Extended Rivaroxaban in Medical Patients Cuts Arterial Events Too

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Extended Rivaroxaban in Medical Patients Cuts Arterial Events Too

Extended prophylaxis with a low dose of the anticoagulant rivaroxaban (Xarelto, Janssen) in selected medically ill patients being discharged from hospital reduced both venous and arterial thrombotic events, including a 50% reduction in stroke, without significantly increasing bleeding, according to a new analysis of the MARINER trial.

“These results really bring it home that medically ill patients are at risk from arterial thromboembolic events as well as venous thrombotic events in the immediate postdischarge period, and if we use an individualized approach, then extended anticoagulant treatment is beneficial for reducing both venous and arterial events,” lead author Alex C. Spyropoulos, MD, professor of medicine at the Hofstra Northwell School of Medicine, Hempstead, New York, told Medscape Medical News

“Our findings have major healthcare implications,” he added. “On a population health basis, use of this therapy in patients selected as having high thrombogenic risk and low bleeding risk could prevent more than 12,000 thrombotic events every year at the cost of less than 3000 major bleeds. That is a very favorable trade-off.” 

“Especially Relevant in COVID Era”

Spyropoulos believes these results are especially relevant in the current COVID-19 era. “COVID-19 causes highly thrombogenic disease. Patients hospitalized with the virus have a much higher risk of both venous and arterial thromboembolism than other medically ill patents — maybe 2 to 10 times the risk. We believe this risk extends to the postdischarge period. So we would expect COVID patients to get a greater absolute benefit from extended anticoagulation treatment.”

The new analysis is published in the June 30 issue of the Journal of the American College of Cardiology.

“What this analysis tells us is that arterial and venous thrombosis is intimately interwoven. The distinction we have traditionally made between venous and arterial thrombotic events is somewhat artificial. Platelets and thrombin pay a role in both systems,” Spyropoulos said.

“This shows us both the venous and arterial systems are at high risk of clotting in the postdischarge period and we can reduce this with a low dose of rivaroxaban.” 

It is accepted now that patients get anticoagulant when they are in the hospital, but this is often stopped when they are discharged, he explained.

The MARINER trial randomly assigned almost 10,000 medically ill patients with additional risk factors for venous thromboembolism (VTE) and at a low risk for bleeding to extended-duration rivaroxaban (10 mg once daily for 45 days or 7.5 mg once daily for those with reduced kidney function) or placebo.

Although the main results of the trial, reported previously, did not demonstrate a reduction in the primary endpoint of symptomatic VTE and VTE-related death, key secondary efficacy endpoints showed a 56% reduction in symptomatic VTE and a 27% reduction in symptomatic VTE and all-cause mortality, the investigators report.

The lower 7.5 mg dose of rivaroxaban used in patients with moderate renal insufficiency was found to be ineffective. 

The 10mg dose has also been demonstrated to be effective in the MAGELLAN study of extended thromboprophylaxis in medically ill patients, although the MAGELLAN study did not select patients based on VTE and bleeding risk and showed an increased bleeding risk with rivaroxaban.

“After 15 years of research, we are now more confident in identifying patients with increased VTE risk using the IMPROVE tool and D dimer tests, and also those at reduced bleeding risk. Selection of these patients is what we did in MARINER and is key to attain the benefits of extended prophylaxis with rivaroxaban without the increased bleeding risk,” Spyropoulos commented.

The US FDA has approved the 10 mg dose of rivaroxaban for the indication of extended prophylaxis of VTE in selected patients at increased VTE risk and low bleeding risk based on a combination of the MAGELLAN and MARINER results.

But Spyropoulos noted that the 2018 American Society of Hematology (ASH) guidelines recommended against extended use; however, they did not consider an individualized approach.

“We are hoping that the current results will lead to change in the next guidelines and encourage more institutions to routinely continue anticoagulation in selected patients during the postdischarge period,” he said. 

The current analysis focuses on the pre-specified secondary endpoint of the MARINER trial — fatal and major venous and arterial thromboembolic events.

This composite efficacy endpoint (symptomatic VTE, MI, nonhemorrhagic stroke, and cardiovascular death) occurred in 1.28% in the rivaroxaban group and 1.77% of the placebo group (hazard ratio [HR], 0.72; P = .049). Major bleeding occurred in 0.27% of rivaroxaban patients and 0.18% of those on placebo (HR, 1.44; P = .398), a nonsignificant difference.

“So now we are showing that in addition to reducing venous thrombotic events, rivaroxaban is also cutting arterial events — mainly stroke,” Spyropoulos said.

He estimated that there are around 8 million patients hospitalized with a medical condition every year in US and at risk of VTE. “By selecting out those at high risk of VTE and low risk of bleeding, that gives us about 2 million patients who should be treated with extended duration low dose rivaroxaban after discharge.”

“An Uphill Journey”

In an accompanying editorial, Samuel Z. Goldhaber, MD, Brigham and Women’s Hospital, Boston, Massachusetts, points out that similar results have been reported with extended use of another anticoagulant, betrixaban, in the APEX study, which showed a 31% reduction of the combined endpoint of MI, stroke, and cardiovascular death compared with standard prophylaxis with enoxaparin.

“The findings with rivaroxaban and betrixaban suggest that we should abandon a silo approach for the prevention of venous or arterial thrombosis and promote a holistic strategy to vascular disease,” Goldhaber writes. 

But he believes implementation of the lessons from APEX and MARINER will be an “uphill journey.”

“It has been challenging to convince US health care providers to ‘buy in’ to the concept of extended-duration VTE prophylaxis after hospitalization for medical illnesses,” Goldhaber states.

He says multiple factors have favored inertia, including the negative ASH recommendations, an FDA checklist of major bleeding exclusions that “is too complicated to deal with” and a relatively small VTE reduction.

“Those physicians who advocate for out-of-hospital VTE prophylaxis will have to convince their colleagues on the hospital formulary committees. The impression remains that this effort would benefit only a small number of patients with VTE,” Goldhaber writes. But he adds that the current report by Spyropoulos et al “informs us that VTE outcomes are interwoven with cardiovascular death and stroke outcomes.”

On the struggle to encourage extended prophylaxis anticoagulation, Spyropoulos added: “Any time we try to introduce a change in practice it takes time. Guidelines need to catch up. Doctors are a very conservative bunch. It took 11 years for extended prophylaxis after surgery to take hold. It will be a similar battle in medical patients but COVID is making this happen quicker. Hopefully it will not be another 11 years before this becomes standard practice in medical patients.”

The MARINER study is sponsored by Janssen. Spyropoulos has served as a consultant for Janssen, Bayer, Portola, Boehringer Ingelheim, and Bristol-Myers Squibb; has received research support from Boehringer Ingelheim and Janssen; and has served on an advisory board for Daiichi-Sankyo. Goldhaber has disclosed no relevant financial relationships.

J Am Coll Cardiol. June 30, 2020 issue. Full text, Editorial

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