November 13, 2020
A COVID-19 Update that is Long Overdue
Background: There have been lots of trials sitting on my computer desktop awaiting my review, but like many of you time has been thin from clinical work and increasing cases of COVID-19 where I work. I thought it might be more effective to give you the Cliff’s Notes highlights of each since the time for deep dives remains elusive. As always, I urge you to read each of the papers yourselves and come to your own conclusions.
Thus far in the pandemic, there have been few treatment options available to manage COVID-19. Many clinicians have been using repurposed drugs with scant data as well as other non-drug interventions. Let’s get into some recent data behind these interventions.
WHO SOLIDARITY Interim Results 
Clinical Question: Does the use of remdesivir reduce mortality in hospitalized patients with COVID-19? (The authors also looked at hydroxychloroquine, lopinavir, and interferon-B1a in this trial, but we are going to focus on remdesivir only)
The WHO expert groups conducted a large, multi-national, open-label, randomized clinical trial of 4 medications: remdesivir, hydroxychloroquine, lopinavir and interferon-B1a. The primary analysis was looking at in-hospital mortality. 405 hospitals in 30 countries with 11,266 adults were randomized. We will specifically focus on remdesivir in this post. 2750 patients allocated to remdesivir and 2708 patients in the control group. There was no placebo used in this trial. Remdesivir dosing was 200mg on day 1 and then 100mg on the next 9 days (10 days total).
- In-hospital Mortality:
- Remdesivir: 11.0%
- Control: 11.2%
- Remdesivir Death Rate Ratio: 0.95; 95% CI 0.81 to 1.11; p = 0.50
- This was an adaptive trial, so unhelpful medications could be dropped. Hydroxychloroquine and Lopinavir were eventually dropped
- None of the 4 medications in this trial reduced mortality, initiation of ventilation, and hospitalization duration
- This interim analysis is only ≈75% of the study population and we will have to wait for the rest of the results.
- Looking at all the RCTs on Remdesivir, there appears to be a niche population where remdesivir has its effect…patients on low flow O2
Author Conclusion: “These Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon and are consistent with meta-analyses of mortality in all major trials.”
Clinical Take Home Point: I have said it before and I will say it again…remdesivir is a drug looking for a disease, and at best is an expensive Tamiflu, working only in a select group of patients in reducing symptoms, having no effect on mortality, and potential side effects.
PLACID Trial 
Clinical Question: Is convalescent plasma + standard care more effective than standard care alone in moderate COVID-19?
This was an open-label, parallel arm, phase II, multicenter randomized controlled trial investigating the effectiveness of convalescent plasma to treat moderate COVID-19 in 464 adults across 39 hospitals in India.
Moderate COVID-19 was defined as PaO2/FiO2 ratio between 200- and 300-mm Hg or a respiratory rate >24/min with an oxygen saturation of < 93% on room air. Patients were randomized to two doses of 200mL of convalescent plasma (CP), transfused 24 hours apart + standard care (SC) vs standard care alone. The main outcome of the trial was a composite of progression of severe disease (PaO2/FiO2 <100mmHg) or all-cause mortality at 28 days post-enrollment.
- Progression to Severe Disease or All-Cause Mortality at 28d:
- CP + SC: 19%
- SC Alone: 18%
- Risk Diff 0.008; 95% CI -0.62 to 0.078
- Risk Ratio: 1.04; 95% CI 0.71 to 1.54
- Mortality at 28d:
- CP + SC: 15%
- SC Alone: 14%
- RR 1.04; 95% CI 0.66 to 1.63
- Although this was a negative study, the level of antiviral neutralizing antibodies was fairly low in this trial. Previous evidence from the US Expanded Access Program, showed that higher titers are more effective than lower titers.
- Important exclusion criteria were critically ill patients with PaO2/FiO2 <200mmHg or shock (requiring vasopressors to maintain a MAP of ≥65mmHg or a MAP of <65mmHg)
- Underpowered study and therefore take the results with caution
- Because this is an open-label trial, treating physicians could have had bias in reporting. For example, no differences in objective outcomes of death, but more resolution of subjective symptoms such as shortness of breath and fatigue
Author Conclusion: “Convalescent plasma was not associated with a reduction in progression to severe COVID-19 or all-cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralizing antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of COVID-19.”
Clinical Take Home Point: Unfortunately, this trial does not help us much about the effectiveness of convalescent therapy in COVID-19, however it is the highest level of evidence we have to date. Despite being a negative trial, it is underpowered, and, most importantly, the neutralizing antibody titer levels were low.
Clinical Question: In patients with severe COVID-19 does therapeutic enoxaparin or standard anticoagulant thromboprophylaxis improve gas exchange over time?
This was a randomized, open-label, phase II study in which COVID-19 patients requiring mechanical ventilation received either therapeutic enoxaparin or standard anticoagulant thromboprophylaxis. The authors evaluated gas exchange over time through a ratio of PaO2/FiO2 at baseline, 7-, and 14-days after randomization in 20 patients.
- PaO2/FiO2 Ratio Over Time:
- Therapeutic AC:
- Baseline: 163
- 7d: 209
- 14d: 261
- Prophylactic AC:
- Baseline: 184
- 7d: 168
- 14d: 195
- Patients on therapeutic AC had a higher ratio of successful liberation from mechanical ventilation (HR 4.0; 95% CI 1.035 to 15.053; p = 0.031) and more ventilator-free days (15d vs 0d) compared to prophylactic AC
- No major bleeding in either group
- Therapeutic AC:
- Previous observational trial of 2,773 patients with COVID-19 showed an association with improved mortality outcomes in patients requiring invasive mechanical ventilation when therapeutic AC was used instead of no anticoagulation.
- There was no difference in 28 day mortality and in-hospital mortality between groups, however there was a trend toward improved outcomes with therapeutic AC (28d mortality 10% vs 30% and in-hospital mortality 20% vs 50%) compared to prophylactic AC
- Single center small trial makes the trial underpowered to assess differences in mortality between two groups
Author Conclusion: “Therapeutic enoxaparin improves gas exchange and decreases the need for mechanical ventilation in severe COVID-19.”
Clinical Take Home Point: In this small trial, patients with COVID-19 on mechanical ventilation had improved gas exchange over time, decreased d-dimer levels and a higher ratio of successful liberation from mechanical ventilation when treated with therapeutic enoxaparin when compared to prophylactic anticoagulation. Due to the small size of the trial, further data is required to guide management.
COVID-19 Related Organ Dysfunction and Management Strategies Review 
Optimal organ support and adjunctive therapies for COVID-19 have not yet been well established by trial-based outcomes thus far. The authors of this paper did a review of relevant pathophysiology and management strategies for critically ill patients with COVID-19 based out of the UK. Of the 100s of papers I have read on COVID-19, this is one of the best reviews I have read to date.
3 Phases of COVID-19
- Median Incubation Period: 4d (Range 2 to 7d)
- Median Time from Symptom Onset to Hospital Admission: 7d (Range 4 to 8d)
- Median Time from Symptom Onset to Development of ARDS: 8d (Range 6 to 12d)
- Although the validity of respiratory phenotypes in COVID-19 is widely debated, it is important to remember ARDS is not a distinct diagnosis but a syndrome with number of sub-phenotypes and different etiologies. Additionally, the L- and H-type phenotypes do not represent discrete entities but a rather two extremes of a continuum of illness
- L-Phenotype: Limited alveolar recruitment
- Lower PEEP 5 to 10cmH20
- Inhaled Pulmonary Vasodilators
- Early Prone Positioning
- Standard TV Targets: 6 to 8 mL/kg
- H-Phenotype: Alveolar recruitment
- Higher PEEP 10 to 15cmH20
- Prone positioning
- Plateau Pressure <30cmH20
- TV 6mL/kg
- Neurological symptoms occur in up to ≈37% of patients
- For the majority of neurological emergencies, the treatment is supportive
- Focusing on gas exchange and blood pressure optimization to limit secondary brain injury
- Sedation challenges are also an issue:
- Higher doses of propofol can cause hypertriglyceridemia
- Adjunctive sedation medications recommended include alpha-2 agonists, benzodiazepines, or ketamine
- There is a growing body of evidence suggesting increased microvascular and macrovascular thrombus burden in COVID-19 with an incidence that exceeds those observed in matched non-COVID-19 severe ARDS patients
- My Recommendation: Currently giving therapeutic anticoagulation to any patient requiring invasive mechanical ventilation with no increased risk of bleeding
- Antiplatelet agents may have a role in pulmonary microvascular thrombosis related to ARDS, has biologic plausibility, but there is a lack of robust evidence at this time (SALIM: Currently I am giving ASA 81mg to any patient admitted to the ICU)
- WHO Solidarity Trial Consortium. Repurposed Antiviral Drugs for COVID-19 – Interim WHO SOLIDARITY Trial Results. MedRxiv 2020. [Pre-Print]
- Agarwal A et al. Convalescent Plasma in the Management of Moderate COVID-19 in Adults in India: Open Label Phase II Multicentre Randomised Controlled Trial (PLACID Trial). BMJ 2020. PMID: 33093056
- Lemos ACB et al. Therapeutic Versus Prophylactic Anticoagulation for Severe COVID-19: A Randomized Phase II Clinical Trial (HESACOVID). Thromb Res 2020. PMID: 32977137
- Sherren PB et al. COVID-19 Related Organ Dysfunction and Management Strategies on the Intensive Care Unit: A Narrative Review. Br J Anaesth 2020. PMID: 32988604
Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)
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