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Introduction

Venous thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary embolism (PE), and splanchnic vein thrombosis, is a frequent complication of cancer.¹ The development of cancer-associated VTE is associated with reduced quality of life and places a significant economic burden on both the patient and the health care system.² VTE is the second-leading cause of death in cancer outpatients receiving chemotherapy and has been shown to be an independent predictor of mortality in the population of patients with cancer.^3,4 The management of cancer-associated VTE can be challenging because the risks of recurrent VTE and anticoagulant-related bleeding are high despite appropriate management.⁵ In addition, drug interactions and cancer-related comorbidities, such as renal and/or hepatic dysfunction, decreased oral intake, chemotherapy-induced nausea and vomiting, and thrombocytopenia also add to treatment complexity by limiting the choice of anticoagulant agent.

Clinical Trials Evaluating Low Molecular Weight Heparin for Treatment of Cancer-Associated VTE

The long-term use of low molecular weight heparin (LMWH) for the treatment of VTE in patients with active cancer is recommended as first-line therapy based on the results of multiple open-label randomized controlled trials (RCTs).^6,7 The two largest studies published to date, the CLOT (Comparison of Low-molecular-weight heparin versus Oral anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) and CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trials, compared a LMWH with vitamin K antagonist therapy in patients with active cancer and acute symptomatic proximal DVT or PE. See showing the design and baseline characteristics of the CATCH and CLOT trials and for the outcome results.^8,9

Both trials used an open-label study design, the same target international normalized ratio (INR) in the vitamin K antagonist control arm, the same active cancer definition, and the same duration of treatment and had comparable patient eligibility criteria.

The CLOT trial, published in 2003, randomized 676 patients to receive dalteparin (200 IU/kg daily for 1 month followed by 150 IU/kg daily for 5 months) or vitamin K antagonist (warfarin or acenocoumarol with target INR 2.5 for a total of 6 months with an initial 5-7 days overlap with dalteparin 200 IU/kg).⁸ Symptomatic recurrent DVT or PE, including death related to PE, was observed in 27 patients (7.0%) randomized to dalteparin and 53 (15%) randomized to vitamin K antagonist (hazard ratio [HR] 0.48; 95% confidence interval [CI], 0.30-0.77; P = 0.002). No difference in the rates of major bleeding (6% versus 4%; P = 0.27), any bleeding (15% versus 19%; P = 0.09), or death (39% versus 41%; P = 0.53) were observed between the two groups.

In the CATCH trial, published about 10 years later in 2015, a total of 900 patients were randomized to tinzaparin (175 IU/kg daily without dose reduction) or warfarin (target INR 2.0-3.0 with initial tinzaparin 175 IU/kg overlap for 5-10 days) for a total of 6 months.⁹ The primary composite endpoint of recurrent VTE including incidental proximal DVT and PE occurred in 31 patients (6.9%) in the tinzaparin arm and 45 patients (10%) in the warfarin arm (HR 0.65; 95% CI, 0.41-1.03; P = 0.07).

Symptomatic DVT occurred in significantly fewer patients treated with tinzaparin (2.7% versus 5.3%; HR 0.48; 95% CI, 0.24-0.96; P = 0.04). Although major bleeding rates were similar in both arms, a significant reduction in clinically relevant, non-major bleeding was observed with tinzaparin (10.9% versus 15.3%; HR 0.58; 95% CI, 0.40-0.84; P = 0.004). Mortality was similar in both groups, with approximately one-third of patients dying during the study period (33.4% versus 30.6%; P = 0.54). Although tinzaparin did not significantly reduce the primary composite endpoint of recurrent VTE, the CATCH study results do support the use of long-term LMWH as the preferred treatment for cancer-associated VTE due to a lower risk of clinically relevant major bleeding and a significant reduction in recurrent DVT.

The failure of the CATCH trial to meet statistical significance for the primary endpoint may be due to the lower-than-expected recurrent VTE rate observed in the warfarin arm. One possible explanation for this observation could be an improvement in warfarin management in the CATCH trial. However, similar levels of INR control in both studies argue against this (time in therapeutic range was 46% in CLOT versus 47% in CATCH; time above the therapeutic range was 24% in CLOT versus 27% in CATCH).

A more likely explanation is a bias in the selection of "less sick" patients for enrollment in the CATCH trial. Although the CATCH and CLOT studies used similar inclusion and exclusion criteria, key differences in baseline characteristics exist between the two patient populations, particularly with respect to thrombotic and prognostic risk factors. A higher proportion of patients in the CLOT trial were receiving active cancer treatment (72% CLOT versus 53% CATCH), had a history of prior VTE (11% CLOT versus 6% CATCH), had evidence of metastatic disease (67% CLOT versus 55% CATCH), and had a poorer performance status (Eastern Cooperative Oncology Group score of 2 in 36% CLOT versus 23% CATCH).

In addition, mortality during the 6-month treatment period was also higher in the CLOT population (39% CLOT versus 32% CATCH). Thus, the CATCH patient population likely had a lower inherent risk of recurrent VTE compared with CLOT study patients. It is highly probable that the investigators did not enroll patients into CATCH if it was felt that LMWH would be more beneficial than warfarin, resulting in the selective enrollment of patients who were less likely to develop recurrent VTE.

Trials Evaluating Direct Oral Anticoagulants in Cancer-Associated VTE

Patient selection bias is even more evident in the recent randomized trials evaluating the efficacy and safety of direct oral anticoagulants (DOACs) for treatment of acute VTE.¹⁰ These oral anticoagulants have been extensively studied over the last decade in atrial fibrillation, VTE treatment, and VTE prevention. In the landmark phase III clinical trials for acute VTE treatment, it was consistently demonstrated that DOACs are non-inferior to warfarin (pooled relative risk [RR] 0.90; 95% CI, 0.77-1.06) in preventing recurrent VTE, and they have a similar or reduced risk of major bleeding (pooled RR 0.40; 95% CI, 0.45-0.83).¹¹

Among patients classified as having "cancer" or "active cancer" in these studies, DOACs also seem to perform similarly to warfarin.¹² But a more in-depth examination of these post-hoc data reveals important patient-selection bias and questions the generalizability of the DOAC trial results to "real life" patients with cancer with VTE. In addition to the heterogeneous definitions of "active cancer" used in these trials that differed from the CLOT and CATCH trials, important determinants of recurrent VTE and bleeding were also very different in the DOAC patients with cancer than the LMWH cancer-specific trials, as shown . These include the presence of metastatic disease and concomitant use of anticancer therapy.

The vast differences in mortality during the study period also argue that very different groups of patients with "cancer" were included in the DOAC versus LMWH trials. Furthermore, unlike LMWH, which is associated with a significant reduction in risk of recurrent VTE compared with vitamin K antagonists (RR 0.52; 95% CI, 0.36-0.74), DOACs did not significantly reduce this risk in a meta-analysis of 1,132 patients with cancer enrolled in the EINSTEIN clinical trial program, HOKUSAI-VTE (Edoxaban Versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism), RECOVER (Efficacy and Safety of Dabigatran Compared to Warfarin for 6-Month Treatment of Acute Symptomatic Venous Thromboembolism), and AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) RCTs (RR 0.66; 95% CI, 0.39-1.11).¹⁰ All these considerations should caution the unselected use of DOACs in patients with active cancer and acute, symptomatic VTE.¹³

Conclusions

All major evidence-based consensus guidelines recommend LMWH for the initial and long-term treatment of cancer-associated VTE.^6,7,13 This recommendation is based on the observation that LMWH not only is more effective than warfarin for the prevention of recurrent VTE, but also offers additional advantages over oral agents including stable anticoagulation in patients with poor oral intake, a lack of drug interactions, and clinical experience in the management of anticoagulation surrounding invasive procedures and thrombocytopenia. Although DOACs are not currently recommended for VTE treatment in patients with cancer, RCTs comparing rivaroxaban and edoxaban with LMWH are currently ongoing and will help to clarify their role in cancer-associated VTE.^6,13

References

1. Khorana AA, et al. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer 2013;119:648-655.

2. Kourlaba G, et al. The humanistic and economic burden of venous thromboembolism in cancer patients: a systematic review. Blood Coagul Fibrinolysis 2015;26:13-31.

3. Kuderer NM, et al. Impact of venous thromboembolism and anticoagulation on cancer and cancer survival. J Clin Oncol 2009;27:4902-4911.

4. Khorana AA, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5:632-4.

5. Prandoni P, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-3488.

6. Lyman GH, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol 2015;33:654-656.

7. Streiff MB, et al. Cancer-Associated Venous Thromboembolic Disease, Version 1.2015. J Natl Compr Canc Netw 2015;13:1079-1095.

8. Lee AY, 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.

9. Lee AY, et al. Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients with Active Cancer: A Randomized Clinical Trial. JAMA 2015;314:677-686.

10. Carrier M, et al. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res 2014;134:1214-1219.

11. van Es N, et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014;124:1968-1975.

12. Vedovati MC, et al. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest 2015;147:475-483.

13. Kearon C, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-352.

14. Agnelli G, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost 2015;13:2187-2191.

15. Prins MH, et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014;1:e37-e46.

16. Raskob GE, et al. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol 2016;3:e379-e387.

17. Schulman S, et al. Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost 2015;114:150-157.

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