Dual Anti-Thrombotic Therapy With Dabigatran After Percutaneous Coronary Intervention in Atrial Fibrillation　― Japanese and East-Asian Subgroup Analysis of the RE-DUAL PCI Trial ―

Abstract

Background: In the RE-DUAL PCI trial, dual anti-thrombotic therapy with dabigatran and a P2Y₁₂ inhibitor had a lower risk of bleeding and similar risk reduction of thromboembolic events, compared with warfarin triple therapy, in patients with NVAF undergoing PCI. This subanalysis investigated whether the efficacy and safety of dabigatran dual therapy in Japanese and East-Asian patients enrolled in the RE-DUAL PCI trial were similar to those of the overall patient population of the trial.

Methods and Results: RE-DUAL PCI was a multicenter, randomized trial. The primary endpoint was the time to first International Society on Thrombosis and Hemostasis major or clinically relevant non-major bleeding events. Of the East-Asian patients (n=240) enrolled in the RE-DUAL PCI trial, 111 were Japanese and received dabigatran 110 mg (n=50) or 150 mg (n=13) dual therapy, or warfarin triple therapy (n=48). The incidence of the primary endpoint in Japanese patients was 26.0% and 29.2% with dabigatran 110-mg dual therapy and the corresponding warfarin triple therapy, and 23.1% and 30.8% with dabigatran 150-mg dual therapy and the corresponding warfarin triple therapy, respectively. Similar results were observed in the East-Asian population.

Conclusions: This subanalysis of the RE-DUAL PCI trial demonstrated that, like in the overall patient population, dabigatran dual therapy may offer physicians additional options for managing Japanese and East-Asian patients with NVAF receiving PCI.

Patients undergoing percutaneous coronary intervention (PCI), a common management strategy for acute coronary syndrome (ACS),¹ often have comorbid atrial fibrillation (AF)² or other vascular comorbidities.^3–5 AF is the most common arrhythmia in the elderly, affecting approximately 7–14% of Western and 2–3% of Japanese and other East-Asian patients aged ≥80 years.^3,6,7 Furthermore, approximately 5–10% of patients undergoing PCI have comorbid AF.² Management of patients with non-valvular AF (NVAF) who are undergoing PCI requires both anticoagulant and dual antiplatelet therapy (i.e., triple therapy).^4,5,8,9 Given, however, that triple therapy is associated with a high risk of bleeding,^8,10–15 new therapeutic strategies are needed.

Dabigatran etexilate is an oral direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with NVAF. The Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (RE-DUAL PCI) trial compared the use of 2 regimens of dual anti-thrombotic therapy that included dabigatran with the use of triple anti-thrombotic therapy that included warfarin in patients with NVAF who had undergone PCI.¹⁶ It was found that the risk of bleeding was lower in those who received dual therapy with dabigatran and a P2Y₁₂ inhibitor (clopidogrel or ticagrelor), compared with those who received triple therapy with warfarin, a P2Y₁₂ inhibitor and aspirin. Dabigatran dual therapy was non-inferior to triple therapy with respect to the risk reduction of thromboembolic events.

The aim of this subanalysis of the RE-DUAL PCI trial was therefore to determine if the efficacy and safety of dabigatran dual therapy in the Japanese and East-Asian patients enrolled in the trial were similar to those of the overall population of patients in the RE-DUAL PCI trial.

Methods

Study Design

Methods of the prospective, multicenter, randomized, open-label, RE-DUAL PCI trial have been published previously.¹⁶ Briefly, 2,725 patients, ≥18 years of age (≥20 years old in Japan), with NVAF (paroxysmal, persistent or permanent) who had successfully undergone PCI with a bare-metal stent (BMS) or drug-eluting stent (DES) in the previous 120 h due to ACS or stable coronary artery disease were enrolled. Patients with bioprosthetic or mechanical heart valves, severe renal insufficiency (creatinine clearance <30 mL/min), or other major coexisting conditions were excluded.

Following standard anti-thrombotic treatment for the PCI procedure, eligible patients were randomized (1:1:1) to dabigatran (110 mg or 150 mg twice daily) plus a P2Y₁₂ inhibitor (clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily; dabigatran dual therapy); or warfarin (dose adjusted to achieve international normalized ratio [INR] 2.0–3.0, or 2.0–2.6 for elderly Japanese patients [≥70 years old]) plus a P2Y₁₂ inhibitor (clopidogrel 75 mg/day or ticagrelor 90 mg twice daily) and aspirin ≤100 mg/day (warfarin triple therapy). Randomization of elderly patients (≥80 years of age; ≥70 years of age in Japan) outside the USA was restricted to dabigatran 110-mg dual therapy or warfarin triple therapy only, based on dose recommendations in Japan and East Asia. For data comparison, patients with the same age range in the warfarin group were targeted. The minimum treatment duration was 6 months, with aspirin given for 1 month in patients with a BMS and 3 months in those with a DES in the warfarin triple therapy group, and P2Y₁₂ inhibitor given for ≥12 months. The choice of P2Y₁₂ inhibitor was at the discretion of the investigator.

Patients were stratified according to age group (non-elderly or elderly: <80 or ≥80 years of age; <70 or ≥70 years of age in Japan) and region (USA, Japan or other countries). The primary endpoint of the trial was the time to first major or clinically relevant non-major bleeding event, as defined by the International Society on Thrombosis and Hemostasis (ISTH).¹⁷ The trial also descriptively summarized dabigatran dual therapy and warfarin triple therapy with respect to the incidence of the primary endpoint as well as a composite efficacy endpoint of thromboembolic events (myocardial infarction [MI], stroke or systemic embolism), death or unplanned revascularization. Patients were followed up every 3 months for the first year, and then visits and telephone contact alternated every 3 months with a final 1-month post-treatment visit.

Patients in this subanalysis were enrolled in Japan, Hong Kong, Korea, and Taiwan. Japanese patients were analyzed as an independent subgroup as well as being included in the East-Asian patient subpopulation. The sample size for Japanese and East-Asian populations was not planned based on power calculation.

This prospectively defined subanalysis examined the incidence of the first ISTH major or clinically relevant non-major bleeding event in Japanese and East-Asian patients, compared with that of the overall population in the RE-DUAL PCI trial.¹⁶ ISTH major bleeding was defined as any fatal, critical organ (including intracranial bleeding) or clinically overt bleeding with fall in hemoglobin ≥2 g/dL. Other endpoints included death, thromboembolic event, or unplanned revascularization; a composite endpoint of thromboembolic events or death; and individual thromboembolic events and definite stent thrombosis.

Statistical Analysis

The incidence of the primary endpoint was compared between the 110-mg or 150-mg dual therapy group and the warfarin triple therapy group on stratified Cox proportional hazards regression modeling. Analysis of all endpoints was performed on the intention-to-treat population, which included all patients who underwent randomization, regardless of whether they received treatment. Analyses of adverse events included patients who had received at least 1 dose of the trial anticoagulant.

Results

A total of 240 East-Asian patients were enrolled from Japan (n=111), Korea (n=81), Taiwan (n=34) and Hong Kong (n=14) in the RE-DUAL PCI trial. Of the 111 Japanese patients, 50, 13 and 48 patients were randomized to treatment with dabigatran 110-mg, 150-mg dual therapy, and warfarin triple therapy, respectively. Of the East-Asian patients, 83, 56, and 101 patients were randomized to receive dabigatran 110-mg, 150-mg dual therapy, and warfarin triple therapy, respectively. Of the patients randomized to warfarin triple therapy, 41 were elderly, and thus the corresponding warfarin triple therapy group for comparison with the dabigatran 150-mg dual therapy group consisted of 60 patients (Table 1).

Table 1. Baseline Patient Demographics and Clinical Characteristics

	Japan				East Asia
	Dabigatran 110-mg dual therapy (n=50)	Warfarin triple therapy (n=48)	Dabigatran 150-mg dual therapy (n=13)	Corresponding warfarin triple therapy (n=13)†	Dabigatran 110-mg dual therapy (n=83)	Warfarin triple therapy (n=101)	Dabigatran 150-mg dual therapy (n=56)	Corresponding warfarin triple therapy (n=60)†
Age (years)	73.7±7.2	73.3±6.1	66.5±2.1	66.5±2.7	71.4±9.8	70.6±8.8	66.7±6.7	66.2±7.9
Age group
Elderly‡	36 (72.0)	35 (72.9)	0	0	43 (51.8)	41 (40.6)	0	0
Non-elderly	14 (28.0)	13 (27.1)	13 (100.0)	13 (100.0)	40 (48.2)	60 (59.4)	56 (100.0)	60 (100.0)
Male sex	42 (84.0)	42 (87.5)	10 (76.9)	10 (76.9)	70 (84.3)	88 (87.1)	40 (71.4)	53 (88.3)
Diabetes mellitus	24 (48.0)	18 (37.5)	4 (30.8)	4 (30.8)	34 (41.0)	41 (40.6)	17 (30.4)	24 (40.0)
Creatinine clearance (mL/min)§	66.5±19.6	63.2±15.7	72.3±17.5	72.5±13.5	71.5±25.7	70.3±25.5	76.5±26.6	78.2±28.4
CHA2DS2-VASc score	3.9±1.6	3.8±1.5	3.5±1.6	3.2±1.4	3.5±1.7	3.5±1.6	2.9±1.5	3.1±1.6
HAS-BLED score	3.1±0.8	3.1±0.8	3.1±1.1	2.9±1.0	2.9±0.9	2.9±0.9	2.7±0.9	2.7±1.1
Previous stroke	6 (12.0)	8 (16.7)	4 (30.8)	2 (15.4)	9 (10.8)	19 (18.8)	7 (12.5)	13 (21.7)
Previous MI	13 (26.0)	9 (18.8)	5 (38.5)	3 (23.1)	18 (21.7)	15 (14.9)	11 (19.6)	8 (13.3)
Previous PCI	21 (42.0)	18 (37.5)	6 (46.2)	5 (38.5)	26 (31.1)	38 (37.6)	15 (26.8)	24 (40.0)
Previous CABG	2 (4.0)	0	0	0	3 (3.6)	0	2 (3.6)	0
Type of NVAF
Persistent	6 (12.0)	9 (18.8)	4 (30.8)	3 (23.1)	14 (16.9)	23 (22.8)	11 (19.6)	15 (25.0)
Permanent	15 (30.0)	15 (31.3)	3 (23.1)	2 (15.4)	28 (33.7)	35 (34.7)	14 (25.0)	21 (35.0)
Paroxysmal	29 (58.0)	24 (50.0)	6 (46.2)	8 (61.5)	41 (49.4)	43 (42.6)	31 (55.4)	24 (40.0)
Indication for PCI
Stable angina or positive stress test	35 (70.0)	32 (66.7)	10 (76.9)	7 (53.8)	42 (50.6)	62 (61.4)	19 (33.9)	35 (58.3)
ACS	8 (16.0)	5 (10.4)	3 (23.1)	3 (23.1)	34 (41.0)	30 (29.7)	35 (62.5)	24 (40.0)
Staged procedure	9 (18.0)	6 (12.5)	0	0	12 (14.5)	15 (14.9)	8 (14.3)	8 (13.3)
Other	4 (8.0)	7 (14.6)	0	3 (23.1)	4 (4.8)	7 (6.9)	0	3 (5.0)
Type of stent
DES	49 (98.0)	48 (100)	11 (84.6)	13 (100)	78 (94.0)	98 (97.0)	50 (89.3)	57 (95.0)
BMS	1 (2.0)	0	2 (15.4)	0	4 (4.8)	3 (3.0)	5 (8.9)	3 (5.0)
DES and BMS	0	0	0	0	0	0	1 (1.8)	0
Unknown	0	0	0	0	1 (1.2)	0	0	0

Data given as mean±SD or n (%). ^†Included only patients who had been eligible to be assigned to the dabigatran 150-mg dual therapy group (i.e., did not include elderly patients). ^‡≥70 years old in Japan and ≥80 years old elsewhere. ^§Calculated using the Cockcroft-Gault equation. ACS, acute coronary syndrome; BMS, bare-metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; NVAF, non-valvular atrial fibrillation; MI, myocardial infarction; PCI, percutaneous coronary intervention.

In Japanese patients receiving warfarin triple therapy, the time in the therapeutic INR range (2.0–3.0) was 57.6%, and 72.3% using the INR range 1.6–2.6 for elderly Japanese patients in accordance with guidelines for pharmacotherapy of AF (JCS 2013).³ The time in the therapeutic INR range in East-Asian patients receiving warfarin (2.0–3.0) was 53.8%, and it was 61.7% in the INR range 1.6–2.6 for elderly patients pursuant to JCS 2013. All Japanese patients received clopidogrel, and most of the East-Asian patients received clopidogrel; only 3.8% of patients received ticagrelor.

Primary Endpoint

In Japanese patients, the incidence of the primary endpoint (i.e., time to first ISTH major or clinically relevant non-major bleeding event) was 26.0% in the 110-mg dual therapy group compared with 29.2% in the warfarin triple therapy group (HR, 0.93; 95% CI: 0.44–1.99), and 23.1% in the 150-mg dual therapy group compared with 30.8% in the corresponding warfarin triple therapy group (HR, 0.78; 95% CI: 0.17–3.48; Table 2). In the East-Asian patients, the incidence of the primary endpoint was 21.7% in the 110-mg dual therapy group compared with 28.7% in the warfarin triple therapy group (HR, 0.69; 95% CI: 0.38–1.25), and 19.6% in the 150-mg dual therapy group compared with 26.7% in the corresponding warfarin triple therapy group (HR, 0.69; 95% CI: 0.32–1.48; Table 2). Differences between the 110-mg dual therapy group and the warfarin triple therapy group, as well as between the 150-mg dual therapy group and the corresponding warfarin triple therapy group, were not significant in either the Japanese (P=0.8553 and P=0.7431, respectively) or the overall East-Asian patient populations (P=0.2237 and P=0.3379, respectively; Table 2). No intracranial bleeding was reported in Japanese patients, and rates of ISTH major bleeding and Thrombolysis in Myocardial Infarction (TIMI)-defined major and/or minor bleeding events were low (Table 3).

Table 2. Primary Endpoint: ISTH Major or Clinically Relevant Non-Major Bleeding

	Dabigatran 110-mg dual therapy, n (%)	Warfarin triple therapy, n (%)	HR (95% CI)	P-value	Dabigatran 150-mg dual therapy, n (%)	Corresponding warfarin triple therapy, n (%)	HR (95% CI)	P-value
Japan	(n=50)	(n=48)			(n=13)	(n=13)†
	13 (26.0)	14 (29.2)	0.93 (0.44–1.99)	0.8553	3 (23.1)	4 (30.8)	0.78 (0.17–3.48)	0.7431
East Asia	(n=83)	(n=101)			(n=56)	(n=60)†
	18 (21.7)	29 (28.7)	0.69 (0.38–1.25)	0.2237	11 (19.6)	16 (26.7)	0.69 (0.32–1.48)	0.3379
Overall‡	(n=981)	(n=981)			(n=763)	(n=764)
	151 (15.4)	264 (26.9)	0.52 (0.42–0.63)	<0.001	154 (20.2)	196 (25.7)	0.72 (0.58–0.88)	0.002

^†Included only patients who had been eligible to be assigned to the dabigatran 150-mg dual therapy group (i.e., did not include elderly patients), ^‡Cannon CP, et al.16 ISTH, International Society on Thrombosis and Hemostasis.

Table 3. Other Safety Outcomes

	Japan				East Asia
	Dabigatran 110-mg dual therapy (n=50)	Warfarin triple therapy (n=48)	Dabigatran 150-mg dual therapy (n=13)	Corresponding warfarin triple therapy (n=13)†	Dabigatran 110-mg dual therapy (n=83)	Warfarin triple therapy (n=101)	Dabigatran 150-mg dual therapy (n=56)	Corresponding warfarin triple therapy (n=60)†
ISTH major bleeding	2 (4.0)	3 (6.3)	0	1 (7.7)	4 (4.8)	6 (5.9)	1 (1.8)	3 (5.0)
ISTH clinically relevant non-major bleeding	12 (24.0)	11 (22.9)	3 (23.1)	3 (23.1)	16 (19.3)	24 (23.8)	11 (19.6)	14 (23.3)
Intracranial bleeding	0	0	0	0	0	1 (1.0)	0	1 (1.7)
GI bleeding	0	2 (4.2)	0	1 (7.7)	2 (2.4)	3 (3.0)	0	2 (3.3)
TIMI major bleeding	1 (2.0)	0	0	0	1 (1.2)	2 (2.0)	0	2 (3.3)
TIMI minor bleeding	0	2 (4.2)	0	0	0	2 (2.0)	0	0
TIMI major or minor bleeding	1 (2.0)	2 (4.2)	0	0	1 (1.2)	4 (4.0)	0	2 (3.3)

Data given as n (%). ^†Included only patients who had been eligible to be assigned to the dabigatran 150-mg dual therapy group (i.e., did not include elderly patients). GI, gastrointestinal; ISTH, International Society on Thrombosis and Hemostasis; TIMI, Thrombolysis in Myocardial Infarction.

Secondary Endpoints

In the Japanese patient group, the incidence of the composite efficacy endpoint of thromboembolic events (MI, stroke or systemic embolism), death, or unplanned revascularization was 17.5% in the 2 dabigatran dual therapy groups combined, and the incidence was 20.8% in the warfarin triple therapy group. Corresponding values in East-Asian patients were 15.1% in the combined dabigatran dual therapy group and 14.9% in the warfarin triple therapy group.

The incidence of another composite endpoint of thromboembolic events or death was 6.3% in the combined dabigatran dual therapy group, and 6.3% in the warfarin triple therapy group in Japanese patients, and 7.9% in the combined dabigatran dual therapy group, and 7.9% in the warfarin triple therapy group in the East-Asian population.

Other efficacy endpoints are listed in Table 4. In the Japanese patient group, MI occurred in 1 patient each in the dabigatran 110-mg dual therapy and warfarin triple therapy groups, and no MI was observed in the 150-mg dual therapy group. Unplanned revascularization occurred in 5, 4 and 8 patients in the dabigatran 110-mg and 150-mg dual therapy and warfarin triple therapy groups, respectively. Stroke occurred in 1 patient in the dabigatran 150-mg dual therapy group, and no stent thrombosis occurred in any of the groups. In the East-Asian population, MI occurred in 2 patients each in the dabigatran 110-mg and 150-mg dual therapy groups and in 1 patient in the warfarin triple therapy group. Unplanned revascularization occurred in 7, 7 and 8 patients in the dabigatran 110-mg and 150-mg dual therapy and warfarin triple therapy groups, respectively. Stroke occurred in 1 patient each in the dabigatran 110-mg and 150-mg dual therapy groups, and in 2 patients in the warfarin triple therapy group. Furthermore, 1 event of stent thrombosis occurred in the dabigatran 150-mg dual therapy group.

Table 4. Efficacy Endpoints

	Japan				East Asia
	Dabigatran 110-mg dual therapy (n=50)	Warfarin triple therapy (n=48)	Dabigatran 150-mg dual therapy (n=13)	Corresponding warfarin triple therapy (n=13)†	Dabigatran 110-mg dual therapy (n=83)	Warfarin triple therapy (n=101)	Dabigatran 150-mg dual therapy (n=56)	Corresponding warfarin triple therapy (n=60)†
Composite efficacy endpoints:
Thromboembolic events, death, or unplanned revascularization	7 (14.0)	10 (20.8)	4 (30.8)	4 (30.8)	12 (14.5)	15 (14.9)	9 (16.1)	7 (11.7)
Thromboembolic events or death	3 (6.0)	3 (6.3)	1 (7. 7)	0	7 (8.4)	8 (7.9)	4 (7.1)	3 (5.0)
Death	2 (4.0)	2 (4.2)	0	0	5 (6.0)	5 (5.0)	1 (1.8)	1 (1.7)
MI	1 (2.0)	1 (2.1)	0	0	2 (2.4)	1 (1.0)	2 (3.6)	0
Stroke	0	0	1 (7.7)	0	1 (1.2)	2 (2.0)	1 (1.8)	2 (2.3)
Definite stent thrombosis	0	0	0	0	0	0	1 (1.8)	0
Unplanned revascularization	5 (10.0)	8 (16.7)	4 (30.8)	4 (30.8)	7 (8.4)	8 (7.9)	7 (12.5)	4 (6.7)

Data given as n (%). ^†Included only patients who had been eligible to be assigned to the dabigatran 150-mg dual therapy group (i.e., did not include elderly patients). MI, myocardial infarction.

Serious Adverse Events

In the Japanese patients, serious adverse events occurred in 20 dabigatran 110-mg (40.0%) and in 5 dabigatran 150-mg (38.5%) dual therapy group patients, and in 22 warfarin triple therapy group patients (45.8%; Supplementary Table 1). Adverse events leading to discontinuation were similar between treatment groups in the Japanese population (6 patients from the dabigatran 110-mg dual therapy group, 1 patient from the dabigatran 150-mg dual therapy group, and 4 patients from the warfarin triple therapy group; Supplementary Table 2).

In the East-Asian population, serious adverse events occurred in 31 dabigatran 110-mg (37.3%) and in 17 dabigatran 150-mg (30.9%) dual therapy and in 35 warfarin triple therapy patients (37.2%; Supplementary Table 1). Furthermore, in the 110-mg and 150-mg dual therapy, and the warfarin triple therapy groups, 11, 7, and 9 patients had adverse events that led to treatment discontinuation, respectively (Supplementary Table 2).

Discussion

In the Japanese and East-Asian patients enrolled in the RE-DUAL PCI trial, dabigatran dual therapy and warfarin triple therapy were similar with regard to the incidence of first ISTH major or clinically relevant non-major bleeding event, while the rates of ISTH major bleeding events were lower in the dual therapy groups. TIMI major bleeding events were low and no instances of intracranial bleeding occurred in Japanese patients who received dabigatran dual therapy, while intracranial bleeding was reported in 1 patient on warfarin triple therapy in the East-Asian subpopulation. In addition, dual therapy with dabigatran was similar to warfarin triple therapy with respect to the composite efficacy endpoint of thromboembolic events, death, or unplanned revascularization. Therefore, dual therapy with dabigatran appeared to have similar efficacy compared with warfarin triple therapy, but with reduced risk of bleeding events.

The rates of MI and definite stent thrombosis were lower in this subgroup of Japanese patients than in the overall RE-DUAL PCI trial, suggesting that these events develop infrequently in the Japanese/Asian population. The rate of the event “unplanned revascularization” was also generally low, although the Japanese groups receiving dabigatran 300-mg dual therapy or warfarin triple therapy tended to have a slightly higher incidence of unplanned revascularization (30.8% in both). This can be explained by the small number of patients in these 2 groups. Because the denominators were low, a single patient makes a substantial contribution to the incidence, leading to the apparently high incidences.

This subanalysis of RE-DUAL PCI trial evaluated the efficacy and safety of dabigatran dual therapy in Japanese and East-Asian patients to see if they were similar to those in the overall trial population. It was found that, although the incidence of the primary endpoint was numerically higher and the 95% CI associated with it were wider in the Japanese and East-Asian patient populations enrolled in RE-DUAL PCI trial than in the overall patient population, dual therapy with dabigatran showed a trend toward better outcome over warfarin triple therapy. In Japanese patients receiving 110-mg dual therapy, the corresponding warfarin triple therapy, 150-mg dual therapy and the corresponding warfarin triple therapy, the incidence of the primary endpoint was 26.0%, 29.2%, 23.1%, and 30.8%, respectively, which was associated with absolute risk reductions of 3.2% and 7.7% with dabigatran 110-mg and 150-mg dual therapy, respectively. In the overall RE-DUAL PCI trial patient population, the incidence was 15.4%, 26.9%, 20.2%, and 25.7%, respectively,¹⁶ and was associated with absolute risk reductions of 11.5% and 5.5% with dabigatran 110-mg and 150-mg dual therapy, respectively. The incidence of the primary endpoint was higher in Japanese patients receiving dabigatran 110-mg dual therapy (26.0%) compared with the group receiving this dose in the overall cohort (15.4%).¹⁶ The higher rate of the primary endpoint in the Japanese cohort resulted mainly from the high rate of clinically relevant non-major bleeding events in the Japanese group receiving dabigatran 110-mg dual therapy (24.0%), because the rate of major bleeding events in the Japanese group receiving dabigatran 110-mg dual therapy (4.0%) was similar to that in the group receiving dabigatran 110-mg dual therapy in the overall cohort (5.0%).¹⁶ More patients in the Japanese dabigatran 110-mg dual therapy group were elderly (72.0%), whereas only 22.9% in the overall dabigatran 110-mg dual therapy group and 51.8% in the East-Asian dabigatran 110-mg dual therapy group were elderly. This resulted in a higher overall mean age (73.7±7.2 years) in the Japanese cohort of patients receiving this regimen than in the overall cohort (71.5±8.9 years) and in the East-Asian cohort (71.4±9.8 years). The risk of bleeding is higher for older patients treated with anticoagulant therapy,^18,19 which may explain why Japanese patients receiving dabigatran 110-mg dual therapy tended to have a higher incidence of clinically relevant non-major bleeding than patients receiving this dose in the overall cohort or in the cohort of East Asian patients.

The rate of ISTH major bleeding in Japanese patients was similar or lower compared with the overall RE-DUAL PCI trial patient population.¹⁶ TIMI major bleeding and intracranial bleeding were also lower in the Japanese population. Furthermore, dual therapy with dabigatran 110-mg or 150-mg was associated with a significantly lower risk of major or clinically relevant non-major bleeding events, compared with warfarin triple therapy (P<0.001 and P=0.002, respectively) in the overall RE-DUAL PCI trial population.¹⁶ It is important to note that there were some differences between the Japanese and East-Asian subpopulations and the overall RE-DUAL PCI trial population, mainly that Japanese and East-Asian patients had a lower creatinine clearance, a lower proportion of patients had undergone PCI due to ACS, spent less time in the therapeutic INR range and a higher proportion of patients had a DES at baseline, compared with the overall RE-DUAL PCI trial population.¹⁶

In this subanalysis, patients who received warfarin triple therapy received aspirin only for 1 or 3 months. Therefore, for most of the trial’s duration, these patients received dual therapy with warfarin and a P2Y₁₂ inhibitor; a consensus document produced by a panel of North American experts validates this practice.²⁰ Despite this, the risk of bleeding was numerically higher in patients on warfarin triple therapy compared with those on dual therapy.

Underuse of anticoagulant therapy, as well as suboptimal intensity, has been reported in several studies conducted in Japanese patients with AF undergoing PCI who were at high risk of thrombosis.² Furthermore, optimal oral anticoagulation is associated with significantly lower incidence of stroke.² In the present subanalysis, dual therapy using dabigatran doses approved worldwide for stroke prevention provided effective anticoagulation therapy in Japanese and/or East-Asian patients with NVAF after PCI, with a reduced risk of bleeding compared with warfarin triple therapy. This is in line with international and Japanese guidelines, which recommend risk-based anti-thrombotic therapy for patients with NVAF after PCI.^3,21,22

While the strengths of this trial included the prospective methodology with direct regimen comparison of real-world dosing, due to the limited number of participants for this subanalysis, results are not statistically powered. The sample size for Japanese and East-Asian populations was not planned based on power calculation. There were only 13 patients in the dabigatran 150-mg dual therapy group because patients ≥70 years of age were not eligible to be assigned to this dosage group in Japan. The open-label nature of the trial may also introduce bias, but this was controlled by a PROBE design and the use of an independent and blinded adjudication committee for analysis of endpoints. In addition, given that patients treated with clopidogrel or ticagrelor, as well as those who received aspirin for 1 or 3 months, were analyzed collectively, the individual contributions of these variations in the warfarin triple therapy regimen could not be assessed. Furthermore, the age group definitions varied between countries (e.g., Japan vs. USA); therefore, direct comparisons could not be made.

Conclusions

The results from the Japanese and East-Asian subanalysis were similar to those of the overall RE-DUAL PCI trial patient population; therefore, conclusions drawn from the overall trial results are also applicable to the Japanese and East-Asian patients. These dabigatran dual therapy regimens, using doses approved worldwide for stroke prevention, may offer physicians additional options for managing Japanese and East-Asian patients with NVAF receiving PCI.

Acknowledgments

We thank all the patients and investigators involved in this trial. The authors would like to thank Andrea Bothwell, who wrote the outline of this manuscript on behalf of in Science Communications, Springer Healthcare; and Georgii Filatov of inScience Communications, Springer Healthcare, who wrote the first draft of this manuscript. This medical writing assistance was funded by Nippon Boehringer Ingelheim. Statistical analysis was provided by Eva Kleine of Boehringer Ingelheim, with publication management and editorial support by Daisuke Kuroki of Nippon Boehringer Ingelheim.

Disclosures

J.A. received lecture fees/scholarship funds from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai Pfizer and Sanofi. K. Okumura received lecture fees from Boehringer Ingelheim. K.N. received lecture fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo and Pfizer. K.K. received lecture fees/scholarship funds from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Sanofi. Y.M. received lecture fees/scholarship funds from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Pfizer and Sanofi. K. Okazaki and T.F. are employees of Nippon Boehringer Ingelheim. T.K. received lecture fees/scholarship funds from Boehringer Ingelheim.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0874

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