Caravaggio Backs Apixaban for Prevention of VTE Recurrence in Cancer Patients

For cancer patients with thromboembolism, the direct oral anticoagulant apixaban (Eliquis; Bristol-Myers Squibb) is noninferior to low-molecular-weight heparin (LMWH) for preventing recurrence of venous thromboembolism (VTE) and is not associated with a greater bleeding risk, results of the multinational Caravaggio trial show.

Reporting the findings Sunday at the virtual American College of Cardiology 2020 Scientific Session, Giancarlo Agnelli, MD (University of Perugia, Italy), said they may enable more cancer patients to be considered eligible for treatment with direct oral anticoagulants (DOACs).

“This is some additional information that is important for completing the story,” he added.

Patients in the study randomized to apixaban 10 mg twice daily for the first 7 days, followed by 5 mg twice daily thereafter, had a 5.6% rate of VTE recurrence over a median follow-up of approximately 6 months. In comparison, the VTE recurrence rate was 7.9% in patients randomized to dalteparin at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily thereafter. Apixaban therefore met the criteria for noninferiority, with a P value of < 0.001.

Importantly, major bleeding occurred in 3.8% of the apixaban group and in 4.0% of the dalteparin group (P = 0.60).

Commenting in a virtual press conference, Sahil Parikh, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), noted that the management of thromboembolic disease in the setting of malignancy is a common problem.

[Apixaban] adds another bullet in the gun, as it were, for us to take care of these patients. Sahil Parikh

“Over the last several years we've seen a number of studies suggest that direct oral anticoagulants will provide adequate coverage for these patients in lieu of low-molecular-weight heparins,” he observed. “What's been interesting, however, is that most of the studies have demonstrated that there’s a slightly greater bleeding risk in this setting of using DOACs versus low-molecular-weight heparins.”  By demonstrating no substantial increase in bleeding hazard in addition to comparable protection from recurrence of VTE, apixaban “adds another bullet in the gun, as it were, for us to take care of these patients,” he added.

In an editorial accompanying the paper, which was simultaneously published in the New England Journal of Medicine, Agnes Y.Y. Lee, MD (University of British Columbia, Vancouver, Canada), notes that the evidence from Caravaggio, as well as other trials like SELECT-D and ADAM VTE, make a compelling case for apixaban to be considered as another anticoagulant option in cancer patients with VTE.

“But given the heterogeneity of available trials, it is inappropriate to conclude that one direct oral anticoagulant is better than another without a head-to-head comparison,” Lee notes.

No Fatal Bleeding With Apixaban

For Caravaggio, Agnelli and colleagues randomized 1,170 patients with confirmed cancer and either deep-vein thrombosis or pulmonary embolism at 119 centers in nine European countries, Israel, and the United States from April 2017 through June 2019. All types of cancer were eligible for inclusion, with the exception of skin, primary brain or known cerebral metastases, and acute leukemia. Patients were followed up for recurrence of VTE at 4 weeks, 3 months, 6 months, and 7 months after randomization.

Major bleeding was defined by International Society on Thrombosis and Haemostasis (ISTH) criteria, and also included bleeding that necessitated acute surgical intervention. Among the major bleeds that occurred, 1.9% in the apixaban group and 1.7% in the dalteparin group were gastrointestinal (HR 1.05; 95% CI 0.44-2.50), while 1.9% and 2.2%, respectively, were nongastrointestinal (HR 0.68; 95% CI 0.21-2.20). Two fatal bleeding episodes occurred in the dalteparin group compared with none in the apixaban group.

Additionally, the combined cumulative incidence of recurrent VTE or major bleeding was 8.9% in the apixaban group and 11.4% in the dalteparin group (HR 0.70; 95% CI 0.45-1.07).

There was a numerically higher incidence of clinically relevant nonmajor bleeding in the apixaban group compared with the dalteparin group (52 vs 35 patients; HR 1.42; 95% CI 0.88-2.30). During his presentation, Agnelli noted that these excess bleeds in the apixaban group were overwhelmingly genitourinary and upper respiratory, not GI.

For the cumulate event rate of VTE and major bleeding, the curves for recurrent VTE separated at 30 days, favoring apixaban, whereas for major bleeding “the two curves are almost superimposable,” Agnelli said. He added that future subanalysis are ongoing to correlate sites of cancer with types of bleeding in an effort to learn more about whether some patients are more at risk for DOAC-related bleeding than others.

“Even in patients with GI cancers, the rate of GI bleeding was quite low,” Agnelli observed. Given the ease of use of oral anticoagulants over subacute LMWHs, he concluded that the practical implications of Caravaggio are significant and can help with decision-making about expanding the use of DOACs for cancer patients.

Echoing these sentiments, Parikh said that because of oral anticoagulants’ convenience and better tolerability, the drugs “are just frankly easier in the management of these patients as outpatients.” He also added that as novel immunotherapies and other chemotherapeutic agents change the landscape of cancer treatment, the ability to evolve and be flexible with oral anticoagulants will become more important.

“While I don't think we'll be setting aside low-molecular-weight heparins completely, this will give us a little bit more opportunity to choose alternate therapies for these patients. It’s certainly a step forward and will add more data for guidelines, which are continually evolving,” Parikh concluded.