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Azithromycin, an antibiotic with potential antiviral and anti-inflammatory properties, has been used to treat COVID-19, but evidence from community randomised trials is lacking. We aimed to assess the effectiveness of azithromycin to treat suspected COVID-19 among people in the community who had an increased risk of complications. In this UK-based, primary care, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE), we randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. The trial had two coprimary endpoints measured within 28 days from randomisation: time to first self-reported recovery, analysed using a Bayesian piecewise exponential, and hospital admission or death related to COVID-19, analysed using a Bayesian logistic regression model. Eligible participants with outcome data were included in the primary analysis, and those who received the allocated treatment were included in the safety analysis. The trial is registered with ISRCTN, ISRCTN86534580. The first participant was recruited to PRINCIPLE on April 2, 2020. The azithromycin group enrolled participants between May 22 and Nov 30, 2020, by which time 2265 participants had been randomly assigned, 540 to azithromycin plus usual care, 875 to usual care alone, and 850 to other interventions. 2120 (94%) of 2265 participants provided follow-up data and were included in the Bayesian primary analysis, 500 participants in the azithromycin plus usual care group, 823 in the usual care alone group, and 797 in other intervention groups. 402 (80%) of 500 participants in the azithromycin plus usual care group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days. We found little evidence of a meaningful benefit in the azithromycin plus usual care group in time to first reported recovery versus usual care alone (hazard ratio 1·08, 95% Bayesian credibility interval [BCI] 0·95 to 1·23), equating to an estimated benefit in median time to first recovery of 0·94 days (95% BCI −0·56 to 2·43). The probability that there was a clinically meaningful benefit of at least 1·5 days in time to recovery was 0·23. 16 (3%) of 500 participants in the azithromycin plus usual care group and 28 (3%) of 823 participants in the usual care alone group were hospitalised (absolute benefit in percentage 0·3%, 95% BCI −1·7 to 2·2). There were no deaths in either study group. Safety outcomes were similar in both groups. Two (1%) of 455 participants in the azothromycin plus usual care group and four (1%) of 668 participants in the usual care alone group reported admission to hospital during the trial, not related to COVID-19. Our findings do not justify the routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community. These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antimicrobial resistance, and there is evidence that azithromycin use increased during the pandemic in the UK. UK Research and Innovation and UK Department of Health and Social Care.

The “very old intensive care patients” (abbreviated to VOPs; greater than 80 years old) are probably the fastest expanding subgroup of all intensive care unit (ICU) patients. Up until recently most ICU physicians have been reluctant to admit these VOPs. The general consensus was that there was little survival to gain and the incremental life expectancy of ICU admission was considered too small. Several publications have questioned this belief, but others have confirmed the poor long-term mortality rates in VOPs. More appropriate triage (resource limitation enforced decisions), admission decisions based on shared decision-making and improved prediction models are also needed for this particular patient group. Here, an expert panel proposes a research agenda for VOPs for the coming years.

ObjectiveTo determine the feasibility of Fluids in Shock, a randomised controlled trial (RCT) of restricted fluid bolus volume (10 mL/kg) versus recommended practice (20 mL/kg).DesignNine-month pilot RCT with embedded mixed-method perspectives study.Setting13 hospitals in England.PatientsChildren presenting to emergency departments with suspected infection and shock after 20 mL/kg fluid.InterventionsPatients were randomly allocated (1:1) to further 10 or 20 mL/kg fluid boluses every 15 min for up to 4 hours if still in shock.Main outcome measuresThese were based on progression criteria, including recruitment and retention, protocol adherence, separation, potential trial outcome measures, and parent and staff perspectives.ResultsSeventy-five participants were randomised; two were withdrawn. 23 (59%) of 39 in the 10 mL/kg arm and 25 (74%) of 34 in the 20 mL/kg arm required a single trial bolus before the shock resolved. 79% of boluses were delivered per protocol in the 10 mL/kg arm and 55% in the 20 mL/kg arm. The volume of study bolus fluid after 4 hours was 44% lower in the 10 mL/kg group (mean 14.5 vs 27.5 mL/kg). The Paediatric Index of Mortality-2 score was 2.1 (IQR 1.6–2.7) in the 10 mL/kg group and 2.0 (IQR 1.6–2.5) in the 20 mL/kg group. There were no deaths. Length of hospital stay, paediatric intensive care unit (PICU) admissions and PICU-free days at 30 days did not differ significantly between the groups. In the perspectives study, the trial was generally supported, although some problems with protocol adherence were described.ConclusionsParticipants were not as unwell as expected. A larger trial is not feasible in its current design in the UK.Trial registration numberISRCTN 15244462.

BackgroundWith emerging global payment structures, medical systems need to understand longer-term impacts of care transition strategies.ObjectiveTo determine the effect of a care transition program using patient navigators (PNs) on health service utilization among high-risk safety-net patients over a 180-day period.DesignRandomized controlled trial conducted October 2011 through April 2013.ParticipantsPatients admitted to the general medicine service with ≥1 readmission risk factor: (1) age ≥ 60; (2) in-network inpatient admission within prior 6 months; (3) index length of stay ≥ 3 days; or (4) admission diagnosis of heart failure or (5) chronic obstructive pulmonary disease. The analytic sample included 739 intervention patients, 1182 controls.InterventionsThrough hospital visits and 30 days of post-discharge telephone outreach, PNs provided coaching and assistance with medications, appointments, transportation, communication with primary care, and self-care.Main MeasuresPrimary outcomes: (1) hospital-based utilization, a composite of ED visits and hospital admissions; (2) hospital admissions; (3) ED visits; and (4) outpatient visits. We evaluated outcomes following an index discharge, stratified by patient age (≥ 60 and < 60 years), using a 180-day time frame divided into six 30-day periods.Key ResultsThe PN program produced starkly different outcomes by patient age. Among older PN patients, hospital-based utilization was consistently lower than controls, producing an 18.7% cumulative decrease at 180 days (p = 0.038); outpatient visits increased in the critical first 30-day period (p = 0.006). Among younger PN patients, hospital-based utilization was 31.7% (p = 0.038) higher at 180 days, largely reflecting sharply higher utilization in the initial 30 days (p = 0.002), with non-significant changes thereafter; outpatient visits experienced no significant changes.ConclusionsA PN program serving high-risk safety-net patients differentially impacted patients based on age, and among younger patients, outcomes varied over time. Our findings highlight the importance for future research to evaluate care transition programs among different subpopulations and over longer time periods.

Abstract Rationale The effect of disease management for chronic obstructive pulmonary disease (COPD) is not well established. Objectives To determine whether a simplified disease management program reduces hospital admissions and emergency department (ED) visits due to COPD. Methods We performed a randomized, adjudicator-blinded, controlled, 1-year trial at five Veterans Affairs medical centers of 743 patients with severe COPD and one or more of the following during the previous year: hospital admission or ED visit for COPD, chronic home oxygen use, or course of systemic corticosteroids for COPD. Control group patients received usual care. Intervention group patients received a single 1- to 1.5-hour education session, an action plan for self-treatment of exacerbations, and monthly follow-up calls from a case manager. Measurements and Main Results We determined the combined number of COPD-related hospitalizations and ED visits per patient. Secondary outcomes included hospitalizations and ED visits for all causes, respiratory medication use, mortality, and change in Saint George's Respiratory Questionnaire. After 1 year, the mean cumulative frequency of COPD-related hospitalizations and ED visits was 0.82 per patient in usual care and 0.48 per patient in disease management (difference, 0.34; 95% confidence interval, 0.15–0.52; P < 0.001). Disease management reduced hospitalizations for cardiac or pulmonary conditions other than COPD by 49%, hospitalizations for all causes by 28%, and ED visits for all causes by 27% (P < 0.05 for all). Conclusions A relatively simple disease management program reduced hospitalizations and ED visits for COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00126776).

We assessed whether proactive care management for artificial intelligence (AI)-identified at-risk patients reduced preventable emergency department (ED) visits and hospital admissions (HAs). Stepped-wedge cluster randomized design. Adults receiving primary care at 48 UCLA Health clinics and determined to be at risk based on a homegrown AI model were included. We employed a stepped-wedge cluster randomized design, assigning groups of clinics (pods) to 1 of 4 single-cohort waves during which the proactive care intervention was implemented. The primary end points were potentially preventable HAs and ED visits; secondary end points were all HAs and ED visits. Within each wave, we used an interrupted time series and segmented regression analysis to compare utilization trends. In the pooled analysis of high-risk and highest-risk patients (n = 3007), potentially preventable HAs showed a statistically significant level drop (-27% [95% CI, -44% to -6%]), without any corresponding change in trends. Potentially preventable ED visits did not show a substantial level drop in response to the intervention, although a nonsignificant differential change in trend was observed, with visit rates decelerating 7% faster in the intervention cohorts (95% CI, -13% to 0%). Nonsignificant drops were observed for all HAs (-19% [95% CI, -35% to 1%]; P = .06) and ED visits (-15% [95% CI, -28% to 1%]; P = .06). A care management intervention targeting AI-identified at-risk patients was followed by a onetime, significant, sizable reduction in preventable HA rates. Further exploration is needed to assess the potential of integrating AI and care management in preventing acute hospital encounters.

Research into adverse events (AEs) has highlighted the need to improve patient safety. AEs are unintended injuries or complications resulting in death, disability or prolonged hospital stay that arise from health care management. We estimated the incidence of AEs among patients in Canadian acute care hospitals. We randomly selected 1 teaching, 1 large community and 2 small community hospitals in each of 5 provinces (British Columbia, Alberta, Ontario, Quebec and Nova Scotia) and reviewed a random sample of charts for nonpsychiatric, nonobstetric adult patients in each hospital for the fiscal year 2000. Trained reviewers screened all eligible charts, and physicians reviewed the positively screened charts to identify AEs and determine their preventability. At least 1 screening criterion was identified in 1527 (40.8%) of 3745 charts. The physician reviewers identified AEs in 255 of the charts. After adjustment for the sampling strategy, the AE rate was 7.5 per 100 hospital admissions (95% confidence interval [CI] 5.7- 9.3). Among the patients with AEs, events judged to be preventable occurred in 36.9% (95% CI 32.0%-41.8%) and death in 20.8% (95% CI 7.8%-33.8%). Physician reviewers estimated that 1521 additional hospital days were associated with AEs. Although men and women experienced equal rates of AEs, patients who had AEs were significantly older than those who did not (mean age [and standard deviation] 64.9 [16.7] v. 62.0 [18.4] years; p = 0.016). The overall incidence rate of AEs of 7.5% in our study suggests that, of the almost 2.5 million annual hospital admissions in Canada similar to the type studied, about 185 000 are associated with an AE and close to 70 000 of these are potentially preventable.

Background Polypharmacy and potentially inappropriate drugs have been associated with negative outcomes in older adults which might be reduced by pharmacist interventions. Objectives Our objective was to evaluate the effect of a pharmacist intervention, consisting of the application of the Rationalization of home medication by an Adjusted STOPP in older Patients (RASP) list and a pharmacist-led medication review on polypharmacy, the quality of prescribing, and clinical outcome in geriatric inpatients. Methods A monocentric, prospective controlled trial was undertaken at the geriatric wards of a large university hospital. Pharmacists applied the RASP list to the drugs reconciled on admission and additionally performed an expert-based medication review, upon which recommendations were provided to the treating physicians. The primary outcome was the composite endpoint of drug discontinuation and dose reduction of drugs taken on admission. Secondary outcomes included RASP-identified potentially inappropriate medications (PIMs), the number of Emergency Department (ED) visits and quality of life (QOL) registered up to 3 months after discharge. Results On average, patients ( n  = 172) took 10 drugs on admission and were 84.5 years (standard deviation 4.8) of age. More drugs were discontinued or reduced in dose in the intervention group {control vs. intervention: median (interquartile range [IQR]) 3 (2–5) vs. 5 (3–7); p  < 0.001}. More PIMs were discontinued in the intervention group, leading to less PIM at discharge [control vs. intervention: median (IQR) 2 (1–3) vs. 0.5 (0–1); p  < 0.001]. No signal of harm was seen, and a significant improvement of QOL and less ED visits without hospitalization were observed. Conclusions The combined intervention safely reduced drug use in very old inpatients and outperformed usual geriatric care. An increased QOL was seen, as well as a trend towards less ED visits. ClinicalTrials.gov Identifier: NCT01513265.

Diuretic unresponsiveness often occurs during hospital admission for acute heart failure (AHF) and is associated with adverse outcome. This study aims to investigate determinants, clinical outcome, and the effects of nesiritide on diuretic response early after admission for AHF. Diuretic response, defined as weight loss per 40 mg of furosemide or equivalent, was examined from hospital admission to 48 hours in 4,379 patients from the ASCEND-HF trial. As an additional analysis, a urinary diuretic response metric was investigated in 5,268 patients using urine volume from hospital admission to 24 hours per 40 mg of furosemide or equivalent. Mean diuretic response was −0.42 kg/40 mg of furosemide (interquartile range −1.0, −0.05). Poor responders had lower blood pressure, more frequent diabetes, long-term use of loop diuretics, poorer baseline renal function, and lower urine output (all P < .01). Randomized nesiritide treatment was not associated with diuretic response (P = .987). Good diuretic response was independently associated with a significantly decreased risk of 30-day all-cause mortality or heart failure rehospitalization (odds ratio 0.44, 95% CI 0.29-0.65, highest vs lowest quintile, P < .001). Diuretic response based on urine output per 40 mg of furosemide showed similar results in terms of clinical predictors, association with outcome, and the absence of an effect of nesiritide. Poor diuretic response early after hospital admission for AHF is associated with low blood pressure, renal impairment, low urine output, and an increased risk of death or rehospitalization early after discharge. Nesiritide had a neutral effect on diuretic response.

The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 μg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV 1) and in postbronchodilator FEV 1, beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov, number NCT00144339. 2739 participants (mean age 64 years [SD 9]) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV 1 of 1·63 L (SD 0·37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV 1 was lower in the tiotropium group than in the control group (43 mL per year [SE 2] vs 49 mL per year [SE 2], p=0·024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV 1 did not differ between groups (35 mL per year [SE 2] vs 37 mL per year [SE 2]; p=0·38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (p≤0·006 for all timepoints). Time to first exacerbation and time to exacerbation resulting in hospital admission were also longer in the tiotropium group than in the control group (hazard ratio 0·82, 95% CI 0·75–0·90, and 0·74, 0·62–0·88, respectively). Tiotropium seemed to reduce the rate of decline of postbronchodilator FEV 1 in patients with GOLD stage II COPD. This finding and the other improvements in outcomes suggest that treatment of COPD should begin at an early stage of the disease. Boehringer Ingelheim and Pfizer Pharmaceuticals.