In their interesting debate ("Drawing First Blood: For Anticoagulation in Cancer-Associated Thrombosis, Is Less More?") in the August issue of ASH Clinical News, David Garcia, MD, and Agnes Lee, MD, discussed the optimal duration (6 months vs. longer than 6 months) of low-molecular-weight heparin (LMWH) for the treatment of an acute venous thrombotic event in individuals with cancer.1
The agreement is that – as opposed to patients without cancer in whom vitamin K inhibitors or target-specific oral anticoagulants are adequate for the treatment of thrombosis – the recommended standard of care for cancer patients is to treat with LMWH for six months, based on results from the 2003 CLOT study.2
The question is whether this is still the case after the recently reported CATCH study, which is similar to CLOT but includes a larger patient population.3 The clear-cut results showed that there were no differences in major bleeding, pulmonary embolism, or death from pulmonary embolism between patients who received six months of daily LMWH or five to 10 days of LMWH plus six months of oral warfarin in patients with active cancer or a recent history of cancer.
Regarding the rate of recurrent thrombosis, it was surprisingly high in both groups, since patients in the study had a good performance status and were on anticoagulants when they developed the recurrent thrombosis. The six-month cumulative incidence for recurrence of venous thromboembolism (VTE) was 7.2 percent for tinzaparin compared with 10.5 percent or warfarin, for an absolute risk of 3.3 percent (p=0.07). Thus, 100 patients would have to be treated with a daily injection of a costly and often painful drug in order to avoid symptomatic recurrent thrombosis in three patients who can then be treated with LMWH without affecting survival.
We can assume that patients with recurrent thrombosis who were on the warfarin-treated arm went on to be treated with LMWH. We do not have the information on how individuals who developed recurrent thrombosis while on LMWH were treated. It is clear that we need better drugs to truly impact on recurrent thrombosis, bleeding, and survival in individuals with cancer.
Maybe there is indeed a group of individuals who could benefit from LMWH, such as those with truly active cancer, but this information is not yet available. Whether LMWH is better for patients with only central venous catheter–related thrombosis or for very high-risk patients (for example, those with pancreatic cancer) is also not known. There are still many questions to resolve.
There is also cost to consider. At the National Cancer Institute in Mexico, where drugs are partially subsidized, the cost of acenocoumarin 4 mg is $5 (every 2 months), the cost of a point-of-care prothrombin time/international normalized ratio test done at the time a patient comes to receive chemotherapy or for a routine oncology consult costs the institute $3.80 per patient. The cost of a LMWH for an average 70 kg is $11 per day ($20 in a regular pharmacy). For comparison, the minimum wage is $4.50 per day.
In summary, until something better comes along, vitamin K inhibitors seem to be a good and equivalent option for the treatment of cancer patients with venous thrombosis.
1. Garcia D, Lee AYY. For anticoagulation in cancer-associated thrombosis, is less more? ASH Clinical News. 2015;1:50-1.
2. Lee AYY, 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.
3. 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;314:677-86.
The Authors Respond
Agnes Y. Lee, MD: I am glad that our article has generated some feedback! I hope it will stir up more research in cancer-associated
thrombosis. I agree with Dr. Cesarman-Maus that there is a group of patients with active cancer who do benefit from LMWH over warfarin, and that there are many questions to resolve.
The CATCH results are certainly thought-provoking and surprising in many ways. As the paper outlined, the patient population in CATCH was quite different from CLOT. Together, I think the two trials generate the hypothesis that LMWH offers the greatest benefit in higher-risk, "sicker" patients.
Despite the "negative" result in CATCH, I think a meta-analysis of the total data on LMWH versus warfarin would still favor LMWH.
Also, I would like to point out that CATCH was not designed or powered to show differences in overall survival, fatal pulmonary embolism, or even major bleeding. It was also not designed to address which agent is better beyond the first six months of therapy – the topic of our debate.
I wish we had more studies to answer these important questions. If only we had as many trials devoted to cancer-associated thrombosis as we have in prophylaxis after major joint replacement.
(Disclaimer: Dr. Lee is the first author and principal investigator of the CATCH trial.)
David A. Garcia, MD: I also agree that the benefit of extended LMWH therapy is probably quite marginal for some patients with cancer-associated VTE (especially after 6 months). As Dr. Cesarman-Maus noted, we need to identify those patients for whom there is little or no benefit associated with long-term LMWH monotherapy.
Indeed, long-term treatment with LMWH is not only costly but also quite cumbersome and uncomfortable for many patients. We need alternatives that are less costly and more convenient, but equally (if not more) effective at preventing recurrence.
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