Dabigatran

Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors, ATC code: B01AE07. Mechanism of action Dabigatran etexilate is a small-molecule prodrug with no pharmacological activity of its own. Following oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran in 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) catalyses the conversion of fibrinogen to fibrin in the coagulation cascade, its inhibition prevents thrombus formation. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation. Pharmacodynamic effects In in vivo and ex vivo animal studies, dabigatran administered intravenously and dabigatran etexilate administered orally demonstrated antithrombotic efficacy and anticoagulant activity in various animal models of thrombosis. Phase II studies have shown a clear correlation between plasma concentrations of dabigatran and the magnitude of the anticoagulant effect. Dabigatran prolongs the thrombin time (TT), ECT and aPTT. The calibrated quantitative diluted TT assay (dTT) provides an estimate of the plasma concentration of dabigatran that can be compared with expected plasma concentrations. When the plasma dabigatran concentration on 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 measure of the activity of direct thrombin inhibitors. The aPTT assay is widely available and provides an approximate indication of the intensity of anticoagulation achieved with dabigatran. However, the aPTT has limited sensitivity and is unsuitable for precise quantification of the anticoagulant effect, particularly at high plasma dabigatran concentrations. Although 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 dabigatran trough concentrations or exceeding a coagulation test threshold (e.g. aPTT) measured at trough (for aPTT thresholds see section 4.4, Table 6) is considered to be associated with an increased bleeding risk. Primary VTE prevention in orthopaedic surgery The geometric mean of peak steady-state plasma dabigatran concentrations (after day 3), measured approximately 2 hours after a 220 mg dose of dabigatran etexilate, was 70.8 ng/mL, with a range of 35.2–162 ng/mL (25th–75th percentile). The geometric mean of trough dabigatran concentrations 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 of trough dabigatran concentrations 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 receiving dabigatran etexilate 220 mg once daily for VTE prevention after hip or knee replacement, the 90th percentile of plasma dabigatran concentrations measured at trough (20–28 hours after the previous dose) was 67 ng/mL (see section 4.9). The 90th percentile of aPTT at trough (20–28 hours after the previous dose) was 51 seconds, equivalent to 1.3 times the upper limit of the normal range. ECT was not measured in patients receiving dabigatran etexilate 220 mg once daily for VTE prevention after hip or knee replacement. Prevention of stroke and systemic embolism in adult patients with NVAF and one or more risk factors (SPAF) The geometric mean of peak steady-state plasma dabigatran concentrations measured approximately 2 hours after a 150 mg dose of dabigatran etexilate twice daily was 175 ng/mL, with a range of 117–275 ng/mL (25th–75th percentile). The geometric mean of trough dabigatran concentrations 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). 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, - ECT at trough (10–16 hours after the previous dose) increased to approximately three times the upper limit of normal corresponds to the observed 90th percentile of ECT prolongation of 103 seconds, - an aPTT ratio greater than two times the upper limit of normal (aPTT prolongation of 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 of trough dabigatran concentrations 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 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, - ECT at trough (10–16 hours after the previous dose) increased approximately 2.3-fold over baseline corresponds to the observed 90th percentile of ECT prolongation of 74 seconds, - the 90th percentile of aPTT at trough (10–16 hours after the previous dose) was 62 seconds, corresponding to a 1.8-fold increase over 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 between Caucasian, African-American, Hispanic, Japanese or Chinese patients. Clinical trials in VTE prevention after major joint replacement surgery In two large, double-blind, randomised, parallel-group dose-confirmation trials, patients undergoing elective major orthopaedic surgery (knee replacement in one trial, 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 after 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, and in the RE-NOVATE trial (hip replacement) 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 a composite of total VTE (including PE, proximal and distal DVT, symptomatic or asymptomatic, detected by routine venography) and all-cause mortality. The secondary endpoint, considered more clinically relevant, was a composite of major venous thromboembolism (including pulmonary embolism and proximal deep vein thrombosis, symptomatic or asymptomatic, detected by routine venography) and VTE-related mortality. The results of both studies showed that the antithrombotic effect of dabigatran etexilate 220 mg and 150 mg was statistically non-inferior to enoxaparin with respect to 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, no differences were observed between men and women in efficacy or 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 VTE prevention 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 for the assessed 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 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 for each of the RE-MODEL and RE-NOVATE trials Trial / Dabigatran etexilate 220 mg once daily / Dabigatran etexilate 150 mg once daily / Enoxaparin 40 mg RE-NOVATE (hip) Number of treated patients (n): 1,146 / 1,163 / 1,154 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 and one or more risk factors Clinical evidence of efficacy of dabigatran etexilate is derived from the RE-LY (Randomised Evaluation of Long-term anticoagulant therapy) study, a multicentre, international, randomised, parallel-group trial that compared 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 composite endpoint of stroke and systemic embolism. Statistical superiority was also analysed. A total of 18,113 patients were randomised in RE-LY, 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 therapeutic range (TTR) (INR 2–3) was 64.4% (median TTR 67%). RE-LY showed that dabigatran etexilate 110 mg twice daily was non-inferior to warfarin in preventing 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 reduced the risk 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 rate 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 over warfarin diminish. Tables 22–24 provide detailed key results for 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) Superiority p-value: 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 death 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 results for the primary efficacy and safety endpoints in the corresponding subpopulations: For the primary endpoint of stroke and systemic embolism, no subgroups (i.e. 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 versus 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 doubled the rate of major bleeding events with both dabigatran etexilate and warfarin. There was no significant interaction of treatment effects in subgroups defined by renal function and 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 to receive the same dose of dabigatran etexilate as in RE-LY. Patients were eligible for RELY-ABLE if they had not permanently discontinued study treatment at the time of their final visit in RE-LY. Enrolled patients continued to receive the same blinded dose of dabigatran etexilate randomly assigned in RE-LY for a follow-up period of up to 43 months after the end of RE-LY (overall mean follow-up duration in RE-LY and RELY-ABLE was 4.5 years). A total of 5,897 patients were enrolled, representing 49% of patients originally randomised to dabigatran etexilate in RE-LY and 86% of patients eligible for RELY-ABLE. During an additional 2.5 years of treatment in 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 the 110 mg twice-daily and 150 mg twice-daily doses studied. No new safety findings were observed. The rate of monitored events including major bleeding and other bleeding events was consistent with the rate observed in RE-LY. 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 prospectively collected (during its second phase). The study enrolled 4,859 patients treated with dabigatran etexilate (55% on 150 mg twice daily, 43% on 110 mg twice daily, 2% on 75 mg twice daily). Patients were followed for 2 years. The mean CHADS2 score was 1.9, and the mean HAS-BLED score was 1.2. The mean follow-up 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 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 NVAF patients (contributing more than 37,500 patient-years of on-treatment follow-up), dabigatran etexilate (84% of patients on 150 mg twice daily, 16% on 75 mg twice daily) was associated, compared with warfarin, with a reduced risk of ischaemic stroke (hazard ratio 0.80; 95% confidence interval [CI] 0.67–0.96), intracranial bleeding (hazard ratio 0.34; CI 0.26–0.46) and mortality (hazard ratio 0.86; CI 0.77–0.96), and an increased risk of gastrointestinal bleeding (hazard ratio 1.28; CI 1.14–1.44). No difference was observed for major bleeding (hazard ratio 0.97; CI 0.88–1.07). These real-world observations are consistent with the established safety and efficacy profile of dabigatran etexilate in this indication in RE-LY. Patients who underwent percutaneous coronary intervention (PCI) with stenting A prospective, randomised, open-label phase IIIb trial with blinded endpoint adjudication (PROBE) was conducted in 2,725 patients with non-valvular atrial fibrillation who underwent PCI with stenting to assess 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 major bleeding by ISTH definition or clinically relevant non-major bleeding. The incidence of the primary endpoint was 15.4% (151 patients) in the dabigatran etexilate 110 mg dual therapy group compared with 26.9% (264 patients) in the warfarin triple therapy group (hazard ratio 0.52; 95% CI 0.42, 0.63; p < 0.0001 for non-inferiority and p < 0.0001 for superiority), and 20.2% (154 patients) in the dabigatran etexilate 150 mg dual therapy group compared with 25.7% (196 patients) in the corresponding warfarin triple therapy group (hazard ratio 0.72; 95% CI 0.58, 0.88; p < 0.0001 for non-inferiority and p = 0.002 for superiority). In a descriptive analysis, the rate of major bleeding events according to TIMI (Thrombolysis In Myocardial Infarction) classification was lower in both dabigatran etexilate dual therapy groups compared with the warfarin triple therapy group: 14 events (1.4%) in the dabigatran etexilate 110 mg dual therapy group versus 37 events (3.8%) in the warfarin triple therapy group (hazard ratio 0.37; 95% CI 0.20, 0.68; p = 0.002), and 16 events (2.1%) in the dabigatran etexilate 150 mg dual therapy group versus 30 events (3.9%) in the corresponding warfarin triple therapy group (hazard ratio 0.51; 95% CI 0.28, 0.93; p = 0.03). In both dabigatran etexilate dual therapy groups, intracranial bleeding rates were lower than in the corresponding warfarin triple therapy group: 3 events (0.3%) in the dabigatran etexilate 110 mg dual therapy group versus 10 events (1.0%) in the warfarin triple therapy group (hazard ratio 0.30; 95% CI 0.08, 1.07; p = 0.06), and 1 event (0.1%) in the dabigatran etexilate 150 mg dual therapy group versus 8 events (1.0%) in the corresponding warfarin triple therapy group (hazard ratio 0.12; 95% CI 0.02, 0.98; p = 0.047). The incidence of the composite efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke or systemic embolism) or unplanned revascularisation was non-inferior in both dabigatran etexilate dual therapy groups compared with the warfarin triple therapy group (13.7% vs 13.4%, respectively; hazard ratio 1.04; 95% CI: 0.84, 1.29; p = 0.0047 for non-inferiority). No statistical differences were identified between the dabigatran etexilate dual therapy groups and the warfarin triple therapy group for the individual components of the efficacy endpoints. This study demonstrated that, in patients with atrial fibrillation 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 determine whether dabigatran etexilate was non-inferior to warfarin in reducing the primary composite endpoint of recurrent symptomatic DVT and/or PE and related deaths during a 6-month treatment period. In the pooled RE-COVER and RE-COVER II studies, a total of 5,153 patients were randomised, and 5,107 of them 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 showed that treatment with dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margins for RE-COVER and RE-COVER II: 3.6 for risk difference and 2.75 for hazard ratio). Table 27: Analysis of primary and secondary efficacy endpoints (VTE comprising DVT and/or PE) in the pooled RE-COVER and RE-COVER II studies through end of 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% CI: 3.52; 5.13 / 3.34; 4.91 Symptomatic DVT: 45 (1.8%) / 39 (1.5%) 95% CI: 1.29; 2.35 / 1.09; 2.08 Symptomatic PE: 27 (1.1%) / 26 (1.0%) 95% CI: 0.70; 1.54 / 0.67; 1.49 VTE-related deaths: 4 (0.2%) / 3 (0.1%) 95% CI: 0.04; 0.40 / 0.02; 0.34 All-cause mortality: 51 (2.0%) / 52 (2.0%) 95% CI: 1.49; 2.62 / 1.52; 2.66 Prevention of recurrent DVT and PE in adults (DVT/PE prevention) Two randomised, double-blind, parallel-group studies were conducted in patients previously treated with anticoagulant therapy. RE-MEDY, a warfarin-controlled study, enrolled patients already treated for 3 to 12 months who required further anticoagulant therapy, and RE-SONATE, a placebo-controlled study, enrolled patients already treated for 6 to 18 months with vitamin K antagonists. 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 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 margins: 2.85 for hazard ratio and 2.8 for risk difference). Table 28: Analysis of primary and secondary efficacy endpoints (VTE comprising DVT and/or PE) in the RE-MEDY study through end of 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% CI: — Non-inferiority margin: 2.8 Secondary efficacy endpoints Recurrent symptomatic VTE and all-cause mortality: 42 (2.9%) / 36 (2.5%) 95% CI: 2.12; 3.95 / 1.77; 3.48 Symptomatic DVT: 17 (1.2%) / 13 (0.9%) 95% CI: 0.69; 1.90 / 0.49; 1.55 Symptomatic PE: 10 (0.7%) / 5 (0.4%) 95% CI: 0.34; 1.28 / 0.11; 0.82 VTE-related deaths: 1 (0.1%) / 1 (0.1%) 95% CI: 0.00; 0.39 / 0.00; 0.39 All-cause mortality: 17 (1.2%) / 19 (1.3%) 95% CI: 0.69; 1.90 / 0.80; 2.07 The objective of RE-SONATE was to evaluate the superiority of dabigatran etexilate over placebo in the prevention of recurrent symptomatic DVT and/or PE in patients who had completed 6 to 18 months of treatment with VKAs. The intended treatment was 6 months of dabigatran etexilate 150 mg twice daily without the need for monitoring. RE-SONATE demonstrated that dabigatran etexilate was superior to placebo in preventing recurrent symptomatic DVT/PE events including unexplained deaths, with a risk reduction from 5.6% to 0.4% (a 92% relative risk reduction based on hazard ratio) during the treatment period (p < 0.0001). All secondary and sensitivity analyses of the primary endpoint and all secondary endpoints showed superiority of dabigatran etexilate over placebo. The study included an observational follow-up of 12 months after end of treatment. After discontinuation of study medication, the effect persisted to the end of follow-up, suggesting 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) in the RE-SONATE study through end of 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) Superiority p-value: < 0.0001 Secondary efficacy endpoints Recurrent symptomatic VTE and all-cause mortality: 3 (0.4%) / 37 (5.6%) 95% CI: 0.09; 1.28 / 3.97; 7.62 Symptomatic DVT: 2 (0.3%) / 23 (3.5%) 95% CI: 0.04; 1.06 / 2.21; 5.17 Symptomatic PE: 1 (0.1%) / 14 (2.1%) 95% CI: 0.00; 0.82 / 1.16; 3.52 VTE-related deaths: 0 (0) / 0 (0) 95% CI: 0.00; 0.54 / 0.00; 0.56 Unexplained deaths: 0 (0) / 2 (0.3%) 95% CI: 0.00; 0.54 / 0.04; 1.09 All-cause mortality: 0 (0) / 2 (0.3%) 95% CI: 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 after surgical mechanical heart valve replacement, both in the early postoperative period (i.e. with treatment initiated during the post-surgical hospital stay) and in patients who had received a mechanical heart valve 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 presented mainly as haemorrhagic pericardial effusions, predominantly 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 after major joint replacement surgery Prevention of stroke and systemic embolism in adult patients with NVAF and one or more risk factors The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing dabigatran etexilate in all subsets of the paediatric population in the indications of primary VTE prevention in patients undergoing elective total hip or knee replacement and prevention of stroke and systemic embolism in patients with NVAF (see section 4.2 for information on paediatric use). Treatment of VTE and prevention of recurrent VTE in paediatric patients The DIVERSITY 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 (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 the number of patients with complete thrombus resolution, absence of recurrent VTE and no 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 were aged 2 to < 12 years, and 35 were under 2 years of age. Of the 267 randomised patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients (42.2%) in the SOC group met the criteria for the composite endpoint (complete thrombus resolution, absence of recurrent VTE and no VTE-related mortality). The corresponding difference in incidence demonstrated non-inferiority of dabigatran etexilate versus SOC. Consistent results were also observed across subgroups overall: there were no significant differences in treatment effect across subgroups defined by age, sex, region or the presence of certain risk factors. In the 3 different age groups, the proportions of patients meeting the primary efficacy endpoint in the dabigatran etexilate group versus the SOC group were 13/22 (59.1%) versus 7/13 (53.8%) in patients from birth to < 2 years, 21/43 (48.8%) versus 12/21 (57.1%) in patients aged 2 to < 12 years, and 47/112 (42.0%) versus 19/56 (33.9%) in patients aged 12 to < 18 years. Adjudicated major bleeding was reported in 4 patients (2.3%) in the dabigatran etexilate group and 2 patients (2.2%) in the SOC group. There was no statistically significant difference in time to first major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients (24.4%) in the SOC arm had any adjudicated bleeding event, 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 from birth to < 18 years of age. Patients were eligible for enrolment if they required further anticoagulant therapy due to clinical risk factors after completing initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study. Patients in the study received dabigatran etexilate doses adjusted by age and body weight in an age-appropriate dosage form (capsules, coated granules or oral solution) until clinical risk factors resolved, or for a maximum of 12 months. The primary endpoints of the study included recurrence of VTE, major and minor bleeding events, and mortality (overall and related to thrombotic or thromboembolic events) at 6 and 12 months. Outcomes were adjudicated by an independent blinded review committee. A total of 214 patients were enrolled; among them, 162 patients in age group 1 (12 to < 18 years of age), 43 patients in age group 2 (2 to < 12 years of age), and 9 patients in age group 3 (birth to < 2 years of age). During the treatment period, recurrent VTE was confirmed in 3 patients (1.4%) within the first 12 months after start of treatment. Adjudicated bleeding events during the treatment period were reported in 48 patients (22.5%) within the first 12 months. Most bleeding events were minor. A major bleeding event confirmed on adjudication occurred in 3 patients (1.4%) within the first 12 months. CRNM bleeding confirmed on 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 worsening PTS within the first 12 months.