The landmark CLOT Study changed practice by demonstrating that dalteparin monotherapy was more effective than LMWH followed by warfarin in treatment of VTE for up to 6 months in patients with cancer [1]. This study, however, was published more than a decade ago, and there has been little improvement in treatment of cancer-associated thrombosis in the ensuing years despite considerable scientific advances in understanding the biology and in the introduction of new anticoagulants. Important problems with the use of dalteparin monotherapy include the need for injections, high cost in some areas and a distressingly high residual rate of recurrence and bleeding. Several DOACs have been approved for treatment of VTE based on large phase 3 studies that typically included only a small proportion of cancer patients. This limited data about treatment of CAT with DOACs forms the background for several ongoing and planned studies to explore their value in this difficult patient group. McBane et al describe a new trial that should provide important new data [2]. The ADAM VTE Trial will randomize patients with active cancer and objectively diagnosed VTE to treatment with either apixaban or dalteparin to test the hypothesis that major bleeing will be less frequent in those receiving apixaban. Safety as measured by major bleeding will be the primary endpoint and several measures of efficacy will be examined as secondary endpoints.
The study has several important strengths including the use of dalteparin as administered in the CLOT Study as the comparator. Also, the study will be prospective and randomized with independent blinded adjudication of endpoints. Both venous and arterial thrombotic events will be recorded, and the follow-up will extend for 3 months beyond the 6 month treatment period. Hopefully, the sample size of 300 will be adequate to answer the questions posed. However, there is some concern regarding statistical considerations. The sample size was determined based on a hypothesized 77% reduction in the frequency of major bleeding over 6 months from 6% with dalteparin to 1.4% with apixaban. Such a reduction seems optimistic in cancer patients. Also, treatment studies of CAT are often plagued by difficulty with high dropout rates due to many deaths from progressive cancer and also patient resistance to months of injections. The investigators have planned for a dropout rate of 5%, and this also seems quite optimistic. These issues could lead to a lack of needed power in the analysis. However, the ADAM VTE Study along with several others will lead the way to understanding the role of DOACs in treatment of VTE.
Prophylaxis is routinely used to prevent CAT in several settings including the period following cancer surgery, during hospitalization for cancer patients with medical illness and for some outpatients receiving chemotherapy that are at high risk such as patients with myeloma. However, thromboprophylaxis is not routinely recommended for most outpatients receiving chemotherapy despite their increased risk. In using prophylaxis, the benefit:risk ratio must be examined very closely, and safety is of paramount importance as patients who will never experience VTE are exposed to the risk of bleeding when anticoagulants are used. Generally, those at highest risk will receive the most benefit, while those at low risk benefit least but may suffer unneeded bleeding complications. This makes risk stratification critical, and several groups have proposed models to estimate VTE risk in cancer patients. The “Khorana Score” is probably the best known approach [3], and it forms the basis for the ongoing CASSINI Study that is described in the report by Khorana et al [4].
A number of prior studies have had mixed results in demonstrating a clinically important reduction in VTE with acceptable bleeding risk in primary prophylaxis in cancer outpatients. The CASSINI Study will test the hypothesis that prophylaxis with rivaroxaban will significantly reduce VTE compared to placebo. The primary safety endpoint will be major bleeding. The study has a number of important strengths. It is prospective, randomized and double-blind with central adjudication of endpoints. Inclusion criteria are sufficiently broad to include a representative population of cancer patients receiving outpatient chemotherapy. Rivaroxaban is an oral agent that would simplify treatment compared with LMWH and likely improve patient compliance if the study is successful. The investigators decided to enroll patients with a Khorana Score of 2 or more that will include both moderate and high risk patients. This is a reasonable and considered choice that will reduce the expected rate of thrombosis in the study but will broaden the population eligible for enrollment. The assumptions underlying the planned sample size of 700 are sound. One limitation may be the long six month treatment period as the population will decrease due to deaths that will occur during this period, and also patient compliance may decline over time. Additionally, many intercurrent events are likely to occur over six months, potentially complicating analysis.
However, we look forward to the results of both the CASSINI and the ADAM VTE studies. There is great interest to moving toward oral therapy for both established VTE treatment and for prophylaxis and the results of these and also other ongoing and planned studies in CAT will guide us in developing better treatment and prevention strategies for our patients.
References
- Lee AYY, Levine MN, Baker RI et al. Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer. N Engl J Med 2003; 349; 146-153.
- McBane II R, Loprinzi CL, Ashrani A, et al. Apixaban and dalteparin in active malignancy associated venous thromboembolism. Thromb and Haemost 2017; 117;
- Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111; 4902-4907.
- Khorana AA, Vadhan-Raj S, Kuderer NM, et al. Rivaroxaban for preventing venous thromboembolism in high-risk ambulatory patients with cancer: rational and design of the CASSINI Trial. Thromb Haemost 2017: 117; 2138-2145