On Episode 3 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two featured articles from the April 2021 issue of Stroke. This episode also features a conversation with Dr. Simon Nagel, from Heidelberg University in Germany, to discuss his article “Predictors for Failure of Early Neurological Improvement After Successful Thrombectomy in the Anterior Circulation.”
Dr. Negar Asdaghi:
1) Is Andexanet a cost-effective treatment for the reversal of coagulopathy in factor Xa-associated intracranial hemorrhage?
2) Are statins safe and efficacious in secondary prevention of stroke in the elderly population?
3) What are the predictors of futile recanalization amongst successfully treated patients with endovascular therapy?
We have the answers to the above and much more in today's podcast. You're listening to Stroke Alert Podcast. Stay with us.
Dr. Negar Asdaghi: From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the April 2021 issue of Stroke, we have an exciting program today where I have the privilege of interviewing Dr. Simon Nagel from Heidelberg University in Germany on predictors of failure of early neurological improvement or futile recanalization after successful thrombectomy. But first I want to review these two interesting articles.
Dr. Negar Asdaghi: Factor Xa inhibitors, such as apixaban, edoxaban and rivaroxaban, are commonly used for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Bleeding is a serious adverse consequence of treatment with anticoagulants, including factor Xa inhibitors, with intracranial hemorrhage representing the most devastating form of such adverse events.
Dr. Negar Asdaghi: Anticoagulant-associated intracranial hemorrhage typically results in larger hematoma volumes, higher risk of expansion, and worst clinical outcomes as compared to their spontaneous counterparts and requires immediate reversal of coagulopathy. Andexanet alfa is a recombinant modified factor Xa protein which is an effective antidote to reverse this coagulopathy, though it comes with an increased risk of thromboembolic events, either from Andexanet itself or delayed or lack of resumption of anticoagulation in the setting of intracranial hemorrhage.
Dr. Negar Asdaghi: It is important to note that the estimated cost of Andexanet is between $25-50,000 US dollars, depending on the standard versus high dose used, and this medication is currently not available in many countries, including in Canada, and even in the United States, it's still not accessible in many centers mainly due to its high cost. Now, when Andexanet is not available, the non-specific antidote of prothrombin complex concentrate, or PCC, is used, carrying an approximate cost of $4-8,000 US dollars, depending on the dosage used.
Dr. Negar Asdaghi: PCC, which is a combination of various clotting factors, together with protein C and protein S, have a limited efficacy and reversal of Xa inhibitors coagulopathy. In the absence of randomized control trials to directly compare Andexanet to PCC, there remains a significant gap in knowledge with regards to comparative efficacy, adverse events, and cost-effectiveness of these therapies for life-threatening bleeding, specifically intracranial hemorrhage, in the setting of Xa inhibitor use.
Dr. Negar Asdaghi: In the current issue of the journal, Dr. Andrew Micieli and colleagues from the Division of Neurology, Department of Medicine, Universities of Toronto and Calgary, in Canada, did a comparative analysis between Andexanet and PCC in a study titled “Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Factor Xa-Associated Intracranial Hemorrhage.” Using a patient population on chronic factor Xa inhibitor treatment, when presenting with an intracranial hemorrhage, the authors applied a probabilistic Markov model over a lifetime horizon for each patient to evaluate the cost and benefits if either Andexanet or PCC was administered to reverse the coagulopathy.
Dr. Negar Asdaghi: Estimates of outcomes, dosing, and administration protocols for Andexanet were derived from the ANNEXA-4 study and from the UPRATE study for the PCC. These are two previously published large cohorts of treatment for these agents, respectively.
Dr. Negar Asdaghi: So, what they found was an overall reduction in the occurrence of fatal intracranial hemorrhage with Andexanet therapy, estimated around 18%, as compared to PCC, estimated at 34%, specifically if the antidote was administered in the first cycle, which is the first 30 days following intracranial hemorrhage. This, of course, came at a cost of a higher thromboembolic event rate measured as composite outcome of myocardial infarction, TIA stroke, deep vein thrombosis or pulmonary embolism of approximately 10% in the Andexanet-treated group as compared to 5% in the PCC-treated group.
Dr. Negar Asdaghi: Now, the cost analysis of the study is very interesting. The authors found that Andexanet, for its incremental effectiveness in gaining quality-adjusted life year, had an incremental cost over PCC. This cost-effectiveness ratio was close to $220,000 US dollar per quality-adjusted life year gain for Andexanet.
Dr. Negar Asdaghi: And as such, as things stand today, this therapy is not cost-effective and represents low value for reversal of factor Xa–associated intracranial hemorrhage over the standard of care, which is PCC. So, this study provides an important insight, not only for the physicians, but also for health policymakers, as they critically evaluate the merits of Andexanet therapy compared to the current standard of care.
Dr. Negar Asdaghi: So, moving on now from oral anticoagulants to statin therapies and other medication commonly used in the secondary prevention of ischemic stroke, the second article we will discuss today in our podcast looks at the use of statins poststroke in the elderly population. About a third of stroke patients are over the age of 80, and with the aging population and increased life expectancy, this proportion is estimated to double by year 2050.
Dr. Negar Asdaghi: Stroke survivors who are over the age of 80 have increased 30-day and one-year mortality rates and remain at higher risk for recurrent cardiovascular events as compared to their younger counterparts. Statin therapy has been shown to reduce the risk of composite cardiovascular events in stroke survivors, but randomized data regarding their safety and efficacy in the elderly population is limited.
Dr. Negar Asdaghi: Treatment with statin is not without its own challenges in the elderly population. These patients are more likely to be on multiple medications that can interact with statins, and there's also some evidence that the frail population may be more prone to statin side effects such as muscle pain, risk of rhabdomyolysis, increased blood glucose levels, increased risk of diabetes, and liver problems that have all been reported in the setting of statin use.
Dr. Negar Asdaghi: In this issue of the journal, Drs. Lefeber and colleagues from the Department of Geriatrics in Utrecht University in Utrecht, Netherlands, study this subject in their paper titled “Statins After Ischemic Stroke in the Oldest: A Cohort Study Using the Clinical Practice Research Datalink Database.” This was a retrospective analysis of over 5,900 patients aged 65 years and older who were hospitalized and then discharged for a first ischemic stroke during a 17-year study period from 1999 to 2016 who were not on statin prescription in the year prior to their index hospitalization.
Dr. Negar Asdaghi: The authors compared the primary outcome, which was a composite of recurrent stroke, myocardial infarction, and cardiovascular-related mortality, within the elderly patients, those over the age of 80, to the younger population, those over 65 but under 80 years of age, based on the number of years that they had a statin prescription poststroke. That is comparing at least two years of statin prescription time with no statin treatment or less than two years of prescription time compared to no treatment at all.
Dr. Negar Asdaghi: So, what they found was that 53% of their population were actually over the age of 80, and in over half of these elderly patients, a statin was prescribed within 90 days of the index date. And not surprisingly, 38% of this elderly population had moderate to severe frailty, an index that has been linked to statin intolerance and its common myalgia side effect. Now, in terms of their main finding, more than two years of statin prescription compared to no statin prescription was significantly associated with a lower risk of the primary endpoint for both the over and the under 80 age groups.
Dr. Negar Asdaghi: This association remained true in their adjusted model, not only for the primary outcome, but also for all-cause mortality rates, which was significantly lower in the statin-treated patients. After a correction for the mortality rate of close to 24% during the first two years, the number needed to treat for reduction of composite recurrent stroke, myocardial infarction, and cardiovascular-related mortality was 64 and the number needed to treat for reduction of all-cause mortality was 19 in the group over 80 on a statin prescription during a median follow-up of 3.9 years.
Dr. Negar Asdaghi: So, in the absence of data from randomized controlled trials, this study provides reassuring results regarding the efficacy of statins in reduction of cardiovascular events in the patients aged 80 and older, keeping in mind that a third of the elderly population in the study was significantly frail, at risk for development of possible statin-related adverse effects.
Dr. Negar Asdaghi: Much has changed in the field of reperfusion therapies since the publication of the positive results of the thrombectomy trials in 2015. Advances in patient selection processes, rapid access to advanced neuroimaging, the use of newer generations of thrombectomy devices, and improvement in systems of care have all played important roles in the growing success of endovascular therapy.
Dr. Negar Asdaghi: But even with today's rigorous selection criteria and fast thrombectomy timelines, there remains a significant proportion of endovascularly treated patients in whom the successful radiographic recanalization do not translate into early neurological improvement. In our previous podcast, we report how the odds of favorable outcomes with thrombectomy decreases with an increase in the number of retrieval attempts during the procedure amongst successfully recanalized patients. Today, we dive deeper and look into other independent variables that may predict odds of futile recanalization.
Dr. Negar Asdaghi: Joining me now is Dr. Simon Nagel from Department of Neurology at Heidelberg University Hospital in Germany, who is the senior author of the study titled “Predictors for Failure of Early Neurological Improvement After Successful Thrombectomy in the Anterior Circulation.” Good morning, Simon, and thank you for joining us.
Dr. Simon Nagel: Good morning, or even good evening, from Germany. Thank you, Negar. It's a pleasure to be here, of course, especially in these times when you don't get to personally speak to a lot of international colleagues.
Dr. Negar Asdaghi: That's great, Simon. Can you start us off, please, with some background on futile recanalization? What do we know about this medical work, and what prompted you to look into this topic in more detail?
Dr. Simon Nagel: I guess, in most studies, futile recanalization is defined as a technically successful recanalization by a TICI score of 2b upwards, but an outcome on day 90 of only three to six points on the modified Rankin scale. And many papers have examined a selected number of parameters for the association with futile recanalization being either clinical, radiological, laboratory or procedural, which is why we wanted to be very comprehensive in our approach by including 38 different variables from the above-mentioned spectrum in our own analysis from our monocentric registry in Heidelberg.
Dr. Negar Asdaghi: Perfect, so a very important concept to keep in mind in light of the increased demand to perform endovascular therapy. So, can you tell us, you alluded to it, but can tell us a bit more about the study design, the population you studied, and specifically why you choose failure of early neurological improvement at the time of discharge as opposed to that more conventional outcome measure of modified Rankin scale at day 90 poststroke?
Dr. Simon Nagel: That's a good point, Negar, and you're right, we did maybe choose an unconventional end point since the definition of early neurological improvement is usually based on the NIHSS at 24 hours, but this study was driven from a very clinical perspective, that is the one from the stroke physician on the ward who is receiving the patient after the procedure, after all the acute decisions have been made. And then we have to do our best during the following days managing the complications, the deficit, and finding out why the stroke happened in the first place, until the patient is then either discharged home or back to the referring facility or to a normal board or to rehabilitation.
Dr. Simon Nagel: But a considerable amount of patients, we found, did not improve until this discharge, although the procedure was a technical success. So some reasons for that are obvious, but some of them are not, and we wanted to find more about this, especially since early neurological improvement has been proposed as a surrogate for good outcome later on.
Dr. Negar Asdaghi: Right. So we're very excited, Simon, to hear about the main study results. What were some of the predictors of failure of early neurological improvement in your study, and were you at all surprised by any of those developments?
Dr. Simon Nagel: A lot of known factors that have been previously described to show an association with early neurological improvement or failure of that were found in our univariate analysis, namely 21 of 38, but only a few remained independent predictors after selecting with the elastic net approach and logistic regression modeling. Some of them are obvious by definition, which is symptomatic intracranial hemorrhage. Then, of course, the ASPECTS on follow-up was a predictor, and this obviously beat the baseline ASPECTS and also potentially the collateral score, which was significant in univariate analysis, but we included also over 20% of patients with a premorbid disability of more than two on the Rankin scale so premorbid condition was an independent predictor.
Dr. Simon Nagel: We had eight patients with end stage renal failure in our analysis, so we did include that as well, and dialysis is a very strong predictor of failure of early neurological improvement. But also, admission glucose was, so higher levels of that, and then procedural parameters like reaching thrombolysis. So, if you do imply this, this was a factor that was positively associated with early neurological improvement. And then, also, the time from groin puncture to final recanalization was associated, so the longer it took, and this obviously beat also the stent retriever attempts in the analysis, the longer it took, the more likely that it was that failure of early neurological improvement was observed. And last but not least, general anesthesia was associated with that, but there is a sense of bias in this analysis because we have a SOP that we generally perform awake sedation. That means only patients that are not eligible for that, that are not doing well, will be treated under general anesthesia, so this variable has to be interpreted with caution.
Dr. Negar Asdaghi: So, very interesting, Simon. I want to emphasize to our listeners that in your study, 20%, that is one in five successfully recanalized patient, did not clinically improve post-thrombectomy up until discharge. This is a considerable percentage to keep in mind. Now, in our day-to-day practice, many of us also accept a TICI 2b as a measure of a successful recanalization. In your study, you included a more rigorous definition of successful recanalization. How do you think your results would have changed had you included those who have achieved a TICI 2b, and why did you exclude that population?
Dr. Simon Nagel: According to the mTICI definition, 2b means that more than half of the previously occluded vessel is reperfused, which also means that almost 50% is not. That might have been a success in the advent of thrombectomy and when this was defined in 2013, but I don't think it's adequate to call this a successful recanalization these days. When this was re-defined by David Liebeskind in 2018 with a eTICI score, 2b is still not considered anything more than two-third of the territory, and only 2c is a nearly complete reperfusion, leaving just 10% of the vessel territory occluded or not reperfused.
Dr. Simon Nagel: This is why we thought it is a more appropriate definition of successful thrombectomy, and this is what we think should be attempted in day-to-day practice. In our cohort, almost 50% achieve TICI 2c or 3, and if we would have included 2b, 83% of patients would have achieved that. I can't tell you what our analysis would have looked like if we included 2b, it might have been different, but I can tell you that that would require a new analysis of the data.
Dr. Negar Asdaghi: Yes, and we keep that in mind for sure that the new way of definition is to keep 2c or better. So Simon, I agree that definitely your study has given us a clear roadmap regarding early outcome expectations in patients undergoing thrombectomy. What should be our final take-away from your study?
Dr. Simon Nagel: I guess, before I can tell you, you have to bear in mind that this is a monocentric retrospective analysis, hence, there is bias to be expected, and choosing a different definition of early neurological improvement then may be useful, might have given us a different result. It is also important to be clear from what perspective you are looking at the data. For example, this analysis does not necessarily help with predictors for outcome that help you make a decision if you should treat the patient or not since we included many parameters that are not yet available at that point in time when you need to make the decision to treat the patient.
Dr. Simon Nagel: But, I think it's fair to say that you should, according to our results, apply thrombolysis whenever indicated, that you should be as quick as possible with your procedure, and that you should manage blood sugar well, as well as other medical complications, and that you should not expect too much early improvement in case the patient has a premorbid condition or if the motor cortex is involved, which was also a significant outcome, which I didn't mention earlier, and, of course, by definition, if symptomatic hemorrhage occurs.
Dr. Simon Nagel: Hemorrhagic transformations, on the other side, do not seem to independently influence failure of early neurological improvement.
Dr. Negar Asdaghi: Dr. Simon Nagel, it's always a pleasure speaking with you, and thank you for being with us. And this concludes our podcast for the April 2021 issue of Stroke. And as I leave you today, I want to remind us all that for every minute left untreated a brain under an ischemic attack loses an average of 1.9 million neurons. So whether you're just starting off or you're a well-established clinician or researcher in the field of vascular neurology, your work and that of your colleagues are part of a quest to save the most valuable commodity of human life, which is the brain, and, for that, we're proud to review your work in stroke and highlight the best in vascular neurology in our future podcasts. So until our next podcast, stay alert with Stroke Alert.