Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Options for dissidents

What can individuals do to deter and oppose suppression? The previous chapters have given some idea of what suppression looks like in practice and what causes it. In this chapter we give an overview of the available avenues for action against suppression, with comments on their advantages and disadvantages. Because suppression takes many forms, and because the best course of action against it depends on the particular circumstances of each case, we do not wish to suggest a single solution, but rather to outline the options so that individuals and groups are better able to choose a successful defence

Intellectual Suppression: Australian Case Histories, Analysis and Respones

Dr John Coulter worked for twenty years as a medical researcher at the Institute of Medical and Veterinary Science (IMVS) in Adelaide, South Australia. During this time he was, in his private capacity, a leading environmentalist. He spoke out on many occasions on issues such as uranium mining and the hazards of environmental chemicals. In addition, Dr Coulter in the late 1970s headed within the IMVS a small mutagens testing unit. By testing substances for their capacity to cause mutations, a good indication of their potential for inducing cancer can be obtained

Introduction

Dr John Coulter worked for twenty years as a medical researcher at the Institute of Medical and Veterinary Science (IMVS) in Adelaide, South Australia. During this time he was, in his private capacity, a leading environmentalist. He spoke out on many occasions on issues such as uranium mining and the hazards of environmental chemicals. In addition, Dr Coulter in the late 1970s headed within the IMVS a small mutagens testing unit. By testing substances for their capacity to cause mutations, a good indication of their potential for inducing cancer can be obtained