Dabigatran Etexilate Accord

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. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran in plasma and the liver by esterase-catalysed hydrolysis. Dabigatran is a potent, competitive, reversible, direct thrombin inhibitor and is the principal active moiety in plasma. Because thrombin (a serine protease) catalyses 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, the 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 have established a clear correlation between plasma dabigatran concentrations and the magnitude of the anticoagulant effect. Dabigatran prolongs thrombin time (TT), ECT and aPTT. The calibrated quantitative diluted thrombin time (dTT) assay provides an estimate of plasma dabigatran concentration that can be compared with expected plasma dabigatran concentrations. When the plasma dabigatran concentration measured by the calibrated dTT assay is at or below the limit of quantification, an additional coagulation assay such as TT, ECT or aPTT should be considered. The ECT provides a direct measure of the activity of direct thrombin inhibitors. The aPTT assay is widely available and provides an approximate indication of the intensity of anticoagulation achieved with dabigatran. However, the aPTT has limited sensitivity and is unsuitable for precise quantification of the anticoagulant effect, particularly at high plasma dabigatran concentrations. Although elevated aPTT values must be interpreted with caution, a high aPTT value indicates that the patient is anticoagulated. In general, these measures of anticoagulant activity may be assumed to reflect dabigatran levels and to provide guidance for assessing bleeding risk; that is, exceeding the 90th percentile of the dabigatran trough concentration or of a coagulation assay such as 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 orthopaedic surgery The geometric mean steady-state peak plasma concentrations of dabigatran (after day 3), measured approximately 2 hours after administration of a 220 mg dose of dabigatran etexilate, were 70.8 ng/mL, with a range of 35.2-162 ng/mL (25th-75th percentile). The geometric mean trough dabigatran concentration measured at the end of the dosing interval (i.e. 24 hours after the 220 mg dose) was on average 22.0 ng/mL, with a range of 13.0-35.7 ng/mL (25th-75th percentile). 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 was on average 47.5 ng/mL, with a range of 29.6-72.2 ng/mL (25th-75th percentile). In patients treated with 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 of aPTT at trough (20-28 hours after the previous dose) was 51 seconds, representing 1.3 times the upper limit of the normal range. 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 steady-state peak plasma concentrations of dabigatran, measured approximately 2 hours after administration of a 150 mg twice-daily dose of dabigatran etexilate, were 175 ng/mL, with a range of 117-275 ng/mL (25th-75th percentile). The geometric mean trough dabigatran concentration measured at the morning trough at the end of the dosing interval (i.e. 12 hours after the 150 mg evening dose) was on average 91.0 ng/mL, with a range of 61.0-143 ng/mL (25th-75th percentile). In NVAF patients treated with dabigatran etexilate 150 mg twice daily for the prevention of stroke and systemic embolism: the 90th percentile of plasma dabigatran concentrations at trough (10-16 hours after the previous dose) was approximately 200 ng/mL; ECT at trough (10-16 hours after the previous dose) increased to approximately three times the upper limit of the normal range, corresponding to the observed 90th percentile of ECT prolongation of 103 seconds; an aPTT ratio greater than two times the upper limit of the normal range (aPTT prolongation to about 80 seconds) at trough (10-16 hours after the previous dose) corresponded 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 150 mg evening dose) was 59.7 ng/mL, with a range of 38.6-94.5 ng/mL (25th-75th percentile). For the treatment of DVT and PE with dabigatran etexilate 150 mg twice daily: the 90th percentile of plasma dabigatran concentrations at trough (10-16 hours after the previous dose) was approximately 200 ng/mL; ECT at trough (10-16 hours after the previous dose) increased approximately 2.3-fold relative to baseline, corresponding to the observed 90th percentile of ECT prolongation of 74 seconds; the 90th percentile of aPTT at trough (10-16 hours after the previous dose) was 62 seconds, representing 1.8-fold the baseline value. No pharmacokinetic data are available for 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 between Caucasian, African-American, Hispanic, Japanese or Chinese patients. Clinical trials in VTE prevention after major joint replacement surgery In two large, double-blind, randomised, parallel-group dose-confirmation trials, patients undergoing elective major orthopaedic surgery (knee replacement in one trial and hip replacement in the other) received dabigatran etexilate 75 mg or 110 mg within 1-4 hours after surgery, followed by 150 mg or 220 mg once daily once haemostasis 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 patients treated 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. Both studies showed that the antithrombotic effect of dabigatran etexilate 220 mg and 150 mg was statistically non-inferior to that of enoxaparin in terms of 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, where the point estimate for 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 phase 3 clinical trials, no differences between men and women were observed with respect to efficacy and safety data. In the RE-MODEL and RE-NOVATE study population (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 VTE prevention or on bleeding rates. Data on the major VTE and VTE-related mortality endpoint were homogeneous with respect to 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 endpoint are presented in Table 21 below. Table 19: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL and RE-NOVATE orthopaedic 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 orthopaedic 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 in 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 patients treated (n) 1,146 1,163 1,154 Number of MBE (%) 23 (2.0) 15 (1.3) 18 (1.6) RE-MODEL (knee) Number of patients treated (n) 679 703 694 Number of MBE (%) 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 of the efficacy of dabigatran etexilate is derived from the RE-LY trial (Randomised Evaluation of Long-term anticoagulant therapy), a multicentre, international, randomised, parallel-group study comparing two doses of dabigatran etexilate (110 mg and 150 mg twice daily) administered in a blinded manner with open-label warfarin in patients with atrial fibrillation at moderate to high risk of stroke and systemic embolism. The primary objective of the trial was to demonstrate whether dabigatran etexilate was non-inferior to warfarin in reducing the composite endpoint of stroke and systemic embolism. Statistical superiority was also analysed. A total of 18,113 patients with a mean age of 71.5 years and a mean CHADS2 score of 2.1 were randomised in the RE-LY trial. The patient population was 64% male, 70% Caucasian and 16% Asian. In patients randomised to warfarin, the mean percentage of time in the therapeutic range (TTR) (INR 2-3) was 64.4% (median TTR 67%). The RE-LY trial showed 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 ischaemic and haemorrhagic stroke, vascular death, intracranial bleeding and total bleeding compared with warfarin. The rate of major bleeding with this dose was comparable to warfarin. The rate of myocardial infarction was modestly increased with dabigatran etexilate 110 mg twice daily (hazard ratio 1.29; p = 0.0929) and dabigatran etexilate 150 mg twice daily (hazard ratio 1.27; p = 0.1240) compared with warfarin. With improved INR monitoring, the observed benefits of dabigatran etexilate over warfarin are reduced. Tables 22-24 present detailed key results in the overall population. Table 22: Analysis of first occurrence of stroke or systemic embolism (primary endpoint) during the RE-LY observation period Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Subjects randomised 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 annual event rate Table 23: Analysis of first occurrence of ischaemic or haemorrhagic stroke during the RE-LY observation period Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Subjects randomised 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 Ischaemic 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 Haemorrhagic 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 annual event rate Table 24: Analysis of all-cause mortality and cardiovascular survival during the RE-LY observation period Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Subjects randomised 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 annual event rate Tables 25-26 present results for the primary efficacy and safety endpoints in the relevant subpopulations. For the primary endpoint of stroke and systemic embolism, no subgroups (e.g. age, body weight, sex, renal function, ethnicity, etc.) were identified with a hazard ratio differing from that for the overall population versus 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 treatment with antiplatelet agents, ASA or clopidogrel approximately doubles the rate of major bleeding events with both dabigatran etexilate and warfarin. There was no significant treatment-effect interaction for 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 multicentre extension of dabigatran treatment in patients with atrial fibrillation who completed the RE-LY trial) The RE-LY extension trial (RELY-ABLE) provided additional safety information for the cohort of patients who continued on the same dose of dabigatran etexilate as in the RE-LY trial. Patients were eligible for the RELY-ABLE trial if they had not permanently discontinued the trial medication at the time of their final visit in the RE-LY trial. Enrolled patients continued to receive the same blinded dose of dabigatran etexilate to which they had been randomised in RE-LY for a follow-up of up to 43 months after the end of RE-LY (overall mean follow-up across RE-LY and RELY-ABLE was 4.5 years). A total of 5,897 patients were enrolled, representing 49% of patients originally randomised to dabigatran etexilate in RE-LY and 86% of patients eligible for RELY-ABLE. During an additional 2.5 years of treatment in the RELY-ABLE trial, with a maximum exposure exceeding 6 years (total exposure across RE-LY and RELY-ABLE), the long-term safety profile of dabigatran etexilate was confirmed for both 110 mg twice-daily and 150 mg twice-daily doses. No new safety findings were observed. The rates of adjudicated 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 on-treatment follow-up duration was 18.3 months. Major bleeding occurred at a rate of 0.97 events per 100 patient-years. Life-threatening bleeding was reported at 0.46 events per 100 patient-years, intracranial bleeding at 0.17 events per 100 patient-years and gastrointestinal bleeding at 0.60 events per 100 patient-years. Stroke occurred at a rate of 0.65 events 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 ischaemic 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 undergoing percutaneous coronary intervention (PCI) with stenting A prospective, randomised, open-label, blinded-endpoint (PROBE) phase IIIb clinical trial was conducted in 2,725 patients with non-valvular atrial fibrillation who had undergone PCI with stenting, to evaluate dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) plus clopidogrel or ticagrelor (a P2Y12 antagonist) compared with triple therapy of warfarin (titrated to INR 2.0-3.0), clopidogrel or ticagrelor and ASA (RE-DUAL PCI). Patients were randomised 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 randomised to dual therapy with dabigatran etexilate 110 mg or to triple therapy with warfarin. The primary endpoint was a composite of ISTH-defined major bleeding 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 TIMI (Thrombolysis In Myocardial Infarction) major bleeding events 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 compared with 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 compared with 30 events (3.9%) in the corresponding warfarin triple-therapy group (hazard ratio 0.51; 95% CI 0.28, 0.93; p = 0.03). In both dabigatran etexilate dual-therapy groups, intracranial bleeding rates were lower than in the corresponding warfarin triple-therapy group: 3 events (0.3%) in the dabigatran etexilate 110 mg dual-therapy group compared with 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 compared with 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 revascularisation was non-inferior in the combined 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). For the individual components of the efficacy endpoints, no statistical differences were identified between the dabigatran etexilate dual-therapy groups and the warfarin triple-therapy group. This study demonstrated that, in patients with atrial fibrillation undergoing PCI with stenting, dual therapy with dabigatran etexilate plus a P2Y12 antagonist significantly reduced the risk of bleeding compared with warfarin triple therapy, 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 evaluated in two multicentre, randomised, double-blind, parallel-group, identical trials, RE-COVER and RE-COVER II. These trials 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 randomised and 5,107 were treated. The duration of fixed-dose dabigatran treatment was 174.0 days, without coagulation monitoring. In patients randomised to warfarin, the median time in therapeutic range (INR 2.0 to 3.0) was 60.6%. The trials demonstrated that treatment with 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 trials through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Warfarin Number of patients treated 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 deaths 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 randomised, double-blind, parallel-group studies were conducted in patients previously treated with anticoagulant therapy. RE-MEDY, a warfarin-controlled study, enrolled patients already treated for 3 to 12 months who required further anticoagulant therapy, and RE-SONATE, a placebo-controlled study, enrolled patients already treated with vitamin K antagonists for 6 to 18 months. 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) in the long-term treatment and prevention of recurrent symptomatic DVT and/or PE. A total of 2,866 patients were randomised and 2,856 patients were treated. The duration of dabigatran etexilate treatment ranged from 6 to 36 months (median 534.0 days). In patients randomised to warfarin, the median time in therapeutic range (INR 2.0-3.0) was 64.9%. The RE-MEDY trial demonstrated that treatment with 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 trial through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Warfarin Number of patients treated 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 deaths 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 monitoring. The RE-SONATE trial demonstrated that dabigatran etexilate was superior to placebo in preventing recurrent symptomatic DVT/PE events, including unexplained deaths, with a reduction in risk from 5.6% to 0.4% (a 92% relative risk reduction based on hazard ratio) during the treatment period (p < 0.0001). All secondary and sensitivity analyses of the primary endpoint and all secondary endpoints demonstrated the superiority of dabigatran etexilate over placebo. The trial included a 12-month observational follow-up after the end of treatment. After discontinuation of the study medication, the effect persisted through the end of follow-up, indicating that the initial therapeutic 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 patients treated with dabigatran etexilate 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 trial through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Placebo Number of patients treated 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 deaths 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 of thromboembolism prevention in patients with prosthetic heart valves A phase II trial 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 was initiated during post-surgical hospitalisation) and in patients who had received a mechanical heart valve replacement more than three months earlier. More thromboembolic events (predominantly stroke 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 presented predominantly as haemorrhagic pericardial effusions, mainly in patients in whom dabigatran etexilate was initiated early (i.e. on day 3) following surgical heart valve replacement (see section 4.3). Paediatric population Clinical trials in 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 the results of studies with the reference product containing dabigatran etexilate in all subsets of the paediatric population in the indications of primary VTE prevention in patients undergoing elective total hip or knee replacement and prevention of stroke and systemic embolism in patients with NVAF (see section 4.2 for information on paediatric use). Treatment of VTE and prevention of recurrent VTE in paediatric patients The DIVERSITY trial was conducted to demonstrate the efficacy and safety of dabigatran etexilate compared with standard of care (SOC) in the treatment of VTE in paediatric patients from birth to less than 18 years of age. The trial was designed as an open-label, randomised, parallel-group non-inferiority study. Enrolled patients were randomised in a 2:1 ratio to either dabigatran etexilate (doses adjusted by age and body weight) in an age-appropriate formulation (capsules, coated granules or oral solution) or to SOC consisting of low-molecular-weight heparins (LMWH), vitamin K antagonists (VKA) or fondaparinux (1 patient aged 12 years). The primary endpoint was a composite of the number of patients with complete thrombus resolution, absence of recurrent VTE and absence of VTE-related mortality. Exclusion criteria included active meningitis, encephalitis and intracranial abscess. A total of 267 patients were randomised. Of these, 176 patients received dabigatran etexilate and 90 patients received SOC (1 randomised patient was not treated). 168 patients were aged 12 to less than 18 years, 64 patients were aged 2 to less than 12 years, and 35 patients were younger than 2 years. Of the 267 randomised 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, absence of recurrent VTE and absence of VTE-related mortality). The corresponding difference in event rates demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent results were also observed overall across subgroups: no significant differences in treatment effect were seen in subgroups defined by age, sex, region or the presence of certain risk factors. In 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 less than 2 years, 21/43 (48.8%) versus 12/21 (57.1%) in patients aged 2 to less than 12 years, and 47/112 (42.0%) versus 19/56 (33.9%) in patients aged 12 to less than 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, most 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, multicentre phase III cohort study (1160.108) was conducted to evaluate the safety of dabigatran etexilate for the prevention of recurrent VTE in paediatric patients from birth to less than 18 years of age. Patients eligible for enrolment were those who required additional anticoagulant therapy due to the presence of clinical risk factors after completion of initial therapy for confirmed VTE (for at least 3 months) or after completion of the DIVERSITY trial. Patients in the trial received doses of dabigatran etexilate adjusted by age and body weight in an age-appropriate formulation (capsules, coated granules or oral solution) until resolution of clinical risk factors or for a maximum of 12 months. The primary endpoints of the trial 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 trial, including 162 patients in age group 1 (12 to less than 18 years), 43 patients in age group 2 (2 to less than 12 years) and 9 patients in age group 3 (birth to less than 2 years). During the treatment period, recurrent VTE was confirmed in 3 patients (1.4%) within the first 12 months after treatment initiation. Confirmed bleeding events during the treatment period were reported in the first 12 months in 48 patients (22.5%). 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 experienced worsening of PTS within the first 12 months.