Dabigatranum etexilatum

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 the plasma and liver via esterase-catalysed hydrolysis. Dabigatran is a potent, competitive, reversible, direct thrombin inhibitor and the principal active moiety in plasma. Because thrombin (a serine protease) enables 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 intravenous dabigatran and oral dabigatran etexilate were demonstrated in various animal models of thrombosis. Phase II studies have shown 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 diluted TT test (dTT) provides an estimate of the plasma dabigatran concentration that can be compared with expected plasma concentrations of dabigatran. When the dabigatran plasma concentration result from the calibrated dTT test is at or below the limit of quantification, 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 test is widely available and provides an approximate indication of the intensity of anticoagulation achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable for the precise quantification of the anticoagulant effect, especially at high plasma dabigatran concentrations. Although high aPTT values must be interpreted with caution, a high aPTT value indicates that the patient is anticoagulated. In general, it can be assumed that these measurements of anticoagulant activity may reflect dabigatran levels and provide guidance for assessing the risk of bleeding; that is, exceeding the 90th percentile of dabigatran trough concentration or of a coagulation test such as aPTT measured at trough (for aPTT threshold values, see section 4.4, Table 6) is regarded as a situation 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 concentrations of dabigatran measured at the end of the dosing interval (i.e. 24 hours after the 220 mg dabigatran dose) averaged 22.0 ng/mL, with a range of 13.0–35.7 ng/mL (25th–75th percentile). In a study performed 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 concentration of dabigatran 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). In patients treated with dabigatran etexilate 220 mg once daily for the prevention of VTE following 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 sections 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 treated with dabigatran etexilate 220 mg once daily for the prevention of VTE following hip or knee replacement. Prevention of stroke and systemic embolism in adult patients with NVAF with 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 dose of dabigatran etexilate twice daily, were 175 ng/mL, with a range of 117–275 ng/mL (25th–75th percentile). The geometric mean morning trough concentrations of dabigatran measured 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). 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 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) increased to approximately three times the upper limit of the normal range corresponds to the observed 90th percentile ECT prolongation of 103 seconds, an aPTT ratio greater than two 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 concentration of dabigatran measured 10–16 hours after the dose 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). 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) increased approximately 2.3-fold compared with baseline corresponds to the observed 90th percentile ECT prolongation of 74 seconds, the 90th percentile of aPTT at trough (10–16 hours after the previous dose) was 62 seconds, corresponding to a 1.8-fold increase compared with baseline. No pharmacokinetic data are available in patients treated with dabigatran etexilate 150 mg twice daily for the prevention of recurrent DVT and PE. Clinical efficacy and safety Ethnic origin No clinically relevant ethnic differences were observed among Caucasian, African-American, Hispanic, Japanese or Chinese patients. Clinical trials in the prevention of VTE following major joint replacement surgery In two large, double-blind, randomised, dose-confirmation, parallel-group trials, patients undergoing elective major orthopaedic surgery (one trial in knee replacement and 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 after 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). A total of 2,076 patients (knee) and 3,494 patients (hip) were treated, respectively. The primary endpoint in both studies was the 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 the composite of major venous thromboembolism (including pulmonary embolism and proximal deep vein thrombosis, symptomatic or asymptomatic, detected by routine venography) and VTE-related mortality. Results from 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 the incidence of major VTE and VTE-related mortality at the 150 mg dose was slightly worse than that of enoxaparin (Table 19). Better results were observed at the 220 mg dose, where the point estimate for major VTE was slightly better than that of enoxaparin (Table 19). The clinical studies were conducted in a patient population with a mean age > 65 years. In the phase 3 clinical studies there were no differences between men and women in terms of efficacy and safety data. In the patient population studied in 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 VTE or bleeding rates. Data for the major VTE and VTE-related mortality endpoint were homogeneous with respect to the primary efficacy endpoint and are presented in Table 19. Data for the total VTE and all-cause mortality endpoint are presented in Table 20. Data on the adjudicated major bleeding endpoints 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 studies Clinical 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 studies Clinical 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 each of the RE-MODEL and RE-NOVATE studies Clinical 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 Number of MBEs (%) 23 (2.0) 15 (1.3) 18 (1.6) RE-MODEL (knee) Number of treated patients (n) 679 703 694 Number of MBEs (%) 10 (1.5) 9 (1.3) 9 (1.3) Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors Clinical evidence of efficacy for 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 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 analysed. In the RE-LY trial, a total of 18,113 patients were randomised, 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. 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 study showed that dabigatran etexilate 110 mg twice daily is non-inferior to warfarin in the prevention of stroke and systemic embolism in subjects with atrial fibrillation, with a reduced risk of intracranial bleeding, total bleeding and major bleeding. The 150 mg twice-daily dose significantly reduces the risk of ischaemic and haemorrhagic stroke, vascular death, 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 compared with warfarin for dabigatran etexilate 110 mg twice daily (hazard ratio 1.29; p = 0.0929) and for dabigatran etexilate 150 mg twice daily (hazard ratio 1.27; p = 0.1240). With improved INR monitoring, the observed benefits of dabigatran etexilate over warfarin diminish. 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 follow-up period of the RE-LY trial Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomised 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 ischaemic or haemorrhagic stroke during the follow-up period of the RE-LY trial Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomised 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 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 the annual event rate Table 24: Analysis of all-cause death and cardiovascular survival during the follow-up period of the RE-LY trial Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomised subjects 6,015 6,076 6,022 All-cause death 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 death 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 relevant subpopulations: For the primary endpoint of stroke and systemic embolism, no subgroups (e.g. age, body weight, sex, renal function, ethnicity, etc.) with a different hazard ratio compared with warfarin were identified. 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 for both dabigatran etexilate and warfarin. There was no significant treatment-effect interaction for the renal function or CHADS2 score subgroups. 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 a cohort of patients who continued on the same dose of dabigatran etexilate as had been assigned 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 visit in the RE-LY trial. The enrolled patients continued to receive the same double-blind dose of dabigatran etexilate randomly assigned in the RE-LY trial, for a follow-up period of up to 43 months after the end of RE-LY (total mean follow-up time across the RE-LY and RELY-ABLE studies was 4.5 years). A total of 5,897 patients were enrolled, representing 49% of patients originally randomised to dabigatran etexilate in the RE-LY trial and 86% of those eligible for the RELY-ABLE study. During an additional 2.5 years of treatment in the RELY-ABLE study with maximum exposure exceeding 6 years (total exposure across the RE-LY and RELY-ABLE studies), the long-term safety profile of dabigatran etexilate was confirmed for both doses studied, 110 mg twice daily and 150 mg twice daily. No new safety findings were observed. The rates of adjudicated outcomes 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 in patients with newly diagnosed NVAF treated in real-world practice were collected prospectively (in its second phase). The study enrolled 4,859 patients treated with dabigatran etexilate (55% received 150 mg twice daily, 43% received 110 mg twice daily, 2% received 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 time on treatment 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 time), dabigatran etexilate (84% of patients received 150 mg twice daily, 16% received 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 from the RE-LY trial. Patients who underwent percutaneous coronary intervention (PCI) with stenting A prospective, randomised, 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, 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 (adjusted to INR 2.0–3.0), clopidogrel or ticagrelor and ASA (RE-DUAL PCI). Patients were randomised to dual therapy with 110 mg dabigatran etexilate twice daily, dual therapy with 150 mg dabigatran etexilate 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 110 mg dabigatran etexilate or to 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 110 mg dabigatran etexilate dual therapy arm compared with 26.9% (264 patients) in the warfarin triple therapy arm (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 150 mg dabigatran etexilate dual therapy arm compared with 25.7% (196 patients) in the corresponding warfarin triple therapy arm (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 incidence of major bleeding by TIMI (Thrombolysis In Myocardial Infarction) classification was lower in both dabigatran etexilate dual therapy arms compared with the warfarin triple therapy arm: 14 events (1.4%) in the 110 mg dabigatran etexilate dual therapy arm versus 37 events (3.8%) in the warfarin triple therapy arm (hazard ratio 0.37; 95% CI 0.20, 0.68; p = 0.002), and 16 events (2.1%) in the 150 mg dabigatran etexilate dual therapy arm versus 30 events (3.9%) in the corresponding warfarin triple therapy arm (hazard ratio 0.51; 95% CI 0.28, 0.93; p = 0.03). The rates of intracranial bleeding in both dabigatran etexilate dual therapy arms were lower than in the corresponding warfarin triple therapy arm: 3 events (0.3%) in the 110 mg dabigatran etexilate dual therapy arm versus 10 events (1.0%) in the warfarin triple therapy arm (hazard ratio 0.30; 95% CI 0.08, 1.07; p = 0.06), and 1 event (0.1%) in the 150 mg dabigatran etexilate dual therapy arm versus 8 events (1.0%) in the corresponding warfarin triple therapy arm (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 both dabigatran etexilate dual therapy arms compared with the warfarin triple therapy arm (13.7% vs. 13.4%, respectively; hazard ratio 1.04; 95% CI: 0.84, 1.29; p = 0.0047 for non-inferiority). No statistically significant differences were observed for the individual components of the efficacy endpoint between the dabigatran etexilate dual therapy arms and the warfarin triple therapy arm. This study showed that in patients with atrial fibrillation who underwent 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 demonstrated for the composite of thromboembolic events. Treatment of DVT and PE in adults (DVT/PE treatment) Efficacy and safety were investigated in two multicentre, randomised, double-blind, identical, parallel-group studies, 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 studies was to demonstrate that dabigatran etexilate was non-inferior to warfarin in reducing the incidence of the primary endpoint, the composite of recurrent symptomatic DVT and/or PE and associated deaths during the 6-month treatment period. In the pooled analysis of the RE-COVER and RE-COVER II studies, 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 margin for RE-COVER and RE-COVER II: 3.6 for risk difference and 2.75 for risk 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 studies 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 death 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 death 4 (0.2%) 3 (0.1%) 95% confidence interval 0.04; 0.40 0.02; 0.34 All-cause death 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, included patients already treated for 3 to 12 months who required additional anticoagulation, and RE-SONATE, a placebo-controlled study, included patients already treated for 6 to 18 months with vitamin K inhibitors. The objective of the RE-MEDY study was to compare the safety and efficacy of oral dabigatran etexilate (150 mg twice daily) versus 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 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 study demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margin: 2.85 for risk 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 death 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 death 1 (0.1%) 1 (0.1%) 95% confidence interval 0.00; 0.39 0.00; 0.39 All-cause death 17 (1.2%) 19 (1.3%) 95% confidence interval 0.69; 1.90 0.80; 2.07 The objective of the RE-SONATE study was to assess the superiority of dabigatran etexilate over placebo in the prevention of recurrent symptomatic DVT and/or PE in patients who had already 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 study 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% (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 study included an observational follow-up of 12 months after treatment cessation. After discontinuation of study medication, the effect persisted to the end of the 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 patients treated with dabigatran etexilate versus 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 death 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 death 0 (0) 0 (0) 95% confidence interval 0.00; 0.54 0.00; 0.56 Unexplained death 0 (0) 2 (0.3%) 95% confidence interval 0.00; 0.54 0.04; 1.09 All-cause death 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, both in the early postoperative period (i.e. dosing was initiated during the post-surgical hospital stay) and in patients who had undergone mechanical heart valve replacement more than three months earlier. More thromboembolic events (mainly 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 manifested predominantly as haemorrhagic pericardial effusions, mainly in patients in whom dabigatran etexilate was initiated early (i.e. on day 3) after surgical heart valve replacement (see section 4.3). Paediatric population Clinical trials in the prevention of VTE following major joint replacement surgery Prevention of stroke and systemic embolism in adult patients with NVAF with 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 paediatric population in the indication of primary prevention of VTE in patients undergoing elective total hip or knee replacement, and in the indication of 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 study 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 < 18 years of age. The study was designed as an open-label, randomised, parallel-group, non-inferiority trial. Enrolled patients were randomised in a 2:1 ratio either to dabigatran etexilate (doses adjusted by age and body weight) in an age-appropriate dosage form (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 patients with complete thrombus resolution, freedom from recurrent VTE and zero VTE-related mortality. Exclusion criteria included active meningitis, encephalitis and intracranial abscess. A total of 267 patients were randomised. Of these, 176 patients were treated with dabigatran etexilate and 90 patients received SOC (1 randomised 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 randomised patients, 81 patients (45.8%) in the dabigatran etexilate arm and 38 patients (42.2%) in the SOC arm met the criteria for the composite endpoint (complete thrombus resolution, freedom from recurrent VTE and zero VTE-related mortality). The corresponding difference in incidence demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent results were also observed overall across subgroups: there were no significant differences in treatment effect across age, sex, region or presence of certain risk-factor subgroups. In the 3 different age groups, the proportions of patients meeting the primary efficacy endpoint in the dabigatran etexilate and SOC arms 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 arm and in 2 patients (2.2%) in the SOC arm. 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 event, 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 arm and in 3 patients (3.3%) in the SOC arm. A prospective, open-label, single-arm, multicentre, phase III cohort study (1160.108) was conducted to evaluate the safety of dabigatran etexilate in the prevention of recurrent VTE in paediatric patients from birth to < 18 years of age. Patients eligible for inclusion were those who required additional anticoagulant treatment 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 study. Patients in the study received doses of dabigatran etexilate adjusted by age and body weight in an age-appropriate dosage form (capsules, coated granules or oral solution) until the resolution of clinical risk factors, or for up to 12 months. Primary endpoints of the study included VTE recurrence, major and minor bleeding events, and mortality (overall and related to thrombotic or thromboembolic events) at 6 and 12 months. Outcomes were assessed by an independent blinded adjudication committee. A total of 214 patients were enrolled in the study; among them 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 initiation. Confirmed bleeding events during the treatment period were reported in 48 patients (22.5%) in the first 12 months. Most bleeding events were minor. In 3 patients (1.4%), a major bleeding event confirmed by adjudication occurred within the first 12 months. CRNM bleeding confirmed by adjudication 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 PTS within the first 12 months.