The standard of treatment in patients with CAT, cancer associated thrombosis, is low molecular weight heparin and low molecular weight heparin needs to be given once a day as a subcutaneous injection. The guidelines actually tell us that it should be given for six months and if the cancer is active actually longer which in reality may mean eight, nine, ten, quite a long time. Although it has been shown to be very effective compared to warfarin the main disadvantage is these injections. So what we did in the Hokusai VTE-cancer study, we compared the standard of low molecular weight heparin once a day subcutaneous injection with edoxaban. Edoxaban is a direct Xa inhibitor and that’s given as a single drug, single pill, per day.
You mentioned some of your patients that were involved in that, can you tell us about the numbers of the cohorts?
We randomised a total of 1050, so more than 500 in both groups, quite comparable. If you like to have some of the data, 98% of these patients had active cancer; 50% had metastasis at the time of entry into the trial and 72 patients actively received anti-cancer therapy. That’s the unique thing that we need to realise here is you’re in the setting of an active cancer complicated by a thrombosis. Both the patient and the oncologist want to get rid of this problem because they want to treat the patient for the primary disease which is cancer. So therefore in our trial what we did is we actually took the combined outcome of a recurrence, which is an unwanted outcome, and a major bleed as a combined or composite outcome. This is unique because it usually is either going for efficacy or for safety. In this case, after consulting with many patients and oncologists worldwide, we came to the conclusion that both of these complications are unwanted and that was the reason to actually make that into our primary outcome.
When it came to the results could you tell us about those?
Our hope was to show non-inferiority and the answer is we did, very convincingly, show non-inferiority. This is important because another unique element of the trial that is everybody was treated for six months but we followed these patients for one year. If the physician made a decision to continue treatment beyond six months that was up to their decision and in actual fact many, many patients went on to eight, nine or even the full twelve months. So our primary outcome was the recurrence of venous thrombosis or bleeding over that entire one year period, that was the primary outcome and that was clearly non-inferior.
Second is we looked at six months, it was one of the sensitivity analyses to actually compare all the way up to six months. Then finally, traditionally, there is an on-protocol analysis and also those two sensitivity analyses came to the same conclusion which is clearly non-inferiority.
Were there any other advantages associated with the oral dose apart from not having to deal with injections?
Yes, we monitored why patients stopped treatment and there was quite a substantial number of patients that were randomised to the low molecular weight heparin that stopped after a while. With an oral pill, yes, you do have some patients with nausea but that’s a rare occasion. So therefore this is important in the interpretation of this study, it’s a comparison of two regimens. So the standard regimen is these injections that work very good and the pill, of course, has its advantage and the whole thing is what in the end for these patients is going to be much more acceptable? It’s obvious that with a pill that’s a no-brainer, it will change practice overnight because until this study we were stuck with subcutaneous injection because that was the best treatment, that’s in all the guidelines, and we now have an alternative.
There’s one interesting observation in that study is that there were less recurrences, if you look at the components of the primary outcome there were less recurrences with edoxaban and there was slightly more bleeding. In the end it was that 12-13% that was non-inferior. However, when we looked, and this was another unique element in the design of the study, we looked at the severity of bleeding when they presented and they were twelve patients and twelve patients in each group. So although you had this slight disbalance in terms of the bleeds that are clinically very significant and are an emergency that was identical. So the bottom line is, dear colleagues, if you have a patient with cancer associated thrombosis an oral course of edoxaban, 60mg once a day, you can lower the dose to 30mg in some patients depending on the renal status, but basically we have now a very attractive alternative.