[Music] welcome to the code tray the podcast of the accp emergency medicine PRN I'm your host Christian croll an emergency medicine and ICU pharmacist at the University of Iowa Hospital and Clinics to view this recorded presentation head to our YouTube channel and youtube.com accp em Ed PRN and for PRN members slides can be found under the libraries entry section of the accp community's website thank you for the introduction as mentioned my name is Sarah Josh the current pgi2 emergency medicine resident at Detroit Receiving Hospital at the Detroit Medical Center we'll be talking about the anexa ey trial that has been highly anticipated I have no particular Financial conflicts of interest to disclose however we will be discussing off label use of some medications today and there is a poll everywhere that I've created just to get some audience participation so the first question is what products do you utilize for the reversal of factor 10A Inhibitors at your specific institution the options are inex four Factor proin complex concentrate three Factor proin complex concentrate activated Factor product some of our other Factor products so our factor 7even or factor eight fresh frozen plasma or no treatment so as the is coming in it looks like our most popular product is four Factor prothid complex concentrate and Then followed by andex a which just for context at my institution we also use four Factor proin complex concentrate so before we delve into the trial itself I think it's important to look back in time of some different data and then when these different products were approved so one of our first PCC products was approved in 2000 with our three fact PCC our oral Factor 10A Inhibitors our River roxan a pixan as well as a doxan was approved in the early 2010 so 2011 to 2015 we have approval of our four-f Factor PCC also in the early 2010s lastly with our approval of andex in 2018 so prior to andex there was a period of time where there was no on-label FDA indication or FDA approved product for reversal of our oral Factor 10A inhibitors so the two products we'll be talking about today mostly will be our four Factor PCC or four Factor protham complex concentrate and then of course andex and a four Factor PCC just as a reminder contains factors 279 10 as well as protein C and S and this is an off Lael indication and the mechanism involves replacing our clotting factors to try to allow these patients to clot and stop their bleeding andex is an activated factor which is an FDA labeled indication and helps try to sequester the drug and reduce anticoagulation that way four-factor PCC does have multiple dosing strategies whether it's fixed or weight-based and that's in all the different types of bleeds and then andex has two different dosing strategies a low dose and a high dose which is given as a Bolis followed by a two-hour infusion in both of those onset of both is fairly rapid but the halflife of four-f factor PCC is noted to be longer so we've talked about the different approval times let's look at some of the different data that has been gone over over the years so as I said there was a period of time where we didn't have andex as a product so what did we use then there was initially a study in 2011 looking at the reversal of River Rocks ban and de batran by a prothrombin complex concentrate product and this was completed outside of the United States so a period of time where the United States didn't have a four-f factor PCC approved but in Europe they had had one so this was a randomized double blinded Placebo controlled trial really a proof of concept trial to see if patients who receive Rivero ban we'll focus on the Rivero ban piece of this so these were healthy volunteers these patients were not bleeding they were given a super therapeutic dose of river oyan so not a dose we typically use 20 milligrams twice a day and they were allowed to get to steady state and then patients either received Placebo or our PCC product and what they found is the protham and time as as well as the endogenous throid potential we're able to return back to Baseline after receiving the PCC product and this seems to be statistically significantly different between our two groups so proof of concept it seems that our four Factor PCC product does work in this specific indication next moving on to our first anexa trial so our anexa A and anexa R trials so this is a similar idea this is some phase two data randomized double blind SEO control trials looking at healthy adults receiving either a pixan or river roxan and that they were reversed with andex they were given a bolus and an infusion or just a bolus so they were trying to see that the drug works and then trying to figure out a dosing strategy because the Bolis and the infusion is what is prescribed now that's the data I have presented here so first they tried to see if antifactor 10A activity was reduced after giving anex a and lo and behold it was they also wanted to see if the endogenous proin potential return back to Baseline and again in both of our different drugs it was able to return back to Baseline so thus far we have some surrogate outcomes looking at bleeding and seeing that both of our products seem to work with those surrogate outcomes but what about actual clinical outcomes so that brings us to the anexa four trial so there were multiple different iterations of this trial the one with a good chunk of the data was published in 2019 by conell and colleagues and this was a multi- center prospective open label single group study so remember no compar group here this was looking specifically at adults with acute ma major bleeding so that could be a major bleed or an in cranial Hemorrhage and they looked at adults who received a pixan river oxan a doxan or an oxop parin within the prior 18 hours so they looked at a composite outcome looking again at antifactor 10A activity and as we can see both Ian and River oxan after given a dose of andox were able to decrease the antifactor 10A activity so this was a composite outcome of the activity as well as hemostatic efficacy so they looked specifically at patients with excellent or good hemostatic efficacy and what they found is that anax had 82% of patients had excellent or good hemostasis after receiving the dose again not compared to a compartive group but it seems once again that anxin a does work however at the time many hospitals are also using our four-f Factor PCC product as we saw earlier in the poll for many reasons a large chunk of it being cost however so how do we compare the two as this phase 3B for trial only looked at indexin a by itself so there have been many different real world comparisons the biggest one being most recently studied in 2023 published by Joes and colleagues and this was looking at it was a retrospective observational cohort study trying to compare patients who received andex versus those that received a four Factor PCC with patients with Factor 10A inhibitor related major bleeding in us-based hospitals and so they looked specifically at adults with a diagnosis code of bleeding due to extrinsic anti-coagulation and they had record of taking either a pixan or rivaroxaban they had received reversal with either of our two agents in the hospital and then had a documented disposition so this was done in a large number of patients over 4,000 patients and what they found they look specifically at inhospital mortality so on our y AIS you can see the percentage of inhospital mortality and then you can see the different groups subdivided from overall I and GI beds so it seems that there is a statistically significant difference here in rates of mortality in hospital between our index and a patients and our patients that did receive four-factor PCC however the patients that received four-factor pccc when looking at Baseline characteristics they had a higher rate of hematoma volumes as well as lower GCS scores as compared to our patients with index a they also had lower rates of Neurosurgical interventions as compared to index so are we really comparing Apples to Apples here was one group sicker than the other and once again this is retrospective and they didn't include any sort of inkling about safety events that were reported so this brings us to our trial uh that we'll talk about so our anexa ey trial this was most recently published in the May edition of the New England Journal of Medicine and this was titled index name for Factor 10A inhibitor Associated acute intracerebral Hemorrhage so going through our study overview it was funded by Porta which was initially owned or who initially owned andex and then switched to it new owner alexion astroica the null hypothesis for this trial is that there would be no difference in efficacy and safety outcomes between the two groups and those two groups were andax and usual care we'll delve into what usual care means as we go through this was a prospective open label randomized control trial similar to many other stroke related trials the objective was to again assess the safety and efficacy of andex as compared with usual care specifically in our patients with intracerebral Hemorrhage this was done between June 2019 and to May 2023 some inclusion criteria so patients had to have an intracerebral Hemorrhage they had to be on an oral Factor 10A inhibitor and the last dose had to be within 15 hours of randomization they had to present within six hours of symptom onset have a specific I volume between 0.5 to 60 MLS and then have an nihss score of less than 35 so anyone unfamiliar with the nihss score lower numbers indicate more mild strokes and higher numbers up to 42 indicate more sever Strokes our trial intervention again was andex either high or low dose as indicated versus usual care which was up to the local protocol so this could have been some places if they used Placebo it would have been Placebo otherwise it would have been whichever formulary PCC product that the hospital had on hand the point was that the comparative group was not receiving andex and a our end points so they had Prim primary secondary as well as safety end points so the primary end point was looking at hemostatic efficacy at 12 hours and this was defined as hematoma expansion with a volume less than 35% change at 12 hours patients had no more than an nihss increase of seven within those 12 hours and then also no receipt of rescue therapy within 3 to 12 hours so this was based on a prior study with war perin and proactor thrombin complex concentrate as well as some guidelines and definitions from the international Society of thrombosis in hemostasis now the society guidelines do recommend assessing these at a later time point so 24 to 48 hours however of note these were assessed in this study at 12 hours there were many secondary outcomes that were proposed for this study percent change in anti antifactor 10A activity at 2 hours something that was looked at prior with the inexa a as well as an ex of four studies the effect of anex a versus usual Care on throm generation again something that was looked at before but not in comparison to four-factor PCC the relationship between antifactor tenna activity and hemostatic efficacy neurological function immunogenicity of the studi drug and de Health rated quality of life the incidence of invasive intracranial procedures after randomization as this could have an effect on the primary outcome and then the incident of rehospitalization at 30 days as for safety thrombotic events and death at 30 days were reported statistical analyses have 90% Power 900 patients were needed to detect a 10-point difference in hemostatic advocacy with an alpha of 5% interim analysis was to occur at 450 patients so halfway through the study and then even though this was an open label design the endpoint adjudication committee was blinded to the different group assignments which is something similar we've seen in some again prior stroke trials looking at the results so first going through the background characteristics overall it does seem that patients were well balanced between the two groups your average patient in the study was older 70 to 80y Old patient they were male they were taking a pixan for atrial fibrillation and they were presenting with non-traumatic interest re roal Hemorrhage and most patients were reversed with lowd dose and exate or PCC and the median dose PCC that they the study had reported was about 3,000 units if the patient was to receive a PCC product so the primary outcome looking at their hemostatic efficacy there was a statistically significant difference between andex and usual care so you can see that 67% of patients had hemostatic efficacy in the indexin a group compared with 53.1 and this had a P value of 0 03 and you'll see some different groups evaluated some different analysis groups evaluated over these different outcomes we will look at it seems that the largest driver of this difference was with our no receipt of rescue therapy and then our nihss score change at less than seven points they also had looked at this outcome in patients who didn't have uh protocol violations what they had deemed as protocol violations and they had saw 68.8% of patients in the indexin a group had hemostatic advocacy and 53.8 in the usual Care Group this portion was statistically significant as it did not cross one looking at our secondary outcomes you saw the list of secondary outcomes that were intended to be reported however only a few were actually reported in the study body so one of those being percent change in antifactor 10A activity and this was similarly looked at prior to but now we are comparing it to our usual Care Group and as expected there was a statistically significant difference between the two groups with index a showing more decrease in antifactor 10A activity they also did report the MS score of percent of patients with mrss of 0 to three and this is one of our functional outcomes that are typically seen at in our stroke trials it was reported at 30 days however and many of our other stroke trials been reported at 90 days however this was not statistically significantly different between our two groups so our patients with andex it was about 28% of patients and then 31% in our usual Care Group lastly looking at our safety outcomes this was thrombotic events and deaths at 30 days it seems that our patients who received andex had a higher number of thrombotic events especially looking at our es schic strokes and this was statistically significantly different between the two groups so overall with the different outcomes it seems that index has hemostatic efficacy has better activity against our enactor 10A so better activity in lowering that however it does seem to have higher rates of thrombotic events and no difference in our functional outcomes thus far so what did the authors conclude about this they concluded that the reduction in hematoma expansion with andex as compared with usual care was accompanied by an increase in thrombotic events including stroke determining the potential net benefit of index and acute intracerebral Hemorrhage is challenging because the relative clinical effects are difficult to assess now remember this trial was stopped early so we said that 900 patients were initially supposed to be evaluated however you can see with these different outcomes about half of that was evaluated with more in our safety and then Less in our advocacy end points so some study critiques here looking at the trial design there were a number of protocols amendments that occurred throughout the time frame of the study some were to make the groups more homogeneous less heterogenous some of these protocol changes included controlling for blood pressure time to reversal Administration and then including only inter cerebral hemorrhages not your subarachnoid or your subdural hemorrhages and these seem to be reasonable protocol changes others were to increase the population size and they also had some statistical analyses changes throughout the course increasing the P value from 01 at the interim analysis to try to stop the trial early to 031 and if you remember our primary outcome had a P value of 0.003 looking at the comparator groups they seem to be well balanced and representative of our real world patients however the comparative group itself seemed to be heterogeneous so only about 85% of the usual Care Group received a PCC product and it doesn't Define what the other 15% of these patients received only about 61% of the patients who did receive a PCC product was the exact product known however of those 61% mostly patients received a four-factor PCC product the median dose that was mentioned in the usual Care Group of those that did receive a PCC product was about 30,000 units however it's not listed whether many patients received a fixed dose whether they received a weight based dose and as we know there are multiple dosing strategies this would have been nice to have a differentiation because we had that for the andex of patients how many received the low dose versus the high dose looking specifically at the patient population it seems as I said before well balanced and representative of real world patients especially patients I would see here at the Detroit Medical Center however when looking at the severity of disease many patients had a high GCS score so the median was about 15 and a low nihs score so about nine between the two groups so unclear if patients with more severe beds would benefit or see this difference between R to interventions again looking at the interventions the usual Care Group as we had mentioned earlier seems to be fairly heterogeneous really unclear what we are comparing indexin to looking at the time to reversal there was an initial part of the protocol where providers were allowed to or pharmacists were allowed to mix up the index prior to knowing if the patient had a bleed or not and as we know this could affect the time to reversal and if this same was not allowed in the usual Care Group then this could create a difference and we are not necessarily comparing our apples to our apples here if that's the case also as we know in the real world this is not feasible due to cost as well as waste of the drug This was later changed in a protocol Amendment but unknown how many in listed in the different study groups that were evaluated did have have the ability to mix this up prior to knowing if the patient had a bleed looking at the end points uh many of the prespecified secondary end points were not reported there were some extras reported in the supplementary appendix to the trial however many were either removed in the different protocol amendments or to be reported in future studies the functional outcomes were mentioned however um as I said earlier many of our stroke trials list the differences in mrss at 90 days not at 30 days so maybe evaluated earlier than we would have liked to see and they did evaluate the different safety events and did report that index did have higher rates of thromboembolism and this was evaluated in all patients who received any of the study drug which I do think is a pro for the study important to not that these different drugs are safe looking at the analysis one of the different protocol amendments that occurred changed the analysis of the primary outcome to this CMH or Cochran mantle Handel test this is is not a new test that is out does compare two outcomes while adjusting for a third so it seems to be reasonable but why they had changed that partway through the study is unclear and raises some red flags P value was also changed at the interim analysis as I had mentioned unclear why this would have been and as you can tell with if they had gone with the initial P value we would not have stopped the trial early and the trial would likely be ongoing and as I had mentioned earlier as well some different populations were analyzed for the different primary secondary as well as our safety outcomes and there are likely other critiques however we do have a limited time to talk about this trial today so now what do we do with all of this data there seem to be some lingering questions truly comparing the product to four-f factor PCC because our usual Care Group was so heterogeneous so the question remains for Health Systems what about formulary status and will there be any further studies looking at these secondary outcomes as well as safety outcomes because the study was stopped early it's currently as reported these are underpowered however if the study were to continue or if they were to report some additional data could this change anyone's mind about adding an exit to formulary if it is not already there so our last audience participation question today do the results of this trial sway your opinion on the debate andex a versus PCC we have yes or no personally for me as I mentioned we do not have index a on formulary here at the DMC and based on the results of this trial it doesn't seem that we have a fair comparison of index and a versus four Factor PCC and I think with no difference in functional outcomes me personally I wouldn't jump to add this to formulary it seems that we do have a difference in our hemostatic efficacy rates however what that means for our clinical outcomes has yet to be determined so with that I'd like to open it up for any questions and thank you for listening today if you have enjoyed this presentation content and would like to hear more subscribe via your favorite podcasting app additionally make sure to check out our YouTube page for all recorded presentations thank you for listening to this week's accp emergency medicine Journal Club presentation join US Weekly for review and discussion a new Journal articles and emergency medicine this podcast provides general 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