Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban With Enoxaparin - MAGELLAN

Feb 18, 2013
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bayer HealthCare Pharmaceuticals and Janssen Research and Development.
Date Presented:
01/01/2011
Date Published:
01/01/2013
Date Updated:
02/18/2013
Original Posted Date:
02/18/2013
References

Description:

The optimal duration of thromboprophylaxis and the acutely ill patient population most likely to benefit from extended thromboprophylaxis is not well characterized. The current trial sought to compare different durations of rivaroxaban with enoxaparin in these patients.

Hypothesis:

  • Ten days of anticoagulation with rivaroxaban would be noninferior to enoxaparin.
  • Thirty-five days of anticoagulation with rivaroxaban would be superior to enoxaparin followed by placebo.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients ≥40 years hospitalized for acute medical illness with decreased level of mobility

    Number of enrollees: 8,101
    Duration of follow-up: 90 days
    Mean patient age: 71.0 years
    Percentage female: 46%

Exclusions:

  • Conditions that contraindicate the use of the low molecular weight heparin enoxaparin
  • High risk of bleeding/bleeding diatheses
  • Severe renal or liver abnormalities
  • Known HIV disease
  • Sustained blood pressure ≥180/110 mm Hg despite treatment
  • Ongoing drug or alcohol abuse
  • Cardiogenic or septic shock
  • Pregnancy or breast-feeding
  • Treatment with or use of mechanical thromboprophylaxis (e.g., pneumatic compression devices, foot pumps) for VTE prevention
  • Required drugs or procedures, such as >2 days of prophylactic use of anticoagulants, or systemic treatment with more than two doses of strong inhibitors of cytochrome P450 3A4, such as ketoconazole or protease inhibitors, within 4 days before randomization or planned treatment during the time period of study drug administration
  • Indication for fibrinolysis or need for continued treatment with anticoagulant agents for more than 14 days

Primary Endpoints:

  • Efficacy:
    • Composite of asymptomatic proximal DVT detected by mandatory ultrasonography, symptomatic DVT (proximal or distal), symptomatic nonfatal PE, and VTE-related death
  • Safety:
    • Composite of major bleeding and nonmajor clinically relevant bleeding observed not later than 2 days after the last intake of double-blind study medication (treatment-emergent)

Secondary Endpoints:

  • Composite of asymptomatic proximal DVT, symptomatic DVT, symptomatic nonfatal PE, and all-cause mortality up to day 10 ± 4 and day 35 ± 4
  • Symptomatic VTE up to day 10 ± 4, day 35 ± 4, and day 90 ± 7
  • All-cause mortality up to day 90 ± 7

Drug/Procedures Used:

Patients were randomized to receive either subcutaneous enoxaparin 40 mg daily for 10 ± 4 days and oral placebo for 35 ± 4 days, or oral rivaroxaban 10 mg daily for 35 ± 4 days and subcutaneous placebo for 10 ± 4 days. The active treatment period for the enoxaparin arm was from day 1 to day 10 ± 4 and for the rivaroxaban arm was from day 1 to day 35 ± 4.

Principal Findings:

A total of 8,101 patients were randomized, of which 4,050 received rivaroxaban and 4,051 received enoxaparin/placebo. Baseline characteristics were fairly similar between the two arms. The mean weight was 77.4 kg, and the median duration of hospitalization was 11 days. About 22% had a creatinine clearance <50 ml/min. The underlying medical conditions were congestive heart failure (CHF) (33%), active cancer (7%), acute infectious diseases (46%), and acute respiratory insufficiency (28%); about 31% had ≥2 underlying medical conditions.

On per-protocol analysis, the primary efficacy outcome at 10 days (asymptomatic proximal deep-vein thrombosis [DVT] detected by mandatory ultrasonography, symptomatic DVT, symptomatic nonfatal pulmonary embolism [PE], and venous thromboembolism [VTE]-related death) was similar between the rivaroxaban and enoxaparin arms (2.7% vs. 2.7%, relative risk [RR] 0.97, 95% confidence interval [CI] 0.71-1.33, p for noninferiority = 0.0025). The individual components were similar as well, including asymptomatic proximal DVT (2.4% vs. 2.4%), symptomatic lower extremity DVT (0.2% vs. 0.2%), and VTE-related death (0.1% vs. 0.2%) (p > 0.05 for all). However, the primary outcome favored rivaroxaban at 35 days over enoxaparin (4.4% vs. 5.7%, RR 0.77, 95% CI 0.62-0.96, p = 0.02) on modified intent-to-treat analysis, mainly due to a reduction in asymptomatic proximal DVT (3.5% vs. 4.4%); symptomatic proximal or distal DVTs were similar (0.4% vs. 0.5%).

Clinically relevant bleeding, the primary safety endpoint at 10 days (major + nonmajor clinically relevant bleeding), was higher in the rivaroxaban arm compared with enoxaparin (2.8% vs. 1.2%, RR 2.30, 95% CI 1.63-3.17, p < 0.0001), as was major bleeding (0.6% vs. 0.3%, p = 0.03). Similarly, clinically relevant bleeding at 35 days was higher in the rivaroxaban arm (4.1% vs. 1.7%, p < 0.0001), as was major bleeding (1.1% vs. 0.4%, p = 0.0004). Fatal bleeding occurred in seven patients in the rivaroxaban arm (pulmonary bleeding in three, intracranial hemorrhage in two, retroperitoneal/gastrointestinal bleeding in two patients) versus one patient in the enoxaparin arm (tracheal bleeding). Other clinical outcomes at 35 days, including any cardiovascular event (1.8% vs. 1.6%) and all-cause mortality (5.1% vs. 4.8%) (p > 0.05 for both), were similar. Serious adverse events other than bleeding were similar between the two arms (15.4% vs. 14.2%).

Interpretation:

Rivaroxaban is an oral, direct factor Xa inhibitor, which has shown benefit in the prevention of VTE after elective hip and knee replacement surgery in adult patients. Other studies have shown that extended-duration anticoagulation regimens are superior to short-term ones in surgical patients. The current trial sought to study the utility of extended-duration rivaroxaban in preventing VTE in patients who were acutely ill with medical conditions such as CHF, infections, and cancer.

The results of the MAGELLAN trial indicate that rivaroxaban is noninferior to enoxaparin at 10 days for efficacy, but superior at 35 days. This is, however, tempered by a significant increase in major and nonmajor clinically relevant bleeding at both time points, as compared with enoxaparin. The increased bleeding is at least partially a reflection of increased bleeding risk in these acutely ill patients in general. Further studies are needed to identify patient subsets that may derive the most benefit with rivaroxaban without a significant increase in bleeding.

References:

Cohen AT, Spiro TE, Buller HR, et al., on behalf of the MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368:513-23.

Presented by Dr. Alexander Cohen at the ACC.11/i2 Summit, New Orleans, LA, New Orleans, April 5, 2011.

Keywords: Risk, Neoplasms, Follow-Up Studies, Morpholines, Pulmonary Embolism, Thiophenes, Respiratory Insufficiency, Venous Thromboembolism, Lower Extremity, Creatinine, Intracranial Hemorrhages, Enoxaparin, Heart Failure, Confidence Intervals, Factor Xa


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