Introduction
The management of cancer-associated thrombosis (CAT) is tricky because of the high risk of recurrent venous thromboembolism (VTE) and bleeding caused by anticoagulant therapy. Besides, factors, such as drug–drug interaction, cancer-related comorbidity, chemotherapy-induced nausea, vomiting, thrombocytopenia and gastro-intestinal issues and high risk of bleeding factors, further increase treatment complexity and decrease the anticoagulant agent choices [1].
The first-line treatment for VTE in patients with active cancer is the long-term use of low-molecular-weight heparin (LMWH). Two large studies, the CLOT [2] and the CATCH [3] trials compared LMWH with vitamin K antagonist therapy in patients with active cancer and acute symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE).
The CATCH study
The CATCH study, published in 2015, was a phase III, multinational, randomized, active-controlled, open-label trial. It enrolled patients with solid and hematological malignancies, 55% of whom had metastatic diseases [3].
The CATCH study was designed to compare the efficacy and safety of tinzaparin versus warfarin therapy for the treatment of VTE in patients with active cancer. The primary efficacy outcome was a composite of centrally adjudicated recurrent DVT, fatal or nonfatal PE and incidental VTE. Safety outcomes included major bleeding, clinically relevant nonmajor bleeding and overall mortality.
In total, 900 patients were divided into two groups: tinzaparin or warfarin. Patients in the first group received a fixed dose of 175 IU/kg tinzaparin daily by subcutaneous injection for 6 months. Patients in the warfarin group received daily warfarin for 6 months overlapping with tinzaparin (175 IU/kg) for the first 5–10 days until the international normalized ratio (INR) was higher than 2.0 for 2 consecutive days. Subsequently, the patients received warfarin alone to maintain the INR in the therapeutic range.
Recurrent VTE arose in 31 patients (6.9%) in the tinzaparin group and in 45 patients (10%) in the warfarin group (hazard ratio [HR]: 0.65; 95% CI: 0.41–1.03; p=0.07). However, patients treated with tinzaparin experienced significantly less symptomatic DVT (2.7 vs 5.3%; HR: 0.48; 95% CI: 0.24–0.96; p=0.04). Major bleeding rates and mortality were similar in both groups, with approximately one-third of patients dying during the study period (33.4 vs 30.6%; p=0.54). Tinzaparin significantly reduced clinically relevant non-major bleeding compared with warfarin (10.9 vs 15.3%; HR: 0.58; 95% CI: 0.40–0.84; p=0.004) [3].
CATCH study summary
In summary, in patients with active cancer and acute symptomatic VTE, tinzaparin (175 IU/kg) daily was associated with a lower clinically relevant nonmajor bleeding rate than warfarin. Still, it did not significantly reduce the composite measure of recurrent VTE, overall mortality or major bleeding.
The new study
A recent publication used a regression model to compare the efficacy and safety of tinzaparin versus warfarin in a CATCH subgroup of patients with metastatic cancer. The aim was to assess the risk of recurrent VTE (rVTE), recurrent DVT (rDVT), and bleeding events (major bleeding [MB], clinically relevant bleeding [CRB] and clinically relevant non-MB [CRNMB]).
In general, patients with metastatic disease had a higher incidence of rVTE, symptomatic nonfatal rDVT and bleeding events when compared with patients without metastatic disease.
Patients with metastatic disease treated with tinzaparin experienced significantly fewer rVTE and rDVT events (6.8% and 3.0%, respectively) than those treated with warfarin (14.4% and 8.4%, respectively).
No significant difference was observed in MB between the two groups (5.3% and 2.3%; HR: 2.17; 95% CI: 0.71–6.65; p=0.177), but patients with metastatic disease treated with tinzaparin were associated with significantly lower risk of CRNMB (12.1 vs 18.0%; HR: 0.53; 95% CI 0.33–0.84; p=0.008) and CRB (19.5 vs 26.9%; HR: 0.63; 95% CI: 0.41–0.97; p=0.037) compared with patients in the warfarin group.
In summary, tinzaparin treatment significantly reduced the risk of rVTE, rDVT, CRB and CRNMB compared with warfarin in CAT patients with metastatic solid tumors. These data indicate that tinzaparin has a favorable risk–benefit profile in the treatment of CAT in patients with metastatic solid tumors.
References
- Papakotoulas P, Tsoukalas N, Christopoulou A, et al. Management of cancer-associated thrombosis (CAT): Symptomatic or Incidental. Anticancer Res. 2020;40(1):305-313.
- Lee AY, 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;349:146-53
- Lee AYY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015;314(7):677-686.
- Lee AY, Kamphuisen PW, Bauersachs R, et al. Efficacy and safety of tinzaparin in CAT patients with metastatic disease. Blood 2020;136(s1):33–34.