Venous thromboembolism is the third most common vascular condition after heart attack and stroke, affecting between 300,000 and 600,000 individuals in the United States each year. Patients with active cancer are at increased risk, with a 9.6% chance of developing symptomatic thrombosis during the first six months of chemotherapy. In this interview with i3 Health, hematologist Philip Wells, MD, FRCPC, MSc, Chair and Chief of the Department of Medicine at the University of Ottawa and The Ottawa Hospital, discusses his research team's findings that apixaban reduces the occurrence of venous thromboembolism in cancer patients who are starting chemotherapy and are at intermediate to high risk for this condition.
What causes underlie the increased risk of venous thromboembolism? Is the increased risk the result of chemotherapy or of the cancer itself?
Philip Wells, MD, FRCPC, MSc: It's actually with the cancer itself. There are three main categories of risks in cancer patients. There are patient-related factors—they are usually of advanced stage, they have comorbidities, they're often not very mobile, they might have had previous thrombosis—and then there are tumor-related factors. We know that there are higher risks associated with certain tumors, if tumors are metastatic, for example, or if they cause localized compression of vessels. Then there are the treatment-related factors: chemotherapy, hormonal therapy, red blood cell transfusions, surgery, radiotherapy, and central venous catheters. All of those together comprise the multiple risk factors. Some chemotherapies have higher risks than others. It's not entirely clear why, but there have definitely been associations with higher risk of thrombosis with cisplatin-based chemotherapies and antiangiogenic agents.
Could you share your perspective on the significance of the trial's findings?
Dr. Wells: Honestly, the trial findings should be practice changing. In my opinion, the outcomes were absolutely outstanding. You have to appreciate that we did two different analyses, the modified intention-to-treat and the on-treatment analyses. The modified intention-to-treat analysis is a classic, epidemiology-type way to evaluate studies, which I personally think doesn't apply to these sorts of trials in cancer patients, but we did that analysis first just to be conservative. Even within that analysis, you can see that the hazard ratio for developing venous thromboembolism was 0.41 in the modified intention-to-treat analysis, but that goes all the way down to 0.14 for the patients who were actually on the drug. There were no real differences in why patients came off the drug, so there's not really a bias in using the on-treatment analysis in my opinion.
The same thing is true for bleeding. Almost all studies, when they look at bleeding, report on bleeding on the drug. Using that analysis, our major bleed rates were 6 patients in the apixaban group versus 3 in the placebo group, which is 2.1% versus 1.1%. Very few of the bleeds were very important bleeds, and there are issues with the definition of major bleeding that overinflate the bleeding risk in the cancer population.
Again, the safety aspects were very good. Overall, when you look at the number needed to treat and the number needed to harm, it's really a big win for patients who receive the apixaban 2.5 mg twice daily.
What should doctors consider in weighing apixaban against alternatives to prevent venous thromboembolism in patients with cancer?
Dr. Wells: Well, there's really only one alternative, and that's to use parenteral treatments with ultra-low-molecular-weight heparins or low-molecular-weight heparins. They are more costly and, of course, more inconvenient for the patient. They also haven't quite demonstrated the efficacy profile that we demonstrated in our trial; our on-treatment hazard ratio of 0.14 was much better than has been demonstrated with other agents. Those parenteral drugs have limitations.
What advice can you give to community hematologists and hematology nurses as they treat patients with cancer?
Dr. Wells: The key thing, which we really have tried to emphasize in our center, is to do an evaluation of venous thromboembolic risk in your cancer patients. If they are higher risk—and we use the Khorana score, but there are other scoring systems—then it's pretty clear that if the patient can afford it, there's really a benefit from taking the apixaban to prevent venous thromboembolism.
As more general advice, it's important to educate cancer patients about the signs and symptoms of venous thrombosis. It's a common problem in this population. It's underemphasized, and patients are undereducated about this risk factor.
What future developments do you anticipate in the prevention of venous thromboembolism in patients with cancer?
Dr. Wells: We'll have other information coming out. Everyone's always interested in knowing subgroup analyses: are there certain subgroups that are higher risk for bleeding, and do certain tumor types have different rates of clotting? Could we improve on the prediction score and select an even higher risk of patient? Is what I'm talking about cost effective? We're in the process of writing all that information up and publishing it, so stay tuned for further details, which I anticipate will all be quite positive.
For More Information
Carrier M, Abou-Nassar K, Mallick R, et al (2019). Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med, 380(8):711-719. DOI:10.1056/NEJMoa1814468
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily represent the views of i3 Health.
Image credit: Ottawa Hospital