Hello, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine CPP section. My name is Megan Janes, a clinical pharmacy specialist in the neuro ICU at Vanderbilt University Medical Center in Nashville, Tennessee, and I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. You can log into mysccm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter by following hashtag SCCM CPP JC and hashtag PharmICU. Please note this presentation is for educational purposes only. The materials presented do not represent an approach, view, statement, or opinion of the presenter that may be helpful. Now I'd like to introduce your speakers for today. Each will get a 15-minute presentation followed by a question and answer session. Our first presenter is Sam Kraybacher, a PGY-2 critical care pharmacy resident at the University of Cincinnati Medical Center in Cincinnati, Ohio. He will present on Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients with Sepsis, the ASTR randomized clinical trial. Our second presenter is Trent Flanagan, a PGY-2 critical care pharmacy resident at Baylor University Medical Center in Dallas, Texas. He will present on Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombotomy. And our third presenter is Priya Patel, a PGY-2 critical care pharmacy resident at Houston Methodist Hospital in Houston, Texas. She will present apixaban or warfarin in patients with an onyx mechanical aortic valve. And now I'll turn things over to our first presenter, Sam Kraybacher. Thank you very much for that introduction. As Megan said, I'll be presenting on Acetaminophen for the Prevention and Treatment of Organ Dysfunction in Critically Ill Patients with Sepsis, the ASTR randomized clinical trial. To start with some background, obviously sepsis and septic shock is associated with significant mortality and organ dysfunction. And so back in 2013, there was a single-centered case-controlled trial looking at the association of free hemoglobin, acetaminophen, and mortality that enrolled nearly 400 patients. The primary outcome of this trial was looking at cell-free hemoglobin at days two and four. Investigators found that non-survivors had a statistically significant higher cell-free hemoglobin. In addition, they noted that more survivors had received acetaminophen within this case-controlled trial. And this protective association persisted even after adjusting for other factors with an adjusted odds ratio of 0.48 in the confidence interval shown there. Later in 2015, there was another multi-centered cohort trial enrolling nearly 15,000 patients looking at acetaminophen therapy and outcomes of critically ill patients. This cohort study split patients into a group of patients who had any exposure to acetaminophen or no exposure to acetaminophen and found in their primary outcome of in-hospital mortality that exposure to acetaminophen was associated with a lower risk of in-hospital mortality that was statistically significant with a p-value of less than 0.01. The adjusted odds ratio of this finding was 0.6. And in addition, looking at subgroups within this multi-centered cohort study, medical patients with fever and infection had an adjusted odds ratio of 0.67 that was not statistically significant, but surgical patients did have a statistically significant lower in-hospital mortality when they had exposure to acetaminophen. In addition, the phase 2a cross trial was a single-centered randomized control trial that enrolled 40 patients comparing one gram of acetaminophen every six hours given enterally compared to placebo. Their primary outcome was F2 isoprostanes, but found no difference in that primary outcome. However, in the secondary outcomes of mortality, they noticed a trend towards lower mortality with acetaminophen group and did find a statistically significant lower serum creatinine in the acetaminophen group. That led to the acetaminophen for prevention and treatment of organ dysfunction in critically ill patients with sepsis, the active randomized control trial, which was published in JAMA Critical Care in May of 2024 this year. So based on those previous trials, investigators hypothesized that intravenous acetaminophen will increase the number of days alive and free of organ support to day 28 among critically ill patients with sepsis and respiratory or circulatory organ dysfunction. And so before getting into the methods of this trial, I'd like to take a quick poll of at your institution, how is acetaminophen currently utilized in septic patients admitted to an ICU? Is it prescribed for all patients assuming normal hepatic function, prescribed as needed for antipyretic or analgesia, never prescribed, or a different practice? And so the answers I'm seeing reflect our current practice here at UCMC where it's prescribed mostly as needed. And so jumping right into the methods of this trial, it was a randomized double-blinded trial of acetaminophen compared to a placebo. It was originally a three-arm trial comparing acetaminophen, IV, vitamin C, and placebo. However, the vitamin C arm was dropped. And so patients were enrolled in a one-to-one or randomized in a one-on-one fashion to receive IV acetaminophen, one gram every six hours for five days, or a placebo of 5% dextrose IV every six hours for five days with a maximum of 20 doses. In addition, patients would only receive study drug if they're located within an ICU. Other protocols involved an unrestricted fluid resuscitation. And for ARDS, or acute respiratory distress syndrome patients, they utilize low tidal volume ventilation with fluid restrictions. For the inclusion criteria, patients had to be 18 years or older, have sepsis defined as clinical evidence of known or suspected infection, and orders for antibiotics. Either vasopressors, despite adequate fluid resuscitation, or respiratory failure defined as at least six liters of supplemental oxygen. In addition, patients had to be randomized within 36 hours of ED presentation and be located within an ICU. Some prominent exclusion criteria included home oxygen or long-term dialysis at home, AST or ALT elevation at baseline, liver or kidney transplant recipient, alcohol use disorder or abuse, or short, less than 24-hour survival anticipation or less than one month life expectancy. The primary endpoints of this study was days alive and free of organ support, including renal replacement, assisted ventilation, or vasopressors, with assisted ventilation being defined as at least five centimeters, or a PEEP, positive expiratory pressure of at least five centimeters, or vasopressors. Secondary endpoints included 28-day morbidity endpoints, 28-day and 90-day in-hospital and all-cause mortality, change in SOFA scores on days one through seven, the development of acute respiratory distress syndrome, or ARDS, within seven days, and safety endpoints, including hypotension, liver dysfunction, kidney dysfunction, and a variety of others. In total, there are 15 secondary endpoints. Looking at the power analysis, the investigators anticipated an absolute difference of 2.5 days of that primary endpoint with an alpha of 0.05 and a power of 85%, and 218, they determined that 218 patients were needed per arm, with 436 patients total being needed. The primary endpoint was analyzed through walled confidence intervals, with secondary endpoints being analyzed from the Poisson regression with walled confidence intervals, chi-squared, or t-test. In total, 4,557 patients were screened, with 3,200 being excluded, some of the most common reasons for, or the most common reason for exclusion from the trial was greater than 36 hours from presentation to randomization. Other common exclusion criteria included elevated baseline AST and ALT, baseline liver cirrhosis, home oxygen, or long-term dialysis. 1,355 patients met criteria, with 448 being randomized, with 228 in the IV acetylmethadone, and 220 to the placebo. Taking a look at the patient demographics and the baseline patient characteristics, we can see the average patient in each group was in their 60s, about 50% were males, and the majority were white within this trial. I would like to point out the baseline SOFA score of 5.2 in the placebo and 5.5 in the IV acetylmethadone group. Nearly three out of four patients were on vasopressors at baseline, and there was a, the rate of ARDS at baseline was 18% in the IV acetylmethadone group, and 13% in the placebo. Forty percent of patients, or roughly 40% of patients received acetylmethadone pre-randomization, and the most common infection type was pneumonia, with intra-abdominal and urinary tract infections being also common. Jumping right into the primary outcome of basal IV and pre-IV organ support, we see no statistical difference in their primary endpoint, and then when looking at the composites of that primary endpoint, ventilation, vasopressor, or renal replacement, we again do not see any statistical difference within any of those subgroups. Looking at 28-day all-cause mortality, we see 17.5% in the IV acetylmethadone and 22.5% in the placebo group, with a P-value of 0.19. Jumping to secondary outcomes of 28-day ICU morbidity, we can see ICU days to day 28 was fairly similar between the two groups, with a P-value of 0.7. Looking at other phase-free to 28-days, we do not see any statistical significance, but may notice a trend towards less phase, or more phase-free of ventilator and vasopressors in the IV acetylmethadone, but once again, not statistically significant. Again noting the 28-90-day mortality, again, a slight trend towards, numerical trend towards lower mortality in our IV acetaminophen group, but just again reiterating that this is not statistically significant. Looking at the change in SOFA scores from days 1 to 7, there was no statistical significance noted. However, authors did note a possible clinically significant reduction in the first four days within the IV acetaminophen group. Looking at the development of ARDS and safety, we do see a statistically significant lower rate of development of ARDS within seven days in our IV acetaminophen group, with 2.2% developing ARDS compared to 8.5 in the placebo, with a P-value of 0.01. Looking at liver dysfunction, there was no statistically significant difference. In addition, no difference in the change in C. amcreatin or any adverse safety or adverse event. Therefore, authors concluded that treatment with acetaminophen 1 gram IV every six hours in septic patients with circulatory respiratory dysfunction was safe, not effective, and acetaminophen group was less likely to develop ARDS within seven days, and a clinically significant reduction in SOFA scores on days 1 through 4. According to my critique of the study, I believe the study question was appropriate and made sense based on the previous literature, and the hypothesis was very sound. Overall, the objective of the study was appropriate. Looking at the design and methods, I think the population that they aim to enroll makes sense. I think it's a common population that we see within our ICUs, and overall, they're able to randomize evenly between the two groups. For their intervention of IV acetaminophen, I think that this was a good change from the previous background trials that all typically looked at enteral acetaminophen. I see a common critique of studies that enroll patients, about 70% of patients on vasopressors would be questioning the bioavailability of that acetaminophen, so I think the switch to IV acetaminophen within this trial was a sound move. The comparison and overall methods of a double-blind placebo control adds to this study, and in addition, the outcome being composite of days free of organ support makes sense and is clinically relevant. As for the patient enrollment, I think the power analysis was good, and they did report their calculations, and the absolute difference of 2.5 days was not based on a lot of available or didn't have a lot of available literature to base it off of, however, I do think it makes sense and was appropriate. Looking at our baseline characteristics of patients that were enrolled, the biggest pieces of information that I took away was there was a slightly elevated or slightly more patients with ARDS in the acetaminophen group at baseline, and the baseline SOPA scores were around 5 to 5.5, which I do think is slightly lower than maybe some of the patients that we frequently take care of at our ICUs. In conclusion, I am wary of the author's conclusion of the development of ARDS in the acetaminophen group. When looking at the overall total incidence, it was about 20% in both groups when accounting for the baseline ARDS being higher in the acetaminophen group, and overall, the study was not powered to evaluate for that difference. There was no difference in the primary outcome, and once again, the study was not powered to evaluate for mortality either, and so I would take that or any possible trend seen in mortality with a grain of salt. In addition, authors note a clinically significant lower or clinically relevant lower respiratory SOPA scores, and again, they did not report the scores were respiratory SOPA scores within the trial, so I would take that with a little bit of skepticism. So my conclusions was that acetaminophen was safe but had no impact on the primary endpoint of days alive and free of any organ support, and further investigation should be or is warranted into acetaminophen's effect on acute respiratory stress or acute respiratory distress syndrome in mortality, and how I'll apply it, I believe that in septic patients requiring acetaminophen for analgesia or antipyretic, I feel comfortable scheduling acetaminophen knowing that it's safe for those patients who do not have elevated baseline liver enzymes or cirrhosis or any of those patients that were excluded within this trial. So, that leads me to my second polling question. Based on these study findings, or how will you implement these study findings at your institution? Re-begin scheduling acetaminophen, avoid acetaminophen in septic patients, no change or different? And so, that's about what I anticipated. No change to the current practice, just having extra knowledge that acetaminophen is safe within this trial. And so, with that, here are my citations, and I'll open it up to any questions you will have. Thanks, Sam. It looks like our first question that came in is, do you think acetaminophen has a pathophysiologic on the outcome of less days in ARDS? That's a great question. I think the theory is that, with the background study, it talks about the free cell hemoglobin, and that there is a theory that acetaminophen works to decrease the damage to the lungs by preventing that free cell hemoglobin to damage the lungs through anti-inflammatory mechanisms. And I think it is a good theory, but I'm not convinced on the basis of this trial alone that it is acetaminophen that we see clinically relevant outcomes from acetaminophen working in that way. But I do think it is an interesting theory and mechanism. Do you think the fact that about 40% of patients in the placebo arm received kind of pre-random acetaminophen, do you think that had the potential to impact the results of the trial? For sure. I think, especially in, as I mentioned in that previous multi-center cohort study, that it simply looked at any exposure to acetaminophen and found that mortality benefit. So I think, in this trial, allowing patients who received acetaminophen prior to randomization could definitely have some implications on the results, and maybe going forward, controlling better for that, not allowing pre-randomized acetaminophen to be given, would be something that I would be interested in seeing. Okay, I think we have time for one more question. So given that the acetaminophen was given IV, can you comment on why that was selected as the preferred route, and how that wouldn't have been met with resistance from pharmacy? Yeah, I think, obviously, the IV route is more expensive, and I think we can push back against the IV route. However, in this patient that enrolled patients on vasopressors at baseline, and nearly three-fourths of patients on vasopressors, we commonly critique studies that give enteral therapies while patients were on vasopressors. So I think switching from PO to IV for this trial makes sense, and sort of dispute or correct for any criticisms that may be given for enrolling, having vasopressors as an inclusion criteria, and then simultaneously giving something PO, and that may account for trying to prevent questions of bioavailability and the true effects of the intervention. All right, I think that will conclude our time for questions today, but thank you, Sam, for talking to us. Now I'd like to introduce our second presenter, Trent Flanagan. Thank you so much, Megan. So my trial today is to next place for ischemic stroke at four-and-a-half to 24 hours without thrombectomy, the TRACE-3 trial. So before we talk about this study, let's take a quick look at the current guideline recommendations for reperfusion options based on time of presentation. So the guidelines recommend initiating therapy as quickly as possible within these windows due to the time-dependent benefits shown in landmark reperfusion trials. So the treatment option is based on time from last to normal in the current guidelines. For zero to four-and-a-half hours, there's a recommendation for use of a thrombolytic agent and or mechanical thrombectomy. And then from the four-and-a-half to 24-hour window, mechanical thrombectomy alone is recommended. So through the use of advanced imaging modalities to determine tissue viability rather than using the time of onset alone, the thrombectomy window has evolved to be far past that of thrombolysis. And this has been primarily the result of two studies that we'll review. So initially, the window for thrombectomy was also based on time from stroke onset presentation, similar to the current practice for the majority of patients considered for thrombolysis. And the MR-CLEAN trial is a good example of that from 2015, where advanced imaging modalities were not part of the inclusion criteria. Though I will mention that MR-CLEAN looked at intra-arterial therapies altogether, not just thrombectomy. So looking at advanced imaging modalities, there are two primary methods for determining eligibility that have been used in recent thrombectomy trials. So perfusion core mismatch is used in DIFFUSE-3, describes having an increased ratio between the area of poor perfusion and the ischemic core, which indicates a relatively large refusable area. Clinical core mismatch is used in DAWN, describes having a mismatch in a clinical presentation compared to the volume of the ischemic core itself. Similar imaging modalities have been used to identify patients who may benefit from thrombolysis, specifically in the WAKE-UP trial. So in that trial, they used FLARE-MRI, which is a different imaging modality to determine that wake-up strokes likely occur within the last four and a half hours. However, these imaging modalities may also have the potential to identify patients with large refusable areas and then extend the thrombolytic window to be closer to the thrombectomy window, even in patients with strokes other than just strokes upon awakening. So since the release of the guidelines in 2019, several large RCTs have been conducted with the intent of extending the thrombolysis window greater than its current four and a half hours. So the EXTEND trial from 2019 was a multicenter RCT that enrolled 225 patients within four and a half to nine hours after stroke onset or on awakening with stroke symptoms. Their imaging modality of choice was perfusion core mismatch, and the intervention was alteplase or placebo. The baseline MRS of patients in this study was 0 to 1, and their primary outcome was excellent functional status at 90 days, being defined as an MRS of 0 to 1. And there was a significant improvement in the alteplase group compared to the placebo group. For their primary safety outcome of symptomatic ICH, there was an absolute but not statistically significant increase in the alteplase group. Additionally, there were no differences in 90-day mortality between the two groups, around 11.5% for alteplase and 9% for placebo. So just earlier this year, the TIMELESS trial looked at extending the thrombolysis window to as far as 24 hours after loss of unwell. So this was another multicenter RCT, 458 patients, and for their imaging modality, they used perfusion core mismatch. And for their intervention, they compared to next place versus placebo. For this study, the baseline MRS was 0 to 2, and it's important to note that they didn't report the distribution of patients with each MRS score at baseline. No difference was found for the primary outcome, being the median MRS score at 90 days, being 3 in both groups, and also no difference in the functional independence at 90 days, around 40 to 45% in both groups, and no difference in symptomatic ICH was noted either. However, an important note in this study was that 77% of patients received mechanical thrombectomy in each group, so they did conduct a subgroup analysis of the patients that didn't receive thrombectomy, but they didn't find a difference for the primary outcome for this subgroup either, but it did only comprise of 52 patients in each group. So that brings us to our trial for today, the TRACE-3 trial, and the objective was to investigate the safety and efficacy of next place between 4 1⁄2 and 24 hours after last known well for ischemic stroke patients that do have salvageable tissue without a planned thrombectomy. For their design, they used a prospective, open-label, blinded outcome assessment, one-to-one randomized design, and this was conducted in 58 centers across China. For their population, they included patients that had a large volume, excuse me, a large vessel ischemic stroke, being an ICA M1 or M2 occlusion. They recruited patients at 4 1⁄2 to 24 hours since last known normal. The pre-stroke MRF was 0 to 1. An NIHS score of 6 to 25, and patients had to have an ischemic core volume of less than 70 mils, the core perfusion mismatch of at least 15 mils, leading to a ratio of at least 1.8. For their exclusion criteria, patients who had a planned thrombectomy were excluded. They were unable to perform CT perfusion or perfusion-weighted imaging to include those patients. They had a large hypodensity comprising greater than one-third of the MCA territory, or if they had a guideline-based contraindication to thrombolytics. For their intervention, they compared to next place doses 0.25 milligrams per kilogram with a maximum of 25 milligrams, compared to standard medical treatment being antiplatelet therapy. For their primary outcome, they looked at absence of disability at 90 days, defined as an MRF of 0 to 1. For select circumstantial outcomes, functional independence at 90 days being defined as an MRF less than or equal to 2, major neurologic improvement at 72 hours, which was considered a reduction from baseline NIHS score of at least 8, or NIHS of 1 or 0 at that 72-hour mark. Brief perfusion at 24 hours was defined as a greater than 90% reduction in volume of lesion of delayed perfusion, and a 90-day MRF distribution as well. For their safety outcomes, they looked at symptomatic ICH within 36 hours, and that was defined as any ICH that was associated with a four or more point increase on the NIHS score, or led to death, and it was identified as the predominant cause of the neurologic deterioration. Moderate or severe systemic bleeding within 90 days, so systemic bleeding was defined using the GUSTO trial criteria, severe bleeding being defined as intracranial hemorrhage or bleeding resulting in hemodynamic compromise, a necessitating intervention, and moderate bleeding is defined as bleeding requiring transfusion, but not resulting in hemodynamic compromise. For their statistical analysis, they used logistic regression to identify absence of disability at 90 days and also the 90-day MRF distribution, and they also performed pre-specified subgroup analyses based on age, sex, stroke severity, last known time well, and large vessel occlusion site. Looking at baseline characteristics, so in both groups, patients were predominantly in their mid-60s. The majority of patients were male, about 65 to 70% in each group, and the overwhelming majority of patients were of Han Chinese ethnicity, comprising 95% in each group. Most patients had an MRF score of zero prior to their stroke. About 55 to 60% had a stroke with a known onset time, about 35 to 40% of patients had a stroke on awakening, and about 7.5% of patients in each group had an unwitnessed stroke onset. The NIHS score at randomization was 11 in the next-to-place group and 10 in the standard treatment group. For the irreversible core volume, around 15 milliliters in both groups, and a perfusion lesion volume around 120 mils in both groups, and so that led to a median mismatch ratio of about 7, and inclusion criteria was being greater than 1.8. So no significant differences were noted between the two groups' baseline. Jumping right into outcomes, so the primary outcome of 90-day MRF is zero to one. There is a significant increase in the to-next-to-place group, being 33% versus 24.2% in the standard treatment group, and the 90-day MRF score of less than or equal to two was also significantly improved in the to-next-to-place group compared to standard treatment. Again, we saw a significant improvement in the major neurologic improvement at 72-hour score, being 16% in to-next-to-place versus six in standard treatment, and then also in reperfusion at 24 hours, 20% versus 11.8%. So this figure shows the distribution of MRF scores at day 90. The common odds ratio was 1.33, with a confidence interval of 0.98 to 1.81, indicating that there was no statistically significant relationship between the intervention and the overall MRF distribution. They did do a post-hoc analysis, and they merged MRF categories five and six, so this has been done in previous stroke trials to avoid counting the shift from death being an MRF 6 to severe disability requiring constant nursing care as a treatment success, but even after that adjustment, the common odds ratio was still not statistically significant. Looking at safety outcomes, so symptomatic ICH within 36 hours after randomization, there was an absolute but not statistically significant increase in the to-next-to-place group, and again, there was, for moderate or severe bleeding within 90 days, an absolute but not statistically significant increase in the to-next-to-place group. Death within 90 days was almost identical, between the two groups being around 13%. So for the analysis, strengths of this study, they did use a baseline MRF of 0 to 1, so this is really comparing to Timeless, which I discussed earlier, that used to-next-to-place in that same 4 to 24-hour window, but then the majority of patients received thrombectomy afterwards. So in that trial, they used baseline MRFs of 0 to 2, not reporting the distribution of those patients at baseline. So using an MRF of 0 to 1 as an inclusion criteria allows for the use of MRF 0 to 1 after treatment as the primary outcome, which is the outcome they used in ECAS 3, which is where the current thrombolysis window has been derived. It's a strength that they included witnessed, unwitnessed, and wake-up strokes, things that are applicable to all stroke presentation types, and they used blinded outcome assessment. For weaknesses, they did exclude patients with planned thrombectomy, and despite planned thrombectomy being addressed in Timeless, again, that baseline MRF was higher, so functional outcome interpretation is limited compared to this study in the setting of thrombectomy. So there was low baseline NIHS and small-volume ischemic cores, so even though they were small overall, I think it's important to note the volume of the cores was actually larger than those from Xtend and Timeless. There was a relatively small effect size, particularly when you compare that to the effects of that seen in late-course thrombectomy trials, so a difference in the primary outcome was 36% in the Dawn trial compared to less than 10% in this trial. There were nine imaging protocol violations, so that would be patients that were not meeting the ischemic core volume or core perfusion mismatch criteria when randomized, and of those nine violations, five had symptomatic ICHs, so that made up about half of all the symptomatic ICHs in the entire study, so that limits our interpretation of that particular safety outcome. And then for applicability of population, the trial was performed exclusively in China, so it's not really applicable to heterogeneous populations. For interpretation of results, so the intervention did significantly increase disability-free recovery at 90 days with a number needed to treat at 12, and non-significantly increased the risk of symptomatic ICH, so a number needed to harm at 45, and the incidence of symptomatic ICH was comparable to both ECAS3 and Xtend. So takeaways of the trial for the design and outcome selection. The outcomes were consistent with trials used for current guideline recommendations, but the data for thrombectomy and thrombolysis during this time period is limited by population differences, again, between TRACE3 and Thymus. And then for poor external validity, as mentioned, large demographic differences between the study population and contemporary US population limit our applicability here at home. So for applying this to practice, I would say that it does have the potential to bring the thrombolysis window closer to the thrombectomy window, but better outcomes with a thrombectomy may limit widespread application. So a scenario that could be useful may be for patients presenting very late in the thrombectomy window that are geographically distant from a thrombectomy-capable center. And with that, we'll move into our polling questions. So which thrombolytic does your institution primarily utilize for the treatment of acute ischemic stroke? Well, for the vast majority, do use tenecteplase. So I think it is notable that this trial used tenecteplase, but predecessors for extending the thrombolytic window and for wake-up strokes primarily utilize alteplase as in wake-up and extent. And then my second question, is your institution considering extending the thrombolysis window beyond four and a half hours based on literature published since the 2019 guideline update? Okay, yeah, so the vast majority said no. I think at our center, it's not something that we're currently considering. Again, just due to that significant benefit that's seen with late presentation thrombectomy as opposed to thrombolysis. Okay, and with that, I would take any questions that you all might have. All right, feel free if you have any questions for Trent to throw those into the question box. We can start off with, why do you think they only included patients that had a National Institute of Health Stroke score of six to 25 in the trial to start? Okay, so I think that's a good question. Yeah, so I believe that this is a relatively standard NHS score that was used in previous trials, but I couldn't say that for certain. But I would imagine these patients also had a pretty large clinical core mismatch as was used in the Dawn study as well. So I believe it's probably a mix of those two things. Cool. Another thing I think that you highlighted was the difference kind of in their primary outcome as far as how they defined the modified rank-in between zero and one in this trial versus zero to two in Timeless. Can you kind of comment on, do you think one of those is more appropriate than the other or do you think they're just kind of looking at trying to target slightly different things? Yeah, I think that's a good question. So I think that is a great question. I think it depends on what your baseline functional status is. So if you're including patients that have a baseline MRS of zero to one and you're using that as your primary outcome, then that's really going to show that the intervention leads to no significant change in functional status before or after the stroke. However, if you're starting with a patient group that has an MRS of zero to two, that's really going to show that if you're starting with a patient group that has an MRS of zero to two, you're looking at the same thing, but you're also giving more room for some level of disability. And so in trials like Timeless that don't define what your initial distribution of baseline MRS scores are, it's really hard for us to gauge how much worse people got after their strokes. So I think using either is appropriate. So MRS two being no significant disability at 90 days, but I do think that it is more difficult to really assess the efficacy of the outcome if you don't have those specific things listed. Awesome. Well, thank you so much for that presentation, Trent. And now I would like to introduce our final presenter, Priya Patel. Thank you for the introduction. So today I'll be talking about apixaban or warfarin in patients with an onyx mechanical aortic valve, also known as the PROACT-10A trial. So before we delve into the PROACT-10A trial, I just wanted to provide some historical background on why this trial was conducted. So going back to the Realign trial that was conducted in 2013, this trial compared to vagotrans to warfarin for mechanical aortic and mitral valve replacements. However, this trial did end prematurely because of an increased embolic and bleeding rate seen in the dabigatran group. And due to this, our current guidelines recommend the use of warfarin for anticoagulation in mechanical heart valves and DOEX and direct dominant inhibitors are contraindicated for use. So why did warfarin show a better outcome as compared to dabigatran? And this could be due to warfarin acting on the tissue factor pathway as well as the common pathway. And it has been postulated that the tissue factor pathway plays the most important role in the development of thrombosis in mechanical heart valves. And dabigatran only inhibits thrombin, therefore making it less potent in patients with a mechanical heart valve. And we can see here that our PROACT-10A inhibitors work on the common pathway as well by inhibiting 10A. So in comparison to why can DOEX be a better option as compared to direct thrombin inhibitors, there are some proposed mechanisms. One of them being that DOEX may be more effective than dabigatran for preventing thrombosis due to mechanical heart valves primarily inducing local generation of thrombin in concentrations that far exceed those of dabigatran. So dabigatran has shown to inhibit thrombin in a one-to-one manner. So a dose of approximately 620 milligrams twice daily would be needed to achieve adequate antithrombotic effects in patients who have a mechanical heart valve. And therefore this would significantly increase the risk of bleeding. DOEX on the other hand, has found to attenuate thrombin generation at much higher concentrations. So each inhibitive molecule of rivaroxaban can block the production of 1000 molecules of thrombin. And there's also evidence that should indicate that the root cause of thrombosis on blood contacting medical devices is through the activation of factor XII. And since we don't have oral factor XII inhibitors, an oral factor 10A may be the next best option. So here, this was a RILA trial conducted in 2021. And this was an open label proof of concept trial. And what they looked at was rivaroxaban versus warfarin in patients with a mechanical heart valve. And they assessed thrombotic and bleeding outcomes between each arm. The dose that they used for rivaroxaban was 15 milligrams twice a day. The primary efficacy outcome was thrombosis and the primary safety outcome was bleeding. And they actually found similar thrombotic and bleeding events in both of the study arms. And therefore, suggesting that a larger trial with a similar design is not an unreasonable strategy. And then moving into the original PROACT trial that was conducted back in 2014. This trial essentially compared standard INR goals to a lower INR goal on the onyx aortic valve. And the standard INR goal was two to three versus the lower goal arm had an INR of two to three for three months. And then it was reduced down to 1.5 to two in combination with aspirin. And the study found that the lower goal resulted in lower bleeding events without a significant increase in thromboembolism. That's why specifically for the onyx aortic mechanical valve we are able to utilize this lower INR goal after three months. Moving into the PROACT-10A trial that was conducted in May of 2023. So the hypothesis of this study was to determine whether apixaban was non-inferior to warfarin in preventing valve thrombosis or valve-related thromboembolism in patients with an onyx mechanical aortic valve. And as seen by the original PROACT trial, we see that the onyx valve has a lower risk of thrombosis as compared to other mechanical heart valves. And additionally, the valve replacement in the aortic position also has a lower risk of thrombosis as compared to the mitral valve. And therefore, I thought that this objective was a feasible objective from a safety and ethical perspective. The study was a multi-centered, prospective, randomized open-label trial that had a blinded endpoint adjudication and it was conducted over two years. They included adult patients who were able to receive warfarin with a target INR of two to three and who had the onyx mechanical valve implant in the aortic position within three months of enrollment. They excluded any patients who had any cardiac surgery or ischemic stroke or intracranial hemorrhages within the previous three months of enrollment or if the patients are contraindicated to any therapy as well. If the patients were on dialysis or any renal dysfunction, they were also excluded or if they had any active pathological bleeding at the time of the study, they were also excluded. So in terms of the estimated sample size that they would need to meet 90% power, the investigators utilized a 1.75% rate to calculate a sample size of 990. They did a one-to-one randomization to a PIXIVAN five milligrams twice a day versus warfarin with an INR goal of two to three and both arms also remained on aspirin. Patients who were previously on the reduced INR goal were switched to two to three for the study duration and patients who met any dose reduction criteria for a PIXIVAN based on age, weight, or renal function were also dose reduced as stated in the package insert. And they also conducted both an as-treated and an on-treatment analysis. The outcome was a co-primary efficacy outcome of composite of valve thermosis or valve-related thromboembolism. And they also conducted a co-primary analysis which also included whether a PIXIVAN provided acceptable anticoagulation for the primary endpoint compared with an objective performance criterion or OPC that is set by the FDA. The primary safety outcome was any major bleeding defined as any episode of internal or external bleeding that caused a death, hospitalization, or permanent injury or necessitated transfusion, pericardial synthesis, or reoperation. And their secondary outcomes was individual components of the primary efficacy endpoints. And they also looked at bleeding based on the BARC and ISTH scales. So in terms of baseline demographics, they were pretty well compared between both of the arms. There were no major differences that I noted. The median age was about 56 years old in both arms and the female gender was approximately 24% in each arm. So in terms of the study results, the study did end early due to a high rate of thrombotic events that was seen in the PIXIVAN group. However, the study investigators still enrolled 883 patients, which is pretty close to the 990 that they needed to meet power. Looking at our primary efficacy outcome, which was a composite of valve thrombosis and valve-related thromboembolism, we can see that the PIXIVAN group had a 4.2% per patient year event rate versus 1.3% in Warfarin, and the rate difference was 2.9. So because the non-inferior priority margin was 1.75, a PIXIVAN did not meet non-inferiority as compared to Warfarin. Additionally, all of the valve-related valve thrombosis also occurred in the PIXIVAN group, as well as the thromboembolic stroke rates events that were seen were also all in the PIXIVAN group as well. And looking at our secondary or primary safety outcome of major bleeding, the event rate was 3.6 versus 4.5%. This was not statistically or clinically significant based off of the criteria that was set in the study. And additionally, the absolute higher number of event rates in the Warfarin group could have been led to the higher INR goal that was utilized in this study. And then looking at our cumulative incidence of valve thrombosis or valve-related thromboembolism from the Kaplan-Meier curve, we can see that at two years, the PIXIVAN group had a 5.5% risk of this event occurring versus Warfarin having a 1.5 event rate. So this study did have several strengths. It was one of the largest studies that assessed DOAC use in mechanical heart valve patients. And it was also a prospective randomized controlled trial. The baseline characteristics were well-balanced between both of the study arms, and the authors tried their best to reduce as much bias as possible by having a blind and edge education committee to assess for the primary safety and efficacy endpoints. Additionally, they standardized the INR goal to be two to three for all participants in the Warfarin arm. I thought this was an added benefit if they utilize the reduced INR goal of 1.5 to two, then a higher thrombotic event rate in this arm could have favored PIXIVAN over Warfarin. It was also a well-designed study that had clearly defined an objective criteria as they utilize specific FDA-approved OPCs or objective criterion to assess if a PIXIVAN would meet the anticoagulation parameters needed for a mechanical heart valve. The endpoints were also direct clinical measures that we as clinicians care about, and they were not surrogate markers, which really allows for its applicability to our practice. In terms of limitations, I thought that the dosing regimen utilized in this study was a limitation given that the original study, the proof of concept study that was conducted, they utilized RIVROXIVAN 15 milligrams twice a day, which is the dosing that we utilize for venous dermal embolism treatment. And in this study, they utilized the PIXIVAN five milligrams twice a day, and they were dose-reduced if the patient met any criteria for dose reduction. So they used the prophylactic dosing as compared to the therapeutic dosing. So it would have been interesting to see the study conducted in RIVROXIVAN at the dosing that was set in the proof of concept study. The trial also occurred during the COVID-19 pandemic. So another interesting thing to see would have been as a baseline parameter, how many patients were COVID-19 positive, as there has been studies published that have shown that COVID-19 can increase dermatic risk. Additionally, baseline laboratory parameters such as complete blood count and renal function, as well as liver function tests were not provided. This would have been interesting to see as there are studies that showcase that there's a potential risk of DOAC accumulation in patients who have liver and renal dysfunction. And additionally, a subgroup analysis in the patients that had an event, it would have been interesting to see what their DOAC concentration was, or their DOAC specific anti-TNA level was at the time of event. And additionally, this trial was only limited to the ONIX mechanical aortic valve. Therefore, this limits generalizability to other mechanical valves that are out there. And also if the valve is in the mitral position as opposed to the aortic position. So the key takeaway is that apixudine five milligrams twice a day does not meet criteria for non-inferiority compared with warfarin with a target INR of two to three for patients with an ONIX mechanical aortic valve. And the authors did state that the dumbbell embolic events rates in the apixudine group was not attributed to any recent valve implants, inappropriate apixudine dosing or apixudine interruption. And additionally, my conclusion is that given that there was a high number of event rates seen in an ONIX valve, which has a low threshold for thrombosis, indicates that apixudine specifically may not be safe or efficacious, even in patients with a non-ONIX valve, given that the thombotic outcomes that we saw in this study. However, again, it would be interesting to see a higher dose of the DOAC or specifically rivaroxaban used in this population. So this brings us to our first polling question. Do you commonly get asked by providers if DOACs can be utilized for mechanical aortic valve? This is what I was expecting. So, the reason why this study was how I chose this study is because when I was conducting my CVIC rotation, the providers actually did bring up the question if there's any recent literature on DOAC use in mechanical aortic valve. So, that's why I thought this was an interesting perspective. And then, the next question is, are DOAC-specific anti-TIN-A levels utilized at your institution to guide therapeutic decision making? So, at Houston Methodist Hospital, we actually do utilize DOAC-specific anti-tinnitus levels to determine the concentration of DOACs that the patients have in their system and to help us transition to therapeutic parenteral anticoagulation, so this was also interesting to see the practice at other institutions. And that concludes my presentation, and I can take any questions. Thank you for that. So, the first question we have is, did they comment on the time within goal INR for the warfarin group in the study? They did comment on this in the study, and approximately the patient's median INR time was 72% for the patients to be within the 2-3 goal. And then also a question about how often were the apixaban doses actually reduced, and do you think that could have been something that confounded the increased rate of apixaban failures, so to speak? So, dose reduction was actually very minimal in the study. I believe only two to three patients met the criteria for dose reduction, so I don't think that that could have been a major contributor to the outcomes that were seen in this study. Thank you for that. That will conclude our question and answer session, and again, we thank you, Priya, for your presentation. Thank you. I want to say thank you again to all of our presenters today and to all of you that attended. Please remember to join us on the third Friday of the month from 2-3 p.m. Eastern Time for our next Journal Club Spotlight on Pharmacy, and this will conclude our presentation for today.

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2024

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TRACE-3 Trial

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