New perspectives for the treatment of cancer-associated thrombosis
Patients with cancer-associated thrombosis (CAT) exhibit a risk of venous thromboembolic (VTE) complications, which exceeds by far those expected in the general population, and prevail in patients with the most advanced stages of cancer.
Several randomized clinical trials, performed in the last 10 years, have demonstrated that the initial and long-term treatment of CAT with therapeutic doses of low-molecular weight heparins (LMWH) is associated with a statistically significant and clinically relevant reduction of recurrent VTE when compared with vitamin K antagonists (VKA) with comparable risk of major bleeding[1-5]. However, LMWHs are very expensive and result in a considerable burden for patients. In addition, the absolute rate (7-9%) of recurrent VTE while on LMWH therapy exceeds by far that observed in non-cancer patients while on VKAs[1-5]. This risk has been reported to persist beyond the first six months of treatment, and is associated with an increasingly high risk of major bleeding complications[6,7]. In a recent prospective cohort study dealing with the 6-month observation of 400 patients with CAT who had been given therapeutic doses of LMWH, the cumulative incidence of heparin discontinuation because of either recurrent VTE or major bleeding approximated 20% of all patients.
Following the demonstration that in subgroups of patients of cancer the novel direct oral anticoagulants (DOAC) show a favorable benefit/risk profile in comparison to conventional anticoagulation for the treatment of VTE, the results of the first two head-to head comparisons between LMWH and DOAC for the initial and long-term treatment of CAT have recently been presented at the American Society of Hematology in Atlanta[10,11].
In an open-label randomized clinical trial addressing the non-inferiority of edoxaban in comparison to LMWH for the treatment of CAT, 1046 patients with CAT were given at least 5 days of parenteral treatment with LMWH or fondaparinux, and were then randomized to receive either subcutaneous dalteparin (200 IU/Kg for one month followed by 150 IU/Kg) or oral edoxaban (60 mg o.i.d, halved in patients with moderate renal failure, low body weight or concomitant treatment with strong inhibitors of P-glycoprotein) for at least six months. The main study outcome was the composite of recurrent symptomatic VTE and major bleeding complications occurring within 12 months of recruitment according to an intention-to-treat analysis.
Similar proportion of patients allocated to the two study arms developed the main study outcome: 67/522 patients (13.8%) randomized to edoxaban and 71/524 (13.5%) allocated to dalteparin. Symptomatic recurrent VTE developed in 41 patients (7.9%) randomized to edoxaban and in 59 (11.3%) allocated to dalteparin; and major bleeding complications in 36 (6.9%) and 21 (4.0%), respectively: both differences were statistically significant. Most major bleedings that developed in the edoxaban group were gastrointestinal bleedings in patients recruited because of gastrointestinal cancer.
Also at the ASH meeting in Atlanta the results of another study (the Select/D study), designed to address the value of rivaroxaban in comparison to LMWH for the treatment of CAT, were presented. Approximately 400 patients with a recent CAT were randomized to receive from the beginning of treatment either subcutaneous dalteparin (same schedule as the Hokusai/K) or oral rivaroxaban (15 mg t.i.d for the first three weeks, followed by 20 mg o.i.d thereafter) for six months. The results of the Select/D study are consistent with those observed in the Hokusai/K. The benefit/risk profile of the two drugs was found to be comparable. In fact, in comparison to dalteparin, rivaroxaban was associated with a statistically significant reduction in the rate of symptomatic recurrent VTE (3.9% as compared to 8.9%), and led to a statistically significant increase in the rate of major (5.4% vs 3.0%) as well as non-major clinically relevant (12.3% vs 3.0%) bleedings. Once again, the difference in the rate of major bleedings between edoxaban and dalteparin was mainly due to the occurrence of gastrointestinal bleedings among patients with gastrointestinal cancers allocated to the edoxaban group.
According to the findings of these two studies, the following conclusions can be drawn:
1) the benefit/risk profile of the two drugs categories is comparable. As the novel drugs are less expensive and result in a considerable reduction of burden and inconveniences for patients in comparison to the LMWHs, their use in place of heparins is justified;
2) at least in patients who fulfil the recruitment criteria of the two clinical trials, the novel drugs are likely to be more effective;
3) they are associated with a higher hemorrhagic risk, especially in patients with gastrointestinal cancer. Among these patients, their use should be discouraged. In conclusion, an outstanding achievement has been obtained for the treatment of CAT, particularly desirable for patients who may require long-term anticoagulation.
- Carrier M & Prandoni P. Controversies in the management of cancer-associated thrombosis. Expert Rev Hematol 2017;10:15-22.
- Meyer G et al. Comparison of low molecular weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: A randomized controlled study. Arch Intern Med 2002;162:1729-35.
- Lee AY et al. Low-molecular weight heparin versus a coumarin for the prevention of venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53.
- Hull RD et al. Long term low-molecular weight heparin versus usual care in proximal vein thrombosis in patients with cancer. Am J Med 2006;119:1062-72.
- Lee AY et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015;314:677-86.
- Francis CW et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost 2015;13:1028-35.
- Jara-Palomares L et al. Tinzaparin in cancer associated thrombosis beyond 6months: TiCAT study. Thromb Res 2017;157:90-6.
- van der Wall SJ et al. Continuation of low-molecular-weight heparin treatment for cancer-related venous thromboembolism: a prospective cohort study in daily clinical practice. J Thromb Haemost 2017;15:74-9
- Vedovati MC et al. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest 2015;147:475-83.
- Raskob GE et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2017 Dec 12. doi: 10.1056/NEJMoa1711948
- Young A et al. Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism: results of the Select-D™ pilot trial. Blood 2017;130:625 [abstract]