Dabigatran

Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors, ATC code: B01AE07. Mechanism of action Dabigatran etexilate is a small-molecule prodrug that exhibits no pharmacological activity. Following oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran in plasma and the liver via esterase-catalyzed hydrolysis. Dabigatran is a potent, competitive, reversible, direct thrombin inhibitor and is the principal active moiety in plasma. Because thrombin (a serine protease) catalyzes the conversion of fibrinogen to fibrin in the coagulation cascade, its inhibition prevents thrombus formation. Dabigatran inhibits free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation. Pharmacodynamic effects In in vivo and ex vivo animal studies, antithrombotic efficacy and anticoagulant activity of dabigatran following intravenous administration, and of dabigatran etexilate following oral administration, were demonstrated in various animal models of thrombosis. Phase II studies established a clear correlation between plasma dabigatran concentration and the degree of anticoagulant effect. Dabigatran prolongs the thrombin time (TT), ECT, and aPTT. The calibrated quantitative dilute TT assay (dTT) provides an estimate of plasma dabigatran concentration that can be compared with expected plasma dabigatran concentrations. When the calibrated dTT assay yields a plasma dabigatran concentration at or below the limit of quantification, performance of an additional coagulation test such as TT, ECT, or aPTT should be considered. The ECT provides a direct measure of the activity of direct thrombin inhibitors. The aPTT is widely available and offers an approximate indication of the anticoagulation intensity achieved with dabigatran. However, the aPTT has limited sensitivity and is not suitable for precise quantification of the anticoagulant effect, particularly at high plasma dabigatran concentrations. Although high aPTT results must be interpreted with caution, an elevated aPTT indicates that the patient is anticoagulated. In general, these measures of anticoagulant activity may reflect dabigatran levels and provide guidance for assessing bleeding risk; that is, exceeding the 90th percentile of the dabigatran trough concentration or of a coagulation test such as the aPTT measured at trough (for aPTT thresholds, see section 4.4, Table 6) is considered to be associated with an increased risk of bleeding. Primary prevention of VTE in orthopedic surgery The geometric mean peak plasma dabigatran concentration at steady state (after day 3), measured approximately 2 hours after administration of a 220 mg dose of dabigatran etexilate, was 70.8 ng/mL, with a range of 35.2–162 ng/mL (25th–75th percentile range). The geometric mean trough dabigatran concentration measured at the end of the dosing interval (i.e., 24 hours after a 220 mg dabigatran dose) averaged 22.0 ng/mL, with a range of 13.0–35.7 ng/mL (25th–75th percentile range). In a study conducted exclusively in patients with moderate renal impairment (creatinine clearance, CrCL 30–50 mL/min) treated with dabigatran etexilate 150 mg once daily, the geometric mean trough dabigatran concentration measured at the end of the dosing interval averaged 47.5 ng/mL, with a range of 29.6–72.2 ng/mL (25th–75th percentile range). In patients receiving dabigatran etexilate 220 mg once daily for VTE prevention after hip or knee replacement, the 90th percentile of plasma dabigatran concentrations measured at trough (20–28 hours after the previous dose) was 67 ng/mL (see section 4.9). The 90th percentile aPTT at trough (20–28 hours after the previous dose) was 51 seconds, representing 1.3 times the upper limit of the normal range. The ECT was not measured in patients receiving dabigatran etexilate 220 mg once daily for VTE prevention after hip or knee replacement. Prevention of stroke and systemic embolism in adult patients with NVAF and one or more risk factors (SPAF) The geometric mean peak plasma dabigatran concentration at steady state, measured approximately 2 hours after administration of a 150 mg twice-daily dose of dabigatran etexilate, was 175 ng/mL, with a range of 117–275 ng/mL (25th–75th percentile range). The geometric mean trough dabigatran concentration measured at the morning trough at the end of the dosing interval (i.e., 12 hours after the evening 150 mg dabigatran dose) averaged 91.0 ng/mL, with a range of 61.0–143 ng/mL (25th–75th percentile range). In NVAF patients receiving dabigatran etexilate 150 mg twice daily for the prevention of stroke and systemic embolism: the 90th percentile of plasma dabigatran concentrations measured at trough (10–16 hours after the previous dose) was approximately 200 ng/mL; the ECT at trough (10–16 hours after the previous dose), elevated approximately 3-fold above the upper limit of the normal range, corresponds to the observed 90th percentile of ECT prolongation of 103 seconds; an aPTT ratio greater than 2 times the upper limit of the normal range (aPTT prolongation to approximately 80 seconds) at trough (10–16 hours after the previous dose) corresponds to the 90th percentile of observations. Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (DVT/PE) In patients treated for DVT and PE with dabigatran etexilate 150 mg twice daily, the geometric mean trough dabigatran concentration measured 10–16 hours after dosing at the end of the dosing interval (i.e., 12 hours after the evening 150 mg dabigatran dose) was 59.7 ng/mL, with a range of 38.6–94.5 ng/mL (25th–75th percentile range). For the treatment of DVT and PE with dabigatran etexilate 150 mg twice daily: the 90th percentile of plasma dabigatran concentrations measured at trough (10–16 hours after the previous dose) was approximately 200 ng/mL; the ECT at trough (10–16 hours after the previous dose), elevated approximately 2.3-fold compared with baseline, corresponds to the observed 90th percentile of ECT prolongation of 74 seconds; the 90th percentile aPTT at trough (10–16 hours after the previous dose) was 62 seconds, corresponding to 1.8-fold compared with baseline. No pharmacokinetic data are available in patients treated for the prevention of recurrent DVT and PE with dabigatran etexilate 150 mg twice daily. Clinical efficacy and safety Ethnic origin No clinically relevant ethnic differences were observed among Caucasian, African American, Hispanic, Japanese, or Chinese patients. Clinical trials of VTE prevention after major joint replacement surgery In two large, double-blind, randomized, parallel-group dose-confirmation trials, patients undergoing elective major orthopedic surgery (one trial in knee replacement, the other in hip replacement) received dabigatran etexilate 75 mg or 110 mg within 1–4 hours of surgery, followed by 150 mg or 220 mg once daily once hemostasis was secured, or enoxaparin 40 mg the day before surgery and once daily thereafter. Treatment lasted 6–10 days in the RE-MODEL trial (knee replacement) and 28–35 days in the RE-NOVATE trial (hip replacement). The total numbers of treated patients were 2,076 (knee) and 3,494 (hip), respectively. The primary endpoint in both studies was a composite of total VTE (including PE, proximal and distal DVT, symptomatic or asymptomatic, detected by routine venography) and all-cause mortality. The secondary endpoint, considered more clinically relevant, was a composite of major venous thromboembolism (including pulmonary embolism and proximal deep vein thrombosis, symptomatic or asymptomatic, detected by routine venography) and VTE-related mortality. The results of both studies showed that the antithrombotic effect of dabigatran etexilate 220 mg and 150 mg was statistically non-inferior to that of enoxaparin with respect to total VTE and all-cause mortality. The point estimate for major VTE and VTE-related mortality with the 150 mg dose was slightly worse than with enoxaparin (Table 19). Better results were observed with the 220 mg dose, for which the point estimate of major VTE was slightly better than with enoxaparin (Table 19). The clinical studies were conducted in a patient population with a mean age >65 years. In the phase 3 clinical studies, no differences were observed between men and women with respect to efficacy and safety data. In the studied patient population of RE-MODEL and RE-NOVATE (5,539 treated patients), 51% had concomitant hypertension, 9% had concomitant diabetes, 9% had concomitant coronary artery disease, and 20% had a history of venous insufficiency. None of these conditions was observed to influence the effect of dabigatran on the prevention of venous thromboembolism or on the bleeding rate. Data on the major VTE and VTE-related mortality endpoint were homogeneous with the primary efficacy endpoint and are presented in Table 19. Data on the total VTE and all-cause mortality endpoint are presented in Table 20. Data on the adjudicated major bleeding endpoints are presented below in Table 21. Table 19: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL and RE-NOVATE orthopedic surgery trials Trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) n 909 888 917 Incidence (%) 28 (3.1) 38 (4.3) 36 (3.9) Hazard ratio vs. enoxaparin 0.78 1.09 95% confidence interval 0.48; 1.27 0.70; 1.70 RE-MODEL (knee) n 506 527 511 Incidence (%) 13 (2.6) 20 (3.8) 18 (3.5) Hazard ratio vs. enoxaparin 0.73 1.08 95% confidence interval 0.36; 1.47 0.58; 2.01 Table 20: Analysis of total VTE and all-cause mortality during the treatment period in the RE-MODEL and RE-NOVATE orthopedic surgery trials Trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) n 880 874 897 Incidence (%) 53 (6.0) 75 (8.6) 60 (6.7) Hazard ratio vs. enoxaparin 0.9 1.28 95% confidence interval (0.63; 1.29) (0.93; 1.78) RE-MODEL (knee) n 503 526 512 Incidence (%) 183 (36.4) 213 (40.5) 193 (37.7) Hazard ratio vs. enoxaparin 0.97 1.07 95% confidence interval (0.82; 1.13) (0.92; 1.25) Table 21: Major bleeding events by treatment for each of the RE-MODEL and RE-NOVATE trials Trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) Number of treated patients (n) 1,146 1,163 1,154 Major bleeding events, n (%) 23 (2.0) 15 (1.3) 18 (1.6) RE-MODEL (knee) Number of treated patients (n) 679 703 694 Major bleeding events, n (%) 10 (1.5) 9 (1.3) 9 (1.3) Prevention of stroke and systemic embolism in adult patients with NVAF and one or more risk factors Clinical evidence for the efficacy of dabigatran etexilate is derived from the RE-LY trial (Randomised Evaluation of Long-term anticoagulant therapY), a multicenter, international, randomized, parallel-group study comparing two doses of dabigatran etexilate (110 mg and 150 mg twice daily) administered in a blinded fashion with open-label warfarin in patients with atrial fibrillation at moderate to high risk of stroke and systemic embolism. The primary objective of this study was to determine whether dabigatran etexilate was non-inferior to warfarin in reducing the incidence of the composite endpoint of stroke and systemic embolism. Statistical superiority was also analyzed. A total of 18,113 patients were randomized in the RE-LY trial, with a mean age of 71.5 years and a mean CHADS2 score of 2.1. The patient population was 64% male, 70% Caucasian, and 16% Asian. Among patients randomized to warfarin, the mean percentage of time in therapeutic range (TTR) (INR 2–3) was 64.4% (median TTR 67%). The RE-LY trial demonstrated that dabigatran etexilate 110 mg twice daily was non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation, with a reduced risk of intracranial bleeding, total bleeding, and major bleeding. The 150 mg twice-daily dose significantly reduced the risk of ischemic and hemorrhagic stroke, vascular mortality, intracranial bleeding, and total bleeding compared with warfarin. The major bleeding rate at this dose was comparable to warfarin. The incidence of myocardial infarction was slightly increased with dabigatran etexilate compared with warfarin, with hazard ratios of 1.29 (p = 0.0929) for 110 mg twice daily and 1.27 (p = 0.1240) for 150 mg twice daily. With improved INR monitoring, the observed benefits of dabigatran etexilate over warfarin are reduced. Tables 22–24 present the detailed key results in the overall population. Table 22: Analysis of the first occurrence of stroke or systemic embolism (primary endpoint) during the RE-LY follow-up period Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomized subjects 6,015 6,076 6,022 Stroke and/or systemic embolism Incidence (%) 183 (1.54) 135 (1.12) 203 (1.72) Hazard ratio vs. warfarin (95% confidence interval) 0.89 (0.73; 1.09) 0.65 (0.52; 0.81) p-value for superiority p = 0.2721 p = 0.0001 % refers to the annual event rate. Table 23: Analysis of the first occurrence of ischemic or hemorrhagic stroke during the RE-LY follow-up period Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomized subjects 6,015 6,076 6,022 Stroke Incidence (%) 171 (1.44) 123 (1.02) 187 (1.59) Hazard ratio vs. warfarin (95% confidence interval) 0.91 (0.74; 1.12) 0.64 (0.51; 0.81) p-value 0.3553 0.0001 Systemic embolism Incidence (%) 15 (0.13) 13 (0.11) 21 (0.18) Hazard ratio vs. warfarin (95% confidence interval) 0.71 (0.37; 1.38) 0.61 (0.30; 1.21) p-value 0.3099 0.1582 Ischemic stroke Incidence (%) 152 (1.28) 104 (0.86) 134 (1.14) Hazard ratio vs. warfarin (95% confidence interval) 1.13 (0.89; 1.42) 0.76 (0.59; 0.98) p-value 0.3138 0.0351 Hemorrhagic stroke Incidence (%) 14 (0.12) 12 (0.10) 45 (0.38) Hazard ratio vs. warfarin (95% confidence interval) 0.31 (0.17; 0.56) 0.26 (0.14; 0.49) p-value 0.0001 < 0.0001 % refers to the annual event rate. Table 24: Analysis of all-cause mortality and cardiovascular survival during the RE-LY follow-up period Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomized subjects 6,015 6,076 6,022 All-cause mortality Incidence (%) 446 (3.75) 438 (3.64) 487 (4.13) Hazard ratio vs. warfarin (95% confidence interval) 0.91 (0.80; 1.03) 0.88 (0.77; 1.00) p-value 0.1308 0.0517 Vascular mortality Incidence (%) 289 (2.43) 274 (2.28) 317 (2.69) Hazard ratio vs. warfarin (95% confidence interval) 0.90 (0.77; 1.06) 0.85 (0.72; 0.99) p-value 0.2081 0.0430 % refers to the annual event rate. Tables 25–26 present the results for the primary efficacy and safety endpoints in the corresponding subpopulations. For the primary endpoint of stroke and systemic embolism, no subgroups (e.g., age, body weight, sex, renal function, ethnicity) were identified with a hazard ratio differing from that observed for warfarin. Table 25: Hazard ratio and 95% confidence interval for stroke/systemic embolism by subgroup Endpoint Dabigatran etexilate 110 mg twice daily vs. warfarin Dabigatran etexilate 150 mg twice daily vs. warfarin Age (years) < 65 1.10 (0.64; 1.87) 0.51 (0.26; 0.98) 65 ≤ and < 75 0.86 (0.62; 1.19) 0.67 (0.47; 0.95) ≥ 75 0.88 (0.66; 1.17) 0.68 (0.50; 0.92) ≥ 80 0.68 (0.44; 1.05) 0.67 (0.44; 1.02) CrCL (mL/min) 30 ≤ and < 50 0.89 (0.61; 1.31) 0.48 (0.31; 0.76) 50 ≤ and < 80 0.91 (0.68; 1.20) 0.65 (0.47; 0.88) ≥ 80 0.81 (0.51; 1.28) 0.69 (0.43; 1.12) For major bleeding, the primary safety endpoint, there was an interaction between treatment effect and age. The relative risk of bleeding with dabigatran compared with warfarin increased with age. The relative risk was highest in patients aged 75 years and older. Concomitant antiplatelet therapy with ASA or clopidogrel approximately doubles the rate of major bleeding events with both dabigatran etexilate and warfarin. There was no significant interaction of treatment effects in subgroups defined by renal function or CHADS2 score. Table 26: Hazard ratio and 95% confidence interval for major bleeding by subgroup Endpoint Dabigatran etexilate 110 mg twice daily vs. warfarin Dabigatran etexilate 150 mg twice daily vs. warfarin Age (years) < 65 0.32 (0.18; 0.57) 0.35 (0.20; 0.61) 65 ≤ and < 75 0.71 (0.56; 0.89) 0.82 (0.66; 1.03) ≥ 75 1.01 (0.84; 1.23) 1.19 (0.99; 1.43) ≥ 80 1.14 (0.86; 1.51) 1.35 (1.03; 1.76) CrCL (mL/min) 30 ≤ and < 50 1.02 (0.79; 1.32) 0.94 (0.73; 1.22) 50 ≤ and < 80 0.75 (0.61; 0.92) 0.90 (0.74; 1.09) ≥ 80 0.59 (0.43; 0.82) 0.87 (0.65; 1.17) ASA use 0.84 (0.69; 1.03) 0.97 (0.79; 1.18) Clopidogrel use 0.89 (0.55; 1.45) 0.92 (0.57; 1.48) RELY-ABLE (long-term multicenter extension of dabigatran treatment in patients with atrial fibrillation who completed the RE-LY trial) The RE-LY extension study (RELY-ABLE) provided additional safety information in a cohort of patients who continued on the same dose of dabigatran etexilate they had received in the RE-LY trial. Patients were eligible for the RELY-ABLE study if they had not permanently discontinued the study medication at the time of their final RE-LY visit. Enrolled patients continued to receive the same double-blind dose of dabigatran etexilate randomly assigned in the RE-LY trial for follow-up of up to 43 months after the end of the RE-LY trial (overall mean follow-up duration in RE-LY and RELY-ABLE combined was 4.5 years). A total of 5,897 patients were enrolled, representing 49% of patients originally randomized to dabigatran etexilate in the RE-LY trial and 86% of those eligible for the RELY-ABLE study. During the additional 2.5 years of treatment in the RELY-ABLE study, with a maximum exposure exceeding 6 years (combined exposure in the RE-LY and RELY-ABLE trials), the long-term safety profile of dabigatran etexilate was confirmed for both 110 mg twice daily and 150 mg twice daily. No new safety findings were observed. The rates of monitored events, including major bleeding and other bleeding events, were consistent with those observed in the RE-LY trial. Data from non-interventional studies In a non-interventional study (GLORIA-AF), data on the safety and efficacy of dabigatran etexilate were collected prospectively (in its second phase) in patients with newly diagnosed NVAF treated in routine clinical practice. The study enrolled 4,859 patients treated with dabigatran etexilate (55% on 150 mg twice daily, 43% on 110 mg twice daily, 2% on 75 mg twice daily). Patients were followed for 2 years. The mean CHADS2 score was 1.9 and the mean HAS-BLED score was 1.2. The mean follow-up duration on treatment was 18.3 months. Major bleeding occurred at a rate of 0.97 per 100 patient-years. Life-threatening bleeding was reported at 0.46 per 100 patient-years, intracranial bleeding at 0.17 per 100 patient-years, and gastrointestinal bleeding at 0.60 per 100 patient-years. Stroke occurred at 0.65 per 100 patient-years. In addition, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157-164] conducted in the United States in more than 134,000 elderly patients with NVAF (contributing more than 37,500 patient-years of on-treatment follow-up), dabigatran etexilate (84% of patients on 150 mg twice daily, 16% on 75 mg twice daily) was associated, compared with warfarin, with a reduced risk of ischemic stroke (hazard ratio 0.80; 95% confidence interval [CI] 0.67–0.96), intracranial bleeding (hazard ratio 0.34; CI 0.26–0.46), and mortality (hazard ratio 0.86; CI 0.77–0.96), and an increased risk of gastrointestinal bleeding (hazard ratio 1.28; CI 1.14–1.44). No difference was observed for major bleeding (hazard ratio 0.97; CI 0.88–1.07). These real-world observations are consistent with the established safety and efficacy profile of dabigatran etexilate in this indication in the RE-LY trial. Patients who underwent percutaneous coronary intervention (PCI) with stenting A prospective, randomized, open-label phase IIIb clinical trial with blinded endpoint adjudication (PROBE) was conducted in 2,725 patients with non-valvular atrial fibrillation who underwent PCI with stenting, comparing dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) and clopidogrel or ticagrelor (a P2Y12 antagonist) versus triple therapy with warfarin (adjusted to INR 2.0–3.0), clopidogrel or ticagrelor, and ASA (RE-DUAL PCI). Patients were randomized to dual therapy with dabigatran etexilate 110 mg twice daily, dual therapy with dabigatran etexilate 150 mg twice daily, or triple therapy with warfarin. Elderly patients outside the United States (≥80 years of age in all countries, ≥70 years of age in Japan) were randomized to either dual therapy with dabigatran etexilate 110 mg or triple therapy with warfarin. The primary endpoint was a composite of major bleeding based on the ISTH definition or clinically relevant non-major bleeding. The incidence of the primary endpoint was 15.4% (151 patients) in the dabigatran etexilate 110 mg dual therapy group compared with 26.9% (264 patients) in the warfarin triple therapy group (hazard ratio 0.52; 95% CI 0.42, 0.63; p < 0.0001 for non-inferiority and p < 0.0001 for superiority), and 20.2% (154 patients) in the dabigatran etexilate 150 mg dual therapy group compared with 25.7% (196 patients) in the corresponding warfarin triple therapy group (hazard ratio 0.72; 95% CI 0.58, 0.88; p < 0.0001 for non-inferiority and p = 0.002 for superiority). In a descriptive analysis, the rate of major bleeding events as classified by TIMI (Thrombolysis In Myocardial Infarction) was lower in both dabigatran etexilate dual therapy groups than in the warfarin triple therapy group: 14 events (1.4%) in the dabigatran etexilate 110 mg dual therapy group versus 37 events (3.8%) in the warfarin triple therapy group (hazard ratio 0.37; 95% CI 0.20, 0.68; p = 0.002), and 16 events (2.1%) in the dabigatran etexilate 150 mg dual therapy group versus 30 events (3.9%) in the corresponding warfarin triple therapy group (hazard ratio 0.51; 95% CI 0.28, 0.93; p = 0.03). Rates of intracranial bleeding were lower in both dabigatran etexilate dual therapy groups than in the corresponding warfarin triple therapy group: 3 events (0.3%) in the dabigatran etexilate 110 mg dual therapy group versus 10 events (1.0%) in the warfarin triple therapy group (hazard ratio 0.30; 95% CI 0.08, 1.07; p = 0.06), and 1 event (0.1%) in the dabigatran etexilate 150 mg dual therapy group versus 8 events (1.0%) in the corresponding warfarin triple therapy group (hazard ratio 0.12; 95% CI 0.02, 0.98; p = 0.047). The incidence of the composite efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, or systemic embolism), or unplanned revascularization was non-inferior in both dabigatran etexilate dual therapy groups compared with the warfarin triple therapy group (13.7% vs. 13.4%, respectively; hazard ratio 1.04; 95% CI: 0.84, 1.29; p = 0.0047 for non-inferiority). No statistical differences were observed between the dabigatran etexilate dual therapy groups and the warfarin triple therapy group for the individual components of the efficacy endpoints. This study demonstrated that, in patients with atrial fibrillation undergoing PCI with stenting, dual therapy with dabigatran etexilate and a P2Y12 antagonist significantly reduced the risk of bleeding compared with triple therapy with warfarin, while non-inferiority was established for the composite of thromboembolic events. Treatment of DVT and PE in adults (DVT/PE treatment) Efficacy and safety were investigated in two multicenter, randomized, double-blind, identical parallel-group trials, RE-COVER and RE-COVER II. These studies compared dabigatran etexilate (150 mg twice daily) with warfarin (target INR 2.0–3.0) in patients with acute DVT and/or PE. The primary objective of these trials was to demonstrate that dabigatran etexilate was non-inferior to warfarin in reducing the incidence of the primary endpoint, a composite of recurrent symptomatic DVT and/or PE and associated deaths during the 6-month treatment period. In the pooled RE-COVER and RE-COVER II analysis, a total of 5,153 patients were randomized and 5,107 were treated. The duration of treatment with the fixed dose of dabigatran was 174.0 days without coagulation monitoring. In patients randomized to warfarin, the median time in therapeutic range (INR 2.0 to 3.0) was 60.6%. The trials demonstrated that dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margins for RE-COVER and RE-COVER II: 3.6 for risk difference and 2.75 for hazard ratio). Table 27: Analysis of primary and secondary efficacy endpoints (VTE comprising DVT and/or PE) for the pooled RE-COVER and RE-COVER II analysis through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Warfarin Number of treated patients 2,553 2,554 Recurrent symptomatic VTE and VTE-related deaths 68 (2.7%) 62 (2.4%) Hazard ratio vs. warfarin (95% confidence interval) 1.09 (0.77; 1.54) Secondary efficacy endpoints Recurrent symptomatic VTE and all-cause mortality 109 (4.3%) 104 (4.1%) 95% confidence interval 3.52; 5.13 3.34; 4.91 Symptomatic DVT 45 (1.8%) 39 (1.5%) 95% confidence interval 1.29; 2.35 1.09; 2.08 Symptomatic PE 27 (1.1%) 26 (1.0%) 95% confidence interval 0.70; 1.54 0.67; 1.49 VTE-related mortality 4 (0.2%) 3 (0.1%) 95% confidence interval 0.04; 0.40 0.02; 0.34 All-cause mortality 51 (2.0%) 52 (2.0%) 95% confidence interval 1.49; 2.62 1.52; 2.66 Prevention of recurrent DVT and PE in adults (DVT/PE prevention) Two randomized, double-blind, parallel-group trials were conducted in patients previously treated with anticoagulant therapy. RE-MEDY, a warfarin-controlled trial, enrolled patients already treated for 3 to 12 months who required further anticoagulation, and RE-SONATE, a placebo-controlled trial, enrolled patients already treated for 6 to 18 months with vitamin K antagonists. The objective of the RE-MEDY trial was to compare the safety and efficacy of oral dabigatran etexilate (150 mg twice daily) with warfarin (target INR 2.0–3.0) for the long-term treatment and prevention of recurrent symptomatic DVT and/or PE. A total of 2,866 patients were randomized and 2,856 were treated. The duration of dabigatran etexilate treatment ranged from 6 to 36 months (median 534.0 days). In patients randomized to warfarin, the median time in therapeutic range (INR 2.0–3.0) was 64.9%. The RE-MEDY trial demonstrated that dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margins: 2.85 for hazard ratio and 2.8 for risk difference). Table 28: Analysis of primary and secondary efficacy endpoints (VTE comprising DVT and/or PE) for the RE-MEDY study through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Warfarin Number of treated patients 1,430 1,426 Recurrent symptomatic VTE and VTE-related deaths 26 (1.8%) 18 (1.3%) Hazard ratio vs. warfarin (95% confidence interval) 1.44 (0.78; 2.64) Non-inferiority margin 2.85 Patients with an event at 18 months 22 17 Cumulative risk at 18 months (%) 1.7 1.4 Risk difference vs. warfarin (%) 0.4 95% confidence interval Non-inferiority margin 2.8 Secondary efficacy endpoints Recurrent symptomatic VTE and all-cause mortality 42 (2.9%) 36 (2.5%) 95% confidence interval 2.12; 3.95 1.77; 3.48 Symptomatic DVT 17 (1.2%) 13 (0.9%) 95% confidence interval 0.69; 1.90 0.49; 1.55 Symptomatic PE 10 (0.7%) 5 (0.4%) 95% confidence interval 0.34; 1.28 0.11; 0.82 VTE-related mortality 1 (0.1%) 1 (0.1%) 95% confidence interval 0.00; 0.39 0.00; 0.39 All-cause mortality 17 (1.2%) 19 (1.3%) 95% confidence interval 0.69; 1.90 0.80; 2.07 The objective of the RE-SONATE trial was to evaluate the superiority of dabigatran etexilate over placebo in the prevention of recurrent symptomatic DVT and/or PE in patients who had completed 6 to 18 months of treatment with a VKA. The intended treatment was 6 months of dabigatran etexilate 150 mg twice daily without the need for monitoring. The RE-SONATE trial demonstrated that dabigatran etexilate was superior to placebo in the prevention of recurrent symptomatic DVT/PE events including unexplained deaths, with a risk reduction from 5.6% to 0.4% (relative risk reduction of 92% based on the hazard ratio) during the treatment period (p < 0.0001). All secondary and sensitivity analyses of the primary endpoint and all secondary endpoints showed superiority of dabigatran etexilate over placebo. The trial included a 12-month observational follow-up after treatment cessation. After discontinuation of the study medication, the effect was sustained through the end of follow-up, indicating that the initial treatment effect of dabigatran etexilate was maintained. No rebound effect was observed. At the end of the follow-up period, VTE events occurred in 6.9% of dabigatran etexilate–treated patients compared with 10.7% in the placebo group (hazard ratio 0.61 [95% CI 0.42; 0.88], p = 0.0082). Table 29: Analysis of primary and secondary efficacy endpoints (VTE comprising DVT and/or PE) for the RE-SONATE study through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Placebo Number of treated patients 681 662 Recurrent symptomatic VTE and VTE-related deaths 3 (0.4%) 37 (5.6%) Hazard ratio vs. placebo (95% confidence interval) 0.08 (0.02; 0.25) p-value for superiority < 0.0001 Secondary efficacy endpoints Recurrent symptomatic VTE and all-cause mortality 3 (0.4%) 37 (5.6%) 95% confidence interval 0.09; 1.28 3.97; 7.62 Symptomatic DVT 2 (0.3%) 23 (3.5%) 95% confidence interval 0.04; 1.06 2.21; 5.17 Symptomatic PE 1 (0.1%) 14 (2.1%) 95% confidence interval 0.00; 0.82 1.16; 3.52 VTE-related mortality 0 (0) 0 (0) 95% confidence interval 0.00; 0.54 0.00; 0.56 Unexplained deaths 0 (0) 2 (0.3%) 95% confidence interval 0.00; 0.54 0.04; 1.09 All-cause mortality 0 (0) 2 (0.3%) 95% confidence interval 0.00; 0.54 0.04; 1.09 Clinical trials in the prevention of thromboembolic disease in patients with prosthetic heart valves A phase II study evaluated dabigatran etexilate and warfarin in a total of 252 patients following surgical mechanical heart valve replacement, in the early postoperative period (i.e., dosing initiated during the post-surgical hospitalization) and in patients who had received a mechanical heart valve more than three months earlier. More thromboembolic events (primarily strokes and symptomatic/asymptomatic prosthetic valve thrombosis) and more bleeding events were observed with dabigatran etexilate than with warfarin. In patients in the early postoperative phase, major bleeding manifested mainly as hemorrhagic pericardial effusions, particularly in patients in whom dabigatran etexilate was initiated early (i.e., on day 3) after surgical heart valve replacement (see section 4.3). Pediatric population Clinical trials of VTE prevention after major joint replacement surgery Prevention of stroke and systemic embolism in adult patients with NVAF and one or more risk factors The European Medicines Agency has waived the obligation to submit results of studies with the reference product containing dabigatran etexilate in all subsets of the pediatric population for the indications of primary prevention of VTE in patients undergoing elective total hip or knee replacement and prevention of stroke and systemic embolism in patients with NVAF (for information on use in the pediatric population, see section 4.2). Treatment of VTE and prevention of recurrent VTE in pediatric patients The DIVERSITY study was conducted to demonstrate the efficacy and safety of dabigatran etexilate compared with standard of care (SOC) in the treatment of VTE in pediatric patients from birth to <18 years of age. The study was designed as an open-label, randomized, parallel-group non-inferiority trial. Enrolled patients were randomized in a 2:1 ratio to either dabigatran etexilate (doses adjusted by age and body weight) in an age-appropriate dosage form (capsules, coated pellets, or oral solution) or to SOC consisting of low molecular weight heparin (LMWH), vitamin K antagonists (VKAs), or fondaparinux (1 patient aged 12 years). The primary endpoint was a composite of the number of patients with complete thrombus resolution, freedom from recurrent VTE, and no VTE-related mortality. Exclusion criteria included active meningitis, encephalitis, and intracranial abscess. A total of 267 patients were randomized. Of these, 176 patients were treated with dabigatran etexilate and 90 received SOC (1 randomized patient was not treated). 168 patients were aged 12 to <18 years, 64 patients were aged 2 to <12 years, and 35 patients were younger than 2 years. Of the 267 randomized patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients (42.2%) in the SOC group met the criteria for the composite endpoint (complete thrombus resolution, freedom from recurrent VTE, and no VTE-related mortality). The corresponding incidence difference demonstrated non-inferiority of dabigatran etexilate over SOC. Consistent results were also observed overall across subgroups: no significant differences in treatment effect were found in subgroups defined by age, sex, region, or the presence of certain risk factors. Across the 3 different age groups, the proportions of patients meeting the primary efficacy endpoint in the dabigatran etexilate and SOC groups were 13/22 (59.1%) versus 7/13 (53.8%) in patients from birth to <2 years, 21/43 (48.8%) versus 12/21 (57.1%) in patients aged 2 to <12 years, and 47/112 (42.0%) versus 19/56 (33.9%) in patients aged 12 to <18 years. Adjudicated major bleeding was reported in 4 patients (2.3%) in the dabigatran etexilate group and 2 patients (2.2%) in the SOC group. There was no statistically significant difference in time to first major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients (24.4%) in the SOC arm had any adjudicated bleeding events, the majority of which were classified as minor. The composite endpoint of adjudicated major bleeding events (MBE) or clinically relevant non-major (CRNM) bleeding (during treatment) was reported in 6 patients (3.4%) in the dabigatran etexilate group and 3 patients (3.3%) in the SOC group. A prospective, open-label, single-arm, multicenter phase III cohort study was conducted to evaluate the safety (1160.108) of dabigatran etexilate in the prevention of recurrent VTE in pediatric patients aged from birth to <18 years. Eligible patients were those requiring further anticoagulant therapy in view of the presence of clinical risk factors after completing initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study. Patients in the study received dabigatran etexilate doses adjusted by age and body weight in age-appropriate dosage forms (capsules, coated pellets, or oral solution) until resolution of clinical risk factors, or for a maximum of 12 months. The primary study endpoints included recurrent VTE, major and minor bleeding events, and mortality (overall and related to thrombotic or thromboembolic events) at 6 and 12 months. Event outcomes were assessed by an independent blinded adjudication committee. A total of 214 patients were enrolled in the study, including 162 patients in age group 1 (12 to <18 years), 43 patients in age group 2 (2 to <12 years), and 9 patients in age group 3 (birth to <2 years). During the treatment period, recurrent VTE was confirmed in 3 patients (1.4%) within the first 12 months of treatment. Confirmed bleeding events during the treatment period were reported in 48 patients (22.5%) within the first 12 months. Most bleeding events were minor. Adjudicated major bleeding events occurred in 3 patients (1.4%) within the first 12 months. Adjudicated CRNM bleeding was reported in 3 patients (1.4%) within the first 12 months. No deaths occurred during treatment. During the treatment period, 3 patients (1.4%) developed post-thrombotic syndrome (PTS) or had worsening of PTS within the first 12 months.