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. After 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 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. Based on phase II studies, there is a clear correlation between plasma dabigatran concentration 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 plasma dabigatran concentrations. When the plasma dabigatran concentration result from the calibrated dTT assay is at or below the limit of quantification, an additional coagulation assay 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 dabigatran concentrations. Although high aPTT values must be interpreted with caution, a high aPTT value indicates that the patient is anticoagulated. In general, these measures of anticoagulant activity can be assumed to reflect dabigatran levels and provide guidance for assessing bleeding risk; that is, exceeding the 90th percentile of the trough dabigatran concentration or of a coagulation test such as aPTT, measured at trough (for aPTT thresholds see section 4.4, Table 6), is considered to be associated with an increased risk of bleeding. Primary prevention of VTE in orthopaedic surgery The geometric mean peak plasma dabigatran concentration at steady state (after day 3), measured approximately 2 hours after a 220 mg dose of dabigatran etexilate, was 70.8 ng/mL, with a range of 35.2–162 ng/mL (25th–75th percentile range). The geometric mean trough dabigatran concentration measured at the end of the dosing interval (i.e. 24 hours after a 220 mg dabigatran dose) was on average 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 was on average 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 surgery, 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 the normal range. ECT was not measured in patients receiving dabigatran etexilate 220 mg once daily for the prevention of VTE following hip or knee replacement surgery. Prevention of stroke and systemic embolism in adult patients with NVAF and one or more risk factors (SPAF) The geometric mean peak plasma dabigatran concentration at steady state, 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 range). The geometric mean trough dabigatran concentration measured at morning trough at the end of the dosing interval (i.e. 12 hours after the evening 150 mg dabigatran dose) was on average 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 concentrations measured at trough (10–16 hours after the previous dose) was approximately 200 ng/mL, ECT at trough (10–16 hours after the previous dose) increased to approximately three times the upper limit of the normal range corresponds to the observed 90th percentile prolongation of ECT 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 the dose 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 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 1.8 times the baseline. No pharmacokinetic data are available in patients treated with dabigatran etexilate 150 mg twice daily for the prevention of recurrent DVT and PE. Clinical efficacy and safety Ethnic origin No clinically relevant ethnic differences were observed 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 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 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. Results from both studies showed that the antithrombotic effect of dabigatran etexilate at 220 mg and 150 mg was statistically non-inferior to enoxaparin with respect to total VTE and all-cause mortality. The point estimate of the incidence of major VTE 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 of the incidence of major VTE was slightly better than with enoxaparin (Table 19). The clinical studies were conducted in a patient population with a mean age > 65 years. In the phase 3 clinical studies, there were no differences between men and women regarding 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. These conditions were not observed to influence the effect of dabigatran on VTE prevention or bleeding rates. Data for the endpoint of major VTE and VTE-related mortality were homogeneous with respect to 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 assessed 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 and one or more risk factors Clinical evidence of the efficacy of dabigatran etexilate is derived from the RE-LY study (Randomised Evaluation of Long-term anticoagulant therapy), a multicentre, international, randomised, parallel-group study that compared 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 demonstrate whether dabigatran etexilate was non-inferior to warfarin in reducing the occurrence of the composite endpoint of stroke and systemic embolism. Statistical superiority was also analysed. In RE-LY, a total of 18,113 patients with a mean age of 71.5 years and a mean CHADS2 score of 2.1 were randomised. The patient population was 64% male, 70% Caucasian, and 16% Asian. In patients randomised to warfarin, the mean percentage of time in the therapeutic range (TTR) (INR 2–3) was 64.4% (median TTR 67%). The RE-LY study showed that dabigatran etexilate 110 mg twice daily is non-inferior to warfarin in the prevention of stroke and systemic embolism in subjects with atrial fibrillation, with a reduced risk of intracranial haemorrhage, total bleeding, and major bleeding. The 150 mg twice-daily dose significantly reduces the risk of ischaemic and haemorrhagic stroke, vascular mortality, intracranial haemorrhage, and total bleeding compared with warfarin. The rate of major bleeding at this dose was comparable to warfarin. The incidence of myocardial infarction was slightly increased compared with warfarin for dabigatran etexilate 110 mg twice daily (hazard ratio 1.29; p = 0.0929) and dabigatran etexilate 150 mg twice daily (hazard ratio 1.27; p = 0.1240), respectively. With improved INR monitoring, the observed benefits of dabigatran etexilate compared with warfarin diminish. Tables 22–24 provide 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 the annual event rate Table 23: Analysis of the first occurrence of ischaemic or haemorrhagic stroke 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 the annual 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 mortality 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 the annual event rate Tables 25–26 present the results of the primary efficacy and safety endpoints in the corresponding subpopulations: For the primary endpoint of stroke and systemic embolism, no subgroups (i.e. age, body weight, sex, renal function, ethnicity, etc.) with a different hazard ratio versus warfarin were identified. Table 25: Hazard ratio and 95% confidence interval for stroke/systemic embolism by subgroup Endpoint Dabigatran etexilate 110 mg twice daily vs warfarin Dabigatran etexilate 150 mg twice daily vs warfarin Age (years) < 65 1.10 (0.64; 1.87) 0.51 (0.26; 0.98) 65 ≤ and < 75 0.86 (0.62; 1.19) 0.67 (0.47; 0.95) ≥ 75 0.88 (0.66; 1.17) 0.68 (0.50; 0.92) ≥ 80 0.68 (0.44; 1.05) 0.67 (0.44; 1.02) CrCL (mL/min) 30 ≤ and < 50 0.89 (0.61; 1.31) 0.48 (0.31; 0.76) 50 ≤ and < 80 0.91 (0.68; 1.20) 0.65 (0.47; 0.88) ≥ 80 0.81 (0.51; 1.28) 0.69 (0.43; 1.12) For major bleeding, the primary safety endpoint, there was an interaction between treatment effect and age. The relative risk of bleeding with dabigatran compared with warfarin increased with age. The relative risk was highest in patients aged 75 years and older. Concomitant therapy with antiplatelet agents, ASA, or clopidogrel approximately doubles the rate of major bleeding events with both dabigatran etexilate and warfarin. There was no significant treatment-effect interaction in subgroups 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 therapy in patients with atrial fibrillation who completed the RE-LY study) The RE-LY extension (RELY-ABLE) provided additional safety information for the cohort of patients who continued on the same dose of dabigatran etexilate as in the RE-LY trial. Patients were eligible for the RELY-ABLE study if they had not permanently discontinued the study medication at the time of their final visit in RE-LY. Enrolled patients continued on the same double-blind dose of dabigatran etexilate randomly assigned in RE-LY for a follow-up period of up to 43 months after the end of RE-LY (overall mean follow-up 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. During an additional 2.5 years of treatment in the RELY-ABLE study, with a maximum exposure duration 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 evaluated doses of 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 the RE-LY study. Data from non-interventional studies In a non-interventional study (GLORIA-AF), safety and efficacy data were prospectively collected (in its second phase) in patients with newly diagnosed NVAF treated with dabigatran etexilate in real-world practice. The study included 4,859 patients treated with dabigatran etexilate (55% received 150 mg twice daily, 43% received 110 mg twice daily, 2% received 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 duration on treatment was 18.3 months. Major bleeding occurred at a rate of 0.97 events per 100 patient-years. Life-threatening bleeding was reported at 0.46 events per 100 patient-years, intracranial bleeding at 0.17 events per 100 patient-years, and gastrointestinal bleeding at 0.60 events per 100 patient-years. Stroke occurred at 0.65 events per 100 patient-years. In addition, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157–164] conducted in the United States in more than 134,000 elderly patients with NVAF (contributing more than 37,500 patient-years of follow-up on treatment), dabigatran etexilate (84% of patients received 150 mg twice daily, 16% received 75 mg twice daily) compared with warfarin 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 an increased risk of gastrointestinal bleeding (hazard ratio 1.28; CI 1.14–1.44). No difference was observed for major bleeding (hazard ratio 0.97; CI 0.88–1.07). These real-world observations are consistent with the established safety and efficacy profile of dabigatran etexilate in this indication in the RE-LY study. Patients who underwent percutaneous coronary intervention (PCI) with stenting A prospective, randomised, open-label phase IIIb clinical trial with blinded endpoint adjudication (PROBE) was conducted in 2,725 patients with non-valvular atrial fibrillation who underwent PCI with stenting to assess dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) and clopidogrel or ticagrelor (a P2Y12 antagonist) compared with triple therapy with warfarin (target 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 triple therapy with warfarin. The primary endpoint was a composite of major bleeding by ISTH definition or clinically relevant non-major bleeding. The incidence of the primary endpoint was 15.4% (151 patients) in the 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 major bleeding events as classified by TIMI (Thrombolysis In Myocardial Infarction) was lower in both dual therapy groups with dabigatran etexilate 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). The rates of intracranial bleeding were lower in both dual therapy groups with dabigatran etexilate 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 dual therapy groups with dabigatran etexilate 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 observed between the dual therapy groups with dabigatran etexilate and the triple therapy group with warfarin. This study demonstrated that in patients with atrial fibrillation undergoing PCI with stenting, dual therapy with dabigatran etexilate and a P2Y12 antagonist compared with triple therapy with warfarin significantly reduced the risk of bleeding 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, 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 occurrence 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 studies, a total of 5,153 patients were randomised and 5,107 were treated. The duration of fixed-dose dabigatran therapy was 174.0 days without coagulation monitoring. In patients randomised to warfarin, the median time in the therapeutic range (INR 2.0 to 3.0) was 60.6%. The studies showed that treatment with dabigatran etexilate 150 mg twice daily is non-inferior to warfarin (non-inferiority margins for RE-COVER and RE-COVER II: 3.6 for risk difference and 2.75 for hazard ratio). Table 27: Analysis of primary and secondary efficacy endpoints (VTE is composed of DVT and/or PE) for the pooled RE-COVER and RE-COVER II studies 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% confidence interval) 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, included patients already treated for 3 to 12 months who required further anticoagulant therapy, and RE-SONATE, a placebo-controlled study, included patients already treated for 6 to 18 months with vitamin K inhibitors. The objective of the RE-MEDY study was to compare the safety and efficacy of oral 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. 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 the therapeutic range (INR 2.0–3.0) was 64.9%. The RE-MEDY study demonstrated that treatment with dabigatran etexilate 150 mg twice daily is non-inferior to warfarin (non-inferiority margins: 2.85 for hazard ratio and 2.8 for risk difference). Table 28: Analysis of primary and secondary efficacy endpoints (VTE is composed of DVT and/or PE) for the RE-MEDY study 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% 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 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 the RE-SONATE study was to evaluate the superiority of dabigatran etexilate over placebo in the prevention of 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. The RE-SONATE study demonstrated that dabigatran etexilate was superior to placebo in the prevention of recurrent symptomatic DVT/PE events including unexplained deaths, with a reduction in risk from 5.6% to 0.4% (92% relative risk reduction based on 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 observational follow-up for 12 months 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 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 primary and secondary efficacy endpoints (VTE is composed of DVT and/or PE) for the RE-SONATE study 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% confidence interval) 0.08 (0.02; 0.25) Superiority p-value < 0.0001 Secondary efficacy endpoints Recurrent symptomatic VTE and all-cause mortality 3 (0.4%) 37 (5.6%) 95% 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 following surgical mechanical heart valve replacement in the early postoperative period (i.e. dosing was initiated during the postoperative hospital stay) and in patients who had received a mechanical heart valve replacement more than three months previously. More thromboembolic events (primarily strokes 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, primarily in patients in whom dabigatran etexilate was initiated early (i.e. on day 3) after surgical heart valve replacement (see section 4.3). Paediatric population Clinical trials in the prevention of VTE following major joint replacement surgery Prevention of stroke and systemic embolism in adult patients with NVAF and one or more risk factors The European Medicines Agency has waived the obligation to submit results of studies with the reference product containing dabigatran etexilate in all subsets of the paediatric population 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 study with parallel groups. Enrolled patients were randomised in a 2:1 ratio either to dabigatran etexilate (doses were 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 (LMWH), vitamin K antagonists (VKA), or fondaparinux (1 patient aged 12 years). The primary endpoint was a composite of the number of patients with complete thrombus resolution, absence of recurrent VTE, and no VTE-related mortality. Exclusion criteria included active meningitis, encephalitis, and intracranial abscess. A total of 267 patients were randomised. Of these, 176 patients were treated with dabigatran etexilate and 90 patients received SOC (1 randomised patient was not treated). 168 patients were aged 12 to < 18 years, 64 patients were aged 2 to < 12 years, and 35 patients were younger than 2 years. Of the 267 randomised patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients (42.2%) in the SOC group met the criteria for the composite endpoint (complete thrombus resolution, absence of recurrent VTE, and no VTE-related mortality). The corresponding difference in incidence demonstrated non-inferiority of dabigatran etexilate versus SOC. Consistent results were also generally observed across subgroups: no significant differences in treatment effect were noted across subgroups by age, sex, region, or presence of certain risk factors. Across the 3 age groups, the proportions of patients who met 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 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 (on 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 safety cohort study (1160.108) was conducted to evaluate the safety of dabigatran etexilate in the prevention of recurrent VTE in paediatric patients from birth to < 18 years of age. Patients eligible for enrolment 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 up to 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. Event outcomes were assessed by an independent blinded adjudication committee. A total of 214 patients were enrolled in the study; among them, 162 patients in age group 1 (12 to < 18 years of age), 43 patients in age group 2 (2 to < 12 years of age), and 9 patients in age group 3 (birth to < 2 years of age). During the treatment period, recurrent VTE was confirmed in 3 patients (1.4%) within the first 12 months after initiation 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%), a major bleeding event confirmed on adjudication occurred within the first 12 months. CRNM bleeding confirmed on adjudication was reported in 3 patients (1.4%) within the first 12 months. No deaths occurred during treatment. During the treatment period, 3 patients (1.4%) developed post-thrombotic syndrome (PTS) or experienced worsening of PTS within the first 12 months.