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 plasma and the 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 vivo and ex vivo animal studies have demonstrated the antithrombotic efficacy and anticoagulant activity of dabigatran following intravenous administration, and of dabigatran etexilate following oral administration, across various animal models of thrombosis. Phase II studies have shown a clear correlation between plasma dabigatran concentrations and the degree of anticoagulant effect. Dabigatran prolongs thrombin time (TT), ECT, and aPTT. The calibrated quantitative diluted TT assay (dTT) provides an estimate of plasma dabigatran concentration that can be compared with expected plasma dabigatran concentrations. When the plasma dabigatran concentration result from the calibrated dTT assay 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 measurement of direct thrombin inhibitor activity. The aPTT assay is widely available and provides an approximate indication of the intensity of anticoagulation achieved with dabigatran. However, the aPTT assay has limited sensitivity and is not suitable for the precise quantification of anticoagulant effect, particularly at high plasma dabigatran concentrations. While high aPTT values must be interpreted with caution, an elevated aPTT 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 the assessment of bleeding risk; that is, exceeding the 90th percentile of dabigatran trough concentration, or of a coagulation test such as aPTT measured at trough (for aPTT thresholds, 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 dabigatran concentrations (after day 3), measured approximately 2 hours after a 220 mg dose of dabigatran etexilate, were 70.8 ng/mL, with a range of 35.2–162 ng/mL (25th–75th percentile range). The geometric mean trough concentration of dabigatran measured at the end of the dosing interval (i.e. 24 hours after a 220 mg 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 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 range). In patients treated with dabigatran etexilate 220 mg once daily for VTE prevention following hip or knee replacement surgery, 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 normal. ECT was not measured in patients receiving dabigatran etexilate 220 mg once daily for VTE prevention following 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 dabigatran concentrations measured approximately 2 hours after a 150 mg dose of dabigatran etexilate twice daily were 175 ng/mL, with a range of 117–275 ng/mL (25th–75th percentile range). The geometric mean trough concentration of dabigatran measured at the morning trough at the end of the dosing interval (i.e. 12 hours after the evening 150 mg dose) averaged 91.0 ng/mL, with a range of 61.0–143 ng/mL (25th–75th percentile range). In NVAF patients treated for the prevention of stroke and systemic embolism 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, - ECT at trough (10–16 hours after the previous dose), elevated approximately three-fold above the upper limit of normal, corresponds to the observed 90th percentile ECT prolongation of 103 seconds, - an aPTT ratio greater than two times the upper limit of normal (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 dosing at the end of the dosing interval (i.e. 12 hours after the evening 150 mg dose) was 59.7 ng/mL, with a range of 38.6–94.5 ng/mL (25th–75th percentile range). For 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, - 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 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 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 following 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 had been secured, or enoxaparin 40 mg the day before surgery and once daily thereafter. In the RE-MODEL trial (knee replacement), treatment lasted 6–10 days; in the RE-NOVATE trial (hip replacement), it lasted 28–35 days. The total number of patients treated was 2,076 (knee) and 3,494 (hip), 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 enoxaparin in terms of total VTE and all-cause mortality. The point estimate for the incidence of major VTE and VTE-related mortality with the 150 mg dose was slightly worse than with enoxaparin (Table 19). Better results were seen with the 220 mg dose, where the point estimate for the incidence of major VTE was slightly better than with enoxaparin (Table 19). Clinical studies were conducted in a patient population with a mean age > 65 years. In the phase 3 clinical trials there were no differences between men and women with respect to efficacy and safety data. In the RE-MODEL and RE-NOVATE study population (5,539 treated patients), 51% had concurrent hypertension, 9% had concurrent diabetes, 9% had concurrent 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 the rate of bleeding. 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 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 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 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 patients treated (n) 1,146 1,163 1,154 Number of MBEs (%) 23 (2.0) 15 (1.3) 18 (1.6) RE-MODEL (knee) Number of patients treated (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 and one or more risk factors Clinical evidence of the efficacy of dabigatran etexilate is derived from RE-LY (Randomised Evaluation of Long-term anticoagulant therapY), a multicentre, international, randomised, parallel-group trial 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 the 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. 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 RE-LY. 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 for the prevention of stroke and systemic embolism in subjects with atrial fibrillation, with reduced risks of intracranial bleeding, total bleeding, and major bleeding. The 150 mg twice daily dose significantly reduces the risks of ischaemic and haemorrhagic stroke, vascular death, intracranial bleeding, and total bleeding compared with warfarin. The rate of major bleeding 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 dabigatran etexilate 150 mg twice daily (hazard ratio 1.27; p = 0.1240). With improved INR monitoring, the observed benefits of dabigatran etexilate compared with warfarin diminish. 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 study observation period 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 first occurrence of ischaemic or haemorrhagic strokes during the RE-LY study observation period 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 mortality and cardiovascular survival during the RE-LY study observation period Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomised 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 results for the primary efficacy and safety endpoint in the corresponding subpopulations: For the primary endpoint of stroke and systemic embolism, no subgroup (e.g. age, body weight, sex, renal function, ethnicity, etc.) was identified with a different hazard ratio compared with 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, an interaction was observed 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 treatment-effect interaction across 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 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 RE-LY study visit. Enrolled patients continued on the same double-blind dose of dabigatran etexilate randomly assigned in RE-LY for a follow-up period of up to 43 months after the conclusion of RE-LY (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 the patients originally randomised to dabigatran etexilate in RE-LY and 86% of patients eligible for RELY-ABLE. During the additional 2.5 years of treatment in RELY-ABLE, with a maximum exposure exceeding 6 years (cumulative exposure across RE-LY and RELY-ABLE), 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 events including major bleeding and other bleeding events were consistent with those observed in RE-LY. Data from non-interventional studies In a non-interventional study (GLORIA-AF), safety and efficacy data were prospectively collected (during its second phase) in patients with newly diagnosed NVAF treated with dabigatran etexilate in real-world practice. The study enrolled 4,859 patients treated with dabigatran etexilate (55% received 150 mg twice daily, 43% received 110 mg twice daily, and 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 duration of follow-up while 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 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 received 150 mg twice daily, 16% received 75 mg twice daily) was associated, compared with warfarin, with reduced risks 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 with 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 study. Patients who underwent 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 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 with warfarin (adjusted 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 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 dabigatran etexilate 150 mg 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 TIMI (Thrombolysis In Myocardial Infarction) major bleeding events was lower in both dabigatran etexilate dual-therapy arms than in the warfarin triple-therapy arm: 14 events (1.4%) in the dabigatran etexilate 110 mg dual-therapy arm compared with 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 dabigatran etexilate 150 mg dual-therapy arm compared with 30 events (3.9%) in the corresponding warfarin triple-therapy arm (hazard ratio 0.51; 95% CI 0.28, 0.93; p = 0.03). Both dabigatran etexilate dual-therapy arms had lower rates of intracranial bleeding than the corresponding warfarin triple-therapy arm: 3 events (0.3%) in the dabigatran etexilate 110 mg dual-therapy arm compared with 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 dabigatran etexilate 150 mg dual-therapy arm compared with 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 statistical differences were observed between the dabigatran etexilate dual-therapy arms and the warfarin triple-therapy arm for the individual components of the efficacy endpoints. This study demonstrated 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 showing non-inferiority 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, parallel-group, identical 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, 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 analyses, 5,153 patients were randomised in total 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 the 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 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 studies 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 anticoagulation, and RE-SONATE, a placebo-controlled study, enrolled patients already treated for 6 to 18 months with vitamin K inhibitors. The objective of RE-MEDY was to compare the safety and efficacy of orally administered 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 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 the therapeutic range (INR 2.0–3.0) was 64.9%. RE-MEDY demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margin: 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 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 RE-SONATE was to assess 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 VKAs. The intended treatment was 6 months of dabigatran etexilate 150 mg twice daily without monitoring. RE-SONATE 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 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 12 months of observational follow-up after the end of treatment. Following discontinuation of study medication, the effect persisted to 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 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 study 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 in the prevention of thromboembolism 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, including patients in the early postoperative period (i.e. dosing was initiated during the post-surgical hospitalisation) and 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 manifested mainly as haemorrhagic pericardial effusions, primarily 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 VTE prevention following 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 for the indication of primary VTE prevention in patients undergoing elective total hip or knee replacement and for 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 to either dabigatran etexilate (with 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, 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 group and 38 patients (42.2%) in the SOC group met the criteria of 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 across subgroups overall: there were no significant differences in treatment effect by subgroups of 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 group and the SOC group were 13/22 (59.1%) and 7/13 (53.8%), respectively, in patients from birth to < 2 years; 21/43 (48.8%) and 12/21 (57.1%), respectively, in patients aged 2 to < 12 years; and 47/112 (42.0%) and 19/56 (33.9%), respectively, 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, most of which were classified as minor. The composite endpoint of adjudicated major bleeding events (MBEs) 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 in the prevention of recurrent VTE in paediatric patients aged from birth to < 18 years. Eligible patients were those who required further anticoagulation owing to 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 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 study 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; of these, 162 were in age group 1 (aged 12 to < 18 years), 43 in age group 2 (aged 2 to < 12 years), and 9 in age group 3 (from birth to < 2 years of age). During the treatment period, 3 patients (1.4%) had a confirmed recurrence of VTE within the first 12 months after initiation 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 experienced worsening of PTS within the first 12 months.