Dabigatran etexilate Polpharma

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 by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active moiety in plasma. Since thrombin (a serine protease) catalyses the conversion of fibrinogen to fibrin in the coagulation cascade, its inhibition prevents thrombus formation. Dabigatran inhibits free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation. Pharmacodynamic effects In 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 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 plasma dabigatran concentration that can be compared with expected plasma concentrations of dabigatran. When the plasma dabigatran concentration measured by the calibrated dTT assay is at or below the limit of quantification, performing an additional coagulation assay such as TT, ECT, or aPTT should be considered. The ECT provides a direct measure of the activity of direct thrombin inhibitors. The aPTT assay is widely available and provides an approximate indication of the intensity of anticoagulation achieved with dabigatran. However, the aPTT assay has limited sensitivity and is not suitable for precise quantification of the anticoagulant effect, particularly at high plasma dabigatran concentrations. While high aPTT values must be interpreted with caution, a high aPTT indicates that the patient is anticoagulated. In general, these measures of anticoagulant activity may be assumed to reflect dabigatran levels and to 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 threshold values, see section 4.4, Table 6) is considered to be associated with an increased risk of bleeding. Primary prevention of VTE in orthopaedic surgery The geometric mean steady-state peak plasma dabigatran concentration (after Day 3), measured approximately 2 hours after 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 the 220 mg dose of dabigatran) 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 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). 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; - the ECT was not measured in patients treated with 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 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 administered twice daily was 175 ng/mL, with a range of 117–275 ng/mL (25th–75th percentile). 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 dose of dabigatran) 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 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; - the 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 ECT prolongation of 103 seconds; - an aPTT ratio greater than two times 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 dose of dabigatran) was 59.7 ng/mL, with a range of 38.6–94.5 ng/mL (25th–75th percentile). For 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; - the ECT at trough (10–16 hours after the previous dose) increased approximately 2.3-fold from baseline corresponds to the observed 90th percentile ECT prolongation of 74 seconds; - the 90th percentile of aPTT at trough (10–16 hours after the previous dose) was 62 seconds, corresponding to a 1.8-fold increase from baseline. In patients treated for prevention of recurrent DVT and PE with dabigatran etexilate 150 mg twice daily, no pharmacokinetic data are available. Clinical efficacy and safety Ethnic origin No clinically relevant ethnic differences were observed between Caucasian, African American, Hispanic, Japanese, or Chinese patients. Clinical trials in prevention of VTE following major joint replacement surgery In two large, double-blind, randomised, parallel-group, dose-confirmation trials, patients undergoing elective major orthopaedic surgery (one trial in knee replacement, the other in hip replacement) received dabigatran etexilate 75 mg or 110 mg within 1–4 hours of 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 to be more clinically relevant, was a composite of major venous thromboembolism (including pulmonary embolism and proximal deep vein thrombosis, symptomatic or asymptomatic, detected by routine venography) and VTE-related mortality. The results of both studies showed that the antithrombotic effect of dabigatran etexilate 220 mg and 150 mg was statistically non-inferior to that of enoxaparin with respect to total VTE and all-cause mortality. The point estimate for 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 for major VTE was slightly better than with enoxaparin (Table 19). Clinical studies were conducted in a patient population with a mean age > 65 years. In phase 3 clinical studies, there were no differences between men and women in efficacy and safety data. In the studied patient population of RE-MODEL and RE-NOVATE (5,539 patients treated), 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 affect the effect of dabigatran on the prevention of VTE or the frequency of bleeding. 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 endpoints of major bleeding are presented in Table 21 below. Table 19: Analysis of major VTE and VTE-related mortality during the treatment period in the orthopaedic surgery studies RE-MODEL and RE-NOVATE 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 orthopaedic surgery studies RE-MODEL and RE-NOVATE Clinical trial / Dabigatran etexilate 220 mg once daily / Dabigatran etexilate 150 mg once daily / Enoxaparin 40 mg RE-NOVATE (hip) n: 880 / 874 / 897 Incidence (%): 53 (6.0) / 75 (8.6) / 60 (6.7) Hazard ratio vs. enoxaparin: 0.9 / 1.28 95% confidence interval: (0.63; 1.29) / (0.93; 1.78) RE-MODEL (knee) n: 503 / 526 / 512 Incidence (%): 183 (36.4) / 213 (40.5) / 193 (37.7) Hazard ratio vs. enoxaparin: 0.97 / 1.07 95% confidence interval: (0.82; 1.13) / (0.92; 1.25) Table 21: Major bleeding events by treatment in each of the RE-MODEL and RE-NOVATE studies Clinical trial / Dabigatran etexilate 220 mg once daily / Dabigatran etexilate 150 mg once daily / Enoxaparin 40 mg RE-NOVATE (hip) Patients treated (n): 1,146 / 1,163 / 1,154 MBE (%): 23 (2.0) / 15 (1.3) / 18 (1.6) RE-MODEL (knee) Patients treated (n): 679 / 703 / 694 MBE (%): 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 the efficacy of dabigatran etexilate is derived from RE-LY (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 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 analysed. A total of 18,113 patients with a mean age of 71.5 years and a mean CHADS2 score of 2.1 were randomised in the RE-LY study. 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 reduced the risk of ischaemic and haemorrhagic stroke, vascular death, intracranial haemorrhage, and total bleeding compared with warfarin. The incidence of major bleeding at this dose was comparable to warfarin. The incidence of myocardial infarction was slightly increased with dabigatran etexilate 110 mg twice daily (hazard ratio 1.29; p = 0.0929) and 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 are reduced. Tables 22–24 present key results in the overall population in detail: Table 22: Analysis of the first occurrence of stroke or systemic embolism (primary endpoint) during the follow-up 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% CI): 0.89 (0.73; 1.09) / 0.65 (0.52; 0.81) p-value for superiority: p = 0.2721 / p = 0.0001 % refers to the annual event rate Table 23: Analysis of the first occurrence of ischaemic or haemorrhagic stroke during the follow-up 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% CI): 0.91 (0.74; 1.12) / 0.64 (0.51; 0.81) p-value: 0.3553 / 0.0001 Systemic embolism Incidence (%): 15 (0.13) / 13 (0.11) / 21 (0.18) Hazard ratio vs. warfarin (95% CI): 0.71 (0.37; 1.38) / 0.61 (0.30; 1.21) p-value: 0.3099 / 0.1582 Ischaemic stroke Incidence (%): 152 (1.28) / 104 (0.86) / 134 (1.14) Hazard ratio vs. warfarin (95% CI): 1.13 (0.89; 1.42) / 0.76 (0.59; 0.98) p-value: 0.3138 / 0.0351 Haemorrhagic stroke Incidence (%): 14 (0.12) / 12 (0.10) / 45 (0.38) Hazard ratio vs. warfarin (95% CI): 0.31 (0.17; 0.56) / 0.26 (0.14; 0.49) p-value: 0.0001 / < 0.0001 % refers to the annual event rate Table 24: Analysis of all-cause mortality and cardiovascular survival during the follow-up 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% CI): 0.91 (0.80; 1.03) / 0.88 (0.77; 1.00) p-value: 0.1308 / 0.0517 Vascular mortality Incidence (%): 289 (2.43) / 274 (2.28) / 317 (2.69) Hazard ratio vs. warfarin (95% CI): 0.90 (0.77; 1.06) / 0.85 (0.72; 0.99) p-value: 0.2081 / 0.0430 % refers to the annual event rate Tables 25–26 present the results for the primary efficacy and safety endpoints in the corresponding subpopulations: For the primary endpoint of stroke and systemic embolism, no subgroups (i.e. age, body weight, sex, renal function, ethnicity, etc.) 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 treatment with antiplatelet agents, ASA, or clopidogrel approximately doubled the rate of major bleeding events with both dabigatran etexilate and warfarin. There was no significant interaction in treatment effect across 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 the RE-LY study) The RE-LY extension study (RELY-ABLE) provided additional safety information for a 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 treatment at the time of their final visit in the RE-LY study. Enrolled patients continued on the same double-blind dose of dabigatran etexilate randomly assigned in the RE-LY study for a follow-up period of up to 43 months after completion of RE-LY (the overall mean follow-up time in the RE-LY and RELY-ABLE studies 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 RELY-ABLE. During the additional 2.5 years of treatment in RELY-ABLE, with maximum exposure exceeding 6 years (total exposure in 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 incidence of observed events including major bleeding and other bleeding events was consistent with the incidence observed in RE-LY. Data from non-interventional studies In the non-interventional GLORIA-AF study, safety and efficacy data were prospectively collected (in its second phase) in patients with newly diagnosed NVAF treated with dabigatran etexilate in routine clinical practice. The study included 4,859 patients treated with dabigatran etexilate (55% treated with 150 mg twice daily, 43% with 110 mg twice daily, 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 treatment follow-up duration was 18.3 months. Major bleeding occurred at a rate of 0.97 events per 100 patient-years. Life-threatening bleeding was reported at 0.46 events per 100 patient-years, intracranial bleeding at 0.17 events per 100 patient-years, and gastrointestinal bleeding at 0.60 events per 100 patient-years. Stroke occurred at 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 (who contributed more than 37,500 patient-years of treatment follow-up time), dabigatran etexilate (84% of patients treated with 150 mg twice daily, 16% with 75 mg twice daily) was associated with a reduced risk of ischaemic stroke (hazard ratio 0.80; 95% confidence interval [CI] 0.67–0.96), intracranial haemorrhage (hazard ratio 0.34; CI 0.26–0.46), and mortality (hazard ratio 0.86; CI 0.77–0.96), and with an increased risk of gastrointestinal bleeding (hazard ratio 1.28; CI 1.14–1.44) compared with warfarin. No difference was observed 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) plus clopidogrel or ticagrelor (a P2Y12 antagonist) compared with triple therapy with warfarin (adjusted to INR 2.0–3.0), clopidogrel or ticagrelor, and ASA (RE-DUAL PCI). Patients were randomised to dual therapy with dabigatran etexilate 110 mg twice daily, dual therapy with dabigatran etexilate 150 mg twice daily, or triple therapy with warfarin. Elderly patients outside the United States (≥ 80 years of age in all countries, ≥ 70 years of age in Japan) were randomised to dual therapy with dabigatran etexilate 110 mg or triple therapy with warfarin. The primary endpoint was a composite of ISTH-defined major bleeding or clinically relevant non-major bleeding. The incidence of the primary endpoint was 15.4% (151 patients) in the dabigatran etexilate 110 mg dual-therapy group compared with 26.9% (264 patients) in the warfarin triple-therapy group (hazard ratio 0.52; 95% CI 0.42, 0.63; p < 0.0001 for non-inferiority and p < 0.0001 for superiority) and 20.2% (154 patients) in the dabigatran etexilate 150 mg dual-therapy group compared with 25.7% (196 patients) in the corresponding warfarin triple-therapy group (hazard ratio 0.72; 95% CI 0.58, 0.88; p < 0.0001 for non-inferiority and p = 0.002 for superiority). In a descriptive analysis, the incidence of major bleeding events as defined by the TIMI (Thrombolysis In Myocardial Infarction) classification was lower in both dabigatran etexilate dual-therapy groups compared with the warfarin triple-therapy group: 14 events (1.4%) in the dabigatran etexilate 110 mg dual-therapy group versus 37 events (3.8%) in the warfarin triple-therapy group (hazard ratio 0.37; 95% CI 0.20, 0.68; p = 0.002), and 16 events (2.1%) in the dabigatran etexilate 150 mg dual-therapy group versus 30 events (3.9%) in the corresponding warfarin triple-therapy group (hazard ratio 0.51; 95% CI 0.28, 0.93; p = 0.03). In both dabigatran etexilate dual-therapy groups, intracranial haemorrhage rates were lower than in the corresponding warfarin triple-therapy group: 3 events (0.3%) in the dabigatran etexilate 110 mg dual-therapy group versus 10 events (1.0%) in the warfarin triple-therapy group (hazard ratio 0.30; 95% CI 0.08, 1.07; p = 0.06), and 1 event (0.1%) in the dabigatran etexilate 150 mg dual-therapy group versus 8 events (1.0%) in the corresponding warfarin triple-therapy group (hazard ratio 0.12; 95% CI 0.02, 0.98; p = 0.047). The incidence of the composite efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, or systemic embolism), or unplanned revascularisation was non-inferior in both dabigatran etexilate dual-therapy groups compared with the warfarin triple-therapy group (13.7% vs. 13.4%, respectively; hazard ratio 1.04; 95% CI: 0.84, 1.29; p = 0.0047 for non-inferiority). No statistical differences were identified between the dabigatran etexilate dual-therapy groups and the warfarin triple-therapy group for the individual components of the efficacy endpoints. This study demonstrated that, in patients with atrial fibrillation who underwent PCI with stenting, dual therapy with dabigatran etexilate and a P2Y12 antagonist significantly reduced the risk of bleeding compared with triple therapy with warfarin, while non-inferiority was demonstrated for the composite of thromboembolic events. Treatment of DVT and PE in adults (DVT/PE treatment) Efficacy and safety were investigated in two multicentre, randomised, double-blind, 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, a composite of recurrent symptomatic DVT and/or PE and associated deaths during a 6-month treatment period. In the pooled RE-COVER and RE-COVER II studies, a total of 5,153 patients were randomised and 5,107 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 2.0–3.0) was 60.6%. The trials showed that treatment with dabigatran etexilate 150 mg twice daily is non-inferior to warfarin (non-inferiority margin for RE-COVER and RE-COVER II: 3.6 for risk difference and 2.75 for risk ratio). Table 27: Analysis of primary and secondary efficacy endpoints (VTE comprises 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 patients treated: 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 mortality: 109 (4.3%) / 104 (4.1%) 95% CI: 3.52; 5.13 / 3.34; 4.91 Symptomatic DVT: 45 (1.8%) / 39 (1.5%) 95% CI: 1.29; 2.35 / 1.09; 2.08 Symptomatic PE: 27 (1.1%) / 26 (1.0%) 95% CI: 0.70; 1.54 / 0.67; 1.49 VTE-related death: 4 (0.2%) / 3 (0.1%) 95% CI: 0.04; 0.40 / 0.02; 0.34 All-cause mortality: 51 (2.0%) / 52 (2.0%) 95% CI: 1.49; 2.62 / 1.52; 2.66 Prevention of recurrent DVT and PE in adults (DVT/PE prevention) Two randomised, double-blind, parallel-group studies were conducted in patients previously treated with anticoagulant therapy. RE-MEDY, a warfarin-controlled study, included patients already treated for 3 to 12 months requiring 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) 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 dabigatran etexilate treatment 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 margin: 2.85 for risk ratio and 2.8 for risk difference). Table 28: Analysis of primary and secondary efficacy endpoints (VTE comprises 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 patients treated: 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 mortality: 42 (2.9%) / 36 (2.5%) 95% CI: 2.12; 3.95 / 1.77; 3.48 Symptomatic DVT: 17 (1.2%) / 13 (0.9%) 95% CI: 0.69; 1.90 / 0.49; 1.55 Symptomatic PE: 10 (0.7%) / 5 (0.4%) 95% CI: 0.34; 1.28 / 0.11; 0.82 VTE-related death: 1 (0.1%) / 1 (0.1%) 95% CI: 0.00; 0.39 / 0.00; 0.39 All-cause mortality: 17 (1.2%) / 19 (1.3%) 95% CI: 0.69; 1.90 / 0.80; 2.07 The objective of the RE-SONATE study was to assess 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 VKA treatment. 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 preventing recurrent symptomatic DVT/PE events including unexplained deaths, with a reduction in 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 analyses and sensitivity analyses of the primary endpoint and of 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 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 comprises 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 patients treated: 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 mortality: 3 (0.4%) / 37 (5.6%) 95% CI: 0.09; 1.28 / 3.97; 7.62 Symptomatic DVT: 2 (0.3%) / 23 (3.5%) 95% CI: 0.04; 1.06 / 2.21; 5.17 Symptomatic PE: 1 (0.1%) / 14 (2.1%) 95% CI: 0.00; 0.82 / 1.16; 3.52 VTE-related 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 mortality: 0 (0) / 2 (0.3%) 95% CI: 0.00; 0.54 / 0.04; 1.09 Clinical trials in the prevention of thromboembolic disease in patients with prosthetic heart valves A phase II study evaluated dabigatran etexilate and warfarin in a total of 252 patients after surgical mechanical heart valve replacement in the early postoperative period (i.e. dosing was initiated during hospitalisation after surgery) and in patients who had received a 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 postoperative phase, major bleeding manifested mainly as haemorrhagic pericardial effusions, predominantly in patients in whom dabigatran etexilate was initiated early (i.e. on day 3) after surgical heart valve replacement (see section 4.3). Paediatric population Clinical trials in prevention of VTE following major joint replacement surgery Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors The European Medicines Agency has waived the obligation to submit the results of studies with a reference product containing dabigatran etexilate in all subgroups 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, parallel-group, non-inferiority study. Enrolled patients were randomised in a 2:1 ratio to either dabigatran etexilate (doses adjusted by age and body weight) in a formulation appropriate for the relevant age category (capsules, coated granules, or oral solution) or to SOC consisting of low-molecular-weight heparins (LMWH), vitamin K antagonists (VKA), or fondaparinux (1 patient aged 12 years). The primary endpoint was a composite of the number of patients with complete thrombus resolution, absence of recurrent VTE, and no VTE-related mortality. Exclusion criteria included active meningitis, encephalitis, and intracranial abscess. A total of 267 patients were randomised. Of these, 176 patients were treated with dabigatran etexilate and 90 patients received SOC (1 randomised patient was not treated). 168 patients were aged from 12 to < 18 years, 64 patients from 2 to < 12 years, and 35 patients were 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 of the composite endpoint (complete thrombus resolution, absence of recurrent VTE, and no VTE-related mortality). The corresponding difference in incidence demonstrated non-inferiority of dabigatran etexilate versus SOC. Consistent results were also observed overall across subgroups: no significant differences in treatment effect were observed in subgroups by age, sex, region, or presence of certain risk factors. In the 3 different age groups, the proportions of patients meeting the primary efficacy endpoint in the dabigatran etexilate and SOC groups were 13/22 (59.1%) versus 7/13 (53.8%) in patients from birth to < 2 years, 21/43 (48.8%) versus 12/21 (57.1%) in patients aged 2 to < 12 years, and 47/112 (42.0%) versus 19/56 (33.9%) in patients aged 12 to < 18 years. Adjudicated major bleeding 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, the majority 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) 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 who required additional anticoagulant therapy due to the presence of clinical risk factors after completion of initial therapy for confirmed VTE (for at least 3 months) or after completion of the DIVERSITY study were eligible for enrolment. Patients in the study received dabigatran etexilate doses adjusted by age and body weight in a formulation appropriate for the relevant age (capsules, coated granules, or oral solution) until the resolution of clinical risk factors, or for a maximum of 12 months. The primary endpoints of the study included recurrent VTE, major and minor bleeding events, and mortality (overall and related to thrombotic or thromboembolic events) at 6 and 12 months. Event outcomes were adjudicated by an independent blinded adjudication committee. A total of 214 patients were enrolled in the study; among them 162 patients in age group 1 (from 12 to < 18 years of age), 43 patients in age group 2 (from 2 to < 12 years of age), and 9 patients in age group 3 (from 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 treatment initiation. Adjudicated bleeding events during the treatment period were reported in 48 patients (22.5%) within the first 12 months. The majority of bleeding events were minor. Three patients (1.4%) experienced an adjudicated major bleeding event within the first 12 months. Three patients (1.4%) reported adjudicated CRNM bleeding within the first 12 months. No deaths occurred during treatment. During the treatment period, post-thrombotic syndrome (PTS) developed or PTS worsened in 3 patients (1.4%) within the first 12 months.