Trial Outcomes & Findings for Dabigatran Etexilate in Extended Venous Thromboembolism (VTE) Prevention After Hip Replacement Surgery (NCT NCT00168818)

Last Updated: 2014-05-19

Results Overview

Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy). All of these components and all deaths were centrally adjudicated by the VTE events committee, which was not aware of the treatment allocation of the patients.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

3494 participants

Primary outcome timeframe

First administration until 31-38 days

Results posted on

2014-05-19

Participant Flow

The treatment period is from first administration of study medication, until 3 days after last administration of study medication. Treatment duration is planned for 28 - 35 days. The study period is from first administration of study medication until day 84 - 91.

Whilst 3494 patients were enrolled/randomised to treatment prior to surgery in this trial, only 3463 started treatment. Therefore, 31 patients were randomised but not treated (treatment was planned to start post surgery).

Participant milestones

Participant milestones
Measure	Dabigatran 220mg Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Overall Study STARTED	1146	1163	1154
Overall Study COMPLETED	1029	1054	1030
Overall Study NOT COMPLETED	117	109	124
Treatment STARTED	1146	1163	1154
Treatment COMPLETED	1013	1012	1021
Treatment NOT COMPLETED	133	151	133

Reasons for withdrawal

Reasons for withdrawal
Measure	Dabigatran 220mg Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Overall Study Adverse Event	23	29	31
Overall Study Protocol Violation	16	11	11
Overall Study Lost to Follow-up	13	4	15
Overall Study Withdrawal by Subject	43	41	37
Overall Study Other	22	24	30
Treatment Adverse Event	77	89	68
Treatment Protocol Violation	8	11	11
Treatment Lost to Follow-up	0	2	1
Treatment Withdrawal by Subject	25	20	22
Treatment Other	23	29	31

Baseline Characteristics

Dabigatran Etexilate in Extended Venous Thromboembolism (VTE) Prevention After Hip Replacement Surgery

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dabigatran 220mg n=1146 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1163 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1154 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.	Total n=3463 Participants Total of all reporting groups
Age, Continuous	64.6 Years STANDARD_DEVIATION 10.4 • n=5 Participants	63.4 Years STANDARD_DEVIATION 11.1 • n=7 Participants	63.8 Years STANDARD_DEVIATION 10.8 • n=5 Participants	63.9 Years STANDARD_DEVIATION 10.8 • n=4 Participants
Sex: Female, Male Female	636 Participants n=5 Participants	667 Participants n=7 Participants	651 Participants n=5 Participants	1954 Participants n=4 Participants
Sex: Female, Male Male	510 Participants n=5 Participants	496 Participants n=7 Participants	503 Participants n=5 Participants	1509 Participants n=4 Participants
Body Mass Index N=(1146;1163;1151;3460)	27.7 kg/m^2 STANDARD_DEVIATION 4.6 • n=5 Participants	27.8 kg/m^2 STANDARD_DEVIATION 4.6 • n=7 Participants	27.5 kg/m^2 STANDARD_DEVIATION 4.3 • n=5 Participants	27.7 kg/m^2 STANDARD_DEVIATION 4.5 • n=4 Participants

PRIMARY outcome

Timeframe: First administration until 31-38 days

Population: Full Analysis Set (all patients who had surgery and were randomised, received treatment, had an evaluable venogram for distal and proximal Deep Vein Thrombosis, or symptomatic Deep Vein Thrombosis, Pulmonary Embolism, or had died)

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=880 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=874 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=897 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period	53 Participants	75 Participants	60 Participants

SECONDARY outcome

Timeframe: First administration until 31-38 days

Population: Full Analysis Set - major (all patients who had surgery and were randomised, received treatment, had an evaluable venogram for proximal Deep Vein Thrombosis, or had confirmed symptomatic Deep Vein Thrombosis, Pulmonary Embolism, or had died by a Venous Thromboembolic Event-related death)

Major Venous Thromboembolic Event (VTE) is defined as proximal DVT and PE, as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=909 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=888 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=917 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period	28 Participants	38 Participants	36 Participants

SECONDARY outcome

Timeframe: First administration until 31-38 days

Population: Full Analysis Set - pDVT (all patients who had surgery and were randomised, received treatment, had an evaluable venogram for proximal Deep Vein Thrombosis, or had confirmed symptomatic Deep Vein Thrombosis)

Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=905 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=885 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=914 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Proximal Deep Vein Thrombosis During Treatment Period	23 Participants	35 Participants	33 Participants

SECONDARY outcome

Timeframe: First administration until 31-38 days

Population: Full Analysis Set - tDVT (all patients who had surgery and were randomised, received treatment, had an evaluable venogram, or had confirmed symptomatic Deep Vein Thrombosis)

Total Deep Vein Thrombosis as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=874 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=871 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=894 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Total Deep Vein Thrombosis During Treatment Period	46 Participants	72 Participants	57 Participants

SECONDARY outcome

Timeframe: First administration until 31-38 days

Population: Full Analysis Set - op (all patients who are treated and operated)

Symptomatic Deep Vein Thrombosis, confirmed by venous compression ultrasound, venography or autopsy, and as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=1137 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1156 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1142 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Symptomatic Deep Vein Thrombosis During Treatment Period	6 Participants	9 Participants	1 Participants

SECONDARY outcome

Timeframe: First administration until 31-38 days

Population: Full Analysis Set - op (all patients who are treated and operated)

Pulmonary embolism confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy, and as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=1137 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1156 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1142 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Pulmonary Embolism During Treatment Period	5 Participants	1 Participants	3 Participants

SECONDARY outcome

Timeframe: First administration until 31-38 days

Population: Full Analysis Set - op (all patients who are treated and operated)

All cause death, as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=1137 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1156 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1142 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Death During Treatment Period	3 Participants	3 Participants	0 Participants

SECONDARY outcome

Timeframe: end of treatment to day 91±7

Population: Patients with any data available during follow-up

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=1106 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1117 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1108 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period death	0 Participants	2 Participants	1 Participants
Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period Total VTE and all-cause mortality	1 Participants	4 Participants	5 Participants
Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period asymptotic Deep Vein Thrombosis	0 Participants	1 Participants	3 Participants
Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period symptotic Deep Vein Thrombosis	1 Participants	1 Participants	0 Participants
Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period Pulmonary Embolism	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: First administration until 31-38 days

Population: Treated set

Major bleeding events were defined as * fatal * clinically overt associated with loss of haemoglobin \>=20g/L in excess of what was expected * clinically overt leading to the transfusion of \>=2 units packed cells or whole blood in excess of what was expected * symptomatic retroperitoneal, intracranial, intraocular or intraspinal * requiring treatment cessation * leading to re-operation Clinically-relevant was defined as * spontaneous skin hematoma greater than or equal to 25 cm² * wound hematoma greater than or equal to 100 cm² * spontaneous nose bleed lasting longer than 5 min * macroscopic hematuria spontaneous or lasting longer than 24 hours if associated with an intervention * spontaneous rectal bleeding (more than a spot on toilet paper) * gingival bleeding lasting longer than 5 min * any other bleeding event considered clinically relevant by the investigator Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above.

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=1146 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1163 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1154 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period Major	23 Participants	15 Participants	18 Participants
Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period Clinical relevant	48 Participants	55 Participants	40 Participants
Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period Minor	70 Participants	72 Participants	74 Participants
Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period None	1005 Participants	1021 Participants	1022 Participants

SECONDARY outcome

Timeframe: Day 1

Blood transfusion for treated and operated patients on Day of surgery.

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=1137 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1156 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1142 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Blood Transfusion Patients with >=1 transfusions	517 participants	531 participants	542 participants
Blood Transfusion Patients with >=1 non-autologous transfusions	259 participants	266 participants	286 participants

SECONDARY outcome

Timeframe: Day 1

Volume of blood loss for treated and operated patients during surgery.

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=1127 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1147 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1133 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Volume of Blood Loss	457 mL Standard Deviation 304	435 mL Standard Deviation 271	463 mL Standard Deviation 291

SECONDARY outcome

Timeframe: First administration to end of study

Population: Treated patients

Frequency of patients with possible clinically significant abnormalities.

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=1103 Participants Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1098 Participants Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1103 Participants Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Laboratory Analyses AST increase N=(1103;1097;1103)	11 participants	16 participants	29 participants
Laboratory Analyses AST decrease N=(1103;1097;1103)	0 participants	0 participants	0 participants
Laboratory Analyses ALT increase N=(1103;1098;1103)	28 participants	29 participants	59 participants
Laboratory Analyses ALT decrease N=(1103;1098;1103)	0 participants	0 participants	0 participants
Laboratory Analyses Bilirubin increase N=(1102;1094;1102)	25 participants	24 participants	34 participants
Laboratory Analyses Bilirubin decrease N=(1102;1094;1102)	0 participants	0 participants	0 participants

Adverse Events

Dabigatran 220mg

Serious events: 89 serious events

Other events: 620 other events

Deaths: 0 deaths

Dabigatran 150mg

Serious events: 91 serious events

Other events: 642 other events

Deaths: 0 deaths

Enoxaparin

Serious events: 82 serious events

Other events: 648 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Dabigatran 220mg n=1146 participants at risk Patients were treated with 220mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Dabigatran 150mg n=1163 participants at risk Patients were treated with 150mg dabigatran etexilate once daily as capsules for oral administration and placebo subcutaneous injections. Placebo injections matching the enoxaparin syringes.	Enoxaparin n=1154 participants at risk Patients were treated with 40mg Enoxaparin once daily for subcutaneous injection and placebo capsules. Placebo capsules matching the dabigatran capsules.
Gastrointestinal disorders Constipation	12.7% 146/1146 • 13 weeks Treatment emergent events (last medication + 3 days)	12.0% 140/1163 • 13 weeks Treatment emergent events (last medication + 3 days)	12.9% 149/1154 • 13 weeks Treatment emergent events (last medication + 3 days)
Gastrointestinal disorders Nausea	20.8% 238/1146 • 13 weeks Treatment emergent events (last medication + 3 days)	22.2% 258/1163 • 13 weeks Treatment emergent events (last medication + 3 days)	25.0% 289/1154 • 13 weeks Treatment emergent events (last medication + 3 days)
Gastrointestinal disorders Vomiting	16.8% 193/1146 • 13 weeks Treatment emergent events (last medication + 3 days)	15.9% 185/1163 • 13 weeks Treatment emergent events (last medication + 3 days)	16.6% 191/1154 • 13 weeks Treatment emergent events (last medication + 3 days)
General disorders Oedema peripheral	5.4% 62/1146 • 13 weeks Treatment emergent events (last medication + 3 days)	6.8% 79/1163 • 13 weeks Treatment emergent events (last medication + 3 days)	4.9% 56/1154 • 13 weeks Treatment emergent events (last medication + 3 days)
General disorders Pyrexia	10.6% 121/1146 • 13 weeks Treatment emergent events (last medication + 3 days)	12.0% 140/1163 • 13 weeks Treatment emergent events (last medication + 3 days)	14.0% 162/1154 • 13 weeks Treatment emergent events (last medication + 3 days)
Injury, poisoning and procedural complications Wound secretion	8.2% 94/1146 • 13 weeks Treatment emergent events (last medication + 3 days)	7.6% 88/1163 • 13 weeks Treatment emergent events (last medication + 3 days)	5.2% 60/1154 • 13 weeks Treatment emergent events (last medication + 3 days)
Psychiatric disorders Insomnia	6.7% 77/1146 • 13 weeks Treatment emergent events (last medication + 3 days)	7.6% 88/1163 • 13 weeks Treatment emergent events (last medication + 3 days)	6.9% 80/1154 • 13 weeks Treatment emergent events (last medication + 3 days)
Vascular disorders Hypotension	7.1% 81/1146 • 13 weeks Treatment emergent events (last medication + 3 days)	6.5% 76/1163 • 13 weeks Treatment emergent events (last medication + 3 days)	7.0% 81/1154 • 13 weeks Treatment emergent events (last medication + 3 days)

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract
Publication restrictions are in place

Restriction type: OTHER