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

Chemical Health Effects Assessment Methodology for Airborne Contaminants

Chemical Health Effects Assessment Methodology (CHEM) is a new procedure for assessing hazardous properties of airborne toxic contaminants. CHEM evaluates substances for four major health effect categories: carcinogenicity, mutagenicity, reproductive/developmental toxicity, and toxic effects other than the first three. Three elements are considered in the assessment: weight of evidence, potency, and severity of effect. This approach produces a profile of toxic properties of chemicals which preserves their unique multidimensional character and highlights data gaps. Copyright © 1987, Wiley Blackwell. All rights reserve

A Methodology for Assessing Carcinogenic Hazards of Chemicals

Assessment of carcinogenic hazards of substances involves evaluation and classification of qualitative and quantitative data, including the attendant uncertainty,. Recently proposed EPA guidelines represent a significant step towards a uniform carcinogenic risk assessment procedure and its appropriate use. The Methodology for Assessing Carcinogenic Hazards of Chemicals proposed here shares common characteristics with the EPA guidelines but it also focuses on other aspects of carcinogen assessment, not addressed by the guidelines, such as: folding together quantitative and qualitative data into a combined hazard index; classification of limited, incomplete or flawed qualitative data; utilization of quantitative risk estimates based on weak qualitative evidence. The elements are used to assess carcinogenic hazards of chemicals, qualitative and quantitative. The qualitative assessment consists of stratification into one of five categories of weight-of evidence, whereas quantitative assessment consists of stratification into one of four potency categories on the basis of carcinogenic unit risk estimate. Carcinogenic hazard index, codified in letters A to E, is derived from the quantitative and qualitative elements of assessment in a two-dimensional matrix. The matrix is designed so that weaker evidence for carcinogenicity requires a correspondingly higher unit risk value for a given score. Assessment of 100 chemicals using our methodology shows a good distribution of scores from A to E. Group B, which can be described as moderately hazardous, is most frequently represented. The methodology represents a mixture of two possible approaches to assessing hazards of carcinogens: one which gives the highest rank to those likely to produce the greatest risk, the other which ranks highest those most likely to produce cancer in humans. By using this combined approach, it is ensured that a chemical hazardous on either count is not missed. The methodology also makes maximum use of all available data without over-interpreting some highly uncertain procedures such as quantitative risk estimation or extrapolation of animal response to humans. © 1986, Sage Publications. All rights reserved

A Methodology for Assessing Mutagenic Hazards of Chemicals

A comprehensive framework for identifying substances which represent a potential threat to public health due to mutagenicity and for relative ranking of their hazards has been developed. The methodology is designed to evaluate a range of genotoxic endpoints of potential significance to humans and is not merely a substitute for, or an adjunct to, the carcinogenicity assessment. A range of endpoints in both somatic and germ cells is considered. The biological test systems utilized here include humans and other mammals, bacteria, Drosophila, yeasts, molds, and plants. Bioassays conducted in vivo and in vitro, with and without metabolic activation, are included. Seventy-five different assays are considered, of which 73 are currently included in the Gene-Tox database. The tests are grouped into three categories on the basis of significance to humans, as well as sensitivity, specificity, validity, and reliability. Seven in vivo mammalian tests comprise Group I. The remaining 68 tests are divided between Groups II and III, in a decreasing order of significance and confidence in the tests. Tests with virtually identical endpoints and organisms are listed together. The system accomplishes two tasks: 1) organizes the data from short-term tests on chemicals, and 2) classifies chemicals into one of five hazard categories, designated by letters A to E, on the basis of that information. Classification into hazard categories depends on the overall strength of evidence that an agent may cause mutations in humans. Generally, score for each chemical is a function of the number and combination of results in each of the three groups of tests. Specifically, it is derived by weighing several variables: the number and type of endpoints measured, the number and type of species represented, the significance of positive and non-positive results, the relevance of specific tests for predicting effects in humans, the group classification (I, II or III) of each test result and the overall pattern presented. Assessment of data for one hundred chemicals shows a good representation of scores from A to E, with category E most commonly represented, followed by D and C. © 1986, Sage Publications. All rights reserved

A Methodology for Assessing Developmental and Reproductive Hazards of Chemicals

A method to evaluate developmental and reproductive toxicity for a wide variety of chemicals has been developed. The assessment includes all effects on male and female reproductive function as well as effects in the developing embryo or fetus. Effects are evalu ated using primary literature. Studies are classified as adequate, supportive or inadequate. Only adequate studies are used in further assessment. Reproductive and developmental toxicity of each chemical is assessed using both qualitative and quantitative infor mation. Three elements are used to describe developmental toxicity of chemicals: Lowest Observed Effect Level (LOEL), weight-of- evidence classification and a Risk Ratio (RR). For reproductive toxicity only two elements are used, LOEL and weight-of-evidence. LOEL is defined as the lowest dose at which statistically significant effects are found. A risk ratio is calculated using the levels of the chemical producing acute maternal lethalilty (LD50 or LC5o) to the levels producing developmental toxicity in the same animal species and route of administration. The risk ratio is used to indicate the extent to which the developing embryo or fetus is more susceptible than the dam to the toxic effects of a chemical. A toxicity score (A through E) is assigned to each chemical from a two- or threedimensional matrix based on the elements of assessment. The score reflects the degree of hazard associated with each chemical. To date, I10 chemicals have been evaluated using this system. From the selected databases, 188 articles were reviewed. Of these, 103 (55Vo) were judged to be adequate, 23 (12%) provide supportive information, and 62 (33%) were inadequate and excluded from the assessment methodology. Scores for 47 chemical with some adequate data available show that high hazard substances (28 A and B) outnumber those associated with lower hazards (a total of 19 C, D and E). This may reflect a selection process for testing which favors substances suspected of causing adverse reproductive and developmental effects. © 1986, Sage Publications. All rights reserved