In a tremendous demonstration of global collaboration, an international team led by clinician-scientists at UPMC and the University of Pittsburgh School of Medicine have pooled data from 121 hospitals in eight countries to find that inexpensive, widely available steroids improve the odds that very sick COVID-19 patients will survive the illness.
The findings were made through the "Randomized Embedded Multifactorial Adaptive Platform-Community Acquired Pneumonia" (REMAP-CAP) trial and are reported today in JAMA as part of a four-article package. The World Health Organization is updating its COVID-19 treatment guidance as a result.
REMAP-CAP includes the UPMC-REMAP-COVID19 trial, the only U.S.-based trial to test corticosteroids — a class of drug that lowers inflammation and modulates immune system activity — for treating critically ill COVID-19 patients. An analysis combining the REMAP-CAP data with that from six other randomized controlled trials to test corticosteroids reinforces the results of the UK RECOVERY trial reported in June, which found the steroid dexamethasone reduced deaths by 29% in ventilated COVID-19 patients.
"It is relatively rare in medicine that you find drugs where the evidence of their effectiveness in saving lives is so consistent," said lead author Derek Angus, M.D., M.P.H., chief health care innovation officer at UPMC and professor and chair of the Department of Critical Care Medicine at Pitt. "This is, in many respects, the single clearest answer we've had so far on how to manage terribly ill COVID-19 patients. People on ventilators or oxygen and under intensive care should definitely be given corticosteroids."
Between March and June, the REMAP-CAP corticosteroid trial randomized 403 adult COVID-19 patients admitted to an intensive care unit to receive the steroid hydrocortisone or no steroids at all. The trial found a 93% probability that giving patients a seven-day intravenous course of hydrocortisone would result in better outcomes than not giving the steroid. The results were consistent across age, race and sex.
"This gives physicians like me, who treat the sickest of the sick, hope," said co-author Bryan McVerry, M.D., UPMC pulmonologist and associate professor of pulmonary, allergy and critical care medicine at Pitt. "We are beginning to get a handle on the deadly side of this disease."
REMAP-CAP and the other corticosteroid trials did not test the drugs in non-hospitalized patients with COVID-19 who did not need respiratory support. Steroids currently are not recommended for these patients because they can dampen the immune system and have serious side effects. In addition, the REMAP-CAP corticosteroid trial was mostly conducted in resource-rich countries across Europe, North America and Australasia, so the findings may not translate to low- and middle-income countries.
Because it is designed to simultaneously test multiple combinations of potential therapies — as opposed to the traditional, slow clinical trial process that tests one therapy at a time — REMAP-CAP is particularly well-suited for rapidly identifying effective treatments during the COVID-19 pandemic. It currently is testing thousands of different treatment regimens, including various doses and combinations of vitamin C, convalescent plasma, blood thinners, antivirals and immune modulators.
"REMAP-CAP and our findings on corticosteroids are possible because of a global community of clinicians and scientists coordinating and sharing data across different languages and countries," said co-author Christopher Seymour, M.D., UPMC intensivist and director of the Translational and Clinical Science Program at the Clinical Research, Investigation and Systems Modeling of Acute Illness (CRISMA) Center in Pitt's School of Medicine. "This is how we get definitive answers as fast as possible on how to best treat patients. Outcomes in Amsterdam are helping patients at UPMC Altoona."
Timothy Girard, M.D., Christopher Horvat, M.D., David Huang, M.D., Kelsey Linstrum, M.S., and Stephanie Montgomery, M.S., all of Pitt's CRISMA Center, also contributed to this research.
Additional authors on the JAMA publication are from the Raymond Poincaré Hospital – AP-HP (Greater Paris University Hospitals), University of Versailles and University Paris Saclay, all in France; King Saud Bin Abdulaziz University for Health Sciences in Saudi Arabia; Imperial College London, Imperial College Healthcare NHS Trust, University of Oxford, Bristol Royal Informatory, University of Bristol, NHS Blood and Transplant, Queen's University Belfast, and Intensive Care National Audit & Research Centre, all in the UK; Berry Consultants, LLC, the Global Coalition for Adaptive Research, University of California at Los Angeles and Harbor-UCLA Medical Center, all in the U.S.; St. Michael's Hospital of Unity Health Toronto, Université de Sherbrooke, University of Toronto, University Health Network, University of British Columbia and University of Manitoba, all in Canada; Jena University Hospital in Germany; Monash University, Alfred Health, Princess Alexandra Hospital University of West Australia, The George Institute for Global Health and St. John of God Hospital, all in Australia; University Medical Center Utrecht, University of Amsterdam and Radboud University Medical Center, all in the Netherlands; Antwerp University Hospital in Belgium; Network for Improving Critical Care Systems and Training in Sri Lanka; Mahidol Oxford Tropical Medicine Research Unit in Thailand; Auckland City Hospital, The Health Research Council of New Zealand and University of Auckland, all in New Zealand; and St. Vincent's University Hospital and University College Dublin, both in Ireland.
This research was funded by The Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) consortium FP7-HEALTH-2013-INNOVATION-1 (#602525), the Australian National Health and Medical Research Council (#APP1101719 and #1116530), the New Zealand Health Research Council (#16/631), the Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant (#158584), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Office of Healthcare Innovation, the Breast Cancer Research Foundation, the French Ministry of Health (PHRC-20-0147), and the Minderoo Foundation.
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