Warfarin and Venous Thromboembolism Prevention in Patients With Active Cancer

Eric A. Dietrich, PharmD, BCPS, and Kyle Davis, PharmD, BCPS

Volume 56 - Issue 2 - February 2016

Patients with active cancer are at an increased risk for venous thromboembolism (VTE), which is a cause of significant morbidity and mortality. Current guidelines recommend the use of low-molecular-weight heparin (LMWH) over vitamin K antagonists in this patient population.1 This recommendation is based solely on a single study2 that demonstrated the superiority of dalteparin over warfarin in reducing the rate of recurrent VTE in patients with active cancer.

While a LMWH may be the preferred option, administration of a subcutaneous injection once or twice daily can be an overwhelming task for patients. Additionally, injection site reactions are painful and can result in significant bruising and discomfort. Moreover, the costs of injectable LMWHs are substantial and may represent a therapy-limiting burden for many patients, especially considering the extended or potentially indefinite duration of treatment that is required. These shortcomings often have patients asking providers for alternative treatment strategies.

Recently, researchers performed a study to again evaluate the use of a LMWH and warfarin in patients with VTE and active cancer. Is warfarin an adequate alternative agent for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT) in patients with cancer?

Case Study

A 58-year-old woman with a past medical history of hypertension and type 2 diabetes mellitus, and who was receiving active treatment for lung cancer, had been hospitalized 1 week ago with a diagnosis of a PE. She had been discharged on a regimen of subcutaneous enoxaparin, 80 mg (1 mg/kg), twice daily for treatment of her PE, and she presents to your clinic for follow-up. At the visit, she states that she is having a difficult time administering her injections, and that she does not have a family member or friend who can assist her. She asks if there are any alternatives, and she refuses to continue to inject the enoxaparin.

Is oral warfarin a reasonable option for this patient?

Evidence

The use of a LMWH for the treatment of VTE was substantiated by the Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT) trial.2 This study evaluated the use of dalteparin at 200 IU/kg for 1 month followed by 150 IU/kg for 5 months vs bridged warfarin for 6 months in patients with cancer and acute DVT, PE, or both. The primary outcome of the study was the first episode of objectively documented, symptomatic, recurrent DVT, PE, or both during the 6-month study period. Patients in the dalteparin group experienced significantly lower rates of VTE at 6 months (27 vs 53; P = .002). Furthermore, there was no difference in the rate of major bleeding between the groups (6% vs 4%, P = .27).

Based on the results of this trial, the guidelines from the National Comprehensive Cancer Network1 state that in patients with advanced metastatic cancer and proximal DVT or PE, a LMWH is preferred for the first 6 months as monotherapy without warfarin for the prevention of recurrent VTE. The guidelines go on to state that dose-adjusted warfarin therapy is a potential option, and that treatment with direct-acting anticoagulants in not recommended.1

In an effort to confirm the results of the CLOT trial in a wider patient population, investigators performed the Comparison of Acute Treatments in Cancer Hemostasis (CATCH) study.3 Unlike the CLOT trial, which was performed exclusively in North America and Europe, the CATCH trial evaluated patients in 44 countries in Asia, Africa, Europe, and North, Central, and South America. Researchers assessed the use of tinzaparin, 175 IU/kg, once daily for 6 months vs bridged warfarin therapy in patients with active cancer (ie, a diagnosis or active therapy within the previous 6 months). Compared with dose-adjusted warfarin, tinzaparin was not associated with a further reduction in composite VTE events (7.2% for tinzaparin vs 10.5% for warfarin; P = .07). Furthermore, there were no differences in the rate of major bleeding (12 patients for tinzaparin vs 11 for warfarin; P = .77).3

Clinical Application

The decision to use a LMWH vs warfarin for prevention of VTE in the setting of active cancer is now less clear. While the CLOT study demonstrated superiority of the LMWH dalteparin over warfarin, the CATCH trial did not confirm these results, as tinzaparin and warfarin were considered equivalent. Ideally, a third study evaluating the use of enoxaparin, the most commonly used LMWH in the United States, would be conducted to break the tie between CLOT and CATCH and elucidate the preferred treatment strategy. While the guidelines do not yet have the CATCH results incorporated into their recommendations, the results call into question the perceived superiority of a LMWH vs warfarin as based on the CLOT study.

In the absence of a tie-breaking study, we feel that the discordant results of CLOT and CATCH indicate that warfarin may be a viable alternative to a LMWH. However, based on recommendations from national guidelines, as well as the lack of a confirmatory third trial, we suggest that a LMWH-based strategy should be preferred initially (based on CLOT). In patients who cannot tolerate, afford, or safely and reliably administer a LMWH, we believe that the results of CATCH indicate that warfarin is a reasonable alternative. Furthermore, warfarin would likely be preferred to (and superior to) a LMWH that is administered incorrectly or inconsistently (leading to subtherapeutic levels) or that is unable to be obtained due to cost concerns (leading to a complete lack of protection against VTE). If it is the chosen therapy, the burdens associated with warfarin (eg, drug-drug interactions, the requirement for dietary consistency, and frequent monitoring of international normalized ratio [INR]) should be considered and discussed with patients.

Case Study Follow-Up

Because our patient is having a difficult time administering the LMWH, there is concern that she would not be achieving consistent therapeutic drug levels; furthermore, due to the reduced patient satisfaction with the therapy and her desire for alternatives, another agent should be considered. Although enoxaparin can be given as a once-daily injection (dosed at 1.5 mg/kg, per the package insert), enoxaparin therapy only would alleviate issues related to nonadherence and would not address the patient’s concerns related to administration. Given the results of the CATCH study, warfarin appears to be a reasonable alternative to the LMWH.

After discussing the potential burdens associated with warfarin, the patient agrees to begin warfarin, 5 mg daily. Because the therapeutic effects of warfarin will be delayed, the patient will be required to continue enoxaparin until a therapeutic INR is achieved. She will be counseled extensively on the proper administration of enoxaparin but reassured that the warfarin will soon provide therapeutic anticoagulation, and that she soon will be able to stop the injections. She is scheduled for a repeat INR in 4 days to monitor the effects of the warfarin.

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of a coumadin clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.

References:

  1. Streiff MB, Holmstrom B, Ashrani A, et al; National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Cancer-Associated Venous Thromboembolic Disease. Version 1.2015. http://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Accessed February 2, 2016.
  2. Lee AYY, Levine MN, Baker RI, et al; Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153.
  3. Lee AYY, Kamphuisen PW, Meyer G, et al; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015;314(7):677-686.