-D110 vs. warfarin, risk reduction assessments could not be assessed due to non-events in D150 and di-D110.
There were no differences in the risk of primary and secondary net clinical outcomes between D150 vs. warfarin, di-D110 vs. warfarin, and di-D110 vs. D150 (Table 4).
. | Warfarin (n = 249) . | co-D110 (n = 83) . | di-D110 (n = 81) . | D150 (n = 83) . | D150 vs. warfarin . | . | di-D110 vs. warfarin . | . | di-D110 vs. D150 . | . |
---|---|---|---|---|---|---|---|---|---|---|
. | n (%) . | n (%) . | n (%) . | n (%) . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||
Thromboembolism | 11 (4.4) | 0 | 5 (6.2) | 5 (6.0) | 1.01 (0.35–2.92) | 0.988 | 1.24 (0.43–3.56) | 0.696 | 1.01 (0.28–3.55) | 0.994 |
Systemic embolism | 0 | 0 | 1 (1.2) | 0 | ||||||
New-onset stroke | 11 (4.4) | 0 | 4 (4.9) | 5 (6.0) | 1.01 (0.35–2.92) | 0.988 | 0.98 (0.31–3.08) | 0.972 | 0.75 (0.19–2.90) | 0.675 |
Embolic stroke | 8 (3.2) | 0 | 4 (4.9) | 4 (4.8) | 1.10 (0.33–3.68) | 0.877 | 1.36 (0.41–4.53) | 0.617 | 1.01 (0.25–4.10) | 0.995 |
Haemorrhagic stroke | 3 (1.2) | 0 | 0 | 0 | ||||||
TIA | 0 | 0 | 0 | 1 (1.2) | ||||||
Major bleeding | 14 (5.6) | 0 | 0 | 0 | ||||||
GI bleeding | 8 (3.2) | 0 | 0 | 0 | ||||||
Mucosal bleeding | 11 (4.4) | 0 | 0 | 0 | ||||||
Intracranial bleeding | 2 (0.8) | 0 | 0 | 0 | ||||||
Secondary endpoints | ||||||||||
Cardiac death | 1 (0.4) | 0 | 0 | 1 (1.2) | 2.53 (0.16–40.88) | 0.513 | ||||
All-cause death | 13 (5.2) | 1 (1.2) | 1 (1.2) | 3 (3.6) | 0.71 (0.19–2.60) | 0.606 | 0.21 (0.03–1.61) | 0.134 | 0.26 (0.03–2.72) | 0.262 |
Hospitalization | 4 (1.6) | 0 | 0 | 0 | ||||||
Myocardial infarction | 1 (0.4) | 0 | 0 | 0 | ||||||
Any bleeding | 51 (20.5) | 3 (3.6) | 3 (3.7) | 4 (4.8) | 0.25 (0.09–0.71) | 0.009 | 0.19 (0.06–0.62) | 0.006 | 0.76 (0.17–3.43) | 0.772 |
Minor bleeding | 36 (14.5) | 3 (3.6) | 3 (3.7) | 4 (4.8) | 0.40 (0.14–1.14) | 0.087 | 0.30 (0.09–0.98) | 0.047 | 0.76 (0.17–3.43) | 0.772 |
Net clinical outcomesa | ||||||||||
Primary | 28 (11.2) | 1 (1.2) | 5 (6.2) | 6 (7.2) | 0.53 (0.22–1.28) | 0.157 | 0.48 (0.19–1.25) | 0.133 | 0.85 (0.26–2.83) | 0.789 |
Secondary | 21 (8.4) | 0 | 5 (6.2) | 5 (6.0) | 0.54 (0.20–1.43) | 0.212 | 0.64 (0.24–1.69) | 0.366 | 1.00 (0.28–3.52) | 0.999 |
. | Warfarin (n = 249) . | co-D110 (n = 83) . | di-D110 (n = 81) . | D150 (n = 83) . | D150 vs. warfarin . | . | di-D110 vs. warfarin . | . | di-D110 vs. D150 . | . |
---|---|---|---|---|---|---|---|---|---|---|
. | n (%) . | n (%) . | n (%) . | n (%) . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||
Thromboembolism | 11 (4.4) | 0 | 5 (6.2) | 5 (6.0) | 1.01 (0.35–2.92) | 0.988 | 1.24 (0.43–3.56) | 0.696 | 1.01 (0.28–3.55) | 0.994 |
Systemic embolism | 0 | 0 | 1 (1.2) | 0 | ||||||
New-onset stroke | 11 (4.4) | 0 | 4 (4.9) | 5 (6.0) | 1.01 (0.35–2.92) | 0.988 | 0.98 (0.31–3.08) | 0.972 | 0.75 (0.19–2.90) | 0.675 |
Embolic stroke | 8 (3.2) | 0 | 4 (4.9) | 4 (4.8) | 1.10 (0.33–3.68) | 0.877 | 1.36 (0.41–4.53) | 0.617 | 1.01 (0.25–4.10) | 0.995 |
Haemorrhagic stroke | 3 (1.2) | 0 | 0 | 0 | ||||||
TIA | 0 | 0 | 0 | 1 (1.2) | ||||||
Major bleeding | 14 (5.6) | 0 | 0 | 0 | ||||||
GI bleeding | 8 (3.2) | 0 | 0 | 0 | ||||||
Mucosal bleeding | 11 (4.4) | 0 | 0 | 0 | ||||||
Intracranial bleeding | 2 (0.8) | 0 | 0 | 0 | ||||||
Secondary endpoints | ||||||||||
Cardiac death | 1 (0.4) | 0 | 0 | 1 (1.2) | 2.53 (0.16–40.88) | 0.513 | ||||
All-cause death | 13 (5.2) | 1 (1.2) | 1 (1.2) | 3 (3.6) | 0.71 (0.19–2.60) | 0.606 | 0.21 (0.03–1.61) | 0.134 | 0.26 (0.03–2.72) | 0.262 |
Hospitalization | 4 (1.6) | 0 | 0 | 0 | ||||||
Myocardial infarction | 1 (0.4) | 0 | 0 | 0 | ||||||
Any bleeding | 51 (20.5) | 3 (3.6) | 3 (3.7) | 4 (4.8) | 0.25 (0.09–0.71) | 0.009 | 0.19 (0.06–0.62) | 0.006 | 0.76 (0.17–3.43) | 0.772 |
Minor bleeding | 36 (14.5) | 3 (3.6) | 3 (3.7) | 4 (4.8) | 0.40 (0.14–1.14) | 0.087 | 0.30 (0.09–0.98) | 0.047 | 0.76 (0.17–3.43) | 0.772 |
Net clinical outcomesa | ||||||||||
Primary | 28 (11.2) | 1 (1.2) | 5 (6.2) | 6 (7.2) | 0.53 (0.22–1.28) | 0.157 | 0.48 (0.19–1.25) | 0.133 | 0.85 (0.26–2.83) | 0.789 |
Secondary | 21 (8.4) | 0 | 5 (6.2) | 5 (6.0) | 0.54 (0.20–1.43) | 0.212 | 0.64 (0.24–1.69) | 0.366 | 1.00 (0.28–3.52) | 0.999 |
GI, gastrointestinal; PS, propensity scores; TIA, transient ischaemic attack; HR, hazard ratio; CI, confidence interval.
Primary net clinical outcomes = the composite of new-onset stroke, systemic embolism, major bleeding and all-cause death; secondary net clinical outcomes = the composite of new-onset stroke, systemic embolism and major bleeding; D150 = patients with dabigatran 150mg; D110 = patients with dabigatran 110mg; co-D110 = patients with guideline-concordant dabigatran dose reduction; di-D110 = patients with guideline-discordant dabigatran dose reduction.
. | Warfarin (n = 249) . | co-D110 (n = 83) . | di-D110 (n = 81) . | D150 (n = 83) . | D150 vs. warfarin . | . | di-D110 vs. warfarin . | . | di-D110 vs. D150 . | . |
---|---|---|---|---|---|---|---|---|---|---|
. | n (%) . | n (%) . | n (%) . | n (%) . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||
Thromboembolism | 11 (4.4) | 0 | 5 (6.2) | 5 (6.0) | 1.01 (0.35–2.92) | 0.988 | 1.24 (0.43–3.56) | 0.696 | 1.01 (0.28–3.55) | 0.994 |
Systemic embolism | 0 | 0 | 1 (1.2) | 0 | ||||||
New-onset stroke | 11 (4.4) | 0 | 4 (4.9) | 5 (6.0) | 1.01 (0.35–2.92) | 0.988 | 0.98 (0.31–3.08) | 0.972 | 0.75 (0.19–2.90) | 0.675 |
Embolic stroke | 8 (3.2) | 0 | 4 (4.9) | 4 (4.8) | 1.10 (0.33–3.68) | 0.877 | 1.36 (0.41–4.53) | 0.617 | 1.01 (0.25–4.10) | 0.995 |
Haemorrhagic stroke | 3 (1.2) | 0 | 0 | 0 | ||||||
TIA | 0 | 0 | 0 | 1 (1.2) | ||||||
Major bleeding | 14 (5.6) | 0 | 0 | 0 | ||||||
GI bleeding | 8 (3.2) | 0 | 0 | 0 | ||||||
Mucosal bleeding | 11 (4.4) | 0 | 0 | 0 | ||||||
Intracranial bleeding | 2 (0.8) | 0 | 0 | 0 | ||||||
Secondary endpoints | ||||||||||
Cardiac death | 1 (0.4) | 0 | 0 | 1 (1.2) | 2.53 (0.16–40.88) | 0.513 | ||||
All-cause death | 13 (5.2) | 1 (1.2) | 1 (1.2) | 3 (3.6) | 0.71 (0.19–2.60) | 0.606 | 0.21 (0.03–1.61) | 0.134 | 0.26 (0.03–2.72) | 0.262 |
Hospitalization | 4 (1.6) | 0 | 0 | 0 | ||||||
Myocardial infarction | 1 (0.4) | 0 | 0 | 0 | ||||||
Any bleeding | 51 (20.5) | 3 (3.6) | 3 (3.7) | 4 (4.8) | 0.25 (0.09–0.71) | 0.009 | 0.19 (0.06–0.62) | 0.006 | 0.76 (0.17–3.43) | 0.772 |
Minor bleeding | 36 (14.5) | 3 (3.6) | 3 (3.7) | 4 (4.8) | 0.40 (0.14–1.14) | 0.087 | 0.30 (0.09–0.98) | 0.047 | 0.76 (0.17–3.43) | 0.772 |
Net clinical outcomesa | ||||||||||
Primary | 28 (11.2) | 1 (1.2) | 5 (6.2) | 6 (7.2) | 0.53 (0.22–1.28) | 0.157 | 0.48 (0.19–1.25) | 0.133 | 0.85 (0.26–2.83) | 0.789 |
Secondary | 21 (8.4) | 0 | 5 (6.2) | 5 (6.0) | 0.54 (0.20–1.43) | 0.212 | 0.64 (0.24–1.69) | 0.366 | 1.00 (0.28–3.52) | 0.999 |
. | Warfarin (n = 249) . | co-D110 (n = 83) . | di-D110 (n = 81) . | D150 (n = 83) . | D150 vs. warfarin . | . | di-D110 vs. warfarin . | . | di-D110 vs. D150 . | . |
---|---|---|---|---|---|---|---|---|---|---|
. | n (%) . | n (%) . | n (%) . | n (%) . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . | Adjusted HR (95% CI) . | P-value . |
Primary endpoints | ||||||||||
Thromboembolism | 11 (4.4) | 0 | 5 (6.2) | 5 (6.0) | 1.01 (0.35–2.92) | 0.988 | 1.24 (0.43–3.56) | 0.696 | 1.01 (0.28–3.55) | 0.994 |
Systemic embolism | 0 | 0 | 1 (1.2) | 0 | ||||||
New-onset stroke | 11 (4.4) | 0 | 4 (4.9) | 5 (6.0) | 1.01 (0.35–2.92) | 0.988 | 0.98 (0.31–3.08) | 0.972 | 0.75 (0.19–2.90) | 0.675 |
Embolic stroke | 8 (3.2) | 0 | 4 (4.9) | 4 (4.8) | 1.10 (0.33–3.68) | 0.877 | 1.36 (0.41–4.53) | 0.617 | 1.01 (0.25–4.10) | 0.995 |
Haemorrhagic stroke | 3 (1.2) | 0 | 0 | 0 | ||||||
TIA | 0 | 0 | 0 | 1 (1.2) | ||||||
Major bleeding | 14 (5.6) | 0 | 0 | 0 | ||||||
GI bleeding | 8 (3.2) | 0 | 0 | 0 | ||||||
Mucosal bleeding | 11 (4.4) | 0 | 0 | 0 | ||||||
Intracranial bleeding | 2 (0.8) | 0 | 0 | 0 | ||||||
Secondary endpoints | ||||||||||
Cardiac death | 1 (0.4) | 0 | 0 | 1 (1.2) | 2.53 (0.16–40.88) | 0.513 | ||||
All-cause death | 13 (5.2) | 1 (1.2) | 1 (1.2) | 3 (3.6) | 0.71 (0.19–2.60) | 0.606 | 0.21 (0.03–1.61) | 0.134 | 0.26 (0.03–2.72) | 0.262 |
Hospitalization | 4 (1.6) | 0 | 0 | 0 | ||||||
Myocardial infarction | 1 (0.4) | 0 | 0 | 0 | ||||||
Any bleeding | 51 (20.5) | 3 (3.6) | 3 (3.7) | 4 (4.8) | 0.25 (0.09–0.71) | 0.009 | 0.19 (0.06–0.62) | 0.006 | 0.76 (0.17–3.43) | 0.772 |
Minor bleeding | 36 (14.5) | 3 (3.6) | 3 (3.7) | 4 (4.8) | 0.40 (0.14–1.14) | 0.087 | 0.30 (0.09–0.98) | 0.047 | 0.76 (0.17–3.43) | 0.772 |
Net clinical outcomesa | ||||||||||
Primary | 28 (11.2) | 1 (1.2) | 5 (6.2) | 6 (7.2) | 0.53 (0.22–1.28) | 0.157 | 0.48 (0.19–1.25) | 0.133 | 0.85 (0.26–2.83) | 0.789 |
Secondary | 21 (8.4) | 0 | 5 (6.2) | 5 (6.0) | 0.54 (0.20–1.43) | 0.212 | 0.64 (0.24–1.69) | 0.366 | 1.00 (0.28–3.52) | 0.999 |
GI, gastrointestinal; PS, propensity scores; TIA, transient ischaemic attack; HR, hazard ratio; CI, confidence interval.
Primary net clinical outcomes = the composite of new-onset stroke, systemic embolism, major bleeding and all-cause death; secondary net clinical outcomes = the composite of new-onset stroke, systemic embolism and major bleeding; D150 = patients with dabigatran 150mg; D110 = patients with dabigatran 110mg; co-D110 = patients with guideline-concordant dabigatran dose reduction; di-D110 = patients with guideline-discordant dabigatran dose reduction.
Discussion
Atrial fibrillation is the most common cardiac arrhythmia, and its prevalence has doubled in the last decade.7,8 Atrial fibrillation is a strong risk factor for stroke and heart failure, and requires that an intensive anticoagulation therapy be used to prevent TE in patients with AF. Warfarin was the first generation of oral anticoagulants. It is difficult to maintain an appropriate therapeutic range (TTR) with the use of warfarin, because of numerous pharmacodynamic interactions. In this circumstance, NOACs including dabigatran have emerged as powerful alternatives to warfarin, with comparable efficacy and safety without requiring dose adjustments or monitoring prothrombin times. As a completely different type of anticoagulant, the optimal dosage of dabigatran—including maximal efficacy and safety—has been determined from global trials.3,9,10 However, most NOACs trials have only included an approximately 10% Asian population. Therefore, the application of the same NOAC dosage criteria to Asians is somewhat debatable, because of their ethnic and lifestyle differences, and as such requires more clinical evidence.
Asian patients have been prone to develop major bleeding compared with Western patients, including intracranial haemorrhaging for the same dose of warfarin, which has been explained as being due to ethnic differences.11,12 These characteristics were reflected in Japanese guidelines for anticoagulation therapy in patients with AF, which suggested an optimal anticoagulation range of warfarin to be an INR of 1.6–2.6 in patients aged over 70 years.13 In addition, the same perception of higher bleeding risks raised questions about the optimal dosage of NOACs in the Asian population. Chan et al.6 reported on the real-world treatment of Asian patients using dabigatran. Most patients (88%) took dabigatran 110 mg, which reflects that clinicians in Asia favour dabigatran 110 mg regardless of the suggested dose reduction guidelines, possibly because of the perception of high-bleeding risks in Asian patients when using a higher dabigatran dose, 150 mg. The present study revealed similar real-world practices; reflecting the real-world practice in Korea, most patients (62%) took dabigatran 110 mg. Furthermore, one-third of patients received 110 mg based on guideline-discordant dose reduction. Considering global guidelines suggest that the standard dose of dabigatran is 150 mg, the real-world practice pattern in Asia can be deemed erroneous. However, this real-world data raises an important question about the optimal dosage of dabigatran in Asian patients.
Subgroup analyses in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial revealed that for the prevention of TE, the doses of dabigatran 150 mg and 110 mg were not different between Asians and non-Asians.4,5 However, the use of dabigatran for reducing the risk for major bleeding was prominent in Asians compared with non-Asians, although these results were found to be statistically non-significant.4,5 The present study revealed similar results, in that dabigatran displayed a comparable efficacy for the prevention of TE (HR 0.96, 95% CI 0.57–1.61, P = 0.872), whereas a lower rate of major bleeding was prominent in patients using dabigatran (HR 0.41, 95% CI 0.22–0.76, P = 0.005). From these results, numerous reviews suggested that dabigatran might be more beneficial in Asians than non-Asians, especially in terms of major bleeding.5,14,15
However, the optimal dose of dabigatran for Asians has yet to be confirmed, because most studies compared dabigatran and warfarin, not dabigatran 150 and 110 mg. Consistent with the RE-LY trials,3 benefits of dabigatran for reducing the risk of major bleeding in the present study originate from dabigatran 110 mg, not from dabigatran 150 mg. However, inconsistent with the RE-LY trials, there was no benefit for using dabigatran 150 mg in the prevention of TE in the present study. Similarly, real-world data from Taiwan showed that dabigatran 150 mg had no benefit for the prevention of TE over 110 mg.6 These results suggest that both doses of dabigatran have a comparable efficacy for the prevention of TE, whereas dabigatran 110 mg is comparable or superior to dabigatran 150 mg for the reduction of major bleeding in Asians. If both doses of dabigatran exert similar efficacy and safety, there is no reason to choose dabigatran 150 mg in Asians; i.e. if dabigatran 110 mg exerts comparable or superior safety than dabigatran 150, dabigatran 110 mg should be considered the better option for Asians.
To determine whether dabigatran 110 mg is indeed the better option in Korean AF patients, the present study compares dabigatran 110 mg with and without adequate indications for dose reduction according to standard guidelines. Dabigatran without adequate dose reduction (di-D110) displayed a similar efficacy and safety compared with D150. In addition, a lower risk of major bleeding was observed in di-D110 compared with warfarin, whereas it was not observed in D150. Similar results could be identified in patients with a previous history of stroke/TIA. Because the present study included patients taking OACs in the Department of Neurology and Cardiology, a large population of patients with a previous history of stroke/TIA (n = 798, 43.5%) were enrolled. In these patients, comparable efficacy and safety outcomes of D150 or di-D110 over warfarin persisted. There were no differences in the efficacy, safety, and primary and secondary net clinical outcomes between di-D110 vs. D150. These results suggest that a fixed dose of dabigatran 110 mg, regardless of dose reduction criteria, might be sufficient for Korean patients with AF.
Limitations
Limitations of the present study need to be addressed. First, the present study is based on a retrospective analysed. As such, these results can only suggest that dabigatran 110 mg may be a better option for Korean patients over dabigatran 150 mg. Prospective, randomized trials are needed in order to comprehensively determine the optimal dose of dabigatran in Asian patients with AF. Second, the sample size was relatively small compared with global studies. Nevertheless, this sample size of anticoagulants was similar to that of the subgroup analysis for the Asian population in the RE-LY study.16 Third, the mean time each patient remained in the TTR was not provided, which indicates the quality of the INR control. Further prospective trials are needed, which include the best methods to obtain optimal TTRs in patients using warfarin.
Conclusions
Both dabigatran 150 and 110 mg displayed similar efficacy outcomes to warfarin for preventing TE in real-world treatment practices of Korean patients with AF. Dabigatran 110 mg reduced the safety outcomes compared with warfarin, whereas dabigatran 150 mg did not. Current guideline-concordant or -discordant dabigatran 110 mg use was ultimately associated with a significant decrease in bleeding events, while maintaining a similar efficacy outcome. Therefore, dabigatran 110 mg may be a sufficient—even optimal—dose in Korean patients with AF. However, further prospective randomized trials are needed in order to evaluate whether D150 or D110 is the optimal dosage in Asian patients with AF.
Conflict of interest: none declared.