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

Foresight for risk – using scenarios for strategic risk assessment and management of emergent disaster risk

Disaster impacts around the world are increasing with 2011 and 2017 the largest on record in terms of total losses from disasters in recorded history (USD 444billion and USD 341billion, respectively). The reasons for the increase in losses are multiple. Climate change is increasing the likelihood and intensity of several natural hazard types, and as the world’s population and economy grow, and humans increasingly develop in areas exposed to natural hazard (e.g. along rivers, and coastal areas), the values exposed are also rapidly increasing. These multiple factors contribute to the complex nature of disaster risk, which is considered to be the combination of natural hazard intensity and extent, exposure (assets, people, other values), and vulnerabilities of the exposed values to the characteristics of the hazards. This can be considered the risk triangle – hazard, exposure and vulnerability – and each of these factors change into the future impacted by a range of drivers; population and economic change, technology, urbanisation rates, political actions etc. To reduce the impacts of disasters, risk management and reduction activities are designed and implemented, and are typically underpinned by risk assessments. Risk assessments use qualitative and/or quantitative approaches to attempt to characterise the likelihood and impact of disaster types for a region or organisation. Currently, risk assessments do not capture future changes across all dimensions of risk in a manner that provides insight into the strategic threats and opportunities of emergent disaster risks. Therefore, there is a need for approaches to consider realistic degrees of complexity within the disaster risk system and account for the uncertainty in emergent risk. By capturing this within disaster risk assessments, treatment options can be developed and tested that strategically manage these risks over time. This research has developed these approaches and provides three key contributions through the use of foresight, primarily scenarios within disaster risk assessment processes, to support effective policy and investment decision making to reduce future impacts. The thesis is organised around three publications, all contributing to the development of a generic framework which integrates foresight into disaster risk management and specific approaches to develop and use scenarios for strategic risk assessment and management of emergent disaster risk. The first paper (Chapter 2) proposes and demonstrates this generic framework for the incorporation of the principles of foresight into risk assessment and management processes. The second paper (Chapter 3) focuses on the design of scenarios to support policy making for disaster risk reduction through several improvements to the methodological approach for constructing relevant and challenging scenarios using an “outcomes of interest” framing. The third paper (Chapter 4) outlines and applies an approach for the use of exploratory scenarios within quantitative disaster risk assessment through the development of alternative pathways of disaster risk using scenarios and integrated risk models.Thesis (Ph.D.) -- University of Adelaide, School of Civil, Environmental and Mining Engineering, 201