ATLANTA-Six months follow-up of the Select-d randomized, open-label, multicenter pilot study with 406 patients has confirmed that therapy with the direct oral anticoagulant (DOAC) rivaroxaban was a safe and effective alternative strategy to standard treatment with the low-molecular-weight heparin dalteparin for avoiding recurrences of venous thromboembolism (VTE) in selected patients with cancer. The findings were reported at the 2017 American Society of Hematology Annual Meeting (Abstract 625).
"We found recurrence rates with dalteparin at 6 months were 11 percent. With rivaroxaban, the recurrence rates were 4 percent," said lead author Annie Young PhD, Professor of Nursing at Warwick Clinical Trials Unit in Warwick Medical School Cancer Research Centre, U.K. "Definitely we found that the rivaroxaban recurrence rates at 6 months were lower than dalteparin."
More Bleeding
Young acknowledged the DOAC added a small penalty in terms of extra bleeding. "Major bleeding at 6 months was 3 percent with dalteparin and 5 percent on rivaroxaban. And most of the major bleeds were gastrointestinal. So that is fairly major," she said.
The study conclusion rated major bleeding rates as "similar" with overlapping 95 percent confidence intervals (CI). There were six bleeds from six patients (3.0%, CI ranging from 1% to 6%) on the dalteparin arm as compared with nine bleeds from eight patients (4.5%, CI from 2% to 8%) on the rivaroxaban arm.
In terms of "clinically relevant non-major bleeds," Young said there was a four-fold increase from using the DOAC. Twelve percent of patients receiving rivaroxaban had such bleeds as compared with 3 percent of patients treated with dalteparin. And these had been mostly gastrointestinal and urological bleeds. "That was very much greater with rivaroxaban. And that's clinically relevant. These are not trivial bleeds."
Bleed Category
While it was clear that major bleeds definitely mattered, Young defined two different categories of clinically relevant non-major bleeds that she split into "trivial" and "not trivial." She explained that most of the "clinically relevant," non-major urological bleeds were classed as "trivial" since they were treated successfully. "We could do something quickly with the patients because they could pick up their hematuria very early. Gastrointestinal clinically relevant bleeds-even though they were not major-were more worrying and more concerning," she said.
Study Details
The study prospectively selected patients who had a variety of cancers and tumor stages, were mostly having current anti-cancer therapy, and had VTE (defined as symptomatic or incidental pulmonary embolism) or symptomatic lower extremity proximal deep vein thrombosis. They were randomized to treatment with dalteparin (200 IU/kg daily, month 1 and 150 IU/kg, months 2-6) or to the selective direct Factor Xa inhibitor rivaroxaban (15 mg twice daily for 3 weeks then 20 mg once daily, for 6 months in total).
Which Patients for DOAC?
When Young was asked about the implications for selecting patients for treatment with DOACs rather than injectable anticoagulation, she recommended having a "big discussion" with each patient.
"Patient choice comes into this, so we have to tell them the data we have in a patient-friendly language and then balance that with the individual patient. I would avoid giving DOACs to patients with big bulky tumors in the gastrointestinal tract because that's where bleeding occurred. Weighing up the balances, I would consider DOACs for most of the other patients," she noted.
"The causes of the bleeds, I believe, are not the anticoagulants but the actual tumors. It's the lesion that bleeds. So you've got to think about whether [patients] have lesion[s] in situ. You have to weigh up the balance of the bleeding with the size of the lesion, whether there is a lesion or not and where the lesion is."
Compliance & Class Effect
Young said their data on compliance (as yet unpublished) had not shown superiority for rivaroxaban. Select-d patients were just as compliant with injectable anticoagulation over 6 months as with the DOAC. "Adherence was surprisingly similar in both arms."
When Young was asked if the differences with rivaroxaban were principally a class effect and-and if all DOACs would turn out to be similar (as they seem to be in the context of stroke prophylaxis for patients with atrial fibrillation), she said their results-even combined with the recent similar findings with the DOAC edoxaban-did not necessarily prove anything. "They are very similar. But we've got to bear in mind that this may not be a class effect, and there are pros and cons of major gastrointestinal bleeding which showed different rates in the AF studies than in our VTE study."
But she acknowledged that further randomized studies would now be difficult to conduct because clear data had emerged from both the rivaroxaban and edoxaban studies. And she also did not think it would be possible to assess whether one of these DOACs was more suitable for treating cancer VTE than the other. "I think a head-to-head study is too expensive and not possible, so I think we will be using the class effect. But we will [also] be bearing in mind huge evidence that has emerged from studies like meta-analyses of atrial fibrillation looking at the differences in bleeding," she said.
Take-Home Message
Young said that her highest priority when considering using a DOAC rather than dalteparin was the risk of bleeding. "We think that DOACs are better at preventing recurrence of VTE, but the reservation would be about where the lesions [are], and [if they] are they going to bleed." In what she described as a "gross generalization," however, she said that if a patient had a large in-situ lesion she would continue to use the "pre-standard" treatment-low-molecular-weight heparin. "And if the patient had no big lesion, I would be using DOACs."
Peter M. Goodwin is a contributing writer.