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Internal Medicine Review 1
Internal Medicine Review 1
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I'd like to thank the organizers of this session and the Internal Medicine section for inviting me to present today in the Internal Medicine's Year in Review. So my half of the presentation is going to focus in on the biggest papers of the year focused on COVID-19 critical illness. And I title this, the Internal Medicine Year in Review, Another Year in COVID-19 as we've completed the second year of the pandemic. Now to give a brief outline, I'm going to focus on three aspects of new therapies for COVID-19 that are geared towards the host response to infection with SARS-CoV-2, namely steroids, anti-interleukin-6 therapies, and Janus kinase or JAK inhibitors. One conceptual way to think about treatment for COVID-19 is to think about what phase patients are in COVID-19 or what stage or severity that they are. And there's been a lot of focus on the early stages when viral replication is high and developing therapies to inhibit viral replication. And that's really the focus of outpatient therapies for COVID-19. Where it starts to get into our specialty is when patients progress into moderate and then severe and eventually critical illness. And it seems that in this phase of the syndrome COVID-19, inflammation and overactive inflammation really drives the organ injury rather than just viral replication. So the role of antivirals seems to be less so later on towards severe illness and critical illness. And that's where we get to targeting the host response to infection by decreasing inflammation. Now, in the first year of the pandemic, in 2020, our treatments for severe COVID-19 were rather limited. They were mostly limited to supportive care, namely high flow nasal cannula oxygen, invasive mechanical ventilation, and then the highest standards of care with ARDS therapies, such as low stretch mechanical ventilation and prone positioning. Now in terms of therapeutics, we had pretty limited therapeutics. The first therapeutic to get emergency use authorization approval was remdesivir, an antiviral drug. Now this drug seemed to show some benefit, but really isn't a game changer for severe COVID-19 treatment. The first treatment to really show a significant benefit in mortality, however, was dexamethasone, which was published first in preprint in late 2020 and then published formally in 2021. I'll briefly review that trial in a few slides. Now in 2021, we've expanded our knowledge to actually have specific treatments that may benefit patients with COVID-19 and severe COVID-19 specifically. And those include treatments targeting the inflammation cascades of interleukin 6 activation and JAK kinase activation. So for the first part of the talk, I'm going to talk about steroids for severe COVID-19. Now I'm not going to spend too much time on this because it was partially covered last year, but I do want to review it because it's been such an important breakthrough in the last in 2021. So the largest study ever to look at steroids in hospitalized patients with COVID-19 is the recovery study. And this is a randomized controlled trial that was performed in the United Kingdom and it randomized patients to receive dexamethasone 6 milligrams daily for up to 10 days versus usual care. And they randomized 2,104 patients to receive dexamethasone and 4,321 patients to receive control. Now their outcome demonstrated a mortality benefit where the mortality in the dexamethasone group was 22.9% and 25.7% in the control group at 28 days. Now at that time, there was equipoise as to whether steroids would benefit patients with COVID-19. There was the potential benefit of reducing inflammation, but also the potential harm of allowing for further viral replication and the prior evidence that showed that in influenza steroids may be harmful. And you can see here in this mortality curve that very early the two curves separate showing a small benefit to dexamethasone in terms of mortality. And if you look at specifically the patients stratified by whether they required invasive mechanical ventilation, oxygen, or were not on oxygen at time of randomization, you'll see that the largest benefits were in patients with invasive mechanical ventilation, but there was also a statistically significant benefit in patients that received oxygen at enrollment. But those that were not on oxygen didn't seem to see a benefit from dexamethasone, although this group was rather small. And now in meta-analysis looking at multiple different studies, all of which are smaller than the recovery study but are significant, we now have a nice signal that dexamethasone or any steroid really shows a benefit in severe COVID-19. Now there's been several different doses of steroids used, several different kinds of steroids. High dose dexamethasone was suggested to be beneficial in ARDS, in the dexa-ARDS study, so that's been considered as a possibility, as well as hydrocortisone and methylprednisolone. Now the highest quality of evidence comes from the recovery study, which used a low dose of dexamethasone, which may be associated with lower risk of side effects from a steroid infusion. However, if dexamethasone is not available, other steroids seem to have a similar benefit. Now the questions that are still being asked are relevant to steroids. The most recent question that's been published is, what dose of steroids should we use? So this was a trial published this year, looking at 12 milligrams versus 6 milligrams of dexamethasone, saying do we need more steroids or less steroids? This was a blinded, randomized controlled trial in Europe and India, the COVID Steroids 2 trial group. They included patients with COVID-19 confirmed and that were on at least 10 liters per minute of oxygen or who were mechanically ventilated. They randomized to IV dexamethasone at 12 milligrams per day versus 6 milligrams per day. Their primary outcome were days alive without life support at 28 days. In this study, they randomized a thousand subjects and they saw that in the higher group, the days alive without life support was about one and a half days higher than the 6 milligram per day group. This just missed statistical significance. The mortality also seemed to trend towards a mortality benefit at 27.1% in the higher dose dexamethasone group versus 32.3% in the lower dose. However, again, this was not statistically significant. But if you look at the time curve to death here, you can see that there seems to be a benefit to 12 milligrams of dexamethasone or potential benefit that doesn't quite reach statistical significance. It leaves the question unanswered as to whether 6 milligrams or 12 milligrams are a benefit in different patient populations. Now it is important that this trial was done specifically to look at steroids and didn't include patients that received other immunomodulators that I'm going to talk about a little later in this talk. So that moves us to the next group of drugs that have developed for COVID-19. And those are the interleukin-6 antagonists in severe COVID-19. Interleukin-6 is a inflammatory cytokine that's released in response to infection and stimulates inflammatory pathways through the interleukin-6 receptor that can lead to sepsis. Tocilizumab and serolumab are monoclonal antibodies that inhibit both membrane-bound and soluble IL-6 receptors. They are used to treat inflammatory conditions such as rheumatoid arthritis and cytokine release syndrome after CAR-T therapy, CAR-T cell therapy. Now early in the pandemic, people were using tocilizumab without randomized controlled trial evidence to potentially treat the inflammatory storm that was being seen with COVID-19. But this year, we actually have several trials that are suggesting a benefit to the use of anti-IL-6 therapy. The first large study to demonstrate a benefit to IL-6 receptor antagonists was the REMAP-CAP study published in 2021. The REMAP-CAP study is very interesting because it's both innovative by identifying a new therapeutic for severe COVID-19, but also employs very innovative study design relying on an adaptive platform trial that employs Bayesian statistics. The trial really demonstrated how COVID-19 has accelerated research in critical care and moved us towards more innovative methods and efficient methods of identifying therapeutics. Now this was an international multifactorial adaptive platform trial. Patients were included if they were adults admitted to an ICU with COVID-19 and required respiratory or cardiovascular support. Now respiratory support was defined as invasive or non-invasive mechanical ventilation, including high flow nasal cannula as long as the FiO2 was greater than 40%. Cardiovascular support was defined as being on vasopressors or inotropes. Now despite having these two forms of organ support, the large majority of enrolled patients met the respiratory support requirement. And even if they met the cardiovascular support requirement, they also tended to meet the respiratory support requirement. Now they were enrolled within 24 hours after starting organ support. And for this part of the platform trial, now as a platform trial, this included testing multiple different therapies. But for the immune modulation therapy domain, they randomized patients to tocilizumab, sarilimab, or control. And they actually had several other arms aimed at other cytokines besides IL-6, but those arms tended to be small and weren't included in this publication. Now they randomized patients was randomized based on a randomized algorithm, but also on availability of the drugs at the particular center. And there were times where sarilimab was not available during the study. Now their primary outcome was number of respiratory and cardiovascular organ support free days up to day 21. And those days were defined the same way the inclusion criteria were defined in terms of respiratory and cardiovascular organ support. And death as a competing risk was assigned the extreme. So it was assigned minus one. Now their statistics are complicated and I can't fully explain them in this forum. But they used a Bayesian design with regular estimates of the posterior probability and stopping rules for efficacy and futility. So the Bayesian study design allows the study to continue with no maximum maximal sample size. So sample size is not calculated a priori, but the trial continues until it reaches one of the stopping criteria. So the study will continue to enroll until the preset specified posterior probabilities of efficacy or futility are met. The benefits to Bayesian approach include the ability to improve efficiency by stopping the trial once the probabilities are met, but also not running into the problem of incorrect sample sizes and underpowering. The problems include difficulty estimating cost up front and difficulties in interpreting among clinicians who are versed, well versed in the frequentist statistics, but may not fully understand Bayesian statistics. Now what they found in their primary outcome is that the median organ support free days in the tosalizumab arm was 10. The sarilimab arm was 11, although this was a much smaller group, 48 patients versus 353. And then among the 402 controls, the median organ support free days was zero. And remember, minus one means that the patient died. Now this was with an adjusted odds ratio for tosalizumab and sarilimab compared to control were statistically significant benefits in organ free support days. And if you look at in-hospital mortality, the in-hospital mortality was 28% in tosalizumab, 22% in sarilimab and 36% in control. Another statistically significant mortality benefit. Now this trial was published in the context of several other trials that are already been published that showed no benefit in mortality to use of IL-6 inhibitors like tosalizumab. But the authors argue there are several differences to this trial compared to the other trials that were previously published. The first is they had a much larger sample size than the prior studies who were likely all underpowered to identify a mortality benefit of IL-6 inhibition. This trial also only includes critically ill patients. Older trials tended to include patients when they first presented with COVID-19 and not just when they progressed to critical illness. And those patients might have actually watered down the effect of tosalizumab. The drug was also given very early in critical illness within the first 24 hours in this study. And most patients in this study also received steroids as opposed to prior studies that were done prior to the publication of the benefit of corticosteroids for COVID-19. Now on the other hand, there's one potential criticism of this study that might explain why there was a benefit identified that wasn't in older studies. And that was that it was open label. Prior studies were blinded and this study was not conducted in a blinded manner and therefore could have influences on the primary outcomes. Now another study that was even larger that confirmed the benefits, the potential benefits of tosalizumab in patients admitted to the hospital with COVID-19 was again the recovery study. And you'll remember this is the same study that identified a benefit of dexamethasone. After they finished dexamethasone, they moved on to looking at tosalizumab. So this was a randomized controlled open label platform trial that is now testing tosalizumab. It included patients that tested positive for COVID-19 who had some degree of hypoxia. And for the purposes of this part of the trial, they also had to have markers of inflammation, specifically the CRP greater than 75 milligrams per liter. Now they were enrolled once they met 21 days after the main enrollment. So patients could be enrolled in the main platform trial testing multiple different therapies once they were admitted with COVID-19 and then they could be followed as long as 21 days for the development of hypoxia and an elevated CRP. If they develop that, they received a dose of tosalizumab and then if they didn't improve within 12 to 24 hours, at the discretion of the treating clinicians, they could get a second dose of tosalizumab. And this was relative to control. Now importantly in this trial, 82% of people will also receiving corticosteroids because of the results of the original recovery trial. Their primary outcome was 28 day mortality and their statistics were the standard frequentist statistics based on an intention to treat analysis. And what they found is that there was a 4% reduction in mortality from 35% to 31% with treatment with tosalizumab. This was highly statistically significant and conferred a relative risk of 0.85. And if you look at the mortality hazard curve, you can see that the usual care group had a higher mortality that separates very early in the curve. Now in subgroup analysis in this trial, it appeared that the benefit was actually highest in the corticosteroid group because there was some concern, is tosalizumab an add-on to corticosteroids or is it an alternative to corticosteroids? And this trial, while it was a subgroup analysis, seems to suggest that it's an add-on therapy on top of corticosteroids. And we now have a large meta-analysis that looks at all the trials, including the smaller and earlier ones that didn't show a benefit at anti-IL-6 agents. What I show here is a forest plot for the tosalizumab-specific trials. And you can see that the largest trials contributing to this are the RECOVERY trial and the REMAP-CAP trial. And they seem to favor anti-IL-6 therapy with an odds ratio of 0.83. And when you specifically break down as to whether the patients received corticosteroids or not, what you can see is with any anti-IL-6 therapy, the 28-day mortality benefit favors in patients that also received corticosteroids. There's a really strong association in those patients that also received corticosteroids, but less so in patients that didn't receive corticosteroids. Now this was also true for progression to invasive mechanical ventilation for those that weren't already mechanically ventilated, ECMO, and death at 28 days. And interestingly, when you look at infections, which is the really concern of getting so much anti-inflammatory therapy is infections, they did not see an increased risk of infections in the patients that received both anti-IL-6 therapy and corticosteroid use. So that completes my part of the talk on anti-IL-6 therapies. And I want to move to another similar therapy, looking at the Janus kinase inhibitor or JAK inhibitors in severe COVID-19. I'm going to specifically focus in on biocitinib because it probably has the best evidence of the JAK kinase inhibitors. So interesting, biocitinib primarily functions as a JAK1-2 inhibitor and is FDA approved for the treatment of rheumatoid arthritis. It was first identified as a potential therapeutic for COVID-19 by an artificial intelligence platform that screens already approved drugs for potential treatments for COVID-19. Biocitinib is hypothesized to potentially impact distinct pathways that may lead to improvements in COVID-19. First, biocitinib inhibits intercellular signaling of cytokines, including IL-6, by inhibiting JAK1-2. Second, biocitinib also binds to GAK and AAK1 and inhibits AAK1, two proteins important in viral entry in pulmonary epithelial cells. Based on this information, several randomized controlled trials were conducted to evaluate the role of biocitinib in combination with other therapies in patients hospitalized with COVID-19. Biocitinib, however, has several important known risks. And we know these risks from prior literature in the rheumatoid arthritis population. Those risks include severe infections, reactivation of tuberculosis, malignancy, and importantly, thrombosis. And you'll see in the next few slides that these risks informed the inclusion criteria for the trials I'm going to discuss and should form the inclusion criteria for patients we select to receive biocitinib. So the first major study published to show a benefit of biocitinib is the ACT-2 study. This was a double-blinded, randomized placebo-controlled trial at 67 sites, mostly in the United States, but including other countries as well. And this is a follow-up study of the ACT-1 study, which was the study that showed a benefit to remdesivir. Now, the inclusion criteria included hospitalized patients with COVID-19 that were adults. And there were a long list of exclusion criteria, but the most important ones I have listed here, which are an elevation in transaminases greater than five times the upper limit of normal, an estimated GFR of less than 30, whether the patient was neutropenic or lymphopenic, which is not uncommon in COVID, a suspicion for other infections, not SARS-CoV-2, but some other kind of viral or bacterial infection or fungal infection, and then a history of VTE, venous thromboembolism, because this drug is known to increase the risk of venous thromboembolism. Now, in this trial, the intervention was baricitinib for 14 days plus remdesivir versus placebo plus remdesivir. Patients were additionally required to be on heparin prophylaxis, anticoagulation prophylaxis. Their primary outcome was time to recovery in 28 days. And they define recovery based on an ordinal scale, the WHO ordinal scale of one, two, or three. And this basically means that either had to be hospitalized, but no longer on oxygen or not hospitalized. And their secondary outcomes were mortality and clinical status at day 15, but they acknowledged that they did not power the study for mortality. And this study enrolled 1,033 patients hospitalized with COVID-19. And in the intervention group, the median time to recovery was seven days as opposed to eight days in the placebo versus plus remdesivir group with about 515 versus 518 patients enrolled in each group. Now, this was statistically significant median time to recovery. And interestingly, the time to recovery was fastest or most different in patients that were most sick. So patients receiving high flow oxygen or non-invasive ventilation, if they received baricitinib, they resolved within 10 days versus 18 days in the placebo plus remdesivir group. The rate of serious adverse events was actually lower in the baricitinib plus remdesivir group than the control group at 16% versus 21%. Now when they looked at mortality, the mortality was 5.1% in the intervention group and 7.8% in the control group, which was unfortunately not statistically significant and really reflects that they enrolled a very diverse group of patients that are hospitalized with COVID-19. Now the effects also appear to be strongest among patients requiring high levels of oxygen, but not invasive mechanical ventilation. Now there are several limitations to the study. They had no statistically significant mortality benefit. It was performed prior to the results of recovery. So steroids were actually not permitted unless there was another indication and the long-term effects were not evaluated. So that brings us to the second study looking at baricitinib for the treatment of hospitalized adults with COVID-19. This is the COVE Barrier Study, a randomized double-blinded parallel group placebo-controlled phase three trial. So they included patients that were hospitalized with COVID-19 that had evidence of pneumonia that were adults and had elevated inflammatory markers. So specifically they had to have an elevated CRP, D-dimer, LDH, or ferritin. Now midway through the trial, they did have a protocol change based on the prior trial I just presented, and patients required to be on O2 at enrollment. Now they excluded very similar groups of patients as the ACT-II trial. In addition, they excluded patients that were mechanically ventilated. Their intervention was baricitinib for 14 days plus standard of care versus placebo plus standard of care. But importantly in this trial, different than the ACT-II trial, standard of care included dexamethasone in the majority of patients. However, high dose steroids were prohibited unless they were needed for another indication. Their primary outcome was the proportion progressing to high flow, non-invasive ventilation, invasive mechanical ventilation, or death by 28 days. Their secondary outcome was mortality. Now they enrolled 1,525 patients between June 2020 and January 2021, huge massive effort. But their primary outcome was not statistically significant. So the percentage of people that progressed to high flow, non-invasive or invasive mechanical ventilation or death by day 28 was 27.8% in the intervention group versus 30.5% in the control group. And this was not statistically significant. However, to their surprise, their secondary outcome, all-cause mortality, was highly statistically significant. So it was 8% in the treatment group versus 13% in the control group. And you can see that here in this mortality curve. Now the limitations to this study are that the primary outcome was not met. 22% of patients progressed within 24 hours. And we wouldn't really expect the baricitinib to work so quickly. So it seems like a lot of people were already on their way to meeting the outcome before even given the opportunity for baricitinib to work. They also had several protocol changes, including their enrollment criteria and their sample size midway through the trial. They don't have long-term follow-up, and there are potential long-term effects of baricitinib. And they excluded patients that were mechanically ventilated. But this does seem to suggest that baricitinib may have a mortality benefit for patients with COVID-19. Now they did follow up this study, the same study group, by looking at patients that were on invasive mechanical ventilation or extracorporeal membrane oxygenation in an exploratory randomized control trial of 101 patients, 86% of whom also received corticosteroids. And they saw a really large mortality benefit. The treatment was 39% mortality versus control, 58% mortality. This was statistically significant, although I'll remind you this is a relatively small trial. And their estimated number needed to treat was six, suggesting baricitinib can also be used in the invasively mechanically ventilated and those patients on ECMO. Now there have been a ton of COVID studies in the last year, and I can't obviously cover all of them. And there are a lot that were really significant that I can't cover today. But namely, I think it's important to acknowledge that some of the topics I didn't cover today are COVID-19 epidemiology, and specifically how the impact of race, socioeconomic status and ethnicity are in COVID-19. A lot of that we recognized two years ago in the very early parts of the pandemic, as well as the impact of air pollution exposure on COVID-19 risk, explaining some of the disparities in COVID-19. I also didn't cover the anticoagulation in COVID-19, which has an extensive body of literature that was developed in the last year, including prophylaxis, intermediate dose or full anticoagulation. I didn't cover specific populations like cancer and transplant that are really showing different flavors of COVID-19. And then I didn't speak of the multisystem inflammatory syndrome that has its highest relevance in children, but is also a syndrome that is occasionally seen in adults and requires unique treatment. Hopefully, we can cover those in a future lecture. I'd like to again, thank everybody for listening. I really appreciate your time.
Video Summary
In this presentation, the speaker discusses the latest research on therapies for COVID-19 critical illness. They focus on three treatments: steroids, anti-interleukin-6 therapies, and Janus kinase (JAK) inhibitors. The speaker explains that in the early stages of COVID-19, antivirals are commonly used to inhibit viral replication. However, as patients progress into moderate and severe illness, inflammation becomes a major driver of organ injury. Steroids, such as dexamethasone, have shown significant benefits in reducing mortality in severe COVID-19 cases. Anti-interleukin-6 therapies, like tocilizumab and sarilumab, have been shown to be effective in reducing mortality and organ support days in critically ill patients. The JAK inhibitor, baricitinib, has also demonstrated potential benefits in reducing mortality. The speaker also highlights other important research areas, such as COVID-19 epidemiology, the impact of air pollution exposure, anticoagulation, and the multisystem inflammatory syndrome.
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Research, Quality and Patient Safety, 2022
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This session will highlight the latest research, lessons learned, and changes taking place in critical care internal medicine practice during the past year.
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Quality and Patient Safety
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COVID-19 critical illness
steroids
anti-interleukin-6 therapies
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mortality
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