Understanding the Tsunami of Evidence for COVID-19 Treatments

As understanding of COVID-19 evolves, additional evidence on treatments for various patient populations continues to be published and making sense of the “tsunami of evidence” can be a challenge, said a speaker at CHEST 2022, held October 16-19, 2022, in Nashville, Tennessee.

The panelists discussed current guidelines for COVID-19 treatments for both critically ill and noncritically ill patients, as well as the evidence behind the treatments.

The National Institutes of Health (NIH) started putting together guidelines on the treatment of COVID-19 as early as mid-March 2020 with 4 separate teams focusing on 4 areas:

• Asymptomatic, mild, moderate disease and other considerations
• Severe disease, direct-acting agents (eg, antivirals, monoclonal antibodies)
• Host-modifying agents (eg, anticoagulants, anti-inflammatory agents)
• Critical care and additional items

In addition, a team focusing on pediatric care was set up. The first guideline was live mid-April 2020 with nearly monthly updates occurring based on the “scads” of COVID-19 literature that continues to come out, explained Steven Q. Simpson MD, FCCP, immediate-past president of CHEST and professor of medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kansas.

Since the National Institute of Allergy and Infectious Diseases had used HIV guidelines for 20 years, the panel followed that procedure and crafted 3 recommendation levels—strong, moderate, and weak—and 4 levels of quality of evidence.

The latest update on September 30 was that therapies for flu and monoclonal antibodies to treat COVID-19 can be used together if needed. On September 26, there were recommendations against using remdesivir, dexamethasone, and baricitinib after discharge, as well as against using molnupiravir in pregnant individuals. In addition, there is an acknowledgement of pulse oximetry limitations, especially in patients with dark skin.

When using antiviral and monoclonal antibody therapies to treat COVID-19, there are really 5 agents to know, explained John Beigel, MD, associate director for clinical research in the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases.

There are 3 antivirals—molnupiravir, Paxlovid, and remdesivir—and 2 monoclonal antibodies—bentelovimab and cilgavimab + tixagevimab. Remdesivir is the only approved treatment, while the rest have emergency use authorization, and cilgavimab + tixagevimab is used for prevention, Beigel explained.

Research on remdesivir has found that it shortened recovery time from 15 days with placebo to 10 days, and the Kaplan-Meier estimate of mortality dropped from 15.2% with placebo to 11.4% on remdesivir.¹ According to Beigel, this study is the only well-powered randomized controlled trial, and it was done prior to dexamethasone becoming standard of care. There have been some observation trials and databases with information supporting the efficacy of remdesivir with dexamethasone, but there are limitations on the data, he added.

In nonhospitalized patients, MOVe-OUT studied molnupiravir in a randomized, double-blinded, placebo-controlled trial.² Patients with at least 1 risk factor for disease progression—60 years or older, obesity, or certain comorbidities—were included. The interim results showed rates of hospitalizations or death dropped from 14.1% with placebo to 7.3% with molnupiravir. However, Beigel noted that the final results were not as impressive: rates of hospitalization/death dropped from 9.7% on placebo to 6.8% on treatment.

The study of Paxlovid³ in high-risk, nonhospitalized patients (>18 years with increased risk of developing severe illness or ≥ 60 years), found rates of hospitalization or death dropped from 7.01% on placebo to 0.7% on treatment, and that Paxlovid reduced the risk of hospitalization or death by 88%.

A subgroup analysis on baseline serology, which excluded vaccinated people, found people who were seronegative—meaning they had no COVID-19 antibodies from previous infection—had the biggest benefit.

Beigel did note that there is the risk of COVID-19 rebound after symptoms improve with Paxlovid, but that research found COVID-19 rebound is common even without Paxlovid treatment. Research found 27% of patients had symptoms rebound, 12% had viral rebound, and 4% had viral and symptom rebound after initial improvement.^4,5

“The data is so sparse…it’s not clear if the rebound after Paxlovid occurs more frequently than in untreated [patients],” Beigel said.

The Pinetree study⁶ on remdesivir in the outpatient setting in patients within 7 days of symptoms onset and at least 1 risk factor for progression found hospitalization from any cause dropped from 5.3% in placebo to 0.7%. There were no deaths in this population. The findings, according to Beigel, suggest that in a high-risk population who are not hospitalized, a 3-day course of remdesivr decreased COVID-19–related hospitalizations by 87%, which was similar to Paxlovid.

Moving onto monoclonal antibodies, the BLAZE-4 trial⁷ studied bentelovimab a monotherapy or a triple therapy and compared it with placebo in an adult population, not restricted to high-risk patients. The therapy had the same hospitalizations as placebo (both 1.6%), but the median time to sustained symptom resolution was 6 days for treatment vs 8 days on placebo.

While bebtelovimab retains good activity against Omicron BA.4/5 strains, it has limited activity against the BQ.1 strain, which is an emerging new variant. Beigel noted this is a minor variant right now and it is unclear if it will take off, but it will be important to follow the current variants, know what’s out there, and understand monoclonal activity, he said.

Anticoagulation treatments are also being used in COVID-19, explained Heather Torbic, PharmD, FCCM, BCCCP, BCPS, Medical Intensive Care Unit clinical specialist, Cleveland Clinic. It has become clear that more critically ill patients are more likely to have thromboembolic events, she said. In addition, there is a better understanding why there is coagulopathy in patients with COVID-19 due to inflammatory reaction, endothelial activation factor, an increase in histones and nucleosomes, platelet activation, and large increases in coagulation cascade.

“We've been trying to look at things like this and see if we can find any inflammatory markers that we can trend or things that will help us really identify patients that may be at greater risk for thromboembolic events,” Torbic said.

She also ran through some of the recent trials that are helping to add to the evidence of anticoagulation intensity in noncritically ill and critically ill patients.

There were 3 studies that evaluated low-molecular-weight and unfractionated heparins (LMWH/UFH) vs primary prophylaxis (PPX) alone in noncritically ill patients: ATTACC/ACTIV-4a/REMAP-CAP,⁸ RAPID,⁹ and HEP-COVID.¹⁰ In addition, the ACTION trial evaluated LMWH/UFH/rivaroxaban vs PPX alone.¹¹

In ATTACC/ACTIV-4a/REMAP-CAP, patients on treatment had greater organ support–free days and an adjusted absolute survival difference of 4% favoring treatment. However, the incidence of major bleed was slightly higher.

In RAPID, there was a composite end point of intensive care admission, noninvasive ventilation (NIV), mechanical ventilation, and death, which was slightly lower for the treatment group (16.2% vs 21.9%). Mortality was significantly lower (1.8% vs 7.6%). Major bleeding was slightly lower for the treatment group.

In HEP-COVID, there was a composite end point of venous thromboembolism (VTE), arterial thromboembolism (ATE), or death from any cause, which was significantly lower in the treatment group (28.7% vs 41.9%). Mortality was lower but not statistically significant (19.4% vs 25.0%). Major bleeding was not statistically significant but was increased in the treatment group (4.7% vs 1.6%).

Finally, in ACTION, the composite end point was time to death, hospital duration, and oxygen use duration. There was not a significant difference in the primary end point (34.8% for treatment vs 41.3% for PPX) and the incidence of major bleed was significantly higher for treatment (8% vs 2%).

“The takeaway from [these studies] is that hospitalized patients who are not critically ill may benefit from high intensity anticoagulation strategy compared to patients who are receiving prophylaxis,” Torbic said. “But I do think that we need to pick the right patient population and really stop the risk of bleeding for these patients before implementing this strategy.”

There were only 2 studies in critically ill patients. ATTACC/ACTIV-4a/REMAP-CAP studied LMWH/UFH vs PPX¹² and INSPIRATION studied intermediate LMWH vs PPX.¹³

ATTACC/ACTIV-4a/REMAP-CAP found no significant differences in survival to discharge (62.7% for treatment vs 64.5% PPX), major thrombosis (6.4% vs 10.4%), and major bleeding (3.8% vs 2.3%).

INSPIRATION that there was no difference in the composite end point of VTE/ATE/extracorporeal membrane oxygenation (ECMO) (45.7% on treatment vs 44.1% PPX), and major bleeding was 2.5% for treatment vs 1.4% on PPX.

The findings of these studies showed that “the findings from the noncritically ill patient study didn't really extrapolate into the critically ill patients,” Torbic said. She added that the critically ill patients are likely sicker with more comorbidities and the risk of bleeding becomes greater for these patients.

In updated guidelines from CHEST, the American Society of Hematology (ASH), and NIH, all 3 agree on no prophylaxis for outpatient or post-discharge patients. In hospitalized patients who are not critically ill, CHEST and ASH agree anticoagulation should be used, while NIH has the caveat that it should be used only if there is no bleeding risk. Finally, all 3 agree that hospitalized patients who are critically ill should only receive prophylaxis because of the risk of bleeding, she said.

Lastly, there is data on the use of anti-inflammatory therapies to treat COVID-19. There are several trials that have looked at systemic corticosteroids, but overall dexamethasone should be used in patients who are hypoxemic on oxygen in the hospital and 6 mg/day is preferred over 12 mg/day, explained Greg Martin MD, FCCP, director of Medical and Coronary Intensive Care Units and chief of pulmonary and critical care at Grady Health Systems, and associate director for critical care and associate professor of medicine in the Division of Pulmonary, Allergy and Critical Care at Emory School of Medicine.

While dexamethasone is preferred, if it is not available, other corticosteroids— methylprednisolone, prednisone, and hydrocortisone—may be used. There were trials for these other therapies, but they stopped or had trouble enrolling patients once the data on dexamethasone came out, Martin explained.

For the interleukin-6 inhibitors, there is the most evidence on tocilizumab, which has been found to increase survival in patients with severe COVID-19 who are rapidly deteriorating. “Overall, we recommend using tocilizumab in patients who are early in the course of their disease,” he said.

Sarilumab had a similar effect as tocilizumab, but not all trials found a mortality benefit, plus it is only available in a subcutaneous formulation. As a result, sarilumab is only recommended when tocilizumab is not available.

In the Janus kinase inhibitor field, baricitinab is approved to treat hospitalized adults with COVID-19 who require supplement oxygen, NIV, intermittent mandatory ventilation, or ECMO. The RECOVERY trial found baricitinib was associated with a survival benefit that was most apparent in patients receiving NIV or high-flow nasal oxygen (HFNO).¹⁴ The therapy is recommended in the more severily ill patients receiving higher levels of oxygen.

Tofacitinib showed a survival benefit in hospitalized patients receiving corticosteroids but was not studied in patients receiving oxygen support. It is considered an alternative to baricitinib.¹⁵

Finally, ruxolitinib showed changes in mortality and intensive care unit/ventilator/vasopressor-free days in an early phase 2 trial of patients with COVID-19–acute respiratory distress syndrome.¹⁶

“COVID-19 continues to evolve, and particularly this tsunami of evidence continues to present itself,” Martin said. “And being able to manage that is still one of the challenges we have.”

References

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2. Bernal AJ, Gomes da Silva MM, Musungaie DB, et al, MOVe-OUT Study Group. Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. N Engl J Med. 2022;386(6):509-520. doi:10.1056/NEJMoa2116044

3. Hammond J, Leister-Tebbe H, Gardner A, et al, EPIC-HR Investigators. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19. N Engl J Med. 2022;386(15):1397-1408. doi:10.1056/NEJMoa2118542

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7. Dougan M, Azizad M, Chen P, et al. Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19. medRxiv. Preprint. Published online March 12, 2022. doi:10.1101/2022.03.10.22272100

8. Lawler PR, Goligher EW, Berger JS, et al, REMAP-CAP Investigators, ACTIV-4a investigators, ATTACC Investigators. Therapeutic anticoagulation with heparin in noncritically ill patients with COVID-19. N Engl J Med. 2021;385(9):790-802. doi:10.1056/NEJMoa2105911

9. Sholzberg M, Tang GH, Rahhal H, et al, RAPID trial investigators. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400. doi:10.1136/bmj.n2400

10. Spyropoulos AC, Goldin M, Giannis D, et al, HEP-COVID investigators. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181(12):1612-1620. doi:10.1001/jamainternmed.2021.6203

11. Lopes RD, de Barros E Silva PGM, Furtado RHM, et al, ACTION Coalition COVID-19 Brazil IV Investigators. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397(10291):2253-2263. doi:10.1016/S0140-6736(21)01203-4

12. Goligher EW, Bradbury CA, McVerry BJ, et al, REMAP-CAP Investigators, ACTIV-4a investigators, ATTACC Investigators. Therapeutic anticoagulation with heparin in critically ill patients with COVID-19. N Engl J Med. 2021;385(9):777-789. doi:10.1056/NEJMoa2103417

13. Sadeghipour P, Talasaz AH, Rashidi F, et al, INSPIRATION investigators. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA. 2021;325(16):1620-1630. doi:10.1001/jama.2021.4152

14. RECOVERY Collaborative Group. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis. Lancet. 2022;400(10349):359-368. doi:10.1016/S0140-6736(22)01109-6

15. Guimarães PO, Quirk D, Furtado RH, et al, STOP-COVID trial investigators. Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;385(5):406-415. doi:10.1056/NEJMoa2101643

16. Rein L, Calero K, Shah R, et al. Randomized phase 3 trial of ruxolitinib for COVID-19-associated acute respiratory distress syndrome. Crit Care Med. Published online October 13, 2022. doi:10.1097/CCM.0000000000005682