Dabigatran

Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors, ATC code: B01AE07. Mechanism of action Dabigatran etexilate is a small-molecule prodrug that exhibits no pharmacological activity. Following oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran in plasma and the liver via esterase-catalysed hydrolysis. Dabigatran is a potent, competitive, reversible, direct thrombin inhibitor and the principal active moiety in plasma. Because thrombin (a serine protease) enables 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 demonstrated antithrombotic efficacy and anticoagulant activity of intravenously administered dabigatran and orally administered dabigatran etexilate across various animal models of thrombosis. Phase II studies show a clear correlation between plasma dabigatran concentration and the degree of anticoagulant effect. Dabigatran prolongs thrombin time (TT), ECT, and aPTT. A calibrated quantitative dilute TT assay (dTT assay) provides an estimate of plasma dabigatran concentration that can be compared with expected plasma concentrations. When the calibrated dTT result is at or below the limit of quantification, an additional coagulation test such as TT, ECT, or aPTT should be considered. ECT allows direct measurement of the activity of direct thrombin inhibitors. The aPTT is widely available and gives an approximate indication of the intensity of anticoagulation achieved with dabigatran. However, the aPTT has limited sensitivity and is not suitable for precise quantification of the anticoagulant effect, particularly at high plasma dabigatran concentrations. Although high aPTT values must be interpreted with caution, an elevated aPTT indicates that the patient is anticoagulated. In general, these measures of anticoagulant activity may reflect dabigatran levels and provide guidance for assessing bleeding risk; that is, exceeding the 90th percentile of trough dabigatran concentration or of a coagulation test such as aPTT measured at trough (for aPTT thresholds, see section 4.4, Table 6) is considered a setting associated with increased bleeding risk. Primary VTE prevention in orthopaedic surgery The geometric mean steady-state peak plasma dabigatran concentration (after Day 3), measured approximately 2 hours after a 220 mg dabigatran etexilate dose, was 70.8 ng/mL, with a range of 35.2–162 ng/mL (25th–75th percentile). The geometric mean trough concentration 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). 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 averaged 47.5 ng/mL, with a range of 29.6–72.2 ng/mL (25th–75th percentile). In patients receiving dabigatran etexilate 220 mg once daily for VTE prevention after hip or knee replacement: the 90th percentile of plasma dabigatran concentrations 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 normal; ECT was not measured in patients receiving 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 dabigatran concentration measured approximately 2 hours after a 150 mg dabigatran etexilate dose given twice daily was 175 ng/mL, with a range of 117–275 ng/mL (25th–75th percentile). The geometric mean trough dabigatran concentration measured at 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). In NVAF patients receiving dabigatran etexilate 150 mg twice daily for stroke and systemic embolism prevention: 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 3 times the upper limit of normal corresponded to the observed 90th percentile ECT prolongation of 103 seconds; an aPTT ratio greater than 2 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 observation. 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 the dose 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). For DVT and PE treatment 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 from 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 1.8 times baseline. No pharmacokinetic data are available in patients treated for prevention of recurrent DVT and PE with dabigatran etexilate 150 mg twice daily. Clinical efficacy and safety Ethnic origin No clinically relevant ethnic differences were observed among Caucasian, African American, Hispanic, Japanese, or Chinese patients. Clinical trials of VTE prevention after major joint replacement surgery In two large, double-blind, randomised, parallel-group dose-confirmation trials, patients undergoing elective major orthopaedic surgery (knee replacement in one trial, hip replacement in the other) received dabigatran etexilate 75 mg or 110 mg within 1–4 hours after surgery, then 150 mg or 220 mg once daily once haemostasis was 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 RE-NOVATE (hip replacement), 28–35 days. Total numbers of treated patients were 2,076 (knee) and 3,494 (hip). 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. Both studies showed that the antithrombotic effect of dabigatran etexilate 220 mg and 150 mg was statistically non-inferior to enoxaparin for 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 enoxaparin (Table 19). Better outcomes were seen with the 220 mg dose, where the point estimate for major VTE was slightly better than enoxaparin (Table 19). Clinical studies were conducted in a patient population with mean age > 65 years. In the phase 3 clinical studies, no differences in efficacy or safety data were seen between men and women. 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 appeared to influence dabigatran's effect on VTE prevention or bleeding rates. Data for the major VTE and VTE-related mortality endpoint were homogeneous with the primary efficacy endpoint and are presented in Table 19. Data for total VTE and all-cause mortality are presented in Table 20. Adjudicated major bleeding endpoint data are shown 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 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) Treated patients (n) 1,146 1,163 1,154 Major bleeding events (%) 23 (2.0) 15 (1.3) 18 (1.6) RE-MODEL (knee) Treated patients (n) 679 703 694 Major bleeding events (%) 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 efficacy for dabigatran etexilate is derived from the RE-LY (Randomised Evaluation of Long-term anticoagulant therapy) study, a multicentre, international, randomised, parallel-group trial 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 was to determine whether dabigatran etexilate was non-inferior to warfarin in reducing the composite endpoint of stroke and systemic embolism. Statistical superiority was also assessed. 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 time in therapeutic range (TTR) (INR 2–3) was 64.4% (median TTR 67%). RE-LY demonstrated that dabigatran etexilate 110 mg twice daily was non-inferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation, with reduced risks 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. Major bleeding rates with this dose were comparable to warfarin. Myocardial infarction rates were slightly elevated relative to warfarin 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). With improved INR monitoring, the observed benefits of dabigatran etexilate over warfarin diminish. Tables 22–24 detail key results in the overall population: Table 22: Analysis of first occurrence of stroke or systemic embolism (primary endpoint) during the RE-LY follow-up period Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin 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% CI) 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 follow-up 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% CI) 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% CI) 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% CI) 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% CI) 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 follow-up 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% CI) 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% CI) 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 primary efficacy and safety endpoint results 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 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 bleeding risk with dabigatran versus 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 in subgroups defined by renal function or CHADS2 score. Table 26: Hazard ratio and 95% confidence interval for major bleeding by subgroup Endpoint Dabigatran etexilate 110 mg twice daily vs warfarin Dabigatran etexilate 150 mg twice daily vs warfarin Age (years) < 65 0.32 (0.18; 0.57) 0.35 (0.20; 0.61) 65 ≤ and < 75 0.71 (0.56; 0.89) 0.82 (0.66; 1.03) ≥ 75 1.01 (0.84; 1.23) 1.19 (0.99; 1.43) ≥ 80 1.14 (0.86; 1.51) 1.35 (1.03; 1.76) CrCL (mL/min) 30 ≤ and < 50 1.02 (0.79; 1.32) 0.94 (0.73; 1.22) 50 ≤ and < 80 0.75 (0.61; 0.92) 0.90 (0.74; 1.09) ≥ 80 0.59 (0.43; 0.82) 0.87 (0.65; 1.17) ASA use 0.84 (0.69; 1.03) 0.97 (0.79; 1.18) Clopidogrel use 0.89 (0.55; 1.45) 0.92 (0.57; 1.48) RELY-ABLE (long-term multicentre extension of dabigatran treatment in patients with atrial fibrillation who completed RE-LY) The RE-LY extension study (RELY-ABLE) provided additional safety information for a cohort of patients who continued on the same dose of dabigatran etexilate they had received in RE-LY. Patients were eligible for RELY-ABLE if they had not permanently discontinued study treatment by their final RE-LY visit. Enrolled patients continued the same double-blinded dose of dabigatran etexilate randomly assigned in RE-LY for follow-up of up to 43 months after the end of RE-LY (mean total 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 those eligible for RELY-ABLE. Over an additional 2.5 years of treatment in RELY-ABLE, with maximum exposure exceeding 6 years (combined RE-LY and RELY-ABLE exposure), the long-term safety profile of dabigatran etexilate at both 110 mg and 150 mg twice daily was confirmed. No new safety findings were observed. Rates of major bleeding events and other bleeding events were consistent with those observed in RE-LY. Non-interventional study data In the non-interventional GLORIA-AF study, safety and efficacy data were prospectively collected (in its second phase) in patients with newly diagnosed NVAF treated with dabigatran etexilate in real-world practice. The study enrolled 4,859 patients receiving 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. Mean treatment follow-up was 18.3 months. Major bleeding occurred at 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 per 100 patient-years, and gastrointestinal bleeding at 0.60 per 100 patient-years. Stroke occurred at 0.65 events per 100 patient-years. Additionally, 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 NVAF patients (contributing more than 37,500 patient-years of 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 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 increased risk of gastrointestinal bleeding (hazard ratio 1.28; CI 1.14–1.44). No difference was seen 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 RE-LY. Patients undergoing percutaneous coronary intervention (PCI) with stenting A prospective, randomised, open-label, blinded-endpoint (PROBE) phase IIIb trial was conducted in 2,725 patients with non-valvular atrial fibrillation undergoing PCI with stenting to evaluate dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) plus clopidogrel or ticagrelor (a P2Y12 antagonist) versus triple therapy with warfarin (adjusted to INR 2.0–3.0), clopidogrel or ticagrelor, and ASA (RE-DUAL PCI). Patients were 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 in all countries; ≥ 70 years 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 versus 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 versus 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 in both dabigatran etexilate dual-therapy arms was lower than in the warfarin triple-therapy arm: 14 events (1.4%) in the dabigatran etexilate 110 mg 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 dabigatran etexilate 150 mg 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). Intracranial bleeding rates in both dabigatran etexilate dual-therapy arms were lower than in the corresponding warfarin triple-therapy arm: 3 events (0.3%) in the dabigatran etexilate 110 mg 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 dabigatran etexilate 150 mg 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 statistical differences between the dabigatran etexilate dual-therapy arms and the warfarin triple-therapy arm were detected for individual components of the efficacy endpoint. This study demonstrated that, in atrial fibrillation patients undergoing PCI with stenting, dual therapy with dabigatran etexilate plus a P2Y12 antagonist significantly reduced bleeding risk compared with warfarin triple therapy, while non-inferiority was shown 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 trials, RE-COVER and RE-COVER II. These studies compared dabigatran etexilate (150 mg twice daily) with warfarin (target INR 2.0–3.0) in patients with acute DVT and/or PE. The primary objective was to demonstrate non-inferiority of dabigatran etexilate to warfarin in reducing the primary endpoint, a composite of recurrent symptomatic DVT and/or PE and related 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 treatment with fixed-dose dabigatran was 174.0 days without coagulation monitoring. In patients randomised to warfarin, the median time in therapeutic range (INR 2.0–3.0) was 60.6%. The trials demonstrated that dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margins for RE-COVER and RE-COVER II: 3.6 for risk difference and 2.75 for hazard ratio). Table 27: Analysis of primary and secondary efficacy endpoints (VTE comprises DVT and/or PE) in the pooled RE-COVER and RE-COVER II analysis through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Warfarin Number of treated patients 2,553 2,554 Recurrent symptomatic VTE and VTE-related deaths 68 (2.7%) 62 (2.4%) Hazard ratio vs warfarin (95% CI) 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 death 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 anticoagulation. RE-MEDY, a warfarin-controlled study, enrolled patients already treated for 3 to 12 months who required continued anticoagulation, and RE-SONATE, a placebo-controlled study, enrolled patients already treated for 6 to 18 months with vitamin K antagonists. The objective of RE-MEDY was to compare the safety and efficacy of oral dabigatran etexilate (150 mg twice daily) versus warfarin (target INR 2.0–3.0) for 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. Treatment duration with dabigatran etexilate 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%. RE-MEDY demonstrated that dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margins: 2.85 for hazard ratio and 2.8 for risk difference). Table 28: Analysis of primary and secondary efficacy endpoints (VTE comprises DVT and/or PE) in RE-MEDY 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% CI) 1.44 (0.78; 2.64) Non-inferiority margin 2.85 Patients with 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 death 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 preventing recurrent symptomatic DVT and/or PE in patients who had completed 6 to 18 months of VKA therapy. 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% (92% relative risk reduction based on hazard ratio) over the treatment period (p < 0.0001). All secondary and sensitivity analyses of the primary and all secondary endpoints showed superiority of dabigatran etexilate over placebo. The study included 12 months of observational follow-up after treatment ended. Following discontinuation of study medication, the effect persisted through the end of follow-up, indicating that the initial treatment effect of dabigatran etexilate was sustained. No rebound effect was observed. At the end of follow-up, VTE events occurred in 6.9% of patients treated with dabigatran etexilate versus 10.7% on placebo (hazard ratio 0.61 [95% CI 0.42; 0.88], p = 0.0082). Table 29: Analysis of primary and secondary efficacy endpoints (VTE comprises DVT and/or PE) in RE-SONATE 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% CI) 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 death 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 prevention of thromboembolism in patients with prosthetic heart valves A phase II study evaluated dabigatran etexilate and warfarin in 252 patients in total following surgical mechanical heart valve replacement, both in the early postoperative period (i.e., dosing initiated during the post-surgery hospitalisation) and in patients who had received a mechanical heart valve more than three months previously. More thromboembolic events (mainly stroke and symptomatic/asymptomatic prosthetic valve thrombosis) and more bleeding events occurred with dabigatran etexilate than with warfarin. In the early postoperative period, major bleeding manifested principally as haemorrhagic pericardial effusions, predominantly in patients in whom dabigatran etexilate was started early (i.e., on Day 3) after surgical heart valve replacement (see section 4.3). Paediatric population Clinical trials of VTE prevention after major joint replacement surgery Prevention of stroke and systemic embolism in adult patients with NVAF and one or more risk factors The European Medicines Agency has waived the obligation to submit results of studies with the reference product containing dabigatran etexilate in all subsets of the paediatric population for the indication of primary VTE prevention in patients undergoing elective total hip or knee replacement and for the indication of stroke and systemic embolism prevention in patients with NVAF (for information on paediatric use, see section 4.2). VTE treatment 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 2:1 to either dabigatran etexilate (with doses adjusted by age and body weight) in an age-appropriate formulation (capsules, coated pellets, 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 zero 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 < 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, absence of recurrent VTE, and zero VTE-related mortality). The corresponding difference in incidence demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent results were also generally seen across subgroups: no significant differences in treatment effect were detected in subgroups defined by age, sex, region, or 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 < 2 years, 21/43 (48.8%) versus 12/21 (57.1%) in patients aged 2 to < 12 years, and 47/112 (42.0%) versus 19/56 (33.9%) in patients aged 12 to < 18 years. Adjudicated major bleeding was reported in 4 patients (2.3%) in the dabigatran etexilate group and 2 patients (2.2%) in the SOC group. There was no statistically significant difference in time to first major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients (24.4%) in the SOC arm experienced 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 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 < 18 years of age. Eligible patients were those who required additional anticoagulant therapy due 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 pellets, or oral solution) until resolution of clinical risk factors, or for a maximum of 12 months. Primary endpoints included recurrence of 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; 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%) in the first 12 months after initiation of treatment. 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%) in the first 12 months. Adjudicated CRNM bleeding was reported in 3 patients (1.4%) in the first 12 months. No deaths occurred during treatment. During the treatment period, 3 patients (1.4%) developed post-thrombotic syndrome (PTS) or experienced PTS worsening in the first 12 months.