Recurrent Thromboembolic and Bleeding Complications in Cancer Patients
ABSTRACT & COMMENTARY
Synopsis: A retrospective analysis of 1303 eligible patients (264 with malignancy) was performed to assess the incidence of venous thromboembolic recurrences and major bleeding complications during oral anticoagulant therapy with vitamin K antagonists among patients with venous thromboembolism. Patients with known malignancy had an increased incidence of recurrent thromboembolism (27.1 vs 9.0/100 patient-years) as well as an increased incidence of major bleeding episodes (13.3 vs 2.1/100 patient-years), when compared with patients without known malignancy. The incidence of thromboembolic episodes was lower when the INR was above 2.0 compared with below 2.0. While vitamin K antagonists are effective in patients with known malignancy, these patients have an increased incidence of thrombotic and bleeding complications compared with patients without known malignancy.
Source: Hutten BA, et al. J Clin Oncol 2000;18:3078-3083.
The clinical manifestation of venous thromboembolism, including deep-venous thrombosis and pulmonary embolism, is well known to occur in patients with cancer.1 Standard treatment for venous thromboembolism includes initial heparinization followed by vitamin K antagonists and is similar both in cancer patients and in patients without cancer.1,2 The initial heparinization can be accomplished either with unfractionated heparins or with low-molecular weight heparins.3,4 Potential advantages of the low-molecular weight heparins include the ability to have subcutaneous administration without laboratory monitoring, thus allowing for the possibility for out-of-hospital treatment. Several studies have demonstrated the safety of low-molecular weight heparins for patients with venous thromboembolism. The initiation of oral anticoagulant therapy with one of the coumarins, vitamin K antagonists, that are used for the long-term treatment of patients with venous thromboembolism, will usually begin within 24 hours of initial heparin treatment.2 Warfarin is the most commonly used coumarin in North America, while other coumarins such as acenocoumarol are used in some European countries.2 The unfractionated heparin or low-molecular weight heparin will be continued for at least four days following initiation of warfarin therapy, and the heparin therapy is usually discontinued when treatment with warfarin has resulted in an increase in the international normalized ratio (INR) of greater than 2.0 for two consecutive days.1,2 Treatment with warfarin will then usually continue for 3-6 months with a target INR of 2.0-3.0. Well-recognized complications during this period of oral anticoagulant therapy include bleeding and recurrent thrombosis.1,2,5
Hutten and colleagues report a retrospective analysis of 1303 eligible patients (264 with malignancy) who were treated with heparin (unfractionated or low-molecular weight) and vitamin K antagonists started within one day of heparin therapy and continued for three months, with a target INR of 2.0-3.0. The patients in this retrospective analysis were involved in one of two open, multicenter, randomized clinical trials evaluating the safety, efficacy, and cost-effectiveness of unfractionated heparin vs. low-molecular weight heparin for patients with symptomatic proximal deep venous thrombosis3 or objectively documented deep venous thrombosis and/or pulmonary embolism.6 The patients with cancer were older on average than the patient without cancer (mean age ± SD of 66 ± 13 vs 59 ± 17, respectively). Cancer diagnoses of the patients with cancer included cancers of the genitourinary tract (29%), the gastrointestinal tract (19%), and the breast (15%). A small, but statistically significant difference was present for percentage of time spent within a therapeutic INR range between 2.0-3.0 between patients with and without cancer (50% vs 54% respectively, P = 0.005). A total of 35 recurrent episodes of venous thromboembolism (31 deep venous thromboses and 4 pulmonary embolisms) occurred during treatment with vitamin K antagonists (14 among patients with cancer and 21 among patients without a known cancer diagnosis). The calculated incidence of recurrent venous thromboembolism in patients with cancer was 27.1 per 100 patient-years and was greater than the 9.0 per 100 patient-years incidence in patients without a known cancer diagnosis (rate ratio 3.0; 95% CI, 1.5-5.9; P = 0.003). The highest incidence of recurrent venous thromboembolism for both patients with and without cancer occurred during periods with an INR below 2.0.
The overall incidence of major bleeding complications was also compared between patients with and without a known cancer diagnosis. A total of 12 major bleeding complications occurred, with seven among patients with cancer and five among patients without a known cancer diagnosis. The calculated incidence of major bleeding complications in patients with cancer was 13.3 per 100 patient-years and was greater than the 2.1 per 100 patient-years incidence in patients without a known cancer diagnosis (rate ratio 6.2; 95% CI, 2.0-19.7; P = 0.002). Surprisingly, while the highest incidence of major bleeding complications in patients without a cancer diagnosis occurred as expected in the INR range over 3.0, this same pattern of excess bleeding risk during times with an INR above 3.0 was not seen in the cancer patients. It was suggested that the small number of patients with major bleeding events in the different INR categories may result in a low precision for the analysis of bleeding complications as a function of INR.
Comment by Mark R. Albertini, MD
Recurrent venous thromboembolism and major bleeding complications are important considerations during therapy of patients with vitamin K antagonists for venous thromboembolism. The results from this study provide quantitative estimates of this risk for patients both with and without a cancer diagnosis. While the data analysis for this study was retrospective, the patients were well characterized and had been previously entered into two large clinical studies. Thus, important insight is provided into the magnitude of this problem for patients with cancer. Cancer patients are clearly identified as a high-risk group for recurrent venous thromboembolism and major bleeding during therapy with vitamin K antagonists for venous thromboembolism. Close monitoring for these complications is needed.
The current monitoring of these patients includes blood sample monitoring to achieve time within a therapeutic INR range between 2.0-3.0. It is suggested that more frequent monitoring of high-risk patients to achieve a greater percentage of time in the therapeutic INR range would be useful. However, the burden of increased monitoring for cancer patients also requires consideration. Alternate treatment strategies of venous thromboembolism for this patient population, such as additional investigation of low-molecular weight heparins as well as development of new anticoagulants, may prove useful.7 Clinical investigation of new management strategies is needed. Until these trials are conducted and evaluated, it is important to recognize cancer patients as a high-risk group for the complications of recurrent venous thromboembolism and major bleeding complications during treatment with vitamin K antagonists for venous thromboembolism.
References
1. Prandoni P, et al. Ann Intern Med 1996;25:1-7.
2. Ginsberg JS. N Engl J Med 1996;335:1816-1828.
3. Koopman MM, et al. N Engl J Med 1996;334:682-687.
4. Levine M, et al. N Engl J Med 1996;334:677-681.
5. Van der Meer FJ, et al. Arch Intern Med 1993;153:1557-1562.
6. The Columbus Investigators. N Engl J Med 1997;337:657-662.
7. Bauer KA. J Clin Oncol 2000;18:3065-3067.
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