For Anticoagulation in Cancer-Associated Thrombosis, Is Less More?

Professor of medicine at the University of Washington School of Medicine in Seattle, Washington
Professor of medicine at the University of British Columbia and director of the thrombosis program at Vancouver General Hospital in British Columbia, Canada

Cancer-associated thrombosis is a major cause of morbidity and mortality in patients with cancer. While low-molecular-weight heparin (LMWH) anticoagulation therapy is a standard regimen for treating acute thrombotic events in these patients, questions remain about its optimal use, including the duration of anticoagulation.

ASH Clinical News invited David A. Garcia, MD, and Agnes Y. Lee, MD, to debate the question: “What is the optimal duration of LMWH treatment in patients with cancer-associated thrombosis – shorter (6 months) or longer?” Dr. Garcia will be arguing “shorter,” while Dr. Lee will be arguing “longer.”


David A. Garcia, MD: As we know, the risk of recurrent thrombosis in cancer patients is very high. Historical studies, especially the one you authored more than a decade ago, Dr. Lee, suggested that it might be as high as 8 or 9 percent after six months – even with aggressive LMWH therapy.1 More recent studies suggest that, with optimal therapy, this risk may be lower; however, it is still higher than patients without cancer.

There is high-quality evidence that administering a LMWH for six months to treat acute deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) in the setting of cancer is the standard of care, and there are strong recommendations from different consensus, evidence-based guidelines to that effect.2,3 I think we can both agree that a LMWH is the treatment of choice, at least for the initial six months after a thrombosis occurs.

Agnes Y. Lee, MD: Yes, I agree that LMWH is the treatment of choice for at least the initial six months. After six months, some form of anticoagulation is needed in the majority of patients in order to reduce the risk of thrombosis recurrence. It’s a simple concept: Anticoagulants reduce the risk of thrombosis. If our goal is to reduce recurrence, we can all agree that – even in the absence of a clinical trial – anticoagulation would be the choice over no anticoagulation at the six-month point.

The million-dollar question is, though, after those six months, how should we treat these patients? Unfortunately, we don’t yet have a definitive answer to that question. The recently published DALTECAN trial did provide some data on the risk of recurrent VTE and major bleeding in patients who continue using LMWH for up to 12 months, showing that the risks of recurrent thrombosis and of major bleeding are both 0.7% per patient-month during months seven to 12 of therapy.4 However, the lack of a comparative group in this study still leaves us in the dark about how LMWH would compare with other anticoagulants beyond six months.

Dr. Garcia: There is uncertainty in this area. For instance, at the most recent European Hematology Association (EHA) Congress, a group from McMaster University led by Chatree Chai-Adisaksopha, MD, presented an analysis of the RIETE registry in which they found an association between extended LMWH use beyond six months and lower risk of VTE recurrence.5 But, again, there are no prospective, randomized controlled trials that prove that extended LMWH therapy is better than any of the alternatives currently available.

Dr. Lee: True, but if we accept that LMWH is superior to warfarin over the first six months – and we do have strong evidence to support that recommendation – there is no reason to assume that the improved efficacy of LMWH over warfarin would suddenly stop at six months. Then, at the six-month mark, it is important to ask if the same risk factors are still present that produced the procoagulant state that resulted in thrombosis.

Dr. Garcia: I totally agree. There are so many factors that define cancer patients’ thrombotic risk, including: whether they have an indwelling catheter, whether they are receiving active chemotherapy, whether that chemotherapy is a type known to be strongly associated with thrombosis, and whether or not they have evidence of disease. The patient’s age, sex, and cancer type also affect the clotting risk. Some of these factors may change after six months of therapy and take a different form than when the cancer and/or thrombosis was initially diagnosed.

Without a doubt, we need better risk-prediction methods to identify patients who would benefit from an extension of more aggressive antithrombotic therapy like LMWH – rather than exposing all patients to extended LMWH.

Dr. Lee: Yes, a validated risk-prediction model would be very helpful in identifying those who would benefit from continuing LMWH and those who might be able to switch to an oral agent or even stop anticoagulation altogether. Unfortunately, such a model is not available; we barely have data to show what happens after the first six months of treatment.

Dr. Garcia: Given that we do not currently have a reliable method for stratifying patients into different risk groups for recurrence, the practical approach is to simply switch to a less burdensome treatment after the initial six months of LMWH. Again, we don’t have a definitive answer as to what that treatment should be – whether it is warfarin or one of the direct oral agents – at this juncture, but simply switching to some less-burdensome treatment for the patient would be beneficial. The patient also needs to be aware and vigilant for signs and symptoms of recurrent thrombosis. If a recurrent thrombosis occurs, the threshold to initiate LMWH would certainly be lower.

The one aspect we can’t ignore in this decision is the financial and lifestyle burden of injectable LMWH therapy. Both are substantial. Without clear-cut proof that extending LMWH therapy is better than switching to an oral agent – say, warfarin or one of the direct oral anticoagulants – after six months, it is hard to make the argument to a patient who is weary of injecting a needle into his or her abdomen every day that he or she needs to continue to do that.

Dr. Lee: Yes, no one likes injections and they are expensive. Personally, when I see patients at that six-month time point, I have a frank conversation with them about their treatment options. I tell them: “We have no evidence to tell us which agent to use at this point. The decision is up to you and how you feel about continuing injections or switching to something else.” That’s the point when I review the available evidence with them.

Surprisingly, many patients choose to remain on LMWH, even if I give them the option to switch. If the alternative is warfarin, many would rather not have to go to a lab for more blood work or have to closely monitor their diet and drug interactions. From a quality-of-life and convenience standpoint, some patients do prefer to just get their daily injection over with and go about their daily activities – without having to constantly worry about going to the lab, what to eat or drink, when their doctor will call with more dosing instructions.

Patient preference is definitely very important – especially with the lack of data to guide treatment decisions. So, I strongly support whatever the patient decides. A higher-risk patient – for instance, a patient with metastatic pancreatic cancer or a patient with progressive tumors unresponsive to chemotherapy – needs no convincing to stick with the LMWH injections. Usually, his or her life is complicated enough without having to get accustomed to a new treatment regimen and more blood tests.

I tell my patients to think about it this way: “I cannot tell you what risk you want to bear, but it is my job to tell you about the risks. As long as you are aware that you might have another clot if you switch to oral therapy and you accept that as a potential consequence, then I support your decision.”

Dr. Garcia: Now, we actually do have quite a bit of evidence showing that LMWH is superior to warfarin, but it has not been compared head-to-head with a direct oral agent. So, while it’s reasonable to consider patient preference after six months of therapy, you would need to be sure that the patient understood that using LMWH injections (rather than any other anticoagulant) for the first six months is the preferred, strong recommendation.

Dr. Lee: Unfortunately, though, the guideline panels don’t ask patients for their opinions. There has always been an assumption that people would prefer an oral therapy over an injectable therapy, but there are actually good data about the effect on quality of life to show that cancer patients actually do not mind injections – especially when weighed against the downsides of warfarin therapy.6

In my experience, many patients are hesitant to use one of the newer direct oral anticoagulants when I present the evidence to them. They are concerned about the lack of comparative data. Subgroup analyses from the large, registration trials have shown some promising evidence against warfarin in highly-selected cancer patients, but it is premature to use these agents in most patients with cancer-associated thrombosis. There are now ongoing trials comparing direct oral anticoagulants with LMWH, but it will be several years before we have the results.

Many of my patients have said, “I don’t want to take the risk of dying from a blood clot. I have accepted that I am struggling with my cancer and I might die from that. I’ve lost my hair, I am nauseated, I look like hell, but I put up with all that because I want the best therapy for my cancer. If I have to inject myself once a day to avoid having another clot, that is not such a big deal in the whole scheme of things.” We should never assume we know what our patients’ preferences are.

Undoubtedly, clinicians are hesitant to prescribe LMWH because it is a burdensome therapy. However, we need to first step back and ask if we should prescribe anticoagulant therapy after six months; if the answer is yes, then it seems that LMWH is still the most effective option. If we consider that we recommend long-term anticoagulation in patients with unprovoked thrombosis because the risk of recurrence is high – 10 percent over the first year2 – then it seems logical that we should also recommend long-term anticoagulation in cancer patients because they have an even higher risk of recurrent thrombosis.

Dr. Garcia: That’s a great point. But what about one exception: the patient who has a thrombosis in the setting of an imminently curable malignancy? For instance, diffuse large B-cell lymphoma in a relatively young person who has good prognostic markers, has finished six cycles of R-CHOP, and has no evidence of disease. The hematologist/oncologist rates him or her as very-low risk for lymphoma recurrence and a high chance of cure. How would you handle that situation?

Dr. Lee: I would stop anticoagulation after six months if the patient has completed chemotherapy and is in remission. The risk of recurrent thrombosis at that point is probably low enough that it does not warrant continuing anticoagulation. However, if the patient has not yet finished chemotherapy at six months, I would continue anticoagulation.

Dr. Garcia: I would take the same approach; I view that patient as having had a “provoked” clot, and the provocative event (i.e., cancer) was probably a time-limited risk factor that has been removed if the patient is, in fact, in remission and has no evidence of disease.

Dr. Lee: Yes, it makes sense to follow the general principle of three to six months of anticoagulation for a provoked VTE; at that point, if there are no risk factors present, then anticoagulation can be stopped. If the same risk factors are still present, though, then it makes sense to continue anticoagulation. Basically, it comes down to common sense.

Dr. Garcia: Exactly, and the instinct that many people have is “if it is working, don’t change it.” That’s not a mindset that is unique to cancer treatment. If a therapy is doing the job and they haven’t had any other complications, they would, understandably, be quite reluctant to change their therapies.

I believe we both agree strongly about one thing: Barring a randomized controlled trial to compare the direct oral agents head-to-head with LMWH, we cannot assume that the direct oral anticoagulants are as effective as LMWH in this particular setting. Patient preference is variable; having this discussion with individual patients and finding out what their own personal priorities and values are is critical.


References

  1. 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;349:146-43.
  2. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S.
  3. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2189-204.
  4. Francis CW, Kessler CM, Goldhaber SZ, et al. J Thromb Haemost. 2015;13:1028-35.
  5. Chai-Adisaksopha C, Crowther M, Iorio A, et al. Optimal duration of anticoagulant therapy for the treatment of cancer-associated thrombosis. Abstract S142. Presented at the European Hematology Association 20th Congress, June 12, 2015, Vienna, Austria.
  6. Seaman S, Nelson A, Noble S. Cancer-associated thrombosis, low-molecular-weight heparin, and the patient experience: a qualitative study. Patient Prefer Adher. 2014;8:453-61.

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