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

On reporting results from randomized controlled trials with recurrent events

Background: Evidence-based medicine has been advanced by the use of standards for reporting the design and methodology of randomized controlled trials (RCT). Indeed, without this information it is difficult to assess the quality of evidence from an RCT. Although a variety of statistical methods are available for the analysis of recurrent events, reporting the effect of an intervention on outcomes that recur is an area that remains poorly understood in clinical research. The purpose of this paper is to outline guidelines for reporting results from RCTs where the outcome of interest is a recurrent event. Methods: We used a simulation study to relate an event process and results from analyses of the gamma-Poisson, independent-increment, conditional, and marginal Cox models. We reviewed the utility of regression models for the rate of a recurrent event by articulating the associated study questions, preenting the risk sets, and interpreting the regression coefficients. Results: Based on a single data set produced by simulation, we reported and contrasted results from statistical methods for evaluating treatment effect from an RCT with a recurrent outcome. We showed that each model has different study questions, assumptions, risk sets, and rate ratio interpretation, and so inferences should consider the appropriateness of the model for the RCT. Conclusion: Our guidelines for reporting results from an RCT involving a recurrent event suggest that the study question and the objectives of the trial, such as assessing comparable groups and estimating effect size, should determine the statistical methods. The guidelines should allow clinical researchers to report appropriate measures from an RCT for understanding the effect of intervention on the occurrence of a recurrent event.Health Care and Epidemiology, Department ofPopulation and Public Health (SPPH), School ofNon UBCMedicine, Faculty ofReviewedFacult

Otago home-based strength and balance retraining improves executive functioning in older fallers: A randomized controlled trial

Objectives: To primarily ascertain the effect of the Otago Exercise Program (OEP) on physiological falls risk, functional mobility, and executive functioning after 6 months in older adults with a recent history of falls and to ascertain the effect of the OEP on falls during a 1-year follow-up period. Design: Randomized controlled trial. Setting: Dedicated falls clinics. Participants: Seventy-four adults aged 70 and older who presented to a healthcare professional after a fall. Intervention: The OEP, a home-based program that consists of resistance training and balance training exercises. Measurements: Physiological falls risk was assessed using the Physiological Profile Assessment. Functional mobility was assessed using the Timed Up and Go Test. Three central executive functions were assessed: set shifting, using the Trail Making Test Part B; updating, using the verbal digits backward test; and response inhibition, using the Stroop Color-Word Test. Falls were prospectively monitored using daily calendars. Results: At 6 months, there was no significant between-group difference in physiological falls risk or functional mobility (P≥ .33). There was a significant between-group difference in response inhibition (P=.05). A falls histogram revealed two outliers. With these cases removed, using negative binomial regression, the unadjusted incidence rate ratio of falls in the OEP group compared with the control group was 0.56. The adjusted incidence rate ratio was 0.47. Conclusion: The OEP may reduce falls by improving cognitive performance

Osteoporosis screening in postmenopausal women 50 to 64 years old: comparison of US Preventive Services Task Force strategy and two traditional strategies in the Women's Health Initiative.

The US Preventive Services Task Force (USPSTF) recommends osteoporosis screening for women younger than 65 years whose 10-year predicted risk of major osteoporotic fracture is ≥ 9.3%. For identifying screening candidates among women aged 50 to 64 years, it is uncertain how the USPSTF strategy compares with the Osteoporosis Self-Assessment Tool (OST) and the Simple Calculated Osteoporosis Risk Estimate (SCORE). We examined data (1994 to 2012) from 5165 Women's Health Initiative participants aged 50 to 64 years. For the USPSTF (Fracture Risk Assessment Tool [FRAX] major fracture risk ≥ 9.3% calculated without bone mineral density [BMD]), OST (score <2), and SCORE (score >7) strategies, we assessed sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to discriminate between those with and without femoral neck (FN) T-score ≤-2.5. Sensitivity, specificity, and AUC for identifying FN T-score ≤-2.5 were 34.1%, 85.8%, and 0.60 for USPSTF (FRAX); 74.0%, 70.8%, and 0.72 for SCORE; and 79.8%, 66.3%, and 0.73 for OST. The USPSTF strategy identified about one-third of women aged 50 to 64 years with FN T-scores ≤-2.5. Among women aged 50 to 64 years, the USPSTF strategy was modestly better than chance alone and inferior to conventional SCORE and OST strategies in discriminating between women with and without FN T-score ≤-2.5

Action Seniors! - secondary falls prevention in community-dwelling senior fallers: study protocol for a randomized controlled trial

Background: Falls are a ‘geriatric giant’ and are the third leading cause of chronic disability worldwide. About 30% of community-dwellers over the age of 65 experience one or more falls every year leading to significant risk for hospitalization, institutionalization, and even death. As the proportion of older adults increases, falls will place an increasing demand and cost on the health care system. Exercise can effectively and efficiently reduce falls. Specifically, the Otago Exercise Program has demonstrated benefit and cost-effectiveness for the primary prevention of falls in four randomized trials of community-dwelling seniors. Although evidence is mounting, few studies have evaluated exercise for secondary falls prevention (that is, preventing falls among those with a significant history of falls). Hence, we propose a randomized controlled trial powered for falls that will, for the first time, assess the efficacy and efficiency of the Otago Exercise Program for secondary falls prevention. Methods/Design A randomized controlled trial among 344 community-dwelling seniors aged 70 years and older who attend a falls prevention clinic to assess the efficacy and the cost-effectiveness of a 12-month Otago Exercise Program intervention as a secondary falls prevention strategy. Participants randomized to the control group will continue to behave as they did prior to study enrolment. The economic evaluation will examine the incremental costs and benefits generated by using the Otago Exercise Program intervention versus the control. Discussion The burden of falls is significant. The challenge is to make a difference – to discover effective, ideally cost-effective, interventions that prevent injurious falls that can be readily translated to the population. Our proposal is very practical – the exercise program requires minimal equipment, the physical therapist expertise is widely available, and seniors in Canada and elsewhere have adopted the program and complied with it. Our innovation includes applying the intervention to a targeted high-risk population, aiming to provide the best value for money. Given society’s limited financial resources and the known and increasing burden of falls, there is an urgent need to test this feasible intervention which would be eminently ready for roll out. Trial registration ClinicalTrials.gov Protocol Registration System: NCT01029171 ; registered 7 December 2009.Other UBCNon UBCMedicine, Faculty ofReviewedFacult