Oral Agents for Cancer-Related VTE: 'New Standard of Care'

Roxanne Nelson, RN, BSN

December 18, 2017

ATLANTA — Another trial shows that an oral anticoagulant could take the place of injectable low-molecular-weight heparin (LWMH) for treating and preventing recurrence of acute venous thromboembolism (VTE) in patients with cancer.  

The results of the Select-d trial found that treatment with rivaroxaban (Xarelto, Janssen) had a lower incidence of VTE at 6 months compared with the LMWH dalteparin (Fragmin, Pfizer) (4% vs 11%).

However, the rate of clinically relevant nonmajor bleeding was more frequent with rivaroxaban than with dalteparin (13% vs 2%).

"The efficacy is without doubt, but we have to balance that with bleeding complications," said lead author, Annie Young, PhD, a professor of nursing at the University of Warwick, United Kingdom.

"My take-home message is to have a careful discussion with the patient, and you have to assess the risk of bleeding as well as the risk of recurrence with every patient," Dr Young told Medscape Medical News. "But now we have another option — it's not the only option, but even without this evidence, it has already started entering into clinical practice."

The findings were presented here at the at the American Society of Hematology (ASH) 2017 Annual Meeting.

Another study also presented at the meeting demonstrated similar findings, in that an oral agent was noninferior to LMWH. As reported by Medscape Medical News, the Hokusai VTE Cancer trial compared the oral factor Xa inhibitor edoxaban (Savaysa, Daiichi Sankyo) with subcutaneous dalteparin in patients with cancer-associated VTE. Both agents produced similar results in terms of recurrent VTE or severe major bleeding, although major bleeding was higher with the oral agent.

The Hokusai trial's lead author, Gary Raskob, PhD, from the University of Oklahoma School of Public Health in Oklahoma City, pointed out that the results of the two trials strengthen support for the use of direct-acting oral anticoagulants (DOACs) as an alternative to LWMH for cancer-associated VTE.

"The results of these trials are more similar than different," said Dr Raskob. "If you apply the statistical confidence intervals to the results from that trial [Select-d] and our trial, they very much overlap significantly."

"I think the best conclusion would be that we now have two trials with consistent results that we can probably, for most patients, replace a low-molecular-weight heparin with an oral direct anticoagulant," Dr Raskob added. He emphasized, however, that the exception may be patients with gastrointestinal bleeding because of the excessive bleeding observed in this subgroup.

Echoing that sentiment, Robert A. Brodsky, MD, professor of medicine and oncology and the director of the Division of Hematology at Johns Hopkins School of Medicine in Baltimore, Maryland, told Medscape Medical News that he believes "this is going to usher in a new standard of care."

This is going to usher in a new standard of care. Dr Robert Brodsky

 Cost is another issue. Hospitals or healthcare systems around the world may balk at the higher price of the oral agents, but that remains to be seen. "But going forward, I think this is going to become a new standard," Dr Brodsky said.

Bleeding Higher With DOAC

Patients with cancer are at risk for thrombotic complications, and LMWH is recommended in most guidelines for initial and long-term therapy. The DOACs have efficacy similar to that of vitamin K antagonists and have been associated with less frequent and less severe bleeding. They are widely used to treat VTEs in individuals without cancer. But whether they can be an alternative for cancer-associated VTE has been unclear.

In the Select-d trial, Dr Young and her colleagues randomly assigned 406 patients with cancer from 58 sites across the United Kingdom (203 in each group) to receive dalteparin (200 IU/kg daily for month 1 and 150 IU/kg for months 2 to 6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for 6 months in total).

The cohort included patients with early or locally advanced disease (n = 156 [38%]), metastatic disease (n = 240 [59%]), or hematologic malignancies (n = 10 [3%]). More than half had incidental pulmonary embolism or symptomatic lower-extremity proximal deep-vein thrombosis (n = 214 [53%] and n = 192 [47%], respectively).

About two thirds of patients (n = 280 [69%]) were receiving active treatment at the time of their VTE, with most getting chemotherapy (n = 232 [83%]) or targeted therapy (n = 41 [15%]).

The researchers noted that major bleeding was similar across both study groups: 6 bleeding episodes in 6 patients (3%; 95% confidence interval [CI], 1% - 6%) in the dalteparin group; 9 bleeding episodes from 8 patients (4%; 95% CI, 2% - 8%) in the rivaroxaban group. However, the rate of clinically relevant nonmajor bleeding was higher among patients receiving rivaroxaban: 28 bleeding episodes in 27 patients (13%; 95% CI, 9% - 19%) vs 5 bleeding episodes in  5 patients (2%; 95% CI, 1% - 6%).

When bleeding episodes were categorized as major bleeding episodes or clinically relevant nonmajor bleeding, there was three times as many with the oral agent; these bleeding episodes were reported in 34 patients (17%; 95% CI, 12% - 22%) receiving rivaroxaban and in 11 (5%; 95% CI, 3% - 9%) of those receiving dalteparin.

Overall survival at 6 months was similar for both groups: 74% (95% CI, 68% - 80%) in the rivaroxaban group vs 70% (95% CI, 63% - 76%) in the dalteparin group.

"A large phase III trial will confirm the use of rivaroxaban for the treatment of VTE in cancer patients" the authors conclude.

The Select-d study was supported by Bayer AG. Dr Young reports honoraria/consultancy and/or research funding from Leo Pharma, Bayer, Helsinn, Kakkar, Daiichi Sankyo, Bayer Healthcare, Boehringer Ingelheim, Janssen, Sanofi SA, and Verseon. Several coauthors also reported relationships with industry, as noted in the abstract. Dr Brodsky disclosed relationships with Achillion, Alexion Pharmaceuticals, and Apellis. Dr Raskob disclosed relationships with BMS, Eli Lilly, Janssen, Johnson & Johnson, Pfizer, Portola, Boehringer-Ingelheim, Medscape, Bayer Healthcare, Daiichi Sankyo, Daiichi Sankyo, and Pfizer.

American Society of Hematology (ASH) 2017 Annual Meeting. Abstract 625. Presented December 11, 2017.

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