In Study of Acutely Ill Patients Rivaroxaban Compares Favorably With Enoxaparin in Preventing Venous Thromboembolism but With an Increased Rate of Bleeding

Update: Xarelto (rivaroxaban) Now FDA Approved - July 1, 2011

Additional Analyses Underway to Determine Which Patients in this Population May Benefit Most From Treatment with Rivaroxaban

NEW ORLEANS--(BUSINESS WIRE)--Apr 5, 2011 - Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD), today announced results from the MAGELLAN Phase 3 trial evaluating the investigational oral anticoagulant rivaroxaban for the prevention of venous thromboembolism (VTE) in hospitalized patients with acute medical illnesses.

In the study, rivaroxaban met its primary clinical efficacy objectives of demonstrating non-inferiority to enoxaparin in short-term use (10 ± 4 days), and superiority in long-term use (35 ± 4 days) when compared to short-term use of enoxaparin followed by placebo. The combined rates of major and clinically relevant non-major bleeding, the primary safety measure in the study, while low overall, were significantly higher in those treated with rivaroxaban compared with those treated with enoxaparin, followed by placebo. The results were presented today as a late-breaker at the American College of Cardiology Annual Scientific Session in New Orleans.

“MAGELLAN investigated the largest and most diverse population of hospitalized, acutely ill patients to date, and managing the risk of blood clots in these patients is extremely complex due to their age, co-morbid conditions and duration of immobilization,” said Dr. Alexander T. Cohen, Honorary Consultant Vascular Physician in the Department of Surgery and Vascular Medicine at King's College Hospital, London and principal investigator of the study. “As observed in previous studies in this area, there is an ongoing risk of venous thrombosis and likewise a consistently positive benefit-risk balance was not seen across the heterogeneous, acutely ill patient population studied. Further analysis is required to identify which groups of patients in MAGELLAN may derive benefit from thromboprophylaxis with rivaroxaban.”

Medically ill is a broad term used to classify a host of hospitalized patients that are typically immobilized during their hospital stay for treatment of a variety of reasons that can include heart failure, active cancer, acute ischemic stroke, acute infections, inflammatory diseases including acute rheumatic diseases, and acute respiratory insufficiency.1,2 Immobilization is a major risk factor for developing a VTE (an unwanted blood clot),1 and patients hospitalized due to medical illness are at high risk for VTE as they often have multiple risk factors which are generally cumulative.2

In MAGELLAN, results for the primary endpoints in the study were:

 

  • In the short-term (10 ± 4 days) evaluation, rivaroxaban achieved non-inferiority compared to enoxaparin (2.7% vs. 2.7%, p=0.0025 for non-inferiority) in the per-protocol population.3
  • In the long-term (35 ± 4 days), rivaroxaban was superior to short-term enoxaparin followed by placebo, demonstrating a 22.9% relative risk reduction (RRR) in the modified intent-to-treat (MITT) population (4.4% vs. 5.7%, respectively, p=0.0211).4 This analysis included patients who received at least one dose study medication and had an adequate assessment of VTE.4

For the primary safety measure – incidence of treatment-emergent major bleeding events and non-major, clinically relevant bleeding events observed no later than two days after the last intake of the double-blind study drug – there was a statistically significant increase at day 10 in patients randomized to the rivaroxaban arm compared with the enoxaparin arm (2.8% v. 1.2%, respectively, p<0.0001). At day 35, the primary safety event rate was 4.1% for rivaroxaban-treated patients compared with 1.7% for patients receiving enoxaparin followed by placebo (p<0.0001). Rates of other adverse events – including liver and cardiovascular – were similar across both study arms and rates for rivaroxaban were consistent with previous clinical trial data.5-10

“The study confirms there is a continued risk of VTE beyond the period of hospitalization or immobilization, and that rivaroxaban reduces this risk,” said Peter M. DiBattiste, M.D., Vice President of Cardiovascular Development at J&JPRD. “As with all anticoagulants, the benefits need to be evaluated in light of the bleeding results, and we are conducting additional analyses to help us better understand which patients in this population may benefit most from treatment with rivaroxaban.”

The company's U.S. filing strategy in this indication is under review, and will depend upon the outcome of our further analyses of the study.

The late-breaker abstract (3015-6) is available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=2722&sKey=15afe352-df59-407a-9d69-a9eae1125217&cKey=7dd09a40-07b2-4c18-97ef-d24e02a2fae2&mKey=%7b79E691F3-9BF2-4C60-B958-A23D68B60921%7d.

About VTE in Medically Ill Patients

VTE is often associated with recent surgery or trauma. However, 50-70% of symptomatic thromboembolic events and 70-80% of fatal pulmonary embolism (PE) occur in nonsurgical patients.1 Hospitalization for medical illness is independently associated with an approximated eightfold increase relative risk for VTE,1,11 and accounts for almost one quarter of all VTE events in the general U.S. population.1

About MAGELLAN Clinical Trial

MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabAN with enoxaparin) was a prospective, randomized, double blind, double-dummy, active comparator controlled, multi-center and multi-national study which evaluated 8,100 acutely ill medical patients from 54 countries, who had been completely immobilized for at least one day during hospitalization. MAGELLAN was designed to demonstrate the superior efficacy of a 35-day treatment period with oral rivaroxaban (10 mg OD) for VTE prophylaxis, compared to a 10-day treatment period with subcutaneous enoxaparin (40 mg OD) in men and women over 40 years of age. Further, the study evaluated the non-inferiority of oral rivaroxaban for VTE prophylaxis compared to subcutaneous enoxaparin in this patient population at 10 days. The demographics and baseline characteristics were balanced between treatment groups, with 32% of patients presenting with congestive heart failure (CHF), 20% with moderate renal insufficiency, 17% with acute ischemic stroke, and 7.3% with active cancer in each arm.

About Rivaroxaban

Rivaroxaban is a novel oral anticoagulant being evaluated for the prevention and treatment of a broad range of disorders in which blood clotting plays a major role. In clinical studies, the compound has shown no requirement for routine laboratory coagulation monitoring, and limited risk for food and drug interactions. The extensive program of clinical trials evaluating rivaroxaban makes rivaroxaban the most studied oral, direct Factor Xa inhibitor in the world today. By the time of its completion, more than 65,000 patients will have participated in the rivaroxaban clinical development program. Rivaroxaban is being developed jointly by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Bayer HealthCare AG.

REFERENCES

 

  1. Geerts, W.H., et al. Prevention of Venous Thromboembolism: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008: 381S–453S.
  2. Francis, C.W. Clinical practice. Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med 2007; 356(14):1438-1444.
  3. A subject is valid for per protocol analysis, if the subject: is (1) valid for modified intent to treat analysis and (2) has an adequate assessment of VTE that was done not later than a pre-defined period after stop of study drug (to be determined prior to unblinding and documented) and (3) met the inclusion criteria regarding medical illness and VTE risk factors and (4) shows no major protocol deviations.
    Major protocol deviations are: (1) intake of prohibited antithrombotic concomitant medication or (2) overall compliance of less than 80% or more than 120%.
  4. A subject is valid for modified intent to treat analysis, if the subject: (1) is valid for safety analysis and (2) has an adequate assessment of VTE. An adequate assessment of VTE is present if at least one of the following conditions is fulfilled: an adequate bilateral lower extremity venous ultrasonography was performed on Day 35 ± 4 days; confirmed asymptomatic proximal lower extremity DVT up to Day 35 + 4 days; confirmed symptomatic lower extremity DVT up to Day 35 + 4 days; confirmed symptomatic PE up to Day 35 + 4 days; confirmed VTE related death up to Day 35 + 4 days.
  5. Eriksson BI. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty. N Engl J Med 2008; 358(26): 2765-2775.
  6. Kakkar AK. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372(9632: 31-39.
  7. Lassen MR. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Total Knee Arthroplasty. N Engl J Med 2008; 358(26): 2777-2786.
  8. Turpie A. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373(9676): 1673-1680.
  9. The EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism (EINSTEIN DVT and EXT). N Engl J Med 2010; 363:2499-2510.
  10. Mahaffey, K. Stroke Prevention Using the Oral Direct Factor Xa inhibitor Rivaroxaban Compared with Warfarin in Patients with Nonvalvular Atrial Fibrillation (ROCKET AF). Presented at the American Heart Association Scientific Sessions, Chicago, Ill., November 15, 2010.
  11. Heit, J.A., et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809–815.

Contact: For more information on rivaroxaban:
Media:
Ernie Knewitz, 908-927-2953
Mobile: 917-697-2318
eknewitz@its.jnj.com
or
Shaun Mickus, 908-927-2416
Mobile: 973-476-7144
smickus@its.jnj.com
or
Investors:
Johnson & Johnson
Louise Mehrotra, 732-524-6491
or
Stan Panasewicz, 732-524-2524

 

 

Posted: April 2011

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