MAGELLAN: Rivaroxaban Prevents VTE, But Bleeding an Issue

April 06, 2011

April 6, 2011 (New Orleans, Louisiana) — Taking the new oral anticoagulant rivaroxaban (Xarelto, Bayer/Johnson & Johnson) once daily for 35 days was associated with a reduction in the risk of venous thrombosis, compared with standard 10-day treatment with enoxaparin (Lovenox, Sanofi-Aventis) by subcutaneous injection, in acutely ill medical patients. But bleeding rates were significantly increased with rivaroxaban, and the new factor Xa inhibitor did not show a net clinical benefit across the whole population.

Presenting the results today at the American College of Cardiology 2011 Scientific Sessions, Dr Alexander Cohen (King's College, London, UK) did not rule out that there could still be a benefit of rivaroxaban in certain patient groups.

He told heartwire : "This trial included a large range of heterogeneous patients with many different acute illnesses. We have only just performed this first overall analysis of the data. We must now go back and look at subgroups to see if there are any groups where rivaroxaban may be associated with a net clinical benefit."

Results Not Surprising?

Dr Alexander Cohen

Commenting on the MAGELLAN results for heartwire , Dr Roy Silverstein (Cleveland Clinic, OH) said he did not find the results surprising. "The drug has been shown to be noninferior to standard treatments in other settings, and this was what was seen in the first part of this trial. Also, since the extended-treatment arm compared the drug with placebo, it is not surprising that bleeding complications were increased. A better comparison would have been to extend treatment with enoxaparin or warfarin."

Silverstein said he thought rivaroxaban could still have a role in this indication. "This is an oral drug, and the study shows noninferiority to a subcutaneous drug for the 10-day period. In some hospitals, the cost and inconvenience of daily injections might make the oral drug more cost-effective."

Cohen told heartwire : "This study hasn't changed my view that some patients need prolonged prophylaxis. But we can't make any recommendations for rivaroxaban in this setting at present. It is too early. We will have to conduct our subgroup analyses first."

Asked if he thought a lower dose might be a better approach for extended prophylaxis, Silverstein said: "It might decrease the bleeding risks while providing some protection from [venous thromboembolism] VTE, but this would need to be tested formally. More practical would be to define some risk factors that could identify a population at higher risk, so that only a subset of patients would need to be treated."

Better Treatment Options Needed

Cohen also emphasized that the trial confirms that there is a continued risk of venous thrombosis beyond the initial period of hospitalization or immobilization in acutely ill patients. "This risk was 5.7% at 35 days in the enoxaparin group. This is higher than we had expected and highlights the need for better treatment options for these patients," he commented to heartwire .

He explained that the venous thrombosis is a major issue for acutely ill medical patients. While it is often associated with recent surgery or trauma, 50% to 70% of symptomatic thromboembolic events and 70% to 80% of fatal pulmonary embolisms (PEs) occur in nonsurgical patients. Cohen estimated that at present about 60% of acutely ill medical patients get some form of thromboprophylaxis--usually just for the hospital stay--but the risk of thrombosis peaks about three weeks after these patients leave the hospital, so longer-term prophylaxis seems to be required. One study of longer-term enoxaparin has been performed--EXCLAIM--but this showed an increased bleeding rate and so it hasn't gained acceptance. The MAGELLAN study was therefore conducted to evaluate oral treatment with rivaroxaban in this setting.

The study, the largest in this indication to date, randomized 8101 patients to 10 mg once daily of rivaroxaban for 35 days or the standard approved dose of enoxaparin (40 mg once daily by subcutaneous injection for 10 days). Blinding was achieved by having patients also take either 35 days of an oral placebo or 10 days of a placebo injection along with their treatment assignment. Patients included had one or more acute medical conditions, including infectious disease, heart failure, respiratory insufficiency, ischemic stroke, active cancer, or inflammatory/rheumatic diseases; 30% had two or more such conditions. They had an average age of 71 years, and 60% had renal impairment. They were in the hospital for an average of 11 days.

The study’s primary efficacy outcome was a composite of asymptomatic proximal deep vein thrombosis (DVT) (detected by ultrasonography), symptomatic DVT, symptomatic nonfatal PE, and VTE-related death. The aim of the trial was to show noninferiority of rivaroxaban at 10 days and superiority at 35 days. This was achieved, with the primary outcome occurring in exactly the same percentage of patents in each group at day 10, and fewer patients in the rivaroxaban group at day 35.

Primary Efficacy Outcome at Day 10

Outcome Rivaroxaban, n=2939 (%) Enoxaparin, 2993 (%)
Composite efficacy outcome* 2.7 2.7
Asymptomatic proximal DVT 2.4 2.4
Symptomatic lower extremity DVT 0.2 0.2
Symptomatic nonfatal PE 0.2 0.1
VTE-related death 0.1 0.2

*p for noninferiority=0.0025

Primary Efficacy Outcome at Day 35

Outcome Rivaroxaban, n=2967 (%) Enoxaparin, n=3057 (%)
Composite efficacy outcome* 4.4 5.7
Asymptomatic proximal DVT 3.5 4.4
Symptomatic lower extremity DVT 0.4 0.5
Symptomatic nonfatal PE 0.3 0.5
VTE-related death 0.6 1.0

HR=0.77 (95% CI 0.62–0.96); p=0.02

The primary safety outcome was a composite of treatment-related major bleeding (International Society on Thrombosis and Haemostasis [ISTH] definition) and clinically relevant nonmajor bleeding. This was increased with rivaroxaban at both 10 and 35 days.

Bleeding Results at Days 1–10

Outcome Rivaroxaban, n=3997

(%)

Enoxaparin, n=4001 (%)
Clinically relevant bleeding* 2.8 1.2
Major bleeding 0.6 0.3
Fall in hemoglobin >2g/dL 0.4 0.2
Transfusions >2 units blood 0.4 0.1
Critical site bleeding 0.1 0.1
Fatal bleeding 0.1 <0.1

HR=2.3; p<0.0001

Bleeding Results at Days 11–35

Outcome Rivaroxaban, n=3997 (%) Enoxaparin, n=4001 (%)
Clinically relevant bleeding* 1.4 0.5
Major bleeding 0.5 0.1
Fall in hemoglobin >2g/dL 0.4 <0.1
Transfusions >2 units blood 0.2 <0.1
Critical site bleeding 0.1 <0.1
Fatal bleeding <0.1 0

HR=3.0; p<0.0001

Because of the higher bleeding rates with rivaroxaban, the net clinical benefit (combination of the two main efficacy and bleeding end points) favored enoxaparin, although the number of deaths favored rivaroxaban--there were six extra fatal bleeds and 11 fewer PE deaths in the rivaroxaban group. But Cohen said the increased number of smaller bleeds tipped the scales in favor of enoxaparin.

Net Clinical Benefit at Day 35 (%)

  Rivaroxaban, n=3997 Enoxaparin, n=4001
Net clinical benefit 9.4 7.8

*A composite of asymptomatic proximal DVT, symptomatic DVT, symptomatic nonfatal PE, VTE-related death, and treatment-emergent major plus nonmajor clinically relevant bleeding

Cohen noted that they had used a sensitive measure of bleeding, and bleeding rates were actually much lower than they had expected across the whole population.

Asked whether, if a less sensitive measure of bleeding had been used, the net clinical benefit would have favored rivaroxaban, he said: "Yes. If we take out the nonmajor bleeding from the net clinical benefit end point, the risk benefit would favor rivaroxaban. But that would be a post hoc analysis. We will be looking at those types of analyses. If we hadn't used such a sensitive measure of bleeding, we would have probably got a completely different result. But we did the trial we did, and the main results are those that have been reported today."

Asked whether these results would have any implications for rivaroxaban in other situations, Cohen said: "No, I don't think so. This trial was entirely different from those in other indications--EINSTEIN, ROCKET, etc. The patients in MAGELLAN were much sicker and more heterogeneous and had much higher mortality rates. There is no crossover to other trials."

He added that it is hoped that the subgroup data would be presented later this year, either at the ISTH meeting in July or the American Society of Hematology (ASH) meeting in December.

Another of the new factor Xa inhibitors, apixaban, is also being investigated for the prophylaxis of VTE in acutely ill medical patients--in the ADOPT trial, which is still under way.

The MAGELLAN study was funded by Bayer and Johnson & Johnson. Cohen reported serving as a medical consultant for and having received honoraria, consultancy fees, and clinical trial funding from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Johnson & Johnson, Mitsubishi Pharma, Pfizer, Sanofi-Aventis, Schering Plough, and Takeda.

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