3.1. Dabigatran for total hip or knee replacement surgery
Prophylaxis of thrombosis in hip and knee replacement surgery is the first indication approved for dabigatran, by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA). The BISTRO I study, which has been commented on above, was a multicentric and sequential phase I trial where dabigatran was used in an escalating-dose schedule on 289 patients [
4]. Results showed a reasonable therapeutic window for the drug, with low risks of thrombosis and hemorrhage, in patients over 12.5 mg once a day, and below 300 mg twice a day [
4]. The BISTRO II was a double-blind phase II trial to compare the efficacy and safety of dabigatran versus daily enoxaparin (40 mg a day) on 1973 patients [
7]. The primary efficacy outcome was the rate of venous thrombosis (measured by venogram), whereas the primary safety endpoint was the risk of major bleeding. Dabigatran showed a clear dose-dependent antithrombotic effect (p < 0.0001). Compared with enoxaparin 40 mg once a day, dabigatran achieved a lower rate of thrombotic events, for the doses of 150 mg twice a day (OR 0.65, p = 0.04), 300 mg once a day (OR 0.61, p = 0.02), and 225 mg twice a day (OR 0.47, p = 0.0007). Compared to the enoxaparin group, dabigatran showed a lower hemorrhagic risk for the dose of 50 mg twice a day (0.3% v 2%, p = 0.047), though the difference was not significant for the doses of 150 mg twice a day (4.1%, p = 0.1), 225 mg twice a day (3.8%, p = 0.15), and 300 mg once a day (4.7%, p = 0.051) [
7].
The RE-MODEL was a randomized, prospective, double-blind, non-inferiority phase III trial which was designed to compare dabigatran and enoxaparin 40 mg once a day on 2076 patients who underwent knee replacement surgery [
12]. Dabigatran was used at a dose of 150 mg or 220 mg once a day. The first dose was one-half of subsequent doses and it was administered 1-4 h after completion of the surgery. Compared to enoxaparin, dabigatran did not show a different profile in terms of prevention of thrombosis and hemorrhage. The primary efficacy outcome was a composite endpoint of venographic thrombosis and/or clinical thrombosis and mortality. This efficacy outcome had a rate of 37.7% in the enoxaparin group vs. 36.4% in the dabigatran 220 mg/24 h group (95% CI -7.3 to 4.6), and 40.5% in the 150 mg/24 h group (95% to CI -3.1 to 8.7). The rate of major hemorrhage was 1.3% in the enoxaparin group, 1.5% in dabigatran 220 mg (p = 0.82) and 1.3% in dabigatran 150 mg (p = 1.0) [
12].
Similar conclusions were achieved by the RE-NOVATE trial for hip replacement [
13]. It was a prospective, phase III, randomized clinical trial on 3494 patients. The primary efficacy endpoint was the composite of total thromboembolic events and all-cause mortality, while the safety outcome was the rate of major hemorrhage. Enoxaparin 40 mg once a day had a rate of 6.7% of thrombosis/mortality. Dabigatran showed a non-inferior efficacy profile for both doses (6% in 220 mg once a day, p < 0.0001 for non-inferiority, and 8.6% for 150 mg one a day, p < 0.0001 for non-inferiority). The rate of major bleeding was also not significant for dabigatran compared to enoxaparin 40 mg once a day. In particular, the enoxaparin group had a hemorrhagic risk of 1.6%, while dabigatran 220 mg had a 1% (p = 0.44), and dabigatran 150 mg had 1.3% (p = 0.60) [
13].
The double-blind RE-MOBILIZE trial, however, reached different results [
14]. It was a prospective, double-blind, randomized phase III trial for the prevention of thrombosis after knee arthroplasty on 2596 patients. In this study, enoxaparin was used at 30 mg twice a day (the American standard) vs dabigatran at 220 or 150 mg once a day [
14]. The primary efficacy and safety outcomes were the same as described for RE-MODEL and RE-NOVATE. Dabigatran failed to show a non-inferior efficacy compared to enoxaparin 30 mg twice a day. The risk difference was 5.8% for dabigatran 220 mg (95% CI, 0.8-10.8, p = 0.0234) and 8.4% for dabigatran 150 mg (95% CI, 3.4-13.3, p = 0.0009). The rate of bleeding events, however, was not statistically significant among groups [
14].
A meta-analysis performed a pooled analysis of these three trials: RE-MODEL, RE-NOVATE and RE-MOBILIZE (8135 patients) [
15]. The pooled rate of thrombosis or thrombosis-related mortality was 3.3% in the enoxaparin group vs 3% of dabigatran 220 mg group (p = 0.20), and 3.8% of the dabigatran 150 mg group (p = 0.91). The rate of major bleeding was 1.4% in the enoxaparin group vs. 1.4% in dabigatran 220 mg (p = 0.61) and 1.1% in dabigatran 150 mg (p = 0.16). Subgroup analyses suggested that bleeding risk appeared to be higher in patients with moderate renal impairment (Cl
CR 30-50 ml/min) and in patients older than 75 years. There was no evidence of statistical heterogeneity among the three trials [
15].
Thus, the current clinical evidence strongly supports the indication of dabigatran for the prevention of thrombosis in patients who underwent hip or knee replacement surgery, with a reasonable efficacy and safety profile. Dabigatran has been approved for this indication in the European Union for the dose of 220 mg once a day, with a starting dose of 110 mg 1-4 h after surgery. For patients with moderate renal impairment, older than 75 years, or on amiodarone treatment, the dose of 75 mg twice a day is recommended (with a starting dose of 75 mg 1-4 h after surgery) [
6].
3.2. Other situations of deep venous thrombosis/pulmonary embolism
The RE-COVER study was a randomized, double-blind and non-inferiority phase III trial where dabigatran and warfarin were evaluated for the treatment of deep venous thrombosis on 2564 patients [
16]. Follow-up was 6 months and low molecular weight heparin was used prior to oral anticoagulation in both groups. Dabigatran was administered at a constant dose of 150 mg twice a day, whereas warfarin was used at a dose to achieve an INR between 2 and 3. The efficacy endpoint was a composite of symptomatic venous thromboembolism or related death. It had a rate of 2.4% in the dabigatran group and 2.1% in the warfarin group (hazard ratio 1.10, 95% CI, 0.65-1.84). Dabigatran proved non-inferior with regards to the prevention of recurrent or fatal venous thromboembolism (p < 0.001 for non-inferiority). Of note, the rate major or clinical relevant non-major bleeding events was 5.6% in the dabigatran group vs. 8.8% in the warfarin group (hazard ratio 0.63%, 95% CI, 0.47-0.84, p = 0.0002 [
16]. Therefore, dabigatran may suppose a future clinical choice for the treatment of deep venous thrombosis/pulmonary embolism.
3.2. Dabigatran for chronic atrial fibrillation
The PETRO randomized phase II trial compared the effect of vitamin K antagonists versus dabigatran at doses at 50, 150 or 300 mg twice a day, with or without aspirin at 82 or 325 mg, on 502 patients [
8]. The primary outcome was the rate of bleeding events. Major bleeding events were limited to the group treated with 300 mg dabigatran twice a day plus aspirin compared to 300 mg dabigatran twice a day alone (p < 0.02). Total bleeding events were lower in the 50 mg group (7%), compared with the 300 mg group (23%, p = 0.0002) and the 150 group (18%, p = 0.01). The group of 50 mg had a rate of 2%of thromboembolic events. Therefore, an optimal dose from 150 mg twice a day to lower than 300 mg twice a day was selected for further studies [
8].
The randomized, double-blind RE-LY phase III trial assessed the efficacy and safety profile of dabigatran (110 or 150 mg twice a day) on 18113 patients, compared to warfarin. The median duration of the follow-up period was 2 years. The primary efficacy outcome was stroke or systemic embolism. The primary safety outcome was a major hemorrhage [
10]. Stroke or systemic embolism had a rate of 1.53% per year in the group of dabigatran 110 mg twice a day, and 1.11% per year in the group of dabigatran 150 mg twice a day. Both doses of dabigatran were non-inferior to warfarin (p < 0.001). For the prevention of thrombotic events, the dose of 150 mg was superior to warfarin (relative risk 0.66, 95% CI, 0.53-0.82, p < 0.001), whereas the dose of 110 mg was not (relative risk 0.91, 95% CI, 0.74-1.11, p = 0.34). In contrast, the rate of major bleeding was 3.36% per year in the warfarin group, while it was 3.11% per year in the 150 mg dabigatran group (relative risk of 0.93, CI 95%, 0.81-1.07, p = 0.31) and 2.71% per year in the 110 mg dabigatran group (relative risk of 0.8, CI 95%, 0.69-0.93, p = 0.003) [
10].
The FDA approved dabigatran for the prevention of thrombosis in atrial fibrillation in October, 2010. Recommended doses are 150 mg twice a day for Cl
CR > 30 ml/min, and 75 mg twice a day for patients with moderate renal impairment (15-30 ml/min) [
17]. This indication has also recently been approved by the EMA [
6].