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 in the liver by esterase-catalysed hydrolysis. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the principal active moiety in plasma. Because thrombin (a serine protease) 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, in various animal models of thrombosis. Phase II studies have established a clear correlation between plasma dabigatran concentrations and the degree of anticoagulant effect. Dabigatran prolongs the thrombin time (TT), ECT and aPTT. The calibrated quantitative dilute TT (dTT) assay provides an estimate of plasma dabigatran concentration that can be compared with expected dabigatran plasma concentrations. When the dabigatran plasma concentration result in the calibrated dTT assay is at or below the limit of quantitation, an additional coagulation assay such as TT, ECT or aPTT should be considered. ECT provides a direct measure 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 precise quantification of the anticoagulant effect, particularly at high plasma dabigatran concentrations. Although high aPTT values must be interpreted with caution, a high aPTT indicates that the patient is anticoagulated. In general, these measures of anticoagulant activity can be assumed to reflect the level of dabigatran and may guide assessment of bleeding risk; that is, exceeding the 90th percentile of dabigatran trough concentrations or of a coagulation test such as aPTT measured at trough (for aPTT thresholds see section 4.4, Table 6) is considered to be associated with an increased risk of bleeding. Primary prevention of VTE in orthopaedic surgery The geometric mean steady-state peak plasma dabigatran concentration (after day 3), measured approximately 2 hours after administration of a 220 mg dose of dabigatran etexilate, was 70.8 ng/mL, with a range of 35.2–162 ng/mL (25th–75th percentile range). The geometric mean trough dabigatran concentration measured at the end of the dosing interval (i.e. 24 hours after the 220 mg dabigatran dose) averaged 22.0 ng/mL, with a range of 13.0–35.7 ng/mL (25th–75th percentile 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 dabigatran concentration 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 the prevention of VTE following hip or knee replacement: The 90th percentile of plasma dabigatran concentration 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, corresponding to 1.3 times the upper limit of normal. ECT was not measured in patients treated with 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 with one or more risk factors (SPAF) The geometric mean steady-state peak plasma dabigatran concentration, measured approximately 2 hours after administration of dabigatran etexilate 150 mg twice daily, was 175 ng/mL with a range of 117–275 ng/mL (25th–75th percentile range). The geometric mean morning trough dabigatran concentration measured 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 patients with NVAF treated with dabigatran etexilate 150 mg twice daily for the prevention of stroke and systemic embolism: The 90th percentile of plasma dabigatran concentration 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 ECT prolongation of 103 seconds. An aPTT ratio greater than twice 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 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 range). For the treatment of DVT and PE with dabigatran etexilate 150 mg twice daily: The 90th percentile of plasma dabigatran concentration 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 of aPTT at trough (10–16 hours after the previous dose) was 62 seconds, corresponding to a 1.8-fold increase from 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 the prevention of VTE following major joint replacement surgery In two large, double-blind, randomised, parallel-group dose-confirmation trials, patients undergoing elective major orthopaedic surgery (one trial in knee replacement, the other in hip replacement) received dabigatran etexilate 75 mg or 110 mg within 1–4 hours after surgery, then 150 mg or 220 mg once daily once haemostasis had been secured, or enoxaparin 40 mg on the day before surgery and 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. A total of 2,076 patients (knee) and 3,494 patients (hip) were treated. 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 that of enoxaparin in terms of total VTE and all-cause mortality. The point estimate for the incidence of major VTE and VTE-related mortality at the 150 mg dose was slightly less favourable than with enoxaparin (Table 19). Better results were observed at the 220 mg dose, where the point estimate for major VTE was slightly more favourable than with enoxaparin (Table 19). The clinical studies were conducted in a patient population with a mean age of >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 studied patient population of 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 affect the efficacy of dabigatran on VTE prevention or the bleeding rate. Data for the endpoint of major VTE and VTE-related mortality were homogeneous with respect to the primary efficacy endpoint and are shown in Table 19. Data for the endpoint of total VTE and all-cause mortality are shown in Table 20. Data for the major bleeding endpoints assessed 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 studies Clinical trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) n 909 888 917 Incidence (%) 28 (3.1) 38 (4.3) 36 (3.9) Hazard ratio vs. enoxaparin 0.78 1.09 95% confidence interval 0.48; 1.27 0.70; 1.70 RE-MODEL (knee) n 506 527 511 Incidence (%) 13 (2.6) 20 (3.8) 18 (3.5) Hazard ratio vs. enoxaparin 0.73 1.08 95% confidence interval 0.36; 1.47 0.58; 2.01 Table 20: Analysis of total VTE and all-cause mortality during the treatment period in the RE-MODEL and RE-NOVATE orthopaedic surgery studies Clinical trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) n 880 874 897 Incidence (%) 53 (6.0) 75 (8.6) 60 (6.7) Hazard ratio vs. enoxaparin 0.9 1.28 95% confidence interval (0.63; 1.29) (0.93; 1.78) RE-MODEL (knee) n 503 526 512 Incidence (%) 183 (36.4) 213 (40.5) 193 (37.7) Hazard ratio vs. enoxaparin 0.97 1.07 95% confidence interval (0.82; 1.13) (0.92; 1.25) Table 21: Major bleeding events by treatment in each of the RE-MODEL and RE-NOVATE studies Clinical trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) Number of treated patients (n) 1,146 1,163 1,154 Number of MBEs (%) 23 (2.0) 15 (1.3) 18 (1.6) RE-MODEL (knee) Number of treated patients (n) 679 703 694 Number of MBEs (%) 10 (1.5) 9 (1.3) 9 (1.3) Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors Clinical evidence for the 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 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 this study was to determine whether dabigatran etexilate was non-inferior to warfarin in reducing the incidence of the composite endpoint of stroke and systemic embolism. Statistical superiority was also analysed. In RE-LY, a total of 18,113 patients were randomised, with a mean age of 71.5 years and a mean CHADS₂ score of 2.1. The patient population was 64% male, 70% Caucasian and 16% Asian. Among 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 the prevention of stroke and systemic embolism in patients with atrial fibrillation, with a reduced risk of intracranial bleeding, total bleeding and major bleeding. The 150 mg twice-daily dose significantly reduced the risk of ischaemic and haemorrhagic stroke, vascular death, intracranial haemorrhage 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 with dabigatran etexilate 110 mg twice daily (hazard ratio 1.29; p = 0.0929) and dabigatran etexilate 150 mg twice daily (hazard ratio 1.27; p = 0.1240) compared with warfarin. With improved INR monitoring, the observed benefits of dabigatran etexilate compared with warfarin are reduced. Tables 22–24 present detailed key results in the overall population: Table 22: Analysis of the 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 the annual event rate Table 23: Analysis of the 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 the 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 the annual event rate Tables 25–26 present results of the primary efficacy and safety endpoint 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, there was an interaction between treatment effect and age. The relative risk of bleeding with dabigatran compared with warfarin increased with age. The relative risk was highest in patients aged 75 years and older. Concomitant treatment with antiplatelet agents, ASA or clopidogrel approximately doubles the rate of major bleeding events with both dabigatran etexilate and warfarin. There was no significant interaction between treatment effects in subgroups by renal function or CHADS₂ score. Table 26: Hazard ratio and 95% confidence interval for major bleeding by subgroup Endpoint Dabigatran etexilate 110 mg twice daily vs. warfarin Dabigatran etexilate 150 mg twice daily vs. warfarin Age (years) < 65 0.32 (0.18; 0.57) 0.35 (0.20; 0.61) 65 ≤ and < 75 0.71 (0.56; 0.89) 0.82 (0.66; 1.03) ≥ 75 1.01 (0.84; 1.23) 1.19 (0.99; 1.43) ≥ 80 1.14 (0.86; 1.51) 1.35 (1.03; 1.76) CrCL (mL/min) 30 ≤ and < 50 1.02 (0.79; 1.32) 0.94 (0.73; 1.22) 50 ≤ and < 80 0.75 (0.61; 0.92) 0.90 (0.74; 1.09) ≥ 80 0.59 (0.43; 0.82) 0.87 (0.65; 1.17) ASA use 0.84 (0.69; 1.03) 0.97 (0.79; 1.18) Clopidogrel use 0.89 (0.55; 1.45) 0.92 (0.57; 1.48) RELY-ABLE (long-term multicentre extension of dabigatran treatment in patients with atrial fibrillation who completed the RE-LY trial) The RE-LY extension trial (RELY-ABLE) provided additional safety information for the cohort of patients who continued on the same dose of dabigatran etexilate as they had received in RE-LY. Patients were eligible for RELY-ABLE if they had not permanently discontinued the study treatment at the time of their final RE-LY visit. Enrolled patients continued to receive the same double-blind dose of dabigatran etexilate to which they had been randomly assigned in RE-LY, with follow-up of up to 43 months after the end of RE-LY (total mean follow-up across RE-LY and RELY-ABLE was 4.5 years). A total of 5,897 patients were enrolled, representing 49% of patients originally randomised to dabigatran etexilate in RE-LY and 86% of those eligible for RELY-ABLE. During the additional 2.5 years of treatment in RELY-ABLE, with maximum exposure of more than 6 years (total exposure across RE-LY and RELY-ABLE), the long-term safety profile of dabigatran etexilate was confirmed for both 110 mg twice daily and 150 mg twice daily doses studied. No new safety findings were observed. The rates of monitored events including major bleeding and other bleeding events were consistent with those observed in RE-LY. Data from non-interventional studies In the non-interventional GLORIA-AF study, data on the safety and efficacy of dabigatran etexilate in patients with newly diagnosed NVAF treated in routine clinical practice were collected prospectively (in its second phase). The study included 4,859 patients treated with dabigatran etexilate (55% on 150 mg twice daily, 43% on 110 mg twice daily, 2% on 75 mg twice daily). Patients were followed for 2 years. The mean CHADS₂ score was 1.9 and the mean HAS-BLED score was 1.2. The mean on-treatment follow-up duration was 18.3 months. Major bleeding occurred at a rate of 0.97 events per 100 patient-years. Life-threatening bleeding was reported at 0.46 events per 100 patient-years, intracranial bleeding at 0.17 events per 100 patient-years and gastrointestinal bleeding at 0.60 events per 100 patient-years. Stroke occurred at a rate of 0.65 events per 100 patient-years. In addition, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157–164] conducted in the United States in more than 134,000 elderly patients with NVAF (contributing more than 37,500 patient-years of on-treatment follow-up), dabigatran etexilate (84% of patients on 150 mg twice daily, 16% on 75 mg twice daily) was associated 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 with an increased risk of gastrointestinal bleeding (hazard ratio 1.28; CI 1.14–1.44) compared with warfarin. No difference was observed in major bleeding (hazard ratio 0.97; CI 0.88–1.07). These real-world observations are consistent with the established safety and efficacy profile of dabigatran etexilate in this indication in the RE-LY study. Patients undergoing 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 undergoing PCI with stenting to assess dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) and 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)–defined major bleeding events was lower in both dabigatran etexilate dual therapy arms compared with 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). In both dabigatran etexilate dual therapy arms, intracranial bleeding rates were lower than in 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 in the individual components of the efficacy endpoints were observed between the dabigatran etexilate dual therapy arms and the warfarin triple therapy arm. This study demonstrated that in patients with atrial fibrillation undergoing PCI with stenting, dual therapy with dabigatran etexilate and a P2Y₁₂ antagonist significantly reduced the risk of bleeding compared with triple therapy with warfarin, while non-inferiority was demonstrated for the composite of thromboembolic events. Treatment of DVT and PE in adults (DVT/PE treatment) Efficacy and safety were investigated in two multicentre, randomised, double-blind, identical parallel-group studies, RE-COVER and RE-COVER II. These studies compared dabigatran etexilate (150 mg twice daily) with warfarin (target INR 2.0–3.0) in patients with acute DVT and/or PE. The primary objective of these studies was to demonstrate that dabigatran etexilate was non-inferior to warfarin in reducing the incidence of the primary endpoint, 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 studies, a total of 5,153 patients were randomised and 5,107 were treated. Treatment duration 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 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 the risk difference and 2.75 for the hazard ratio). Table 27: Analysis of the primary and secondary efficacy endpoints (VTE comprises DVT and/or PE) for the pooled RE-COVER and RE-COVER II studies up to 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 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 continued anticoagulation, and RE-SONATE, a placebo-controlled study, enrolled patients already treated with vitamin K inhibitors for 6 to 18 months. The objective of RE-MEDY was to compare the safety and efficacy of oral dabigatran etexilate (150 mg twice daily) with warfarin (target INR 2.0–3.0) for the long-term treatment and prevention of recurrent symptomatic DVT and/or PE. A total of 2,866 patients were randomised and 2,856 patients were treated. 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 treatment with dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margin: 2.85 for the hazard ratio and 2.8 for the risk difference). Table 28: Analysis of the primary and secondary efficacy endpoints (VTE comprises DVT and/or PE) for the RE-MEDY study up to 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 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 evaluate the superiority of dabigatran etexilate over placebo in preventing recurrent symptomatic DVT and/or PE in patients who had already completed 6 to 18 months of VKA therapy. The planned 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 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 demonstrated the superiority of dabigatran etexilate over placebo. The study included an observational follow-up of 12 months after the end of treatment. After discontinuation of study medication, the effect persisted until 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 dabigatran etexilate–treated patients 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 the primary and secondary efficacy endpoints (VTE comprises DVT and/or PE) for the RE-SONATE study up to 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 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 thromboembolic disease in patients with prosthetic heart valves A phase II study evaluated dabigatran etexilate and warfarin in a total of 252 patients who had undergone surgical mechanical heart valve replacement, either in the early postoperative period (i.e. dosing was initiated during the post-surgical hospitalisation) or 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 were observed with dabigatran etexilate than with warfarin. In patients in the early postoperative phase, major bleeding manifested predominantly as haemorrhagic pericardial effusions, especially in patients in whom dabigatran etexilate dosing was initiated early (i.e. on day 3) after surgical heart valve replacement (see section 4.3). Paediatric population Clinical trials in the prevention of VTE following major joint replacement surgery Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors The European Medicines Agency has waived the obligation to submit the results of studies with the reference product containing dabigatran etexilate in all subsets of the paediatric population in the indication of primary prevention of VTE in patients who have undergone elective total hip or knee replacement, and in the indication of prevention of stroke and systemic embolism in patients with NVAF (see section 4.2 for information on paediatric use). Treatment of VTE and prevention of recurrent VTE in paediatric patients The DIVERSITY study was conducted to demonstrate the efficacy and safety of dabigatran etexilate compared with standard of care (SOC) in the treatment of VTE in paediatric patients from birth to < 18 years of age. The study was designed as an open-label, randomised, non-inferiority, parallel-group 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 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 patients with complete thrombus resolution, freedom from 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 were treated with dabigatran etexilate and 90 received SOC (1 randomised patient was not treated). 168 patients were aged from 12 to < 18 years, 64 patients from 2 to < 12 years, and 35 patients 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, freedom from recurrent VTE and no 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 across subgroups by 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 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 in 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 (MBE) or clinically relevant non-major (CRNM) bleeding (during treatment) was reported in 6 patients (3.4%) in the dabigatran etexilate group and in 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. Eligible patients were those who required continued anticoagulation due to the presence of clinical risk factors following the completion of initial treatment for a confirmed VTE (for at least 3 months) or after completion of the DIVERSITY study. Patients in the study received dabigatran etexilate at doses 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. 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. Outcomes were assessed by an independent blinded adjudication committee. A total of 214 patients were enrolled, including 162 patients in age group 1 (12 to < 18 years), 43 patients in age group 2 (2 to < 12 years), and 9 patients in age group 3 (birth to < 2 years). During the treatment period, recurrent VTE was confirmed in 3 patients (1.4%) within the first 12 months after initiation of therapy. Confirmed bleeding events during the treatment period within the first 12 months were reported in 48 patients (22.5%). Most bleeding events were minor. Adjudicated major bleeding events occurred in 3 patients (1.4%) within the first 12 months. Adjudicated CRNM bleeding was reported in 3 patients (1.4%) within the first 12 months. There were no deaths during treatment. During the treatment period, 3 patients (1.4%) developed post-thrombotic syndrome (PTS) or had a worsening of PTS within the first 12 months.