Xarelto (Page 12 of 18)

14.5 Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

The efficacy and safety of XARELTO for prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding was evaluated in the MAGELLAN study ( Multicenter, r Andomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically i LL patients comparing rivaroxab aN with enoxaparin [NCT00571649]). MAGELLAN was a multicenter, randomized, double-blind, parallel-group efficacy and safety study comparing XARELTO to enoxaparin, in the prevention of VTE in hospitalized acutely ill medical patients during the in-hospital and post-hospital discharge period. Eligible patients included adults who were at least 40 years of age, hospitalized for an acute medical illness, at risk of VTE due to moderate or severe immobility, and had additional risk factors for VTE. The population at risk of VTE was required to have one or more of the following VTE risk factors, i.e. prolonged immobilization, age ≥75 years, history of cancer, history of VTE, history of heart failure, thrombophilia, acute infectious disease contributing to the hospitalization and BMI ≥35 kg/m 2). The causes for hospitalization included heart failure, active cancer, acute ischemic stroke, acute infectious and inflammatory disease and acute respiratory insufficiency. Patients were randomized to receive either XARELTO 10 mg once daily for 35 ±4 days starting in hospital and continuing post hospital discharge (n=4050) or enoxaparin 40 mg once daily for 10 ±4 days starting in hospital followed by placebo post-discharge (n=4051).

The major efficacy outcome in the MAGELLAN trial was a composite endpoint that included asymptomatic proximal deep venous thrombosis (DVT) in lower extremity, symptomatic proximal or distal DVT in the lower extremity, symptomatic non-fatal pulmonary embolism (PE), and death related to venous thromboembolism (VTE).

A total of 6024 patients were evaluable for the major efficacy outcome analysis (2967 on XARELTO 10 mg once daily and 3057 on enoxaparin/placebo). The mean age was 68.9 years, with 37.1% of the subject population ≥ 75 years. VTE risk factors included severe immobilization at study entry (99.9%), D-dimer > 2× ULN (43.7%), history of heart failure (35.6%), BMI ≥ 35 kg/m 2 (15.2%), chronic venous insufficiency (14.9%), acute infectious disease (13.9%), severe varicosis (12.5%), history of cancer (16.2%), history of VTE (4.5%), hormone replacement therapy (1.1%), and thrombophilia (0.3%), recent major surgery (0.8%) and recent serious trauma (0.2%). The population was 54.7% male, 68.2% White, 20.4% Asian, 1.9% Black and 5.3% Other. Admitting diagnoses for hospitalization were acute infectious diseases (43.8%) followed by congestive heart failure NYHA class III or IV (33.2%), acute respiratory insufficiency (26.4%), acute ischemic stroke (18.5%) and acute inflammatory diseases (3.4%).

Table 24 shows the overall results from the prespecified, modified intent-to-treat (mITT) analysis for the efficacy outcomes and their components. This analysis excludes approximately 25% of the patients mainly due to no ultrasonographic assessment (13.5%), inadequate assessment at day 35 (8.1%), or lack of intake of study medication (1.3%).

Table 24: Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in the MAGELLAN Study
mITT: modified intent-to-treat; PP: per protocol; DVT: Deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; CI: Confidence Interval; RR: Relative Risk
Events from Day 1 to Day 35, mITT analysis set XARELTO 10 mg N=2967 n (%) Enoxaparin 40 mg/placebo N=3057 n (%) RR (95% CI)
Primary Composite Endpoint at Day 35 131 (4.4%) 175 (5.7%) 0.77 (0.62, 0.96)
Symptomatic non-fatal PE 10 (0.3) 14 (0.5)
Symptomatic DVT in lower extremity 13 (0.4) 15 (0.5)
Asymptomatic proximal DVT in lower extremity 103 (3.5) 133 (4.4)
VTE related death 19 (0.6) 30 (1.0)
Events from Day 1 to Day 10, PP analysis set XARELTO 10 mg N=2938 n (%) Enoxaparin 40 mg N=2993 n (%) RR (95% CI)
Primary Composite Endpoint at Day 10 78 (2.7) 82 (2.7) 0.97 (0.71, 1.31)
Symptomatic non-fatal PE 6 (0.2) 2 (<0.1)
Symptomatic DVT in lower extremity 7 (0.2) 6 (0.2)
Asymptomatic proximal DVT in lower extremity 71 (2.4) 71 (2.4)
VTE related death 3 (0.1) 6 (0.2)
mITT analysis set plus all-cause mortality N=3096 n (%) N=3169 n (%) RR (95% CI)
Other Composite Endpoint at Day 35 266 (8.6) 293 (9.2) 0.93 (0.80, 1.09)
Symptomatic non-fatal PE 10 (0.3) 14 (0.4)
Symptomatic DVT in lower extremity 13 (0.4) 15 (0.5)
Asymptomatic proximal DVT in lower extremity 103 (3.3) 133 (4.2)
All-cause mortality 159 (5.1) 153 (4.8)

Patients with bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months (19.4%) all had an excess of bleeding with XARELTO compared with enoxaparin/placebo. Therefore, patients meeting these criteria were excluded from the following analyses presented below.

Table 25 provides the efficacy results for the subgroup of patients not at a high risk of bleeding.

Table 25: Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in patients not at a high risk of bleeding in the MAGELLAN Study *
mITT: modified intent-to-treat; PP: per protocol; DVT: Deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; CI: Confidence Interval; RR: Relative Risk
*
Patients at high risk of bleeding (i.e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded.
Events from Day 1 to Day 35, mITT analysis set XARELTO 10 mg N=2419 n (%) Enoxaparin 40 mg/placebo N=2506 n (%) RR (95% CI)
Primary Composite Endpoint at Day 35 94 (3.9) 143 (5.7) 0.68 (0.53, 0.88)
Symptomatic non-fatal PE 7 (0.3) 10 (0.4)
Symptomatic DVT in lower extremity 9 (0.4) 10 (0.4)
Asymptomatic proximal DVT in lower extremity 73 (3.0) 110 (4.4)
VTE related death 15 (0.6) 26 (1.0)
Events from Day 1 to Day 10, PP analysis set XARELTO 10 mg N=2385 n (%) Enoxaparin 40 mg N=2433 n (%) RR (95% CI)
Primary Composite Endpoint at Day 10 58 (2.4) 72 (3.0) 0.82 (0.58, 1.15)
Symptomatic non-fatal PE 5 (0.2) 2 (<0.1)
Symptomatic DVT in lower extremity 6 (0.3) 4 (0.2)
Asymptomatic proximal DVT in lower extremity 52 (2.2) 62 (2.5)
VTE related death 2 (<0.1) 6 (0.2)
mITT analysis set plus all-cause mortality N=2504 n (%) N=2583 n (%) RR (95% CI)
Other Composite Endpoint at Day 35 184 (7.3) 225 (8.7) 0.84 (0.70, 1.02)
Symptomatic non-fatal PE 7 (0.3) 10 (0.4)
Symptomatic DVT in lower extremity 9 (0.4) 10 (0.4)
Asymptomatic proximal DVT in lower extremity 73 (2.9) 110 (4.3)
All-cause mortality 107 (4.3) 112 (4.3)

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