Alok A. Khorana, MD, presented results of the CASSINI trial. Photo by © ASH/Scott Morgan.
Results of a recent study suggest that direct oral anticoagulants can reduce the risk of thromboembolism in patients with cancer who are starting a new systemic therapy regimen, without significantly increasing the risk of major bleeding.
Data presented at the 2018 ASH Annual Meeting & Exposition1 showed that adult ambulatory patients randomly assigned to rivaroxaban had a significantly reduced risk of venous thromboembolism and venous thromboembolism–related death vs placebo during the on-treatment period but not during the full-study period because patients remained at high risk of clots after stopping the drug. Moreover, based on the Khorana risk score cutoff of 2 or higher used to identify patients at high risk of venous thromboembolism, approximately 17% of patients in the placebo group experienced thrombotic events either at baseline or during the study period.
“Because nearly one-third of these events were at baseline before patients had even started on chemotherapy and before they had started on the drug, we wonder whether baseline screening should be considered in patients who are starting systemic treatment,” said lead author of the study, Alok A. Khorana, MD, of Cleveland Clinic Lerner College of Medicine and Case Western Reserve University. “Regardless of that issue, we believe that future recommendations regarding primary prevention of thrombotic events in cancer should be informed by the findings of this study.”
We believe that future recommendations regarding primary prevention of thrombotic events in cancer should be informed by the findings of this study.— Alok A. Khorana, MD
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As Dr. Khorana explained, it’s been known for more than a century that patients with cancer are at increased risk of blood clots, especially deep-vein thrombosis and pulmonary embolism. These thrombotic events can have detrimental effects including hospitalization, morbidity, treatment delays, substantial resource utilization, and death.
Two prior large, randomized, controlled trials in outpatients with cancer showed a reduction in venous thromboembolism with prophylaxis, said Dr. Khorana, but event rates were low. In one study, treatment with nadroparin reduced the incidence of thromboembolic events in ambulatory patients from 3.9% on placebo to 2% on treatment,2 while a study of semuloparin showed a reduction from 3.4% on placebo to 1.2% on treatment.3 According to Dr. Khorana, however, a risk-adapted approach using a validated score could be used to target prophylaxis for greater clinical benefit.
“Based on these studies, the number needed to treat is around 50 patients, which is really high considering these are injectable drugs,” said Dr. Khorana, who developed a validated scoring system 10 years ago to predict which patients were at risk of developing a blood clot.
CASSINI Trial Design
For the double-blind, placebo-controlled, parallel-group, multicenter CASSINI study, Dr. Khorana and colleagues enrolled adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for venous thromboembolism (defined as a Khorana score≥ 2). As Dr. Khorana reported, this study is applicable to the larger cancer population because patients with all types of solid tumors and one hematologic malignancy were enrolled.
CASSINI TRIAL
- Rivaroxaban significantly reduced venous thromboembolism and venous thromboembolism–related death during the on-treatment period of the randomized, placebo-controlled CASSINI trial, but not during the full study period after patients had stopped the drug.
- Approximately 17% of patients at high risk for clots in the placebo group experienced thrombotic events either at baseline or during the study period.
Investigators screened enrolled subjects for deep-vein thrombosis; if no clots were found, they were randomly assigned to either -rivaroxaban (10 mg, once daily) or placebo up to day 180. Subjects were also screened with lower-extremity ultrasonography every 8 weeks on study. The primary efficacy endpoint was a composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal deep-vein thrombosis, symptomatic upper- or lower-extremity distal deep-vein thrombosis, symptomatic or incidental pulmonary embolism, and venous thromboembolism–related death. The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis bleeding scale.
Clear Benefits With Rivaroxaban Prophylaxis
As Dr. Khorana reported, the reduction in venous thromboembolism did not achieve statistical significance for the primary analysis period of 180 days, as more than half of the patients assigned to placebo and 44% assigned to rivaroxaban did not complete the regimen for the full 6 months. Nevertheless, rivaroxaban was “clearly effective in reducing rates of venous thromboembolism on treatment,” he said, noting that more than one-third of clotting events occurred after participants had discontinued treatment.
Moreover, when the on-treatment period was analyzed, a statistically significant reduction was observed. Data showed that 6.41% of patients assigned to placebo experienced a clot vs 2.6% of patients taking rivaroxaban (P = .007). A composite of the primary endpoint and all-cause mortality also demonstrated a substantial reduction in events, from a 29.5% cumulative event rate on placebo to a 23.1% rate on rivaroxaban (P = .03).
“This adds to the potential clinical benefit that patients could receive while on a primary prevention approach,” said Dr. Khorana.
Safety Profile
Researchers also reported no abnormal safety signals with rivaroxaban. The incidence of major bleeding, the primary safety endpoint, was 0.99% in the placebo arm compared to 1.98% in the treatment arm, and the incidence of clinically relevant nonmajor bleeding was low in both groups as well (1.98% on placebo vs 2.72% on rivaroxaban). Based on these data, said Dr. Khorana, if 101 patients took the drug, only 1 would have a major bleeding episode, and if 135 patients took the drug, only 1 would have a clinically relevant nonmajor bleeding episode.
[Rivaroxaban was] clearly effective in reducing rates of venous thromboembolism on treatment.— Alok A. Khorana, MD
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“It’s important to keep in mind that this is a population of patients with cancer, many of whom have gastrointestinal cancers and are undergoing systemic therapy with chemotherapy with low platelet counts,” said Dr. Khorana. “So, overall, we found the incidence of bleeding incidents to be low.”
When secondary endpoints were included with the primary endpoint, the number needed to treat with rivaroxaban to prevent 1 blood clot dropped to 17. According to Dr. Khorana, when compared to the benchmark of 50 patients needed to treat to prevent 1 clot found in previous trials, these results demonstrate a clear clinical benefit for rivaroxaban while supporting the hypothesis that selected high-risk patients benefit from prophylaxis. ■
DISCLOSURE: Dr. Khorana reported financial relationships with Parexel, Sanofi, Pfizer, Janssen, TriSalus, Halozyme, Seattle Genetics, AngioDynamics, Leo Pharma, Medscape/WebMD, Pharmacyclics, PharmaCyte, and Bayer.
REFERENCES
1. Khorana, AA, Soff GA, Kakkar AK, et al: Rivaroxaban thromboprophylaxis in high-risk ambulatory cancer patients receiving systemic therapy: Results of a randomized clinical trial (CASSINI). 2018 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 4, 2018.
2. Agnelli G, Gussoni G, Bianchini C, et al: Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: A randomised, placebo-controlled, double-blind study. Lancet Oncol 10:943-949, 2009.
3. Agnelli G, George DJ, Kakkar AK, et al: Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 366:601-609, 2012.
