Dabigatranum etexilatum

Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors, ATC code: B01AE07. Mechanism of action Dabigatran etexilate is a small-molecule prodrug that has no pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and the liver. 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 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 concentrations and the degree of anticoagulant effect. Dabigatran prolongs thrombin time (TT), ECT and aPTT. The calibrated quantitative diluted TT (dTT) assay provides an estimate of the plasma dabigatran concentration that can be compared with expected plasma dabigatran concentrations. When the result of 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. ECT allows direct measurement of the activity of direct thrombin inhibitors. The aPTT test is widely available and provides an approximate indication of the intensity of anticoagulation achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable for the precise quantification of 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 may guide the assessment of bleeding risk; that is, exceeding the 90th percentile of trough dabigatran concentration or a coagulation test such as aPTT measured at trough (for aPTT thresholds, see section 4.4, Table 6) is regarded as 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). The geometric mean trough dabigatran concentration measured at the end of the dosing interval (i.e., 24 hours after a 220 mg dose) averaged 22.0 ng/mL, with a range of 13.0–35.7 ng/mL (25th–75th percentile). In a study conducted exclusively in patients with moderate renal impairment (creatinine clearance [CrCL] 30–50 mL/min) treated with dabigatran etexilate 150 mg once daily, the geometric mean trough concentration of dabigatran measured at the end of the dosing interval averaged 47.5 ng/mL, with a range of 29.6–72.2 ng/mL (25th–75th percentile). 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, representing 1.3 times the upper limit of normal. - ECT was not measured in patients receiving dabigatran etexilate 220 mg once daily for VTE prevention after 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 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 morning trough concentration of dabigatran 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). 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 3 times the upper limit of normal corresponded to the observed 90th percentile prolongation of ECT to 103 seconds. - An aPTT ratio greater than 2 times the upper limit of normal (aPTT prolongation to about 80 seconds) at trough (10–16 hours after the previous dose) corresponds to the 90th percentile observation. Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (DVT/PE) In patients treated for DVT and PE with dabigatran etexilate 150 mg twice daily, the geometric mean trough dabigatran concentration measured 10–16 hours after dosing at the end of the dosing interval (i.e., 12 hours after the evening 150 mg dose) was 59.7 ng/mL, with a range of 38.6–94.5 ng/mL (25th–75th percentile). 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 compared with baseline corresponds to the observed 90th percentile prolongation of ECT 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 compared with baseline. No pharmacokinetic data are available for patients treated for prevention of recurrent DVT and PE with dabigatran etexilate 150 mg twice daily. Clinical efficacy and safety Ethnicity No clinically relevant ethnic differences have been observed among Caucasian, African American, Hispanic, Japanese or Chinese patients. Clinical trials in VTE prevention after major joint replacement surgery In two large, double-blind, randomised dose-confirmation trials with parallel group design, patients undergoing elective major orthopaedic surgery (one trial in knee replacement and the other in hip replacement) received dabigatran etexilate at a dose of 75 mg or 110 mg within 1–4 hours after surgery, then 150 mg or 220 mg once daily once haemostasis was secured, or enoxaparin 40 mg the day before surgery and once daily thereafter. In the RE-MODEL trial (knee replacement), treatment lasted 6–10 days, and in RE-NOVATE (hip replacement) it lasted 28–35 days. The total number of treated patients was 2,076 (knee) and 3,494 (hip), respectively. The primary endpoint in both studies was the composite of total VTE (including PE, proximal and distal DVT, symptomatic or asymptomatic, detected by routine venography) and all-cause mortality. The secondary endpoint, considered more clinically relevant, was the composite of major VTE (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 with respect to total VTE and all-cause mortality. The point estimate for major VTE and VTE-related mortality was slightly worse for the 150 mg dose than for enoxaparin (Table 19). Better results were observed with the 220 mg dose, where the point estimate for major VTE was slightly better than for enoxaparin (Table 19). The clinical studies were conducted in a patient population with a mean age of >65 years. In phase 3 clinical studies, there were no differences between men and women with respect to efficacy and 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 shown in Table 20. Data for the adjudicated major bleeding endpoint are presented below in Table 21. Table 19: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL and RE-NOVATE orthopaedic surgery trials Trial | Dabigatran etexilate 220 mg once daily | Dabigatran etexilate 150 mg once daily | Enoxaparin 40 mg RE-NOVATE (hip) n: 909 / 888 / 917 Incidence (%): 28 (3.1) / 38 (4.3) / 36 (3.9) Hazard ratio vs enoxaparin: 0.78 / 1.09 95% CI: 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% CI: 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% CI: (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% CI: (0.82; 1.13) / (0.92; 1.25) Table 21: Major bleeding events by treatment in the RE-MODEL and RE-NOVATE trials Trial | Dabigatran etexilate 220 mg once daily | Dabigatran etexilate 150 mg once daily | Enoxaparin 40 mg RE-NOVATE (hip) Treated patients (n): 1,146 / 1,163 / 1,154 Major bleeding events (%): 23 (2.0) / 15 (1.3) / 18 (1.6) RE-MODEL (knee) Treated patients (n): 679 / 703 / 694 Major bleeding events (%): 10 (1.5) / 9 (1.3) / 9 (1.3) Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors Clinical evidence for the efficacy of dabigatran etexilate is derived from the RE-LY trial (Randomised Evaluation of Long-term anticoagulant therapY), a multicentre, international, randomised, parallel-group study comparing two doses of dabigatran etexilate (110 mg and 150 mg twice daily) administered in a blinded fashion with open-label warfarin in patients with atrial fibrillation at moderate to high risk of stroke and systemic embolism. The primary objective of the study was to demonstrate 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 within the therapeutic range (TTR) (INR 2–3) was 64.4% (median TTR 67%). The RE-LY trial showed that dabigatran etexilate 110 mg twice daily was non-inferior to warfarin for 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 bleeding and total bleeding compared with warfarin. Major bleeding rates with this dose were comparable to those of warfarin. The incidence 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 over warfarin diminish. Tables 22–24 present the key results in the overall population in detail. Table 22: Analysis of first occurrence of stroke or systemic embolism (primary endpoint) during the RE-LY follow-up period | Dabigatran etexilate 110 mg twice daily | Dabigatran etexilate 150 mg twice daily | Warfarin Randomised subjects: 6,015 / 6,076 / 6,022 Stroke and/or systemic embolism, Incidence (%): 183 (1.54) / 135 (1.12) / 203 (1.72) Hazard ratio vs warfarin (95% CI): 0.89 (0.73; 1.09) / 0.65 (0.52; 0.81) p-value for superiority: p = 0.2721 / p = 0.0001 % refers to annual event rate Table 23: Analysis of first occurrence of ischaemic or haemorrhagic strokes 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 and 26 present the results for the primary efficacy and safety endpoints 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% CI 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 antiplatelet therapy with ASA or clopidogrel approximately doubles the rate of major bleeding events with both dabigatran etexilate and warfarin. There was no significant interaction of treatment effect with the subgroups defined by renal function or CHADS2 score. Table 26: Hazard ratio and 95% CI 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 (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 double-blind dose of dabigatran etexilate randomly allocated in RE-LY for a follow-up period of up to 43 months after RE-LY ended (the overall 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 patients eligible for RELY-ABLE. Over an additional 2.5 years of treatment in RELY-ABLE, with maximum exposure exceeding 6 years (total exposure across RE-LY and RELY-ABLE), the long-term safety profile of dabigatran etexilate was confirmed for both doses studied (110 mg twice daily and 150 mg twice daily). No new safety findings were observed. The rates of monitored events including major bleeding and other bleeding events were consistent with those observed in RE-LY. Data from non-interventional studies In a non-interventional study (GLORIA-AF), real-world safety and efficacy data were prospectively collected (in its second phase) for patients with newly diagnosed NVAF treated with dabigatran etexilate. The study enrolled 4,859 patients treated with dabigatran etexilate (55% on 150 mg twice daily, 43% on 110 mg twice daily and 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 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 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% CI 0.67–0.96), intracranial bleeding (hazard ratio 0.34; 95% CI 0.26–0.46) and mortality (hazard ratio 0.86; 95% CI 0.77–0.96), and an increased risk of gastrointestinal bleeding (hazard ratio 1.28; 95% CI 1.14–1.44). No difference was observed for major bleeding (hazard ratio 0.97; 95% CI 0.88–1.07). These real-world observations are consistent with the established safety and efficacy profile of dabigatran etexilate in this indication in RE-LY. Patients undergoing percutaneous coronary intervention (PCI) with stenting In 2,725 patients with non-valvular atrial fibrillation who underwent PCI with stenting, a prospective, randomised, open-label, blinded endpoint (PROBE) phase IIIb trial was conducted to assess dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) plus clopidogrel or ticagrelor (a P2Y12 antagonist) versus triple therapy with warfarin (titrated to an INR of 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 warfarin triple therapy. Elderly patients outside the United States (≥80 years of age in all countries; ≥70 years in Japan) were randomised to dual therapy with dabigatran etexilate 110 mg or to warfarin triple therapy. 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 110 mg dabigatran etexilate dual-therapy group versus 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 150 mg dabigatran etexilate dual-therapy group versus 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 TIMI (Thrombolysis In Myocardial Infarction) major bleeding events was lower in both dabigatran etexilate dual-therapy groups than in the warfarin triple-therapy group: 14 events (1.4%) in the 110 mg dabigatran etexilate 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 150 mg dabigatran etexilate 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 110 mg dabigatran etexilate 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 150 mg dabigatran etexilate 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 detected 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 undergoing PCI with stenting, dual therapy with dabigatran etexilate and a P2Y12 antagonist significantly reduced the risk of bleeding compared with warfarin triple therapy, 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, identically designed parallel-group trials, RE-COVER and RE-COVER II. These trials 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 related deaths during the 6-month treatment period. In the pooled RE-COVER and RE-COVER II analysis, a total of 5,153 patients were randomised and 5,107 were treated. The duration of fixed-dose dabigatran treatment was 174.0 days without coagulation monitoring. In patients randomised to warfarin, the median time within the 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 primary and secondary efficacy endpoints (VTE composed of DVT and/or PE) for the pooled RE-COVER and RE-COVER II trials through the end of the post-treatment period | Dabigatran etexilate 150 mg twice daily | Warfarin Treated patients: 2,553 / 2,554 Recurrent symptomatic VTE and VTE-related death: 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 death: 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 death: 4 (0.2%) / 3 (0.1%) 95% CI: 0.04; 0.40 / 0.02; 0.34 All-cause death: 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 anticoagulants. RE-MEDY, a warfarin-controlled study, enrolled patients who had already been treated for 3 to 12 months and required additional anticoagulant therapy, and RE-SONATE, a placebo-controlled study, enrolled patients who had already been treated for 6 to 18 months with vitamin K inhibitors. The aim of RE-MEDY was to compare the safety and efficacy of orally administered dabigatran etexilate (150 mg twice daily) versus 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 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 within the therapeutic range (INR 2.0–3.0) was 64.9%. RE-MEDY demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margins: 2.85 for the hazard ratio and 2.8 for the risk difference). Table 28: Analysis of primary and secondary efficacy endpoints (VTE composed of DVT and/or PE) for RE-MEDY through the end of the post-treatment period | Dabigatran etexilate 150 mg twice daily | Warfarin Treated patients: 1,430 / 1,426 Recurrent symptomatic VTE and VTE-related death: 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% CI: — Non-inferiority margin: 2.8 Secondary efficacy endpoints Recurrent symptomatic VTE and all-cause death: 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 death: 1 (0.1%) / 1 (0.1%) 95% CI: 0.00; 0.39 / 0.00; 0.39 All-cause death: 17 (1.2%) / 19 (1.3%) 95% CI: 0.69; 1.90 / 0.80; 2.07 The aim 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 treatment with a VKA. 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 death, with risk reduction 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 showed superiority of dabigatran etexilate over placebo. The study included 12 months of observational follow-up after treatment ended. After discontinuation of study medication, the effect persisted through 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% of patients 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 composed of DVT and/or PE) for RE-SONATE through the end of the post-treatment period | Dabigatran etexilate 150 mg twice daily | Placebo Treated patients: 681 / 662 Recurrent symptomatic VTE and VTE-related death: 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 death: 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 death: 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 death: 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 following surgical mechanical heart valve replacement, both in the early postoperative period (i.e., dosing was initiated during the post-surgical hospitalisation) 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 manifested mainly as haemorrhagic pericardial effusion, particularly in patients in whom dabigatran etexilate was initiated early (i.e., on day 3) following 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 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 undergoing 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, parallel-group non-inferiority study. Enrolled patients were randomised in a 2:1 ratio either to dabigatran etexilate (with doses adjusted for age and body weight) in an age-appropriate formulation (capsules, coated granules or oral solution) or to SOC including low-molecular-weight heparins (LMWH), vitamin K antagonists (VKA) or fondaparinux (1 patient aged 12 years). The primary endpoint was a composite of the number of patients with complete thrombus resolution, freedom from recurrent VTE, and zero VTE-related mortality. Exclusion criteria included active meningitis, encephalitis and intracranial abscess. A total of 267 patients were randomised. Of these, 176 were treated with dabigatran etexilate and 90 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 younger than 2 years. Of the 267 randomised patients, 81 (45.8%) in the dabigatran etexilate group and 38 (42.2%) in the SOC group met the criteria for the composite endpoint (complete thrombus resolution, freedom from recurrent VTE, and zero VTE-related mortality). The corresponding difference in incidence demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent results were also generally found 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 and SOC groups were 13/22 (59.1%) versus 7/13 (53.8%) in patients from birth to <2 years, 21/43 (48.8%) versus 12/21 (57.1%) in patients aged 2 to <12 years, and 47/112 (42.0%) versus 19/56 (33.9%) in patients aged 12 to <18 years. Adjudicated major bleeding was reported in 4 patients (2.3%) in the dabigatran etexilate group and 2 patients (2.2%) in the SOC group. There was no statistically significant difference in time to first major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients (24.4%) in the SOC arm experienced any adjudicated bleeding event, most of which were classified as minor. The composite endpoint of adjudicated major bleeding events (MBE) or clinically relevant non-major (CRNM) bleeding (during treatment) was reported in 6 patients (3.4%) in the dabigatran etexilate group and 3 patients (3.3%) in the SOC group. A prospective, open-label, single-arm, multicentre phase III cohort study (1160.108) evaluating the safety of dabigatran etexilate in the prevention of recurrent VTE in paediatric patients from birth to <18 years of age was conducted. Patients eligible for enrolment were those who required additional anticoagulant therapy due to the presence of clinical risk factors after completing initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study. Patients in the study received dabigatran etexilate at doses adjusted for age and body weight in age-appropriate formulations (capsules, coated granules or oral solution) until resolution of clinical risk factors, or for a maximum of 12 months. The primary endpoints included recurrent VTE, major and minor bleeding events, and mortality (overall and related to thrombotic or thromboembolic events) at 6 and 12 months. Event outcomes were assessed by an independent blinded adjudication committee. A total of 214 patients were enrolled; among them, 162 patients in age group 1 (12 to <18 years), 43 patients in age group 2 (2 to <12 years) and 9 patients in age group 3 (birth to <2 years). During the treatment period, recurrent VTE was confirmed in 3 patients (1.4%) in the first 12 months after the start of treatment. 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 in the first 12 months. CRNM bleeding adjudicated as confirmed was reported in 3 patients (1.4%) in the first 12 months. No deaths occurred during treatment. During the treatment period, 3 patients (1.4%) developed post-thrombotic syndrome (PTS) or experienced worsening of PTS within the first 12 months.