DOAC Treatments for CAT

Major guidelines including the National Comprehensive Cancer Network (NCCN) 2018, American Society of Clinical Oncology (ASCO) 2019, International Society on Thrombosis and Haemostasis (ISTH) 2018 and European Society of Cardiology (ESC) 2019 updates recommend the use of low molecular-weight heparin (LMWH) for the treatment of cancer-associated venous thromboembolism (VTE) and have recently added the use of direct oral anticoagulants (DOACs)  edoxaban or rivaroxaban^1–8. However, the clinical benefit of these oral agents is limited by an increased risk of bleeding compared with LMWH, mainly occurring at gastrointestinal (GI) sites as shown by the Hokusai VTE and SELECT-D trials. More recently, the oral factor Xa inhibitor apixaban has shown favourable efficacy and safety in the general population with VTE in the CARAVAGGIO trial and we will review the findings from this landmark trial here as well as taking a brief look at the Hokusai VTE and SELECT-D trials^9–11.

EHRA, ISTH, and NCCN have recently incorporated DOACs into their recommendations¹².

Evidence behind the guidelines

The Hokusai VTE Cancer trial was a randomised, open-label, noninferiority trial of LMWH versus edoxaban. All patients received dalteparin for at least 5 days. At randomisation, patients continued on LMWH or transitioned to the DOAC. The dalteparin dose was 200 IU/kg daily for 1 month, followed by dalteparin 150 IU/kg daily; the edoxaban dose was 60 mg/d. Treatment was given for at least 6 months and up to 12 months. The hazard ratios for the composite end point of recurrent VTE or major bleeding (MB) were very similar but with the consequence of a higher rate of major bleeding, mainly due to upper GI bleeds in patients with primary GI cancers. The results of this study showed that edoxaban was noninferior to dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin¹⁰.

In the Select-D trial, a randomised, open-label, pilot trial, the LMWH dalteparin was compared with the DOAC rivaroxaban. The dalteparin dose was 200 IU/kg daily for 1 month, followed by dalteparin 150 IU/kg daily for months 2 to 6; the rivaroxaban dose was 15 mg twice daily for 3 weeks, followed by rivaroxaban 20 mg daily for 6 months. Results of this pilot study showed that was associated with relatively low VTE recurrence but higher rates of clinically relevant and major bleeding. These tended to correlate with upper GI cancers¹¹.

The CARAVAGGIO study

The CARAVAGGIO trial was a multinational, randomised, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. Consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism were randomly assigned to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or a subcutaneous administration of the LMWH 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)⁹.

The primary efficacy outcome was objectively confirmed recurrent VTE during the trial period of 6 months with MB as the primary safety outcome (Table 1)⁹.

Table 1. Clinical outcomes during the CARAVAGGIO trial period (adapted from Agnelli et al, 2020⁹). The overall trial period for the primary efficacy outcome was the time from randomisation through 6 months.

* The primary efficacy outcome (objectively confirmed recurrent VTE) during the 6-month trial period was also the primary outcome. † Two of the recurrences of VTE in the apixaban group were upper-extremity deep-vein thrombosis. ‡ A total of 3 patients in the apixaban group and 3 patients in the dalteparin group died from unexplained causes for which pulmonary embolism could not be ruled out. § One patient in the apixaban group had an event that was categorized as MB since it resulted in a surgical intervention. ** In patients who had more than one event, only the first event was counted. ††Death was assessed up to 210 days after randomisation. ¶ Event-free survival was defined as the absence of recurrent VTE, major bleeding, or death.

We spoke to the lead investigator of the CARAVAGGIO trial, Professor Agnelli, from the University of Perugia, to hear more about the investigation and its findings.

Overall, oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated VTE without an increased risk of major bleeding⁹.

Results from the trial demonstrated that recurrent VTE occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority)⁹.

It was also shown that MB occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (HR, 0.82; 95% CI, 0.40 to 1.69; P = 0.60). Listen to Professor Agnelli discuss the potential clinical implications of this study and whether the results could impact current guidelines.

Overall, oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated VTE without an increased risk of major bleeding.⁹ Let’s find out if DOACs offer the potential to overcome current issues faced by healthcare professionals in the management of cancer associated VTE?

There are several studies ongoing which assess the efficacy and safety of DOACs compared with LMWH in patients with cancer-associated VTE, including the randomised CASTA-DIVA (rivaroxaban), and CANVAS studies (Table 2)^13,14.

Table 2. Current and ongoing studies evaluating the role of DOACs in cancer-associated VTE (adapted from Bauersachs et al., 2020¹⁵; Agnelli et al., 2020⁹, NCT02744092¹⁴). VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; DOAC, direct oral anticoagulant; LMWH, low molecular weight heparin; VKA, vitamin K antagonist; PO, by mouth; BID, twice daily; SC, subcutaneously; IU, international units; kg = kilogram, d = day, wk = week; MI, myocardial infarction; QOL, quality of life.

Other ongoing studies

In addition, patient reported outcomes with rivaroxaban are under investigation in CONKO-011, a randomized open-label study which is part of the CALLISTO programme.¹⁶ Let’s discover which DOAC therapies are currently being evaluated in trials for the treatment of CAT?

CASTA-DIVA is a pilot study comparing the efficacy and safety of oral rivaroxaban and subcutaneous (SC) dalteparin in patients with cancer associated thrombosis. It is designed as a non-inferiority, open label, randomized, multicentre trial with blinded adjudication of outcome events¹³. The primary objective of the CANVAS study is to determine the efficacy of LMWH ± warfarin versus DOAC for preventing recurrent VTE in cancer patients. DOAC therapy includes edoxaban, apixaban, rivaroxaban, or dabigatran and the comparator is LMWH ± warfarin. The aim of these two studies is to provide evidence that will empower cancer patients and physicians to make more informed choices regarding anticoagulation strategies and the management of VTE in the future¹⁴.

Real world evidence for DOACs in the treatment of CAT provides additional insights into how the treatments are used and how they are managed. To date, most of the evidence comes from rivaroxaban studies, whereas real world evidence for apixaban in CAT is limited and as yet unpublished for dabigatran and edoxaban¹⁵.  

A prospective, real world, Quality Assessment Initiative (QAI) cohort study conducted at Memorial Sloan Kettering Cancer Center (MSKCC) evaluated the efficacy and safety of rivaroxaban within the CALLISTO program. The QAI study has, to date, examined 1072 patients with CAT managed with rivaroxaban in the MSKCC clinical pathway. The primary efficacy outcome was 6‐month cumulative incidence rate of recurrent VTE which was found to be 4.2% (95% CI, 2.7%‐5.7%). The primary safety outcome of 6‐month cumulative incidence rate of MB was 2.2% (95% CI, 1.1%‐3.2%). The recurrent VTE rate was similar to rates observed in SELECT‐D, a randomised, open label, pilot trial comparing rivaroxaban with dalteparin (as discussed above), however MB was less frequent in the QAI study. The lower incidence of bleeding in the QAI cohort is likely due to the suggested avoidance of or caution with rivaroxaban in patients with known GI and genitourinary lesions. SELECT‐D only excluded patients with esophageal and gastroesophageal cancers during the study, which highlights the fact that DOACs are suitable for some but not all patients with cancer¹⁵.

Results were recently presented on patient‐reported treatment satisfaction and outcomes from the single‐arm, noninterventional COSIMO study, which enrolled patients with cancer and VTE who were changing from LMWH, fondaparinux, or vitamin K antagonist (VKA) to rivaroxaban therapy for the treatment of CAT. Treatment satisfaction was evaluated through the Anti‐Clot Treatment Scale (ACTS), a 17‐item measure of the negative and positive aspects of anticoagulation treatment, on subscales for ACTS Burdens and ACTS Benefits, respectively. The primary outcome was a change in the ACTS Burdens score at week 4 compared with baseline. Patients with CAT reported a durable improvement in anticoagulation‐associated treatment satisfaction, specifically a reduction in the perceived burdens of therapy, following the change to rivaroxaban. This study showed that patients with CAT who changed from standard of care to rivaroxaban primarily preferred to take an orally administered anticoagulant. These results are important because, thus far, little was known regarding specific preferences of patients with CAT with respect to anticoagulation therapy. These result demonstrate that individual preferences should be considered for the initiation and long‐term treatment of VTE in patients with CAT because this may result in improved treatment adherence and consequently better efficacy and safety in routine clinical practice¹⁷. What does the future look like for the treatment of CAT?

Congresses

References

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8. NCCN. NCCN Flash Updates^TM: NCCN Guidelines® & NCCN Compendium Updated®. 2020. https://www.nccn.org/about/news/ebulletin/ebulletindetail.aspx?ebulletinid=629. Accessed 15 October 2020.
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13. NCT02746185. Cancer associated thrombosis, a pilot treatment study using rivaroxaban. 2018. https://clinicaltrials.gov/ct2/show/NCT02746185. Accessed 15 September 2020.
14. NCT02744092. Direct oral anticoagulants (DOACs) versus LMWH +/- warfarin for VTE in cancer (CANVAS). 2020. https://clinicaltrials.gov/ct2/show/NCT02744092. Accessed 15 September 2020.
15. Bauersachs R, Khorana AA, Lee AYY, Soff G. Cancer‐associated venous thromboembolism: Treatment and prevention with rivaroxaban. Res Pract Thromb Haemost. 2020;4(4):532–549.
16. NCT02583191. Rivaroxaban in the treatment of venous thromboembolism (VTE) in cancer patients. 2019. https://clinicaltrials.gov/ct2/show/NCT02583191. Accessed 15 September 2020.
17. Cohen AT, Maraveyas A, Beyer-Westendorf J, Lee AYY, Folkerts K, Bach M, et al. Patient-reported outcomes associated with switching to rivaroxaban for the treatment of venous thromboembolism (VTE) in patients with active cancer. Ann Oncol. 2019;30(Suppl 5):718–746.