Cardiovascular outcomes during treatment with dabigatran: comprehensive analysis of individual subject data by treatment

Figures & data

Table 1 Summary of MI rates in studies of stroke prevention in AF

Study	Total treated (number on test treatment)	Test treatment	MI rate (% per year)	Comparator	MI rate (% per year)
ACTIVE-W^Citation5	6,706 (1,557)	Clopidogrel, ASA qd	0.86	Warfarin	0.55
ACTIVE-A^Citation8	7,554	ASA qd	0.9	N/A
ACTIVE-A^Citation8	7,554	Clopidogrel/ASA	0.7	N/A
AMADEUS^Citation7	4,576	Idraparinux	0.8	Warfarin	0.6
SPORTIF III^Citation3	3,407	Ximelagatran	1.1	Warfarin	0.6
SPORTIF V^Citation4	3,922	Ximelagatran	1.0	Warfarin	1.4
BAFTA^Citation6	973	ASA	1.2	Warfarin	1.1
RE-LY^Citation1,Citation2,a	18,113	Dabigatran 110 mg bid	0.82	Warfarin	0.64
RE-LY^Citation1,Citation2,a	18,113	Dabigatran 150 mg bid	0.81	Warfarin	0.64
AVERROES^Citation9	5,599	Apixaban 5 mg bid	0.8	ASA	0.9
ARISTOTLE^Citation11,b	18,201	Apixaban 5 mg bid	0.53	Warfarin	0.61
ROCKET^Citation10,a	14,236	Rivaroxaban 20 mg	0.91	Warfarin	1.12
RELY-ABlE^Citation46	5,851	Dabigatran 110 mg bid	0.72	N/A	N/A
RELY-ABlE^Citation46	5,851	Dabigatran 150 mg bid	0.69	N/A	N/A

Notes:

a New oral anticoagulation trial with MI definition including any cardiac enzyme elevations greater than the ULN

b new oral anticoagulant trial with MI definition only including cardiac enzyme elevations >2 × ULN.

Abbreviations: AF, atrial fibrillation; ASA, acetylsalicylic acid; bid, twice daily; MI, myocardial infarction; qd, once daily; N/A, not available; ACTIVE, Atrial fibrillation Clopidogrel Trial with irbesartan for prevention of Vascular Events; AMADEUS, Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation; SPORTIF, Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation; BAFTA, Birmingham Atrial Fibrillation Treatment of the Aged; RE-LY, Randomized Evaluation of long-term anticoagulation therapY; AVERROES, Apixaban Versus Acetylsalicylic acid (ASA) to Prevent Strokes; ARISTOTLE, Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation; ROCKET, Rivaroxaban Once-daily for prevention of stroke and Embolism Trial in Atrial Fibrillation; RELY-ABLE, Long Term Multi-center Extension of Dabigatran Treatment in Patients With Atrial Fibrillation Who Completed RE-LY Trial; ULN, upper limit of normal.

Table 2 Overview of dabigatran trials included in analysis

Indication and trials	Comparator; other notes
Primary VTE prevention (n = 6)	Enoxaparin (n = 5);<br/> placebo (n = 1)
BISTRO II^Citation20	Enoxaparin; no approved dabigatran dose for this indication was tested
Japanese TKR^Citation24	Placebo; no CV events occurred
RE-MODEL^Citation21	Enoxaparin
RE-NOVATE^Citation22	Enoxaparin
RE-MOBILIZE^Citation23	Enoxaparin
RE-NOVATE II^Citation25	Enoxaparin
Stroke prophylaxis in AF (n = 3)
PETRO^Citation26	Adjusted-dose warfarin;<br/> no CV events occurred
Japanese AF^Citation27	Adjusted-dose warfarin;<br/> no CV events occurred
RE-LY^Citation1,Citation2	Adjusted-dose warfarin
Secondary VTE prevention (n = 2)
RE-MEDY^Citation28	Adjusted-dose warfarin
RE-SONATE^Citation29	Placebo
Acute VTE treatment (n = 2)
RE-COVER^Citation30	Adjusted-dose warfarin
RE-COVER II^Citation31	Adjusted-dose warfarin
ACS (n = 1)
RE-DEEM^Citation32	Placebo

Abbreviations: AF, atrial fibrillation; ACS, acute coronary syndrome; CV, cardiovascular; VTE, venous thromboembolism; TKR, total knee replacement; BISTRO, Boehringer Ingelheim Study in Thrombosis; PETRO, Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation; RE-DEEM, RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multi-centre, Prospective, Placebo Controlled, Cohort Dose Escalation Study; RE-LY, Randomized Evaluation of Long-term anticoagulation therapY; RE-COVER, A Randomized Trial of Dabigatran Versus Warfarin in the Treatment of acute Venous Thromboembolism; RE-MODEL, Regulation of Coagulation in Orthopedic surgery to pRevent Deep venous thrombosis and pulmonary embolism; RE-NOVATE, Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty; RE-MOBILIZE, prevention of venous thromboembolism after total knee arthroplasty trial; RE-MEDY, A Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg bid) Compared to Warfarin (INR 2.0–3.0) for the Secondary Prevention of Venous Thromboembolism; RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE.

Table 3 Summary of studies included in the meta-analyses

Study	Trial registration numbers	Total treated (number on dabigatran)	Dose (mg)	Duration	Comparator	Best data	Events adjudicated	Washout period (days)
Primary VTE prevention in orthopedic surgery
BISTRO II^Citation20	NCT01225822, 1160.19	1,949 (1,557)	50, 150, 225 bid, 300 qd	6–10 days	Enoxaparin	AE	None	7
RE-MODEL^Citation21	NCT00168805, 1160.25	2,596 (1,728)	150, 220 qd	6–10 days	Enoxaparin	ACSb	MI	3
RE-NOVATE^Citation22	NCT00168818, 1160.48	3,463 (2,309)	150, 220 qd	28–35 days	Enoxaparin	ACSb	MI	3
RE-MOBILIZE^Citation23	NCT00152971, 1160.24	2,076 (1,382)	150, 220 qd	12–15 days	Enoxaparin	ACSb	MI	3
Japanese TKR^Citation24	NCT00246025, 1160.50	512 (388)	110,150, 220 qd	11–14 days	Placebo	AE	None	3
RE-NOVATE II^Citation25	NCT00657150, 1160.64	2,013 (1,010)	220 qd	28–35 days	Enoxaparin	AE	None	3
Stroke prevention in AF
PETRO^Citation26	NCT01227629, 1160.20	502 (432)	50, 150, 300 bida	12 weeks	Warfarin	OUTC	None	6
Japanese AF^Citation27	NCT01136408, 1160.49	166 (104)	110, 150 bid	12 weeks	Warfarin	OUTC	None	6
RE-LY^Citation1,Citation2	NCT00262600, 1160.26	18,040 (12,042)	110, 150 bid	2 years	Warfarin	TIMEV	MI, CVA, CVD, VD	6
Secondary VTE prevention
RE-MEDY^Citation28	NCT00329238, 1160.47	2,856 (1,430)	150 bid	6–36 months	Warfarin	ACSc	MI, CVD	6
RE-SONATE^Citation29	NCT00558259, 1160.63	1,343 (684)	150 bid	6 months	Placebo	ACSc	MI, CVD, VD	6
Acute VTE treatment
RE-COVER^Citation30	NCT00291330, 1160.53	2,539 (1,273)	150 bid	6 months	Warfarin	ACSc	MI	6
RE-COVER II^Citation31	NCT00680186, 1160.46	2,568 (1,280)	150 bid	6 months	Warfarin	ACSc	MI	6
ACS
RE-DEEM^Citation32	NCT00621855, 1160.67	1,861 (1,490)	50, 75, 110, 150 bid	6 months	Placebo	TIMEV	MI, CVD	6

Notes: For best data of ACS and TIMEV, the event-adjudicated column shows the specific event endpoints that were analyzed for a specific study.

a Alone or combined with 81 or 325 mg of aspirin

b ACS captured by use of MedDRA triggers

c ACS events captured by investigator evaluation for ACS.

Abbreviations: ACS, MedDRA terms triggering blinded adjudication; AE, adverse event data; AF, atrial fibrillation; bid, twice daily; CVA, stroke; CVD, cardiovascular death; MI, myocardial infarction; qd, once daily; OUTC, outcome event, prespecified and investigator reported, but not adjudicated; TKR, total knee replacement; MedDRA, Medical Dictionary for Regulatory Authorities; TIMEV, time to an outcome event with blinded adjudication; VD, vascular death; VTE, venous thromboembolism; BISTRO, Boehringer Ingelheim Study in Thrombosis; PETRO, Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation; RE-DEEM, RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multicentre, Prospective, Placebo Controlled, Cohort Dose Escalation Study; RE-LY, Randomized Evaluation of Long-term anticoagulation therapY; RE-COVER, A Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RE-MODEL, Regulation of Coagulation in Orthopedic surgery to pRevent Deep venous thrombosis and pulmonary embolism; RE-NOVATE, Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty; RE-MOBILIZE, prevention of venous thromboembolism after total knee arthroplasty trial; RE-MEDY, A Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0–3.0) for the Secondary Prevention of Venous Thromboembolism; RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the long Term Prevention of Recurrent Symptomatic VTE.

Figure 1 (A) Cardiovascular events for dabigatran 150 mg twice daily (n = 10,042) versus warfarin (n = 9,987) in treated patients (randomization to study termination), (B) cardiovascular events for dabigatran 110 mg twice daily (n = 5,983) versus warfarin (n = 5,998) in treated patients (randomization to study termination). (A) The analysis includes RE-LY, RE-MEDY, RE-COVER, and RE-COVER II.^1,2,28,30,31 Two studies also compared dabigatran 150 mg twice daily versus warfarin, but no cardiovascular events occurred in these studies and they are not included in this comparison.^26,27 Heterogeneity was seen in the following composite endpoints: MI and stroke not leading to vascular death and cardiovascular death, P = 0.07; MI and stroke and vascular death, P = 0.05. (B) This analysis includes RE-LY.^1,2 One study also compared dabigatran 110 mg twice daily versus warfarin, but there were no cardiovascular events in that study.²⁷

Notes: MI (including silent) = clinical MI and silent MI as determined by electrocardiogram changes from baseline; nonfatal stroke = stroke + not vascular death; cardiovascular death = nonfatal MI + nonfatal stroke + cardiovascular death.
Abbreviations: bid, twice daily; CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; OR, odds ratio; RE-LY, Randomized Evaluation of Long-term anticoagulation therapY; RE-COVER, A Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RE-MODEL, Regulation of Coagulation in Orthopedic surgery to pRevent Deep venous thrombosis and pulmonary embolism; RE-MEDY, A Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0–3.0) for the Secondary Prevention of Venous Thromboembolism.

Table 4 Rates of MI and CV events in RE-LY,^1,2,12 randomized set

	Dabigatran 110 mg bid (n = 6,015)	Dabigatran 150 mg bid (n = 6,076)	Warfarin (n = 6,022)	Dabigatran 110 mg bid versus warfarin (n = 12,037)		Dabigatran 150 mg bid versus warfarin (n = 12,098)
	n (%)	n (%)	n (%)	RR (95% CI)	P-value	HR (95% CI)	P-value
All stroke	171 (1.44)	122 (1.01)	186 (1.58)	0.91 (0.74–1.12)	0.38	0.64 (0.51–0.81)	<0.001
Total MI	98 (0.82)	97 (0.81)	75 (0.64)	1.29 (0.96–1.75)	0.09	1.27 (0.94–1.71)	0.12
Clinical MI	87 (0.73)	89 (0.74)	66 (0.56)	1.30 (0.95–1.80)	0.10	1.32 (0.96–1.18)	0.09
Silent MI	11 (0.09)	8 (0.07)	9 (0.08)	1.22 (0.55–2.93)	0.66	0.87 (0.34–2.27)	0.72
Fatal MIa	16 (0.13)	13 (0.11)	12 (0.10)	1.32 (0.63–2.80)	0.46	1.06 (0.49–2.33)	0.88
Vascular death	289 (2.43)	274 (2.28)	317 (2.69)	0.90 (0.77–1.06)	0.21	0.85 (0.72–0.99)	0.04
CV deathb	177 (1.49)	161 (1.34)	174 (1.48)	1.01 (0.82–1.24)	0.94	0.91 (0.73–1.12)	0.37
All-cause mortality	446 (3.75)	438 (3.64)	487 (4.13)	0.91 (0.80–1.03)	0.13	0.88 (0.77–1.00)	0.05
Clinical MI and CV death	243 (2.04)	235 (1.95)	228 (1.93)	1.06 (0.88–1.27)	0.55	1.01 (0.84–1.21)	0.91
Clinical MI and all-cause death	505 (4.24)	498 (4.14)	532 (4.51)	0.94 (0.83–1.06)	0.31	0.92 (0.81–1.04)	0.16
Stroke, SEE, PE, all MI, and vascular death	507 (4.26)	443 (3.68)	513 (4.35)	0.98 (0.87–1.11)	0.75	0.84 (0.74–0.96)	0.009
Clinical MI by baseline history of CAD
No	40 (0.5)	42 (0.5)	29 (0.3)	1.36 (0.84–2.20)	0.21	1.43 (0.89–2.30)	0.14
Yes	47 (1.4)	47 (1.4)	37 (1.1)	1.27 (0.82–1.95)	0.28	1.22 (0.79–1.87)	0.37
Clinical MI by baseline history of MI
No	60 (0.6)	52 (0.5)	38 (0.4)	1.57 (1.04–2.36)	0.03	1.35 (0.89–2.05)	0.16
Yes	27 (1.4)	37 (1.8)	28 (1.5)	0.94 (0.55–1.59)	0.80	1.25 (0.77–2.05)	0.37
Clinical MI by baseline history of VHD
No	60 (0.64)	60 (0.64)	58 (0.63)	1.02 (0.71–1.46)	0.93	1.02 (0.71–1.46)	0.93
Yes	27 (1.06)	29 (1.08)	8 (0.31)	3.44 (1.57–7.58)	0.002	3.51 (1.60–7.67)	0.002

Notes:

a Within 30 days of event

b sudden and nonsudden cardiac death. Part of this table is adapted from The New England Journal of Medicine, Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L, Newly identified events in the RE-LY trial, 363(19):1875–1876.1 Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Part of this table is adapted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: Circulation. Hohnloser SH, Oldgren J, Yang S, et al, Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. 2012;125(5):669–676.12 Copyright © 2012.

Abbreviations: bid, twice daily; CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; PE, pulmonary embolism; RR, relative ratio; SEE, systemic embolic event; VHD, valvular heart disease; RE-LY, Randomized Evaluation of Long-term anticoagulation therapY.

Table 5 Effect of INR control on MI rates in warfarin-treated patients in RE-LY

	INR TTR <65%	INR TTR ≥65%
Subject number (n)	2,595	3,194
Subject years (n)	4,451	6,175
MI (n, % per year)	32 (0.72)	30 (0.49)

Abbreviations: INR, international normalized ratio; MI, myocardial infarction; TTR, time in therapeutic range; RE-LY, Randomized Evaluation of Long-term anticoagulation therapY.

Table 6 Timing of MI with respect to treatment in RE-LY, randomized set

	Dabigatran 110 mg bid (n = 6,015)	Dabigatran 150 mg bid (n = 6,076)	Warfarin (n = 6,022)
	n (%)	n (%)	n (%)
Total number of MI cases, n (%)	87 (1.5)	89 (1.5)	66 (1.1)
MI on or ≤6 days off study drug, n (%)	69 (1.1)	69 (1.1)	54 (90.9)
On study drug, n (%)	56 (0.9)	59 (1.0)	46 (0.8)
Off study drug, n (%)
≤6 days off study drug	13 (0.2)	10 (0.2)	8 (0.1)
>6 days off study drug	17 (0.3)	20 (0.3)	12 (0.2)
6 and ≤30 days	2 (0.0)	3 (0.0)	4 (0.1)
30 and ≤90 days	2 (0.0)	3 (0.0)	2 (0.0)
>90 days	13 (0.2)	14 (0.2)	6 (0.1)
Randomized and not treated, n (%)	1 (0.0)	0 (0.0)	0 (0.0)

Abbreviations: bid, twice daily; MI, myocardial infarction; RE-LY, Randomized Evaluation of Long-term anticoagulation therapY.

Table 7 CV events in dabigatran VTE treatment, secondary VTE prophylaxis, and primary VTE prophylaxis in orthopedic surgery trials

	Acute VTE treatment				Secondary VTE prevention				Primary VTE prevention after orthopedic surgery^Citation13
	RE-COVER^Citation30		RE-COVER II^Citation31		RE-MEDYb,^Citation28		RE-SONATEb,^Citation29		RE-MOBILIZE,^Citation23 RE-MODEL,^Citation21 and RE-NOVATE^Citation22
	Dab	Warf	Dab	Warf	Dab	Warf	Dab	Plac	Dab	Enox
Subjects,a n	1,226b	1,266	1,280	1,288	1,430	1,426	684	659	5,419	2,716
Subjects with definite/likely	4 (0.3)	3 (0.2)	5 (0.4)	3 (0.2)	13 (0.9)	3 (0.2)	NR	NR	42 (0.8)	20 (0.7)
ACS events, n (%)
Subjects with definite	4 (0.3)	3 (0.2)	5 (0.4)	1 (0.1)	12 (0.9)	2 (0.1)	1 (0.1)	1 (0.2)	28 (0.5)	17 (0.6)
ACS events, n (%)
CV death, n	0	0	0	0	0	0	0	0	NR	NR
MI events, n	3	2	5	1	9	1	1	1	NR	NR
Ischemia, angina, n	1	1	0	0	3	1	0	0
Deaths,c n (%)	25/1,274 (2.0)	25/1,265 (2.0)	29/1,279 (2.3)	26/1,289 (2.0)	17 (1.2)	19 (1.3)	0	1 (0.2)	16 (0.3)	6 (0.2)

Notes:

a Number of subjects treated

b based on number of patients randomized and treated with dabigatran

c number of subjects randomized.

Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; Dab, dabigatran; Enox, enoxaparin; MI, myocardial infarction; NR, not reported; Plac, placebo; VTE, venous thromboembolism; Warf, warfarin; RE-COVER, A Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RE-MODEL, Regulation of coagulation in Orthopedic surgery to pRevent Deep venous thrombosis and pulmonary embolism; RE-NOVATE, Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty; RE-MOBILIZE, prevention of venous thromboembolism after total knee arthroplasty trial; RE-MEDY, A Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0–3.0) for the Secondary Prevention of Venous Thromboembolism; RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE.

Figure 2 CV events for dabigatran 220 mg once daily (n = 3,692) versus enoxaparin (n = 3,719) in treated patients (randomization to study termination). This analysis includes RE-MOBILIZE, RE-MODEL, RE-NOVATE, and RE-NOVATE II.^21–23,25

Abbreviations: CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; OR, odds ratio; RE-MODEL, Regulation of Coagulation in Orthopedic surgery to pRevent Deep venous thrombosis and pulmonary embolism; RE-NOVATE, Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty; RE-MOBILIZE, prevention of venous thromboembolism after total knee arthroplasty trial; RE-MEDY, a Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0–3.0) for the Secondary Prevention of Venous Thromboembolism.

Figure 3 (A) CV events for dabigatran 150 mg twice daily (n = 1,023) versus placebo (n = 1,031) in treated patients (randomization to study termination), (B) CV events for dabigatran 110 mg twice daily (n = 406) versus placebo (n = 371) in treated patients (randomization to study termination). (A) This analysis includes RE-SONATE²⁹ and RE-DEEM.³² (B) This analysis includes RE-DEEM.³²

Note: *In RE-DEEM no nonfatal strokes were observed in the dabigatran 110 mg twice daily treatment group and there was one in the placebo group; therefore OR cannot be calculated.
Abbreviations: CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; OR, odds ratio; VTE, venous thromboembolism; RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE; RE-DEEM, RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multicentre, Prospective, Placebo Controlled, Cohort Dose Escalation Study.

Table S1 Patient characteristics

Trial	Age, mean (SD)	Males, %	Concomitant disorders, % (n/N)
			Prior CAD	Prior MI	Diabetes	Hypertension
BISTRO II^Citation20	65.9 (10.6)	38.9	4.1 (80/1,949)	1.4 (28/1,949)	3.8 (74/1,949)	38.0 (740/1,949)
RE-MODEL^Citation21	67.7 (8.9)	34.0	11.9 (247/2,075)	1.4 (29/2,076)	11.2 (232/2,075)	59.4 (1,232/2,075)
RE-NOVATE^Citation22	63.9 (10.8)	43.6	8.9 (309/3,459)	0.8 (27/3,463)	7.1 (247/3,458)	46.3 (1,601/3,460)
RE-MOBILIZE^Citation23	66.1 (9.5)	42.3	11.2 (292/2,596)	1.7 (45/2,596)	15.8 (410/2,596)	62.6 (1,625/2,596)
Japanese TKR^Citation24	71.6 (7.8)	17.0	7.2 (37/512)	0 (0/512)	15.8 (81/512)	59.6 (305/512)
RE-NOVATE II^Citation25	62.0 (11.4)	48.2	6.4 (129/2,011)	0.5 (11/2,013)	8.4 (168/2,011)	46.1 (927/2,012)
PETRO^Citation26	69.7 (8.2)	81.9	61.0 (306/502)	NA	25.1 (126/502)	70.9 (356/502)
Japanese AF^Citation27	68.4 (8.6)	88.0	24.1 (40/166)	6.0 (10/166)	27.7 (46/166)	69.9 (116/166)
RE-LY^Citation1,Citation2	71.5 (8.7)	63.6	27.8 (5,010/18,040)	16.6 (2,994/18,040)	23.3 (4,204/18,040)	78.8 (14,221/18,040)
RE-MEDY^Citation28	54.6 (15.2)	61.0	7.2 (207/2,856)	1.2 (34/2,856)	9.0 (258/2,856)	38.6 (1,102/2,856)
RE-SONATE^Citation29	55.8 (15.3)	55.5	6.8 (91/1,343)	2.0 (27/1,343)	8.0 (107/1,343)	38.8 (521/1,343)
RE-COVER^Citation30	54.7 (16.0)	58.4	6.5 (166/2,539)	1.4 (35/2,539)	8.3 (211/2,539)	35.9 (911/2,539)
RE-COVER II^Citation31	54.9 (16.2)	60.6	7.7 (198/2,568)	1.3 (33/2,568)	9.8 (251/2,568)	35.6 (913/2,568)
RE-DEEM^Citation32	61.8 (11.4)	75.9	37.6 (699/1,860)	29.7 (5,552/1,860)	32.3 (600/1,886)	67.8 (1,261/1,860)

Note: Demographic data were collected for randomized or safety set, as available.

Abbreviations: AF, atrial fibrillation; CAD, coronary artery disease; MI, myocardial infarction; NA, no available data; SD, standard deviation; TKR, total knee replacement; VTE, venous thromboembolism; BISTRO, Boehringer Ingelheim Study in Thrombosis; PETRO, Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation; RE-DEEM, RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multicentre, Prospective, Placebo controlled, Cohort Dose Escalation Study; RE-LY, Randomized Evaluation of Long-term anticoagulation therapY; RE-COVER, A Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RE-MODEL, Regulation of coagulation in Orthopedic surgery to pRevent Deep venous thrombosis and pulmonary embolism; RE-NOVATE, Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty; RE-MOBILIZE, prevention of venous thromboembolism after total knee arthroplasty trial; RE-MEDY, A Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0–3.0) for the Secondary Prevention of Venous Thromboembolism; RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE.

Table S2 Definition of MI/ACS events

Trial	Definition of MI/ACS events
BISTRO II^Citation20	Events were selected as AEs according to sub-SMQ MI. Events were not adjudicated
RE-MODEL^Citation21	Events were labeled as MI or reinfarction based on cardiac enzyme or ECG evidence in the blinded medical record
	ACS adjudication using MedDRA lower-level terms
RE-NOVATE^Citation22	Events were labeled as MI or reinfarction based on cardiac enzyme or ECG evidence in the blinded medical record
	ACS adjudication using MedDRA lower-level terms
RE-MOBILIZE^Citation23	Events were labeled as MI or reinfarction based on cardiac enzyme or ECG evidence in the blinded medical record
	ACS adjudication using MedDRA lower-level terms
Japanese TKR^Citation24	Events were selected as AEs according to sub-SMQ MI
	Events were not adjudicated
RE-NOVATE II^Citation25	Events were labeled as MI or reinfarction based on cardiac enzyme or ECG evidence in the blinded medical record
PETRO^Citation26	Events were prespecified outcome events, but were not adjudicated
Japanese AF^Citation27	Events were prespecified outcome events, but were not adjudicated
RE-LY^Citation1,Citation2	Events were adjudicated in a blinded manner
	Clinical MI was defined as the presence of at least two of the following three criteria:
	• Typical prolonged severe chest pain or related symptoms or signs (eg, ST changes or T-wave inversion in the ECG) suggestive of MI
	• Elevation of troponin or creatine kinase-MB to more than the upper level of normal, or if creatine kinase-MB was elevated at baseline, re-evaluation to >50% increase above the previous level
	• Development of significant Q waves in at least two adjacent ECG leads
RE-MEDY^Citation28	Investigators identified possible ACS events that were then prospectively adjudicated by an independent committee.
	Adjudicated events were then categorized as definite, likely, unlikely, or not ACS
RE-SONATE^Citation29	Investigators identified possible ACS events that were then prospectively adjudicated by an independent committee.
	Adjudicated events were then categorized as definite, likely, unlikely, or not ACS
RE-COVER^Citation30	Investigators identified possible ACS events that were then prospectively adjudicated by an independent committee.
	Adjudicated events were then categorized as definite, likely, unlikely, or not ACS
RE-COVER II^Citation31	Investigators identified possible ACS events that were then prospectively adjudicated by an independent committee.
	Adjudicated events were then categorized as definite, likely, unlikely, or not ACS
RE-DEEM^Citation32	ACS events were prespecified as adverse events of special interest, and included MI, CV death, vascular death, and unstable angina

Abbreviations: ACS, acute coronary syndrome; AE, adverse event; AF, atrial fibrillation; CV, cardiovascular; ECG, echocardiogram; MedDRA, Medical Dictionary for Regulatory Authorities; MI, myocardial infarction; SMQ, standardized MedDRA query; TKR, total knee replacement; VTE, venous thromboembolism; BISTRO, Boehringer Ingelheim Study in Thrombosis; PETRO, Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation; RE-DEEM, RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multicentre, Prospective, Placebo Controlled, Cohort Dose Escalation Study; RE-LY, Randomized Evaluation of Long-term anticoagulation therapY; RE-COVER, A Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RE-MODEL, Regulation of Coagulation in Orthopedic surgery to pRevent Deep venous thrombosis and pulmonary embolism; RE-NOVATE, Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty; RE-MOBILIZE, prevention of venous thromboembolism after total knee arthroplasty trial; RE-MEDY, A Phase III, Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0–3.0) for the Secondary Prevention of Venous Thromboembolism; RE-SONATE, Twice-daily Oral Direct Thrombin inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE.

Table S3 Clinical endpoints in RE-DEEM³² patients

	Placebo (n = 371)	Dabigatran
		50 mg bid (n = 369)	75 mg bid (n = 368)	110 mg bid (n = 406)	150 mg bid (n = 348)
All death, n (%)	14 (3.8)	8 (2.2)	10 (2.7)	7 (1.7)	7 (2.0)
CV death, n (%)	9 (2.4)	8 (2.2)	9 (2.5)	5 (1.2)	4 (1.2)
All MI, n (%)	6 (1.6)	11 (3.0)	10 (2.7)	7 (1.7)	8 (2.3)
Fatal MI, n (%)	2 (0.5)	2 (0.5)	2 (0.5)	0 (0.0)	0 (0.0)
Nonfatal MI, n (%)	4 (1.1)	9 (2.4)	8 (2.2)	7 (1.7)	8 (2.3)
Stroke, n (%)	3 (0.8)	0 (0.0)	1 (0.3)	0 (0.0)	0 (0.0)

Note: Part of this table is adapted from Oldgren J, Budaj A, Granger CB, et al. Dabigatran versus placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32(22):2781–2789,³² by permission of Oxford University Press and the European Society of Cardiology. Copyright © 2011.

Abbreviations: bid, twice daily; CV, cardiovascular; MI, myocardial infarction; RE-DEEM, RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multicentre, Prospective, Placebo Controlled, Cohort Dose Escalation Study.

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