Dabigatran etexilate is an orally active pro-drug which is rapidly converted to dabigatran by esterase-mediated hydrolysis in the plasma and the liver . Dabigatran directly and reversibly inhibits both free and fibrin-bound thrombin, thereby interrupting the coagulation cascade. The oral bioavailability of this drug is approximately 6%-7%, which is much lower than that of the other three oral anticoagulants [1, 4]. It has a half-life of 14 to 17 hours. Dabigatran is predominately (80%) excreted unchanged by the kidneys and its plasma levels are increased in patients with renal insufficiency [37, 38]. It is contraindicated in patients with severe renal dysfunction (creatinine clearance <30 ml/min) .
Dabigatran is not metabolized by cytochrome P450 isoenzymes. Co-administration of dabigatran with atorvastatin (a substrate for CYP3A4 and P-glycoprotein) , digoxin (a P-glycoprotein substrate)  or diclofenac (a CYP2C9 substrate)  did not result in clinically relevant drug interactions. However, dabigatran etexilate (not the active dabigatran) acts as a substrate for Pglycoprotein. Therefore, drugs that inhibit P-glycoprotein, such as quinidine, verapamil and amiodarone, will increase the plasma levels of dabigatran . Administration of dabigatran etexilate with food prolonged the time to peak plasma levels by approximately 2 hours without significantly affecting overall exposure .
On the basis of the results of phase 2 studies demonstrating that dabigatran is effective for the prevention of venous thromboembolism (VTE), phase 3 studies for thromboprophylaxis after hip or knee arthroplasty were conducted. In the RENOVATE I trial , 3494 patients undergoing total hip replacement were randomized to treatment for 28 to 35 days with 220 mg or 150 mg dabigatran once daily initiated after surgery, or subcutaneous enoxaparin 40 mg once daily, initiated preoperatively. The primary efficacy outcome (total VTE or death) occurred in 6%, 8.6% and 6.7% of patients in the dabigatran 220 mg, 150 mg and enoxaparin groups, respectively. Risk differences were −0.7% (95% CI, -2.9 to 1 · 6%) and 1.9% (95% CI, −0 · 6 to 4 · 4%) for dabigatran 220 mg and 150 mg, respectively, compared with enoxaparin. Moreover, the incidence of major bleeding events did not differ significantly with either dose of dabigatran compared with enoxaparin (p = 0.44 for 220 mg, p = 0.60 for 150 mg). Similarly, in the REMODEL trial  enrolling 2076 patients undergoing total knee replacement, 6 to 10 days of treatment with either dose of dabigatran had efficacy similar to that of enoxaparin (enoxaparin 37.7%; 220 mg dabigatran, 36.4%; 150 mg dabigatran, 40.5%). Also, the incidence of major bleeding events did not differ significantly between the three groups (1.3% versus 1.5% and 1.3%, respectively).
The RENOVATE II trial  compared 28 to 35 days of treatment with dabigatran 220 mg once daily with subcutaneous enoxaparin 40 mg once daily for prevention of VTE in 2055 patients undergoing total hip arthroplasty. In this trial, the primary efficacy outcome occurred in 7.7% of the patients receiving dabigatran versus 8.8% of the patients receiving enoxaparin. Risk difference was −1.1% (95% CI, -3.8 to 1.6%); p < 0.0001 for the pre-specified non-inferiority margin. The rates of primary efficacy outcome observed in this trial were consistent with those observed in REVOVATE I . Major bleeding events occurred in 1.4% of the patients in the dabigatran group and in 0.9% of the patients in the enoxaparin group (P = 0.40).
In the RE-MOBILIZE trial  of 1896 patients undergoing total knee arthroplasty, the North American enoxaparin regimen (30 mg BID postoperatively) was used. Treatment with either dose (220 mg or 150 mg) of dabigatran for 12 to 15 days was found to be statistically inferior to enoxaparin treatment for a similar duration (venous thromboembolism rates of 31% for 220 mg dabigatran [p = 0.02 vs. enoxaparin], 34% for 150 mg dabigatran [p < 0.001 vs. enoxaparin], and 25% with enoxaparin). This suggests that enoxaparin 30 mg twice daily is substantially more effective than enoxaparin 40 mg once daily for the prevention of VTE in patients undergoing knee arthroplasty. However, there were no significant differences in the incidence of major bleeding events (0.6%, 0.6%, and 1.4%, respectively).
The Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial  enrolled 18,113 patients with atrial fibrillation who were at risk for stroke. Two doses of dabigatran, 110 mg or 150 mg twice daily, administered in a blinded fashion, were compared with adjusted-dose warfarin, which was administered in an unblended fashion. The rate of primary outcome (systemic embolism or stroke) was 1.69% per year for warfarin, as compared with 1.11% per year for dabigatran at dose of 150 mg twice daily (relative risk, 0.66; 95% CI, 0.53 to 0.82; p < 0.001 for superiority) and 1.53% per year for dabigatran at a dose of 110 mg twice daily (relative risk with dabigatran, 0.91; 95% CI, 0.74 to 1.11; p < 0.001 for noninferiority.) Compared with warfarin (3.36% per year), however, the risk of major bleeding was 2.71% per year for dabigatran at a dose of 110 mg (p = 0.003), but similar (3.11% per year) for dabigatran at a dose of 150 mg (p = 0.31). Both doses of dabigatran were therefore better than warfarin.
Acute coronary syndrome
In patients with recent ST-elevation or non ST-elevation MI, dabigatran was given in addition to dual antiplatelet therapy in a double-blind, placebo-controlled, dose-escalation phase 2 (RE-DEEM) trial . A total of 1861 patients were randomized to twice daily treatment with dabigatran 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406), 150 mg (n = 347), or placebo (n = 371). This trial showed that 3.8% of the patients in the placebo group had an MI, stroke or died compared with dabigatran at different doses; 4.6% in patients treated with 50 mg, 4.9% for 75 mg, 3% for 110 mg and 3.5% for those treated with 150 mg dabigatran.
Additionally, the incidence of major or clinically relevant minor bleeding events during the 6-month treatment period increased in a dose-dependent manner with dabigatran; the hazard ratio was 1.77 for 50 mg, 2.17 for 75 mg, 3.92 for 110 mg and 4.27 for 150 mg dabigatran compared with placebo.
The RE-LY trial  suggested an increased risk of MI with the use of dabigatran versus warfarin in patients with atrial fibrillation. In order to evaluate the risk of MI or ACS with dabigatran, a meta-analysis of seven trials of dabigatran was conducted . Control agents in the studies included warfarin, enoxaparin and placebo administration. The results showed that the risk of MI or ACS was significantly higher in the 20,000 dabigatran patients than in the 10,514 control patients (1.19% vs. 0.79%, p = 0.03). The risk of MI or ACS was similar when using revised RE-LY trial results (95% CI, 1.00 to 1.61; p = 0.05).
Symptomatic venous thromboembolism
In the RE-COVER 1 trial , patients with acute venous thromboembolism were randomized double-blind to six months of treatment with either dabigatran 150 mg twice daily or warfarin that was dose-adjusted to achieve an INR of 2.0 to 3.0 after initial treatment with a parenteral anticoagulant. Recurrent venous thromboembolism or related deaths occurred in 30 of the 1274 patients (2.4%) in the dabigatran group as compared with 27 of the 1265 patients (2.1%) in the warfarin group (95% CI, −0.8 to 1.5; p < 0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes in patients assigned to dabigatran (1.6%) were also at the same rate (1.9%) as for patients assigned to warfarin (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48).