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 by esterase-catalysed hydrolysis. Dabigatran is a potent, competitive, reversible, direct thrombin inhibitor and is the main 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 after intravenous administration and of dabigatran etexilate after oral administration in various animal models of thrombosis. Phase II studies have shown a clear correlation between plasma dabigatran concentration and the degree of anticoagulant effect. Dabigatran prolongs thrombin time (TT), ECT and aPTT. The calibrated quantitative diluted TT assay (dTT) provides an estimate of plasma dabigatran concentration that can be compared with expected plasma dabigatran concentrations. When the dabigatran plasma concentration result from the calibrated dTT assay is at or below the limit of quantification, additional coagulation testing such as TT, ECT or aPTT should be considered. ECT permits direct measurement 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 assay has limited sensitivity and is not suitable for accurate quantification of the anticoagulant effect, particularly at high plasma concentrations of dabigatran. Although high aPTT values must be interpreted with caution, a high aPTT indicates that the patient is anticoagulated. In general, these measurements of anticoagulant activity may reflect dabigatran levels and provide guidance for the assessment of bleeding risk; that is, exceeding the 90th percentile of the dabigatran trough concentration, or 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 peak steady-state 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 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 VTE prevention after hip or knee replacement surgery: - 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, representing 1.3 times the upper limit of the normal range. ECT was not measured in patients treated with dabigatran etexilate 220 mg once daily for VTE prevention after hip or knee replacement surgery. Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF) The geometric mean peak steady-state plasma dabigatran concentration measured approximately 2 hours after a 150 mg dose of dabigatran etexilate given twice daily was 175 ng/mL, with a range of 117–275 ng/mL (25th–75th percentile range). The geometric mean trough dabigatran concentration measured at the morning trough at the end of the dosing interval (i.e. 12 hours after the evening 150 mg dabigatran dose) averaged 91.0 ng/mL, with a range of 61.0–143 ng/mL (25th–75th percentile 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), elevated approximately to three times the upper limit of the normal range, corresponds to the observed 90th percentile of ECT prolongation to 103 seconds, - an aPTT ratio greater than twice the upper limit of the normal range (aPTT prolongation to approximately 80 seconds) at trough (10–16 hours after the previous dose) corresponds to the 90th percentile of observations. Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (DVT/PE) In patients treated for DVT and PE with dabigatran etexilate 150 mg twice daily, the geometric mean trough dabigatran concentration measured 10–16 hours after dosing at the end of the dosing interval (i.e. 12 hours after the evening 150 mg dabigatran dose) was 59.7 ng/mL, with a range of 38.6–94.5 ng/mL (25th–75th percentile 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), elevated approximately 2.3-fold from baseline, corresponds to an 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 in 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 among Caucasian, African American, Hispanic, Japanese or Chinese patients. Clinical trials of VTE prevention following major joint replacement surgery In two large, double-blind, randomised, parallel-group dose-confirmation trials, patients undergoing elective major orthopaedic surgery (knee replacement in one trial, hip replacement in the other) received dabigatran etexilate 75 mg or 110 mg within 1–4 hours after surgery, followed by 150 mg or 220 mg once daily once haemostasis 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 regard to total VTE and all-cause mortality. The point estimate for the incidence of major venous thromboembolism and VTE-related mortality was slightly worse with the 150 mg dose than with enoxaparin (Table 19). Better results were observed with the 220 mg dose, for which the point estimate for major venous thromboembolism was slightly better than with enoxaparin (Table 19). Clinical studies were conducted in patient populations with a mean age > 65 years. In the phase 3 clinical trials there were no differences between men and women in efficacy or safety data. In the RE-MODEL and RE-NOVATE study population (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 in the prevention of venous thromboembolism or the frequency of bleeding. Data for the endpoint of major venous thromboembolism and VTE-related mortality were homogeneous with the primary efficacy endpoint and are presented in Table 19. Data for the endpoint of total VTE and all-cause mortality are presented in Table 20. Data for the adjudicated major bleeding endpoints are presented below in Table 21. Table 19: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL and RE-NOVATE orthopaedic surgery 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 for each of the RE-MODEL and RE-NOVATE studies Clinical trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) Number of treated patients (n) 1,146 1,163 1,154 Number of MBEs (%) 23 (2.0) 15 (1.3) 18 (1.6) RE-MODEL (knee) Number of treated patients (n) 679 703 694 Number of MBEs (%) 10 (1.5) 9 (1.3) 9 (1.3) Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors Clinical evidence of efficacy for dabigatran etexilate comes from the RE-LY study (Randomised Evaluation of Long-term anticoagulant therapy), a multicentre, international, randomised, parallel-group trial comparing two doses of dabigatran etexilate (110 mg and 150 mg twice daily) administered in a blinded manner with open-label warfarin in patients with atrial fibrillation at moderate to high risk of stroke and systemic embolism. The primary objective of this study was to determine whether dabigatran etexilate was non-inferior to warfarin in reducing the incidence of the composite endpoint of stroke and systemic embolism. Statistical superiority was also assessed. In the RE-LY study, a total of 18,113 patients were randomised, with a mean age of 71.5 years and a mean CHADS2 score of 2.1. The patient population was 64% male, 70% Caucasian and 16% Asian. In patients randomised to warfarin, the mean percentage time in therapeutic range (TTR) (INR 2–3) was 64.4% (median TTR 67%). The RE-LY study showed that dabigatran etexilate 110 mg twice daily was non-inferior to warfarin for the prevention of stroke and systemic embolism in subjects with atrial fibrillation, with a reduced risk of intracranial bleeding, total bleeding and major bleeding. The 150 mg twice daily dose significantly 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 that of 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 for dabigatran etexilate 150 mg twice daily (hazard ratio 1.27; p = 0.1240). With improved INR monitoring, the observed benefits of dabigatran etexilate over warfarin 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 observation period of the RE-LY study Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomised subjects 6,015 6,076 6,022 Stroke and/or systemic embolism Incidence (%) 183 (1.54) 135 (1.12) 203 (1.72) Hazard ratio vs warfarin (95% confidence interval) 0.89 (0.73; 1.09) 0.65 (0.52; 0.81) Superiority p-value p = 0.2721 p = 0.0001 % refers to annualised event rate Table 23: Analysis of the first occurrence of ischaemic or haemorrhagic strokes during the observation period of the RE-LY study Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomised subjects 6,015 6,076 6,022 Stroke Incidence (%) 171 (1.44) 123 (1.02) 187 (1.59) Hazard ratio vs warfarin (95% confidence interval) 0.91 (0.74; 1.12) 0.64 (0.51; 0.81) p-value 0.3553 0.0001 Systemic embolism Incidence (%) 15 (0.13) 13 (0.11) 21 (0.18) Hazard ratio vs warfarin (95% confidence interval) 0.71 (0.37; 1.38) 0.61 (0.30; 1.21) p-value 0.3099 0.1582 Ischaemic stroke Incidence (%) 152 (1.28) 104 (0.86) 134 (1.14) Hazard ratio vs warfarin (95% confidence interval) 1.13 (0.89; 1.42) 0.76 (0.59; 0.98) p-value 0.3138 0.0351 Haemorrhagic stroke Incidence (%) 14 (0.12) 12 (0.10) 45 (0.38) Hazard ratio vs warfarin (95% confidence interval) 0.31 (0.17; 0.56) 0.26 (0.14; 0.49) p-value 0.0001 < 0.0001 % refers to annualised event rate Table 24: Analysis of all-cause mortality and cardiovascular survival during the observation period of the RE-LY study Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Randomised subjects 6,015 6,076 6,022 All-cause mortality Incidence (%) 446 (3.75) 438 (3.64) 487 (4.13) Hazard ratio vs warfarin (95% confidence interval) 0.91 (0.80; 1.03) 0.88 (0.77; 1.00) p-value 0.1308 0.0517 Vascular death Incidence (%) 289 (2.43) 274 (2.28) 317 (2.69) Hazard ratio vs warfarin (95% confidence interval) 0.90 (0.77; 1.06) 0.85 (0.72; 0.99) p-value 0.2081 0.0430 % refers to annualised event rate Tables 25–26 present results for the primary efficacy and safety endpoints in the relevant subpopulations: No subgroups (e.g. age, body weight, sex, renal function, ethnicity) with a different hazard ratio versus warfarin were identified for the primary endpoint of stroke and systemic embolism. 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 antiplatelet therapy with ASA or clopidogrel approximately doubled the rate of major bleeding events both for dabigatran etexilate and for warfarin. No significant interaction of treatment effects was found 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 study) The RE-LY extension study (RELY-ABLE) provided additional safety information for the cohort of patients who continued to receive the same dose of dabigatran etexilate they had received in the RE-LY trial. Patients were eligible for the RELY-ABLE study if they had not permanently discontinued the study treatment at the time of their final visit in the RE-LY study. Enrolled patients continued to take the same double-blind dose of dabigatran etexilate to which they had been randomised in the RE-LY study, for a follow-up period of up to 43 months after the end of the RE-LY study (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 the RE-LY study and 86% of patients eligible for the RELY-ABLE study. During an additional 2.5 years of treatment in the RELY-ABLE study, with a maximum exposure of more than 6 years (total exposure in 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 rates of monitored events including major bleeding and other bleeding events were consistent with those observed in the RE-LY study. 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 routine clinical practice were prospectively collected (in its second phase). The study enrolled 4,859 patients treated with dabigatran etexilate (55% were treated with 150 mg twice daily, 43% with 110 mg twice daily, and 2% with 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 was 18.3 months. Major bleeding occurred at a rate of 0.97 events per 100 patient-years. Life-threatening bleeding was reported at 0.46 events per 100 patient-years, intracranial bleeding at 0.17 events per 100 patient-years and gastrointestinal bleeding at 0.60 events per 100 patient-years. Stroke occurred at 0.65 events per 100 patient-years. In addition, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157–164] conducted in the United States in more than 134,000 elderly patients with NVAF (contributing more than 37,500 patient-years of on-treatment follow-up), dabigatran etexilate (84% of patients treated with 150 mg twice daily, 16% with 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 with an increased risk of gastrointestinal bleeding (hazard ratio 1.28; CI 1.14–1.44). No difference was found 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 for this indication in the RE-LY study. Patients who underwent percutaneous coronary intervention (PCI) with stenting A prospective, randomised, open-label, blinded endpoint (PROBE) phase IIIb clinical trial was conducted in 2,725 patients with non-valvular atrial fibrillation who underwent PCI with stenting, to evaluate dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) plus clopidogrel or ticagrelor (a P2Y12 antagonist) compared with triple therapy with warfarin (INR target 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 major bleeding or clinically relevant non-major bleeding. The incidence of the primary endpoint was 15.4% (151 patients) in the dual therapy group with dabigatran etexilate 110 mg compared with 26.9% (264 patients) in the triple therapy group with warfarin (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 dual therapy group with dabigatran etexilate 150 mg compared with 25.7% (196 patients) in the corresponding triple therapy group with warfarin (hazard ratio 0.72; 95% CI 0.58, 0.88; p < 0.0001 for non-inferiority and p = 0.002 for superiority). In a descriptive analysis, the incidence of TIMI (Thrombolysis In Myocardial Infarction) major bleeding events was lower in both dabigatran etexilate dual therapy groups compared with the triple therapy group with warfarin: 14 events (1.4%) in the dual therapy group with dabigatran etexilate 110 mg compared with 37 events (3.8%) in the triple therapy group with warfarin (hazard ratio 0.37; 95% CI 0.20, 0.68; p = 0.002) and 16 events (2.1%) in the dual therapy group with dabigatran etexilate 150 mg compared with 30 events (3.9%) in the corresponding triple therapy group with warfarin (hazard ratio 0.51; 95% CI 0.28, 0.93; p = 0.03). In both dabigatran etexilate dual therapy groups the rates of intracranial bleeding were lower than in the corresponding triple therapy group with warfarin: 3 events (0.3%) in the dual therapy group with dabigatran etexilate 110 mg compared with 10 events (1.0%) in the triple therapy group with warfarin (hazard ratio 0.30; 95% CI 0.08, 1.07; p = 0.06) and 1 event (0.1%) in the dual therapy group with dabigatran etexilate 150 mg compared with 8 events (1.0%) in the corresponding triple therapy group with warfarin (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 triple therapy group with warfarin (13.7% vs 13.4%, respectively; hazard ratio 1.04; 95% CI: 0.84, 1.29; p = 0.0047 for non-inferiority). For the individual components of the efficacy endpoints, no statistical differences were identified between the dabigatran etexilate dual therapy groups and the warfarin triple therapy group. This study demonstrated that, in patients with atrial fibrillation who underwent PCI with stenting, dual therapy with dabigatran etexilate and a P2Y12 antagonist significantly reduced the risk of bleeding compared with triple therapy with warfarin, while showing non-inferiority for the composite of thromboembolic events. Treatment of DVT and PE in adults (DVT/PE treatment) Efficacy and safety were investigated in two multicentre, randomised, double-blind, parallel-group, identical studies, RE-COVER and RE-COVER II. These studies compared dabigatran etexilate (150 mg twice daily) with warfarin (target INR 2.0–3.0) in patients with acute DVT and/or PE. The primary objective of these studies was to demonstrate that dabigatran etexilate is non-inferior to warfarin in reducing the incidence of the primary endpoint, which was a composite of recurrence of symptomatic DVT and/or PE and related deaths during a 6-month treatment period. In the pooled RE-COVER and RE-COVER II studies, 5,153 patients were randomised in total, of whom 5,107 were treated. The duration of fixed-dose dabigatran treatment was 174.0 days without coagulation monitoring. In patients randomised to warfarin, the median time in therapeutic range (INR 2.0 to 3.0) was 60.6%. The trials 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 risk ratio). Table 27: Analysis of primary and secondary efficacy endpoints (VTE is composed of DVT and/or PE) for the pooled RE-COVER and RE-COVER II studies through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Warfarin Number of treated patients 2,553 2,554 Recurrence of symptomatic VTE and VTE-related death 68 (2.7%) 62 (2.4%) Hazard ratio vs warfarin (95% confidence interval) 1.09 (0.77; 1.54) Secondary efficacy endpoints Recurrence of 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 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 aim of the RE-MEDY study 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 were treated. The duration of treatment 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%. The RE-MEDY study showed that treatment with dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margins: 2.85 for the risk ratio and 2.8 for the risk difference). Table 28: Analysis of primary and secondary efficacy endpoints (VTE is composed of DVT and/or PE) for the RE-MEDY study through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Warfarin Number of treated patients 1,430 1,426 Recurrence of symptomatic VTE and VTE-related death 26 (1.8%) 18 (1.3%) Hazard ratio vs warfarin (95% confidence interval) 1.44 (0.78; 2.64) Non-inferiority margin 2.85 Patients with an event at 18 months 22 17 Cumulative risk at 18 months (%) 1.7 1.4 Risk difference vs warfarin (%) 0.4 95% confidence interval Non-inferiority margin 2.8 Secondary efficacy endpoints Recurrence of 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 aim of the RE-SONATE study 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 treatment with a VKA. The intended treatment was 6 months of dabigatran etexilate 150 mg twice daily without the need for monitoring. The RE-SONATE study showed that dabigatran etexilate was superior to placebo in preventing recurrent symptomatic DVT/PE events including unexplained deaths, reducing the risk from 5.6% to 0.4% (relative risk reduction of 92% based on the hazard ratio) during the treatment period (p < 0.0001). All secondary and sensitivity analyses of the primary endpoint and all secondary endpoints demonstrated the superiority of dabigatran etexilate over placebo. The study included a 12-month observational follow-up after the end of treatment. After discontinuation of the study medication, the effect persisted to the end of follow-up, indicating that the initial treatment effect of dabigatran etexilate was maintained. No rebound effect was observed. At the end of the follow-up period, VTE events occurred in 6.9% of patients treated with dabigatran etexilate 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 is composed of DVT and/or PE) for the RE-SONATE study through the end of the post-treatment period Dabigatran etexilate 150 mg twice daily Placebo Number of treated patients 681 662 Recurrence of symptomatic VTE and VTE-related death 3 (0.4%) 37 (5.6%) Hazard ratio vs placebo (95% confidence interval) 0.08 (0.02; 0.25) Superiority p-value < 0.0001 Secondary efficacy endpoints Recurrence of 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 of thromboembolic disease prevention in patients with prosthetic heart valves A phase II study evaluated dabigatran etexilate and warfarin in a total of 252 patients following surgical mechanical heart valve replacement in the early post-operative period (i.e. dosing was initiated during the post-surgical hospitalisation) and in patients who had undergone mechanical heart valve replacement 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 post-operative phase, major bleeding manifested primarily as haemorrhagic pericardial effusions, particularly 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 of VTE prevention 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 medicinal product containing dabigatran etexilate in all subsets of the paediatric population in the indication of primary VTE prevention in patients who have undergone elective total hip or knee replacement, and in the indication of stroke and systemic embolism prevention 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 according to age and body weight) in an age-appropriate dosage form (capsules, coated pellets or oral solution) or to SOC consisting of low molecular weight heparins (LMWHs), vitamin K antagonists (VKAs) 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 were treated with dabigatran etexilate and 90 patients received SOC (1 randomised patient was not treated). One hundred sixty-eight 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 composite endpoint (complete thrombus resolution, absence of recurrent VTE and no VTE-related mortality). The corresponding difference in incidence demonstrated the non-inferiority of dabigatran etexilate to SOC. Consistent results were also observed overall across subgroups: there were no significant differences in treatment effect across subgroups by age, sex, region or the presence of certain risk factors. Across the three age groups, the proportions of patients meeting the primary efficacy endpoint in the dabigatran etexilate group and the SOC group were 13/22 (59.1%) 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 events were 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 (MBE) or clinically relevant non-major (CRNM) bleeds (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 assess the safety of dabigatran etexilate in the prevention of recurrent VTE in paediatric patients from birth to < 18 years of age. Patients eligible for inclusion were those who required further 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 according to age and body weight in an age-appropriate dosage form (capsules, coated pellets or oral solution) until resolution of clinical risk factors or for a maximum of 12 months. Primary study endpoints included recurrence of VTE, major and minor bleeding events, and mortality (all-cause and related to thrombotic or thromboembolic events) at 6 and 12 months. Event outcomes were adjudicated by an independent blinded review committee. A total of 214 patients were enrolled in the study; of these, 162 patients were in age group 1 (12 to < 18 years), 43 patients in age group 2 (2 to < 12 years) and 9 patients in age group 3 (birth to < 2 years). During the treatment period, recurrent VTE was confirmed in 3 patients (1.4%) within the first 12 months of treatment initiation. Confirmed bleeding events during the treatment period were reported in 48 patients (22.5%) in the first 12 months. Most bleeding events were minor. In 3 patients (1.4%) an adjudicated major bleeding event occurred within the first 12 months. In 3 patients (1.4%) an adjudicated CRNM bleed was reported within the first 12 months. No deaths occurred during treatment. During the treatment period, post-thrombotic syndrome (PTS) developed or worsened in 3 patients (1.4%) within the first 12 months.