Table 2 Intracranial hemorrhage rates reported in phase 3 clinical trials of dabigatran, rivaroxaban and apixaban related to stroke prevention and treatment of acute venous thromboembolism

RE-LY

Stroke prevention in nonvalvular atrial fibrillation

AF patients with moderate to high risk of stroke or systemic embolism with at least one of the following: age >75 years; h/o TIA or stroke; LVEF <40%; NYHA class II or higher; age 65 to 74 years with either DM, CAD, hypertension

Dabigatran 110 mg or 150 mg BID; warfarin with target INR 2 to 3

Prevention of stroke/systemic embolism: dabigatran 110 mg, 1.54%/year; dabigatran 150 mg, 1.11%/year; warfarin, 1.71%/year

AICH: dabigatran 110 mg, 0.23%/year; dabigatran 150 mg, 0.30%/year (P < 0.05); warfarin, 0.74%/year

ROCKET-AF

Stroke prevention in nonvalvular atrial fibrillation

AF with history of stroke or TIA. AF with two or more of the following: symptomatic heart failure or LVEF <35%; age >75 years; DM

Rivaroxaban 20 mg daily; warfarin with target INR 2 to 3

Prevention of stroke/systemic embolism: rivaroxaban, 2.12%/year; warfarin, 2.42%/year

AICH (all): rivaroxaban, 0.49%/year (P < 0.05); warfarin, 0.74%/year. ICH: rivaroxaban, 0.33%/year; warfarin, 0.49%/year. SDH: rivaroxaban, 0.13%/year; warfarin, 0.27%/year

ARISTOTLE

Stroke prevention in nonvalvular atrial fibrillation

AF with one or more of following: TIA or systemic embolism; symptomatic CHF or LVEF ≤40%; DM or hypertension on pharmacological treatment

Apixaban 5 mg BID; warfarin with target INR 2 to 3

Prevention of stroke/systemic embolism: apixaban, 1.27%/year; warfarin, 1.60%/year

AICH: apixaban, 0.33%/year; warfarin, 0.80%/year

RE-COVER

VTE recurrence prevention

Acute symptomatic DVT of legs or PE

Dabigatran 150 mg BID; warfarin with target INR 2 to 3

Thromboembolism or related deaths: dabigatran, 2.4%; warfarin, 2.1%

AICH: dabigatran, 0; warfarin, 0.24%

RECOVER II

VTE recurrence prevention

Acute symptomatic DVT of legs or PE

Dabigatran 150 mg BID; heparin/enoxaparin followed by warfarin with target INR 2 to 3

Recurrent VTE: dabigatran, 2.3%; warfarin, 2.2%

Not reported

EINSTEIN-DVT

Prevention of VTE recurrence

Acute symptomatic DVT

Rivaroxaban 15 mg BID × 3 weeks followed by 20 mg daily. Standard therapy: enoxaparin 1 mg/kg BID; bridging warfarin or acenocoumarol therapy with target INR 2 to 3

Recurrent VTE: rivaroxaban, 2.1%; enoxaparin-VKA, 3.0%

AICH data not reported separately. Bleeding in critical location: rivaroxaban, 0.2%; enoxaparin-VKA, 0.2%

EINSTEIN-PE

VTE prevention

Acute PE

Rivaroxaban 15 mg BID × 3 weeks followed by 20 mg daily. Standard therapy: enoxaparin 1 mg/kg BID; bridging warfarin or acenocoumarol therapy with target INR 2 to 3

Recurrent VTE: rivaroxaban, 2.1%; standard therapy, 1.8%

AICH: rivaroxaban, 0.12%; standard therapy, 0.50%