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. 2023 Jan 3;329(1):39-51.
doi: 10.1001/jama.2022.23257.

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial

Writing Committee for the REMAP-CAP Investigators; Alisa M Higgins  1 , Lindsay R Berry  2 , Elizabeth Lorenzi  2 , Srinivas Murthy  3 , Zoe McQuilten  1   4 , Paul R Mouncey  5 , Farah Al-Beidh  6 , Djillali Annane  7   8 , Yaseen M Arabi  9 , Abi Beane  10 , Wilma van Bentum-Puijk  11 , Zahra Bhimani  12 , Marc J M Bonten  11 , Charlotte A Bradbury  13 , Frank M Brunkhorst  14 , Aidan Burrell  1 , Adrian Buzgau  1 , Meredith Buxton  15 , Walton N Charles  5 , Matthew Cove  16 , Michelle A Detry  2 , Lise J Estcourt  17 , Elizabeth O Fagbodun  6 , Mark Fitzgerald  2 , Timothy D Girard  18 , Ewan C Goligher  19   20 , Herman Goossens  21 , Rashan Haniffa  22   23 , Thomas Hills  24 , Christopher M Horvat  25 , David T Huang  18 , Nao Ichihara  26 , Francois Lamontagne  27 , John C Marshall  12 , Daniel F McAuley  28   29 , Anna McGlothlin  2 , Shay P McGuinness  1   30 , Bryan J McVerry  18 , Matthew D Neal  18 , Alistair D Nichol  1   31 , Rachael L Parke  30   32 , Jane C Parker  1 , Karen Parry-Billings  5 , Sam E C Peters  5 , Luis F Reyes  33   34 , Kathryn M Rowan  5 , Hiroki Saito  35 , Marlene S Santos  12 , Christina T Saunders  2 , Ary Serpa-Neto  1   36 , Christopher W Seymour  18 , Manu Shankar-Hari  37   38 , Lucy M Stronach  6 , Alexis F Turgeon  39   40 , Anne M Turner  24 , Frank L van de Veerdonk  41 , Ryan Zarychanski  42 , Cameron Green  1 , Roger J Lewis  2   43 , Derek C Angus  18 , Colin J McArthur  30 , Scott Berry  2 , Lennie P G Derde  11 , Anthony C Gordon  6   44 , Steve A Webb  1   45 , Patrick R Lawler  19   20
Collaborators, Affiliations

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial

Writing Committee for the REMAP-CAP Investigators et al. JAMA. .

Abstract

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.

Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.

Design, setting, and participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.

Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).

Main outcomes and measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.

Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.

Conclusions and relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr L. Berry reported receiving grants from and being employed by Berry Consultants, which received payments for statistical analysis and design of REMAP-CAP, during the conduct of the study. Dr Lorenzi reported receiving personal fees from and being employed by Berry Consultants Employee, which receives payments for statistical modeling and design of REMAP- CAP, during the conduct of the study. Dr Murthy reported receiving grants from the Health Research Foundation outside the submitted work. Dr Annane reported receiving grants from Assistance Publique – Hôpitaux de Paris and obtained public funding from programme National de Recherche Clinique to support participating sites in France during the conduct of the study. Dr Beane reported receiving grants from and salary being partly funded by Wellcome and receiving grants from UK Research and Innovation(no salary support) during the conduct of the study. Dr Bradbury reported receiving personal fees from Amgen, Bristol-Myers Squibb-Pfizer, Novartis Eli Lilly, Bayer, and Bristows outside the submitted work. Dr Cove reported receiving grants from the National University Health System Research Office during the conduct of the study and grants from the National Medical Research Council (CSAINV20NOV-0014) and personal fees from Baxter, Medtronic, Jaffron, and B Braun Medical outside the submitted work. Dr Girard reported receiving grants from the National Institutes of Health and Ceribell and personal fees from Haisco Pharmaceutical Group and Lungpacer Medical outside the submitted work. Dr Goligher reported receiving personal fees from Getinge, Vyaire, and BioAge and nonfinancial support from LungPacer outside the submitted work. Dr Haniffa reported receiving grants from Medical Reserve Corps, Wellcome Trust, ICODA, and the National Institute for Health and Care Research outside the submitted work. Dr Hills reported receiving grants from the Health Research Council of New Zealand outside the submitted work. Dr Horvat reported receiving grants from the National Institute of Child Health and Human Development during the conduct of the study. Dr Marshall reported receiving personal fees from AM Pharma and Adrenomed during the conduct of the study. Dr McAuley reported receiving grants from Randox, the National Institute for Health and Care Research, Wellcome Trust, Innovate UK, MRC, and Ireland HSC R&D Division and personal fees from Faron Pharmaceuticals, SOBI, Bayer, Glaxo SmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, and Vir Biotechnology, outside the submitted work; having a patent for patent for an anti-inflammatory treatment issued to Queen’s University Belfast for novel treatment for inflammatory disease (US8962032); and serving as co-director of research for the Intensive Care Society and director of the National Institute for Health and Care Research/Medical Research Council Efficacy and Mechanism Evaluation Programme. Dr McVerry reported receiving grants from National Institutes of Health/National Heart, Lung, and Blood Institute and personal fees from Boehringer Ingelheim, Synairgen, and BioAegis outside the submitted work. Dr Neal reported serving on an advisory board for and having equity stake in Haima Therapeutics; receiving grants from the National Institute of General Medical Sciences National Heartl, Lung, and Blood Institute, and Instrumentation Laboratory; personal fees from Janssen Pharmaceuticals and Haemonetics; and travel support from Meredian Bio outside the submitted work. Dr Nichol reported receiving nonfinancial support from Ampharma for consultancy paid to the university outside the submitted work. Dr Parke reported receiving grants from Fisher and Paykel Healthcare outside the submitted work. Dr Reyes reported receiving grants and personal fees from Merck and personal fees from GSK outside the submitted work. Dr Saito reported receiving grants from Saraya Co. outside the submitted work. Dr Serpa Neto reported receiving personal fees from Drager outside the submitted work. Dr Seymour reported receiving grants from the National Institutes of Health/National Institute of General Medical Sciences during the conduct of the study and personal fees from Inotrem outside the submitted work. Dr Shankar-Hari reported being funded by a clinician scientist fellowship 2016‐16‐011 from the National Institute for Health Research, and receiving grants from the Chief Scientists Office, Scotland, for time‐critical precision medicine in adult critically ill patients (TRAITS Programme) and highlights industry support for TRAITS research programme (https://www.ed.ac.uk/inflammation-research/clinical-trials/traits-ci-trial). Dr Turgeon reported receiving grants from Canadian Institutes of Health Research during the conduct of the study. Dr Turner reported receiving grants from Health Research Council of New Zealand during the conduct of the study. Dr Zarychanski reported receiving grants from Canadian Institutes for Health Research, LifeArc, Research Manitoba, and CancerCare Manitoba Foundation during the conduct of the study. Dr Lewis reported being the senior medical scientist at Berry Consultants, a statistical consulting firm that specializes in the design, implementation, oversight, and interpretation of Bayesian adaptive and platform clinical trials, during the conduct of the study. Dr S. Berry reported being part owner of Berry Consultants, which receives funding for statistical support of REMAP-CAP. Dr Derde reported being a member of the International Advisory Board Sepsis Canada, the Taskforce Acute Infectious Threats of Dutch National Intensivist Society, and the Dutch Royal Academy of Sciences (KNAW) Pandemic Preparedness Plan committee and chair of the ESICM Education and Training Committee. Dr Gordon reported receiving nonfinancial support from Roche UK, Sanofi, and SOBI for the drug supply for the trial and personal fees from 30 Respiratory, AstraZeneca, and Janssen and grants from the National Institute for Health and Care Research Imperial BRC outside the submitted work. Dr Lawler reported receiving grants from Canadian Institutes for Health Research and the Heart and Stroke Foundation of Canada during the conduct of the study and personal fees from Novartis, CorEvitas, Partners Healthcare, and American College of Cardiology outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Cohort Development in an Analysis of Longer-term Follow-up of Critically Ill Participants in the REMAP-CAP COVID-19 Clinical Trial
aAn additional 910 non–critically ill patients were enrolled in domains. bAdditional 42 patients with unknown vital status at 90 d were from sites not participating in 180-d follow-up. cQuality of life on the EQ-5D-5L; scores from −0.593 to 1.00 (full health). dSelf-reported present health state, ranging from 0 (worst) to 100 (best). eCovers 6 domains of functioning; 0 (no difficulty) to 4 (extreme difficulty).
Figure 2.
Figure 2.. Kaplan-Meier Curves for Mortality Through 180 Days
The probability of superiority of each active intervention to control for 180-day mortality is reported from the fully adjusted bayesian model (adjusting for other treatments from other domains, site, time, sex, and age). Censored participants are indicated with vertical tick marks. CrI indicates credible interval.
Figure 3.
Figure 3.. Mortality at 180 Days
aDue to censoring, reported 180-day mortality rates are restricted to patients at sites participating in 180-day follow-up with known 180-day vital status. The Kaplan-Meier curves include additional exposure and events from patients who were censored before day 180 or enrolled at sites that did not participate in 180-day follow-up. bHazard ratios <1 indicate improved survival and hazard ratios >1 indicate worsened survival. cThe difference in 180-day mortality is determined from the 180-day mortality rates which are estimated from the primary analysis model. For each domain, day 180 mortality rates are estimated for the population of patients randomized within that domain based on their baseline covariates and the estimated model parameters. For each patient within the domain population, separate survival curves are predicted assuming the patient received each intervention within the domain. The mean of the survival curves was taken across patients to summarize the mean survival for each intervention within the domain population. dThe probability of superiority (hazard ratio <1) and futility (hazard ratio >0.83) is computed from a bayesian piecewise exponential model using the posterior distribution. eOrgan support–free days are a composite ordinal scale consisting of survival to hospital discharge and days free of organ support to day 21. Probabilities may differ from those presented in the original trial reports for each domain due to changes in patient consent. fDomains are ordered based on the total number of patients enrolled in the domain from largest to smallest. gA total of 35 patients within the antiplatelet and anticoagulation domains were randomized to the prespecified combination of therapeutic anticoagulation and an antiplatelet agent. The combination effect provides the effect of giving both therapeutic anticoagulation and antiplatelet interventions together in combination (relative to giving control in both domains). This is estimated by multiplying the hazard ratio for antiplatelet, therapeutic anticoagulation and the interaction effect for antiplatelet and therapeutic anticoagulation. The hazard ratio for the combination effect is 1.34 (95% credible interval [CrI], 0.82-2.23) with a probability of superiority of 11.6%. The hazard ratio for the therapeutic anticoagulation/antiplatelet interaction is 1.39 (95% CrI, 0.87-2.19).
Figure 4.
Figure 4.. Health-Related Quality of Life at 180 Daysa
aResults for the EQ visual analog scale and the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 are available in eTables 17-19 in Supplement 2. bThe probability of superiority and adjusted mean difference are computed from the posterior distribution of a bayesian 2-part/mixture model that multiply imputes 5-level EuroQol-5 Dimension (EQ-5D-5L) utility scores using patients’ baseline covariates for patients censored alive before 6 months and patients known to be alive at 6 months with unknown health-related quality of life. For patients who were censored before 6 months, first 6-month mortality outcomes are multiply imputed from the piecewise exponential component of the bayesian 2-part/mixture model. For patients who were known or imputed to be alive at 6 months, a value of EQ-5D-5L is multiply imputed from the continuous component of the 2-part/mixture model. For patients who were imputed as dead by 6 months, EQ-5D-5L was set to 0 and they did not contribute to the analysis of EQ-5D-5L in survivors. In this analysis, 4307 of 4791 patients (90%) had known survival status at 6 months and a mortality outcome was multiply imputed for the remaining 484 patients (10%). Of the 2590 patients known to be alive at 6 months, 852 (33%) had a known EQ-5D-5L utility score and the remaining 1738 (67%) were imputed. cDomains are ordered based on the total number of patients enrolled in the domain from largest to smallest.
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