Benefits of apixaban among venous thromboembolism patients with active cancer
Dr Alexander Cohen - Guys and St Thomas, London, UK
The abstract I’m presenting relates to an observational study where we looked at over 14,000 patients with cancer associated venous thrombosis. These were patients with active cancer and they were followed up to six months. What we found was that when we compared DOACs, in particular apixaban, with low molecular weight heparin and with warfarin, we found the patients with apixaban had a lower rate of major bleeding when compared to low molecular weight heparin and they also had a lower rate of recurrences. So there was about a 40% reduction in major bleeding, the most feared complication of treating patients with anticoagulants, and there was about a 40% reduction in venous thromboembolism recurrences which is the aim of treating those patients to prevent those recurrences. That compared to low molecular weight heparin.
That’s unusual because a lot of the studies, particularly the randomised trials, have shown that DOACs in this setting might reduce recurrences but they are often associated with more bleeding. But in the case of apixaban we saw the reduction of the recurrences associated with about a 40% reduction in major bleeding.
We looked at four large US databases: we looked at Humana, Optum, PharMetrics and MarketScan. These have massive amounts of data and we were able to define a cohort of patients with active cancer, meaning those patients that have had a recent diagnosis of cancer or have had recent therapy for cancer – chemotherapy, radiotherapy and so on. We then followed those patients for six months after they developed a venous thromboembolism event, so after they developed a DVT or a pulmonary embolism which is a common complication in the early phase of active cancer. We then carefully matched the patients. So we used propensity score matching with inverse proportional treatment weights and we got what we considered were three cohorts that were very similar – a cohort on apixaban, a cohort on low molecular weight heparin and a cohort on warfarin. We managed to match them for all the risk factors that would be associated with recurrences and bleeding and then we analysed these patients using a Cox proportional hazards model. What we showed when we did that were the positive results for apixaban with the reductions in major bleeding, in clinically relevant non-major bleeding and recurrences compared to low molecular weight heparin. When we compared low molecular weight heparin to warfarin we didn’t see any differences and then when we compared apixaban to warfarin we didn’t see differences in bleeding but we saw differences in recurrences in favour of apixaban.
So this is very encouraging news for people that want to treat venous thromboembolism associated with active cancer with oral therapies because by far patients prefer oral therapies to injectable therapies for this particular condition.
We did a sub-group analysis where we took the whole population and we divided them into three cohorts based on a modified Khorana score. The Khorana score looks at the risk of venous thromboembolism; it divides patients into very high risk or high risk or not high risk. We looked very carefully to see if there was any evidence of heterogeneity in the results with respect to the different subgroups. First of all we looked at major bleeding and clinically relevant non-major bleeding in the patients comparing apixaban with low molecular weight heparin, comparing apixaban with warfarin and comparing low molecular weight heparin with warfarin. In each of the three subgroup analyses we saw no evidence of heterogeneity which meant that the results were consistent amongst all the subgroups and that the advantages of apixaban with respect to bleeding were not affected by the risk of venous thrombosis.
However, when we came to recurrences we did see some heterogeneity. We saw the main heterogeneity was where we expected to see heterogeneity when we compared low molecular weight heparin to warfarin. We’ve known for some time, since the CLOT and CATCH study, that patients at very high risk of thrombosis do better with low molecular weight heparin than with warfarin. So we saw heterogeneity there where the advantage for low molecular weight heparin was clear in the very high risk of thrombosis group. There was also some heterogeneity when we compared apixaban with low molecular weight heparin. Overall, it favoured apixaban but when we looked at the subgroups the advantage for apixaban was in the patients at lower risk of venous thrombosis and those at very high risk had similar efficacy to low molecular weight heparin.
The clinical implications are very good for patients because, as I said earlier, patients greatly prefer oral therapies to injectable therapies and we know that the adherence and persistence with oral therapies is much greater. Many patients receiving injections stop using them and that affects outcomes. If patients adhere and persist with therapies then their outcomes are going to be better, they’re going to have fewer recurrences and in the case of apixaban, on the basis of this data, they seem to have fewer major bleeds as well. So that’s really good news for patients.
One of the questions that is still unanswered is what is the optimal length of anticoagulant therapy. We know that it’s generally recommended by all the guidelines, both in North America and Europe, that these patients are treated for six months. We looked at six months in our study but should they get nine months or twelve months and which patients would benefit from longer therapy? We know there are other questions too – how do we manage patients with unusual site thromboses, so thrombosis occurring in the splanchnic veins or in the intracerebral veins? How do we deal with catheter associated thrombosis in cancer patients? These are all questions we need to look into in the future.
The striking feature of our study was that previous research with DOACs compared with low molecular weight heparin have shown advantages with respect to efficacy but at the expense of safety in some patients where there’s more major bleeding with the DOACs than with low molecular weight heparin. Our study didn’t show that, our study showed that we got the efficacy benefit with about a 40% improvement in recurrence rates but we also got a safety benefit and that distinguishes our study from other studies in this area.