Stimulus Podcast 61 - Outpatient COVID-19 Therapy with Salim Rezaie, MD

The treatment of non-hospitalized patients suffering from COVID-19 is a hot topic and constantly changing. Today we have a conversation with Salim Rezaie, MD whose dive into this literature couldn’t be much deeper. We discuss which subgroup of patients might benefit from monoclonal antibodies, why the jury is still out on the benefit of ivermectin, the role of inhaled budesonide, and outpatient anticoagulation which hasn’t been studied, but hopefully will be someday.

Guest Bio:  Salim Rezaie completed his medical school training at Texas A&M Health Science Center and continued his medical education with a combined Emergency Medicine/Internal Medicine residency at East Carolina University.  He currently works as a community emergency physician at Greater San Antonio Emergency Physicians (GSEP) where he is the director of clinical education.  Salim is the creator and founder of REBEL EM and REBEL Cast, a free, critical appraisal blog and podcast that tries to cut down knowledge translation gaps of research to bedside clinical practice. Hear more from Salim on Stimulus #16 Accumulation of Marginal Gains.

 

The treatment of non-hospitalized patients suffering from COVID-19 is a hot topic and constantly changing. Today we have a conversation with Salim Rezaie, MD whose dive into this literature couldn’t be much deeper. We discuss which subgroup of patients might benefit from monoclonal antibodies, why the jury is still out on the benefit of ivermectin, the role of inhaled budesonide, and outpatient anticoagulation which hasn’t been studied, but hopefully will be someday.

Guest Bio:  Salim Rezaie completed his medical school training at Texas A&M Health Science Center and continued his medical education with a combined Emergency Medicine/Internal Medicine residency at East Carolina University.  He currently works as a community emergency physician at Greater San Antonio Emergency Physicians (GSEP) where he is the director of clinical education.  Salim is the creator and founder of REBEL EM and REBEL Cast, a free, critical appraisal blog and podcast that tries to cut down knowledge translation gaps of research to bedside clinical practice. Hear more from Salim on Stimulus #16 Accumulation of Marginal Gains.

 

We Discuss:   The fact that the best treatment of COVID is prevention through vaccination [2:30]; “Study after study has shown that the risks of bad things happening are much worse if you get COVID than if you get the vaccine.” The value and purported benefit of monoclonal antibodies [03:21]; The Recovery Trial found that if you give monoclonal antibodies to everyone with COVID, they don’t appear to have much benefit. The subgroup of patients who did benefit from monoclonal antibodies, however, were those who didn’t have a robust immune response to COVID (those who were seronegative). This includes patients who are immunocompromised, elderly, have comorbid disease, and, perhaps, are unvaccinated. The trial found both a survival and a disease severity benefit for those who were seronegative. Monoclonal antibodies boost the immune response for those who do not mount a great enough response on their own. The problem is that in the US, we’re not checking for seronegativity. So we have to estimate a patient’s risk to determine if this multi-thousand dollar medication should be given. Whether a rapid antibody test would help predict seronegativity [06:30]; Unfortunately, while it’s possible a rapid test would suffice, that’s not the way the study was done. They were doing quantitative antibody values. “I guess if you have a rapid test that tells you there’s no IgG or much IgM, I could see that working. It's better than what we're currently doing, which is driving blind.” Specifically which monoclonal antibodies are being used in Salim’s shop [07:40]; Initially they were using bamlanivimab, but then they found it didn’t work so well for those with Delta or other new variants. The ones that seem to show the most benefit are those that combine different types of monoclonal antibodies in one, like Regeneron. At Salim’s hospital, they are giving Regeneron only to people who meet strict criteria (ie., high risk and early in the disease process). Early on, they were trying to meet the demands of everyone who wanted it, but then supplies started to diminish and they were running out of it for the people who needed it most. The irony of people demanding monoclonal antibodies, but refusing vaccination because they don’t know what's in it [08:50]; “You know what else we don't know exactly what's in it? Chicken McNuggets. There's so many things in life that we don't really know what's in it. But yet we take it. Unfortunately, many people draw the line at the COVID vaccine.” Why you can’t trust everything you read about COVID therapy in a news headline [12:40]; “The plural of anecdote is not data.” Just because you believe something works or you think you’re seeing a positive effect from it doesn't mean that it actually works. You need a randomized controlled trial to compare a therapy with placebo to ensure that it’s the drug and not another variable which is having the impact. When making decisions about therapies, you need to do your own research (which is not the same as listening to someone’s opinion on YouTube or reading a newspaper). You must look at the studies, the outcomes, the methodology, and then make a scientific decision based on that evidence. Using ivermectin studies as an example, there have been 30-40 trials and the one that was methodologically sound was pulled due to falsified data. While the headline might read, “Ivermectin Works”, the truth is that oftentimes confounding factors, something other than the ivermectin, are what’s making that difference. One of the largest ivermectin studies which was based on falsified data, yet continues to influence the results of meta-analyses [15:30]; A randomized trial out of Egypt looked at 800 patients who received either ivermectin or no ivermectin. They found a benefit, but the study was retracted because the data was falsified. Meta analyses that continue to include this data show benefit, but those that exclude it show no ivermectin benefit. Even if we believed that ivermectin works, there’s still so much we don’t know about it -- such as ideal dose, duration of therapy, etc. Bottom line -- the jury is still out on ivermectin. Inhaled budesonide for COVID-19 symptom control [22:00]; The STOIC Trial randomized patients to inhaled budesonide vs. no budesonide and found no improvement in mortality or severity of disease, but there was improvement in symptoms. Salim prescribes budesonide to COVID-19 patients who have symptoms of dyspnea but don’t have hypoxemia. His hope is that it might reduce the number of return ED visits or need for hospitalization. The slippery slope of outpatient anticoagulation [23:39]; 2 multi-platform, controlled trials were published on the topic of anticoagulation. One looked at COVID-19 patients who were critically ill (ie. required ICU level care) and the other included only non-critically ill patients (ie. hospitalized, but not in the ICU). Of note, any patient who required high flow nasal cannula, noninvasive ventilation or greater was considered ICU level of care. The study of critically ill patients showed that therapeutic anticoagulation (compared to prophylactic) caused harm in these sicker patients, primarily due to bleeding complications. So the recommendation is prophylactic anticoagulation for ICU patients. Non-critically ill patients (those who could be managed with nasal cannula, non-rebreathers, or oxymizers) appeared to benefit from therapeutic anticoagulation in terms of severity of disease and mortality. Why might this be? Salim’s conjecture is that COVID-19 patients get caught in a cycle of hypoxemia which leads to pulmonary vasoconstriction which further leads to worsening hypoxemia. In addition, COVID-19 is a thrombogenic disease which damages the vascular endothelium. So, if you can anticoagulate patients early enough, before they have microthrombi, then they’ll get less hypoxemia, less pulmonary vasoconstriction, and a greater chance of clinical improvement. The slippery slope is wondering about the potential benefit of outpatient anticoagulation. The things Salim might do if he had symptomatic COVID-19 and was well enough to be managed as an outpatient [27:25]; Prone sleep position. Sleeping on your stomach has been shown to shift vascular blood flow which can help with hypoxemia. Incentive spirometry. It works similarly to non-invasive ventilation, helping recruit alveoli. Inhaled budesonide. As discussed, this may help with symptomatology. Take antioxidants. Vitamin C, vitamin D and melatonin are touted to have antioxidant and immune boosting effects. They may help and likely wouldn’t hurt. And more.   Shownotes by Melissa Orman, MD   The fact that the best treatment of COVID is prevention through vaccination [2:30]; “Study after study has shown that the risks of bad things happening are much worse if you get COVID than if you get the vaccine.” The value and purported benefit of monoclonal antibodies [03:21]; The Recovery Trial found that if you give monoclonal antibodies to everyone with COVID, they don’t appear to have much benefit. The subgroup of patients who did benefit from monoclonal antibodies, however, were those who didn’t have a robust immune response to COVID (those who were seronegative). This includes patients who are immunocompromised, elderly, have comorbid disease, and, perhaps, are unvaccinated. The trial found both a survival and a disease severity benefit for those who were seronegative. Monoclonal antibodies boost the immune response for those who do not mount a great enough response on their own. The problem is that in the US, we’re not checking for seronegativity. So we have to estimate a patient’s risk to determine if this multi-thousand dollar medication should be given. Whether a rapid antibody test would help predict seronegativity [06:30]; Unfortunately, while it’s possible a rapid test would suffice, that’s not the way the study was done. They were doing quantitative antibody values. “I guess if you have a rapid test that tells you there’s no IgG or much IgM, I could see that working. It's better than what we're currently doing, which is driving blind.” Specifically which monoclonal antibodies are being used in Salim’s shop [07:40]; Initially they were using bamlanivimab, but then they found it didn’t work so well for those with Delta or other new variants. The ones that seem to show the most benefit are those that combine different types of monoclonal antibodies in one, like Regeneron. At Salim’s hospital, they are giving Regeneron only to people who meet strict criteria (ie., high risk and early in the disease process). Early on, they were trying to meet the demands of everyone who wanted it, but then supplies started to diminish and they were running out of it for the people who needed it most. The irony of people demanding monoclonal antibodies, but refusing vaccination because they don’t know what's in it [08:50]; “You know what else we don't know exactly what's in it? Chicken McNuggets. There's so many things in life that we don't really know what's in it. But yet we take it. Unfortunately, many people draw the line at the COVID vaccine.” Why you can’t trust everything you read about COVID therapy in a news headline [12:40]; “The plural of anecdote is not data.” Just because you believe something works or you think you’re seeing a positive effect from it doesn't mean that it actually works. You need a randomized controlled trial to compare a therapy with placebo to ensure that it’s the drug and not another variable which is having the impact. When making decisions about therapies, you need to do your own research (which is not the same as listening to someone’s opinion on YouTube or reading a newspaper). You must look at the studies, the outcomes, the methodology, and then make a scientific decision based on that evidence. Using ivermectin studies as an example, there have been 30-40 trials and the one that was methodologically sound was pulled due to falsified data. While the headline might read, “Ivermectin Works”, the truth is that oftentimes confounding factors, something other than the ivermectin, are what’s making that difference. One of the largest ivermectin studies which was based on falsified data, yet continues to influence the results of meta-analyses [15:30]; A randomized trial out of Egypt looked at 800 patients who received either ivermectin or no ivermectin. They found a benefit, but the study was retracted because the data was falsified. Meta analyses that continue to include this data show benefit, but those that exclude it show no ivermectin benefit. Even if we believed that ivermectin works, there’s still so much we don’t know about it -- such as ideal dose, duration of therapy, etc. Bottom line -- the jury is still out on ivermectin. Inhaled budesonide for COVID-19 symptom control [22:00]; The STOIC Trial randomized patients to inhaled budesonide vs. no budesonide and found no improvement in mortality or severity of disease, but there was improvement in symptoms. Salim prescribes budesonide to COVID-19 patients who have symptoms of dyspnea but don’t have hypoxemia. His hope is that it might reduce the number of return ED visits or need for hospitalization. The slippery slope of outpatient anticoagulation [23:39]; 2 multi-platform, controlled trials were published on the topic of anticoagulation. One looked at COVID-19 patients who were critically ill (ie. required ICU level care) and the other included only non-critically ill patients (ie. hospitalized, but not in the ICU). Of note, any patient who required high flow nasal cannula, noninvasive ventilation or greater was considered ICU level of care. The study of critically ill patients showed that therapeutic anticoagulation (compared to prophylactic) caused harm in these sicker patients, primarily due to bleeding complications. So the recommendation is prophylactic anticoagulation for ICU patients. Non-critically ill patients (those who could be managed with nasal cannula, non-rebreathers, or oxymizers) appeared to benefit from therapeutic anticoagulation in terms of severity of disease and mortality. Why might this be? Salim’s conjecture is that COVID-19 patients get caught in a cycle of hypoxemia which leads to pulmonary vasoconstriction which further leads to worsening hypoxemia. In addition, COVID-19 is a thrombogenic disease which damages the vascular endothelium. So, if you can anticoagulate patients early enough, before they have microthrombi, then they’ll get less hypoxemia, less pulmonary vasoconstriction, and a greater chance of clinical improvement. The slippery slope is wondering about the potential benefit of outpatient anticoagulation. The things Salim might do if he had symptomatic COVID-19 and was well enough to be managed as an outpatient [27:25]; Prone sleep position. Sleeping on your stomach has been shown to shift vascular blood flow which can help with hypoxemia. Incentive spirometry. It works similarly to non-invasive ventilation, helping recruit alveoli. Inhaled budesonide. As discussed, this may help with symptomatology. Take antioxidants. Vitamin C, vitamin D and melatonin are touted to have antioxidant and immune boosting effects. They may help and likely wouldn’t hurt. And more.   Shownotes by Melissa Orman, MD