EMERGE: Evaluating the value of Measuring Random Plasma Glucose Values for Managing Hyperglycemia in the Inpatient Setting.

IMPORTANCE: A diagnosis of diabetes is considered when a patient has hyperglycemia with a random plasma glucose ≥200 mg/dL. However, in the inpatient setting, hyperglycemia is frequently non-specific, especially among patients who are acutely unwell. As a result, patients with transient hyperglycemia may be incorrectly labeled as having diabetes, leading to unnecessary treatment, and potential harm. DESIGN, SETTING, AND PARTICIPANTS: We conducted a multicenter cohort study of patients hospitalized at six hospitals in Ontario, Canada, and identified those with a glucose value ≥200 mg/dL (including standing measurements and randomly drawn). We validated a definition for diabetes using manual chart review that included physician notes, pharmacy notes, home medications, and hemoglobin A1C. Among patients with a glucose value ≥200 mg/dL (11.1 mmol/L), we identified patients without diabetes who received a diabetes medication, and the number who experienced hypoglycemia during the same admission. MAIN OUTCOMES AND MEASURES: To determine the diagnostic value of using random blood glucose to diagnose diabetes in the inpatient setting, and its impact on patient outcomes. RESULTS: We identified 328,786 hospitalizations from hospital between 2010 and 2020. A blood glucose value of ≥200 mg/dL (11.1 mmol/L) had a positive predictive value of 68% and a negative predictive value of 90% for a diagnosis of diabetes. Of the 76,967 patients with an elevated glucose value reported, 16,787 (21.8%) did not have diabetes, and of these, 5375 (32%) received a diabetes medication. Hypoglycemia was frequently reported among the 5375 patients that received a diabetes medication, with 1406 (26.2%) experiencing hypoglycemia and 405 (7.5%) experiencing severe hypoglycemia. CONCLUSIONS AND RELEVANCE: Hyperglycemia in hospital is common but does not necessarily indicate a patient has diabetes. Furthermore, it can lead to treatment with diabetes medications with potential harm. Our findings highlight that clinicians should be cautious when responding to elevated random plasma glucose tests in the inpatient setting.

Press Releases of Drug-Related Randomized Trial Results Prior to Publication in High-Impact Journals: an Observational Study.

IMPORTANCE: Results from high-profile randomized controlled trials (RCTs) are routinely reported through press release months prior to peer-reviewed publication. There are potential benefits to press releases (e.g., knowledge dissemination, ensuring regulatory compliance), but also potential drawbacks (e.g., selective reporting, positive "spin"). OBJECTIVE: To characterize the practice of press release predating the publication of a drug-related RCT in a peer-reviewed journal ("preemptive press release"), including factors associated with this practice. DESIGN, SETTING, AND PARTICIPANTS: We systematically reviewed all RCTs of medications published between 2015 and 2019 in the New England Journal of Medicine (NEJM), Journal of the American Medical Association (JAMA), and Lancet. Press releases were identified using a systematic search of the grey literature (e.g., press release databases, study sponsor websites). An RCT was considered to have a preemptive press release if the press release was published at least three months (90 days) prior to the date of publication in a peer-reviewed journal. MAIN OUTCOMES AND MEASURES: Presence of preemptive press release, defined as a press-release at least 90 days prior to the date of publication in a peer-reviewed journal. As secondary measures for dissemination, we also assessed citation count and Altmetric score. RESULTS: We identified 988 RCTs, of which 172 (17%) had a press release published at least 90 days before the date of peer-reviewed publication. Press releases were published a median of 246 days (interquartile range [IQR] 169-366 days) before publication in a peer-reviewed journal. In the multivariable logistic regression model, the strongest predictor of having a preemptive press release was funding by a pharmaceutical company (odds ratio 13, 95% CI 7, 25). Approximately 85% of RCTs with preemptive press releases had a positive primary outcome and, concordantly, 81% of the corresponding press releases had a positive headline. Multivariable regression models identified studies with a preemptive press release had a similar Altmetric score (median - 15, 95% CI - 33, 12) and higher median citation count (median 22 [95% CI 10 to 33] compared to studies without a preemptive press release. CONCLUSIONS AND RELEVANCE: Preemptive press releases were common, most often issued for trials funded by a pharmaceutical company, and typically preceded publication in a peer-reviewed journal by approximately eight months.

Physician antimicrobial prescribing and patient outcomes on general medical wards: a multicentre retrospective cohort study.

BACKGROUND: Variability in antimicrobial prescribing may indicate an opportunity for improvement in antimicrobial use. We sought to measure physician-level antimicrobial prescribing in adult general medical wards, assess the contribution of patient-level factors to antimicrobial prescribing and evaluate the association between antimicrobial prescribing and clinical outcomes. METHODS: Using the General Medicine Inpatient Initiative (GEMINI) database, we conducted a retrospective cohort study of physician-level volume and spectrum of antimicrobial prescribing in adult general medical wards in 4 academic teaching hospitals in Toronto, Ontario, between April 2010 and December 2019. We stratified physicians into quartiles by hospital site based on volume of antimicrobial prescribing (days of therapy per 100 patient-days and antimicrobial-free days) and antibacterial spectrum (modified spectrum score). The modified spectrum score assigns a value to each antibacterial agent based on the breadth of coverage. We assessed patient-level differences among physician quartiles using age, sex, Laboratory-based Acute Physiology Score, discharge diagnosis and Charlson Comorbidity Index. We evaluated the association of clinical outcomes (in-hospital 30-day mortality, length of stay, intensive care unit [ICU] transfer and hospital readmission) with antimicrobial volume and spectrum using multilevel modelling. RESULTS: The cohort consisted of 124 physicians responsible for 124 158 hospital admissions. The median physician-level volume of antimicrobial prescribing was 56.1 (interquartile range 51.7-67.5) days of therapy per 100 patient-days. We did not find any differences in baseline patient characteristics by physician prescribing quartile. The difference in mean prescribing between quartile 4 and quartile 1 was 15.8 days of therapy per 100 patient-days (95% confidence interval [CI] 9.6-22.0), representing 30% higher antimicrobial prescribing in the fourth quartile than the first quartile. Patient in-hospital deaths, length of stay, ICU transfer and hospital readmission did not differ by physician quartile. In-hospital mortality was higher among patients cared for by prescribers with higher modified spectrum scores (odds ratio 1.13, 95% CI 1.04-1.24). INTERPRETATION: We found that physician-level variability in antimicrobial prescribing was not associated with differences in patient characteristics or outcomes in academic general medicine wards. These findings provide support for considering the lowest quartile of physician antimicrobial prescribing within each hospital as a target for antimicrobial stewardship.

The Landscape of COVID-19 Research in the United States: a Cross-sectional Study of Randomized Trials Registered on ClinicalTrials.Gov.

IMPORTANCE: SARS-CoV-2 has infected over 200 million people worldwide, resulting in more than 4 million deaths. Randomized controlled trials are the single best tool to identify effective treatments against this novel pathogen. OBJECTIVE: To describe the characteristics of randomized controlled trials of treatments for COVID-19 in the United States launched in the first 9 months of the pandemic. Design, Setting, and Participants We conducted a cross-sectional study of all completed or actively enrolling randomized, interventional, clinical trials for the treatment of COVID-19 in the United States registered on www.clinicaltrials.gov as of August 10, 2020. We excluded trials of vaccines and other interventions intended to prevent COVID-19. Main Outcomes and Measures We used descriptive statistics to characterize the clinical trials and the statistical power for the available studies. For the late-phase trials (i.e., phase 3 and 2/3 studies), we compared the geographic distribution of the clinical trials with the geographic distribution of people diagnosed with COVID-19. RESULTS: We identified 200 randomized controlled trials of treatments for people with COVID-19. Across all trials, 87 (43.5%) were single-center, 64 (32.0%) were unblinded, and 80 (40.0%) were sponsored by industry. The most common treatments included monoclonal antibodies (N=46 trials), small molecule immunomodulators (N=28), antiviral medications (N=24 trials), and hydroxychloroquine (N=20 trials). Of the 9 trials completed by August 2020, the median sample size was 450 (IQR 67-1113); of the 191 ongoing trials, the median planned sample size was 150 (IQR 60-400). Of the late-phase trials (N=54), the most common primary outcome was a severity scale (N=23, 42.6%), followed by a composite of mortality and ventilation (N=10, 18.5%), and mortality alone (N=6, 11.1%). Among these late-phase trials, all trials of antivirals, monoclonal antibodies, or chloroquine/hydroxychloroquine had a power of less than 25% to detect a 20% relative risk reduction in mortality. Had the individual trials for a given class of treatments instead formed a single trial, the power to detect that same reduction in mortality would have been greater than 98%. There was large variability in access to trials with the highest number of trials per capita in the Northeast and the lowest in the Midwest. CONCLUSIONS AND RELEVANCE: A large number of randomized trials were launched early in the pandemic to evaluate treatments for COVID-19. However, many trials were underpowered for important clinical endpoints and substantial geographic disparities were observed, highlighting the importance of improving national clinical trial infrastructure.

Systematic review of hematuria and acute renal failure with tranexamic acid.

OBJECTIVES: To conduct a systematic review of tranexamic acid (TXA) and the risk of renal failure from urinary clots in adult patients with hematuria. METHODS: A systematic review of Medline, Embase, CENTRAL, www. CLINICALTRIALS: gov, and Google Scholar were searched. Randomized control trials (RCTs) and observational studies that assessed the risk of renal failure with use of TXA among adults with hematuria were included. The primary outcome was renal failure due to urinary tract clots with TXA compared to no TXA (or placebo) or comparator. RESULTS: We identified three RCTs (N = 466 patients) and three retrospective cohort studies (N=220 patients), and a total of 342 patients that had hematuria and received TXA. The patient population of the six studies included medical and surgical patients, with two of the three RCTs comprised patients undergoing percutaneous nephrolithotomy, and the third RCT comprised patients undergoing transurethral resection of the prostate. Documentation of renal function before and after TXA administration was documented in only two studies (N = 28 patients), and neither identified worsening renal function in those exposed to TXA. CONCLUSIONS: There are limited studies evaluating the risk of renal failure in patients with hematuria who were exposed to TXA, and the available data does not suggest an increased risk.

Outcomes in patients with and without disability admitted to hospital with COVID-19: a retrospective cohort study.

BACKGROUND: Disability-related considerations have largely been absent from the COVID-19 response, despite evidence that people with disabilities are at elevated risk for acquiring COVID-19. We evaluated clinical outcomes in patients who were admitted to hospital with COVID-19 with a disability compared with patients without a disability. METHODS: We conducted a retrospective cohort study that included adults with COVID-19 who were admitted to hospital and discharged between Jan. 1, 2020, and Nov. 30, 2020, at 7 hospitals in Ontario, Canada. We compared in-hospital death, admission to the intensive care unit (ICU), hospital length of stay and unplanned 30-day readmission among patients with and without a physical disability, hearing or vision impairment, traumatic brain injury, or intellectual or developmental disability, overall and stratified by age (≤ 64 and ≥ 65 yr) using multivariable regression, controlling for sex, residence in a long-term care facility and comorbidity. RESULTS: Among 1279 admissions to hospital for COVID-19, 22.3% had a disability. We found that patients with a disability were more likely to die than those without a disability (28.1% v. 17.6%), had longer hospital stays (median 13.9 v. 7.8 d) and more readmissions (17.6% v. 7.9%), but had lower ICU admission rates (22.5% v. 28.3%). After adjustment, there were no statistically significant differences between those with and without disabilities for in-hospital death or admission to ICU. After adjustment, patients with a disability had longer hospital stays (rate ratio 1.36, 95% confidence interval [CI] 1.19-1.56) and greater risk of readmission (relative risk 1.77, 95% CI 1.14-2.75). In age-stratified analyses, we observed longer hospital stays among patients with a disability than in those without, in both younger and older subgroups; readmission risk was driven by younger patients with a disability. INTERPRETATION: Patients with a disability who were admitted to hospital with COVID-19 had longer stays and elevated readmission risk than those without disabilities. Disability-related needs should be addressed to support these patients in hospital and after discharge.

Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

The discovery of insulin in Toronto: beginning a 100 year journey of research and clinical achievement.

There has been a great deal of controversy regarding priority of discovery of insulin. Indeed, many scientists made important and, in some cases, seminal contributions to identifying the endocrine role of the pancreas and the potential for pancreatic extracts to have a glucose-lowering effect. The purpose of this article is to describe the early experiences with respect to research leading to the discovery of insulin in Toronto (ON, Canada). The experiments conducted at the University of Toronto resulted in the first demonstration that a pancreatic extract could be prepared that would consistently lower glucose, reverse ketosis and arrest the catabolic effects of type 1 diabetes. The remarkably rapid commercial production of insulin soon followed. The Toronto story begins on 17 May 1921, when Frederick Banting and Charles Best began their summer research project in the laboratory of John James Rickard Macleod, and we are now celebrating the 100th anniversary of this landmark achievement. The article herein outlines the steps leading up to the discovery of insulin and provides an overview of some of the key developments in insulin therapy over the past 100 years.

Identifying Risk Factors for Diabetic Ketoacidosis Associated with SGLT2 Inhibitors: a Nationwide Cohort Study in the USA.

INTRODUCTION: Sodium glucose co-transporter-2 inhibitors (SGLT2) are commonly prescribed to patients with type 2 diabetes mellitus, but can increase the risk of diabetic ketoacidosis. Identifying patients prone to diabetic ketoacidosis may help mitigate this risk. METHODS: We conducted a population-based cohort study of adults initiating SGLT2 inhibitor use from 2013 through 2017. The primary objective was to identify potential predictors of diabetic ketoacidosis. Two machine-learning methods were applied to model high-dimensional pre-exposure data: gradient boosted trees and least absolute shrinkage and selection operator (LASSO) regression. We rank ordered the variables produced from LASSO by the size of their estimated coefficient (largest to smallest). With gradient boosted trees, a relative importance measure for each variable is provided rather than a coefficient. The "top variables" were identified after reviewing the distributions of the effect estimates from LASSO and gradient boosted trees to identify where there was a substantial decrease in variable importance. The identified predictors were then assessed in a logistic regression model and reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We identified 111,442 adults who started SGLT2 inhibitor use. The mean age was 57 years, 44% were female, the mean hemoglobin A1C was 8.7%, and the mean creatinine was 0.89 mg/dL. During a mean follow-up of 180 days, 192 patients (0.2%, i.e., 2 per 1000) were diagnosed and hospitalized with diabetic ketoacidosis (DKA) and 475 (0.4%, i.e., 4 per 1000) were diagnosed in either an inpatient or outpatient setting. Using gradient boosted trees, the strongest predictors were prior DKA, baseline hemoglobin A1C level, baseline creatinine level, use of medications for dementia, and baseline bicarbonate level. Using LASSO regression not including laboratory test results due to missing data, the strongest predictors were prior DKA, digoxin use, use of medications for dementia, and recent hypoglycemia. The logistic regression model incorporating the variables identified from gradient boosted trees and LASSO regression suggested the following pre-exposure characteristics had the strongest association with a hospitalization for DKA: use of dementia medications (OR = 7.76, 95% CI 2.60, 23.1), prior intracranial hemorrhage (OR = 11.5, 95% CI 1.46, 91.1), a prior diagnosis of hypoglycemia (OR = 5.41, 95% CI 1.92,15.3), prior DKA (OR = 2.45, 95% CI 0.33, 18.0), digoxin use (OR = 4.00, 95% CI 1.21, 13.2), a baseline hemoglobin A1C above 10% (OR = 3.14, 95% CI 1.95, 5.06), and baseline bicarbonate below 18 mmol/L (OR 5.09, 95% CI 1.58, 16.4). CONCLUSION: Diabetic ketoacidosis affected approximately 2 per 1000 patients starting to use an SGLT2 inhibitor. We identified both anticipated, e.g., low baseline serum bicarbonate, and unanticipated, e.g., digoxin, dementia medications, risk factors for SGLT2 inhibitor-induced DKA.

Sodium-glucose co-transporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors and the risk of heart failure: A nationwide cohort study of older adults with diabetes mellitus.

AIMS: To analyse the rate of heart failure hospitalization for older adults prescribed a sodium-glucose co-transporter-2 (SGLT2) inhibitor. MATERIALS AND METHODS: The study cohort included adults aged 66 years and older diagnosed with diabetes mellitus in Ontario, Canada, between July 2015 and March 2019, who received either an SGLT2 inhibitor or a dipeptidyl peptidase-4 (DPP-4) inhibitor. The primary outcome was a composite of heart failure hospitalization and all-cause mortality. Secondary outcomes included diabetic ketoacidosis and hypoglycaemia. RESULTS: A total of 29 916 adults prescribed an SGLT2 inhibitor were compared with 29 916 adults prescribed a DPP-4 inhibitor. The mean age was 72 years, 60% were men, the baseline glycated haemoglobin concentration was 8.2% and the baseline creatinine was 89 µmol/L. The incidence rate of the primary outcome was 19/1000 person-years for adults prescribed an SGLT2 inhibitor compared to 38/1000 person-years in those prescribed a DPP-4 inhibitor. This resulted in a hazard ratio (HR) of 0.49 (95% confidence interval [CI] 0.45, 0.54) and a rate difference (RD) of 19 fewer events per 1000 person-years (RD -19 [95% CI -22, -17]). Patients prescribed an SGLT2 inhibitor also had a lower rate of hypoglycaemia (HR 0.61 [95% CI 0.46, 0.81); RD -1.6 [95% CI -2.4, -0.8]), but a higher rate of diabetic ketoacidosis (HR 1.84 [95% CI 1.26, 2.70]; RD 1.0 [95% CI 0.4, 1.6]). CONCLUSIONS: Older adults prescribed an SGLT2 inhibitor had a lower rate of heart failure hospitalization or death, and a lower rate of hypoglycaemia, but an increased rate of diabetic ketoacidosis compared to older adults prescribed a DPP-4 inhibitor.

Using machine learning to predict severe hypoglycaemia in hospital.

AIM: To predict the risk of hypoglycaemia using machine-learning techniques in hospitalized patients. METHODS: We conducted a retrospective cohort study of patients hospitalized under general internal medicine (GIM) and cardiovascular surgery (CV) at a tertiary care teaching hospital in Toronto, Ontario. Three models were generated using supervised machine learning: least absolute shrinkage and selection operator (LASSO) logistic regression; gradient-boosted trees; and a recurrent neural network. Each model included baseline patient data and time-varying data. Natural-language processing was used to incorporate text data from physician and nursing notes. RESULTS: We included 8492 GIM admissions and 8044 CV admissions. Hypoglycaemia occurred in 16% of GIM admissions and 13% of CV admissions. The area under the curve for the models in the held-out validation set was approximately 0.80 on the GIM ward and 0.82 on the CV ward. When the threshold for hypoglycaemia was lowered to 2.9 mmol/L (52 mg/dL), similar results were observed. Among the patients at the highest decile of risk, the positive predictive value was approximately 50% and the sensitivity was 99%. CONCLUSION: Machine-learning approaches can accurately identify patients at high risk of hypoglycaemia in hospital. Future work will involve evaluating whether implementing this model with targeted clinical interventions can improve clinical outcomes.

Comparative effectiveness and safety of sodium-glucose cotransporter-2 inhibitors versus metformin in patients with type 2 diabetes: An observational study using data from routine care.

AIM: To assess the effectiveness and safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors in treatment-naïve patients compared with metformin. PARTICIPANTS AND METHODS: We conducted a cohort study of US adults with type 2 diabetes mellitus who had not filled a prescription for a diabetes medication in the preceding year. We then identified patients who newly filled a prescription for an SGLT2 inhibitor or metformin between 2013 and 2018. The primary outcome was a composite of heart failure, myocardial infarction or stroke. Safety outcomes included hypoglycaemia, diabetic ketoacidosis, genital infection, lactic acidosis and acute kidney injury. After 1:1 propensity-score (PS) matching, proportional hazards models were fit to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: We identified 9964 individuals newly prescribed an SGLT2 inhibitor who were PS-matched to 9964 individuals newly prescribed metformin. The mean age was 54 years, 52% were women, and the duration of follow-up was 213 days for metformin and 147 days for SGLT2 inhibitors. The primary outcome occurred in 54 patients (7.2 events per 1000 person-years) who received an SGLT2 inhibitor, compared to 84 patients (8.5 per 1000 person-years) who received metformin (HR  0.82, 95% CI 0.58, 1.15). Similar results (HR 0.87, 95% CI 0.69, 1.09) were observed in an analysis with longer follow-up (ie, approximately 600 days). The rates of genital infection (HR 2.28, 95% CI 1.87, 2.78) and diabetic ketoacidosis (HR 1.58, 95% CI 0.92, 2.70) were higher for patients prescribed an SGLT2 inhibitor compared to metformin, while the rates of acute kidney injury (HR 0.94, 95% CI 0.60, 1.47) or hypoglycaemia (HR 0.83, 95% CI 0.48, 1.42) were not. CONCLUSIONS: We observed a numerically lower rate of short-/mid-term cardiovascular events for patients newly prescribed an SGLT2 inhibitor compared to metformin, albeit with wide CIs that include the possibility of a null effect. SGLT2 inhibitors were associated with a higher rate of genital infection and diabetic ketoacidosis. Larger cohort studies and long-term clinical trials powered to assess cardiovascular events are necessary to understand the risk-benefit profile of SGLT2 inhibitors as first-line therapy for adults with type 2 diabetes mellitus.

Diagnosis-wide analysis of COVID-19 complications: an exposure-crossover study.

BACKGROUND: Many studies reporting coronavirus disease 2019 (COVID-19) complications have involved case series or small cohorts that could not establish a causal association with COVID-19 or provide risk estimates in different care settings. We sought to study all possible complications of COVID-19 to confirm previously reported complications and to identify potential complications not yet known. METHODS: Using United States health claims data, we compared the frequency of all International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis codes occurring before and after the onset of the COVID-19 pandemic in an exposure-crossover design. We included patients who received a diagnosis of COVID-19 between Mar. 1, 2020, and Apr. 30, 2020, and computed risk estimates and odds ratios (ORs) of association with COVID-19 for every ICD-10-CM diagnosis code. RESULTS: Among 70 288 patients with COVID-19, 69 of 1724 analyzed ICD-10-CM diagnosis codes were significantly associated with COVID-19. Disorders showing both strong association with COVID-19 and high absolute risk included viral pneumonia (OR 177.63, 95% confidence interval [CI] 147.19-214.37, absolute risk 27.6%), respiratory failure (OR 11.36, 95% CI 10.74-12.02, absolute risk 22.6%), acute kidney failure (OR 3.50, 95% CI 3.34-3.68, absolute risk 11.8%) and sepsis (OR 4.23, 95% CI 4.01-4.46, absolute risk 10.4%). Disorders showing strong associations with COVID-19 but low absolute risk included myocarditis (OR 8.17, 95% CI 3.58-18.62, absolute risk 0.1%), disseminated intravascular coagulation (OR 11.83, 95% CI 5.26-26.62, absolute risk 0.1%) and pneumothorax (OR 3.38, 95% CI 2.68-4.26, absolute risk 0.4%). INTERPRETATION: We confirmed and provided risk estimates for numerous complications of COVID-19. These results may guide prognosis, treatment decisions and patient counselling.

Characteristics and outcomes of hospital admissions for COVID-19 and influenza in the Toronto area.

BACKGROUND: Patient characteristics, clinical care, resource use and outcomes associated with admission to hospital for coronavirus disease 2019 (COVID-19) in Canada are not well described. METHODS: We described all adults with COVID-19 or influenza discharged from inpatient medical services and medical-surgical intensive care units (ICUs) between Nov. 1, 2019, and June 30, 2020, at 7 hospitals in Toronto and Mississauga, Ontario. We compared patient outcomes using multivariable regression models, controlling for patient sociodemographic factors and comorbidity level. We validated the accuracy of 7 externally developed risk scores to predict mortality among patients with COVID-19. RESULTS: There were 1027 hospital admissions with COVID-19 (median age 65 yr, 59.1% male) and 783 with influenza (median age 68 yr, 50.8% male). Patients younger than 50 years accounted for 21.2% of all admissions for COVID-19 and 24.0% of ICU admissions. Compared with influenza, patients with COVID-19 had significantly greater in-hospital mortality (unadjusted 19.9% v. 6.1%, adjusted relative risk [RR] 3.46, 95% confidence interval [CI] 2.56-4.68), ICU use (unadjusted 26.4% v. 18.0%, adjusted RR 1.50, 95% CI 1.25-1.80) and hospital length of stay (unadjusted median 8.7 d v. 4.8 d, adjusted rate ratio 1.45, 95% CI 1.25-1.69). Thirty-day readmission was not significantly different (unadjusted 9.3% v. 9.6%, adjusted RR 0.98, 95% CI 0.70-1.39). Three points-based risk scores for predicting in-hospital mortality showed good discrimination (area under the receiver operating characteristic curve [AUC] ranging from 0.72 to 0.81) and calibration. INTERPRETATION: During the first wave of the pandemic, admission to hospital for COVID-19 was associated with significantly greater mortality, ICU use and hospital length of stay than influenza. Simple risk scores can predict in-hospital mortality in patients with COVID-19 with good accuracy.

Assessing the Risk for Gout With Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Type 2 Diabetes: A Population-Based Cohort Study.

Background: Hyperuricemia is common in patients with type 2 diabetes mellitus and is known to cause gout. Sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent glucose reabsorption and lower serum uric acid levels. Objective: To compare the rate of gout between adults prescribed an SGLT2 inhibitor and those prescribed a glucagon-like peptide-1 (GLP1) receptor agonist. Design: Population-based new-user cohort study. Setting: A U.S. nationwide commercial insurance database from March 2013 to December 2017. Patients: Persons with type 2 diabetes newly prescribed an SGLT2 inhibitor were 1:1 propensity score matched to patients newly prescribed a GLP1 agonist. Persons were excluded if they had a history of gout or had received gout-specific treatment previously. Measurements: The primary outcome was a new diagnosis of gout. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of the primary outcome and 95% CIs. Results: The study identified 295 907 adults with type 2 diabetes mellitus who were newly prescribed an SGLT2 inhibitor or a GLP1 agonist. The gout incidence rate was lower among patients prescribed an SGLT2 inhibitor (4.9 events per 1000 person-years) than those prescribed a GLP1 agonist (7.8 events per 1000 person-years), with an HR of 0.64 (95% CI, 0.57 to 0.72) and a rate difference of -2.9 (CI, -3.6 to -2.1) per 1000 person-years. Limitation: Unmeasured confounding, missing data (namely incomplete laboratory data), and low baseline risk for gout. Conclusion: Adults with type 2 diabetes prescribed an SGLT2 inhibitor had a lower rate of gout than those prescribed a GLP1 agonist. Sodium-glucose cotransporter-2 inhibitors may reduce the risk for gout among adults with type 2 diabetes mellitus, although future studies are necessary to confirm this observation. Primary Funding Source: Brigham and Women's Hospital.

Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study.

Background: Apixaban and rivaroxaban are the most commonly prescribed direct oral anticoagulants for adults with atrial fibrillation, but head-to-head data comparing their safety and effectiveness are lacking. Objective: To compare the safety and effectiveness of apixaban versus rivaroxaban for patients with nonvalvular atrial fibrillation. Design: New-user, active-comparator, retrospective cohort study. Setting: A U.S. nationwide commercial health care claims database from 28 December 2012 to 1 January 2019. Patients: Adults newly prescribed apixaban (n = 59 172) or rivaroxaban (n = 40 706). Measurements: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial hemorrhage or gastrointestinal bleeding. Results: 39 351 patients newly prescribed apixaban were propensity score matched to 39 351 patients newly prescribed rivaroxaban. Mean age was 69 years, 40% of patients were women, and mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users. The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for adults prescribed apixaban compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.98]; rate difference, 1.4 fewer events per 1000 person-years [CI, 0.0 to 2.7]). Adults prescribed apixaban also had a lower rate of gastrointestinal bleeding or intracranial hemorrhage (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years), corresponding to an HR of 0.58 (CI, 0.52 to 0.66) and a rate difference of 9.0 fewer events per 1000 person-years (CI, 6.9 to 11.1). Limitation: Unmeasured confounding, incomplete laboratory data. Conclusion: In routine care, adults with atrial fibrillation prescribed apixaban had a lower rate of both ischemic stroke or systemic embolism and bleeding compared with those prescribed rivaroxaban. Primary Funding Source: Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital.

Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors could increase the risk for diabetic ketoacidosis (DKA). OBJECTIVE: To assess whether SGLT-2 inhibitors, compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, are associated with an increased risk for DKA in patients with type 2 diabetes. DESIGN: Population-based cohort study; prevalent new-user design between 2013 and 2018. (ClinicalTrials.gov: NCT04017221). SETTING: Electronic health care databases from 7 Canadian provinces and the United Kingdom. PATIENTS: 208 757 new users of SGLT-2 inhibitors were matched by using time-conditional propensity scores to 208 757 recipients of DPP-4 inhibitors. MEASUREMENTS: Cox proportional hazards models estimated site-specific hazard ratios (HRs) with 95% CIs of DKA comparing receipt of SGLT-2 inhibitors with receipt of DPP-4 inhibitors, which were pooled by using random-effects models. Secondary analyses were stratified by molecule, age, sex, and prior receipt of insulin. RESULTS: Overall, 521 patients were diagnosed with DKA during 370 454 person-years of follow-up (incidence rate per 1000 person-years, 1.40 [95% CI, 1.29 to 1.53]). Compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with an increased risk for DKA (incidence rate, 2.03 [CI, 1.83 to 2.25] versus 0.75 [CI, 0.63 to 0.89], respectively; HR, 2.85 [CI, 1.99 to 4.08]). Molecule-specific HRs were 1.86 (CI, 1.11 to 3.10) for dapagliflozin, 2.52 (CI, 1.23 to 5.14) for empagliflozin, and 3.58 (CI, 2.13 to 6.03) for canagliflozin. Age and sex did not modify the association; prior receipt of insulin appeared to decrease the risk. LIMITATIONS: There was unmeasured confounding and no laboratory data were available for the majority of patients, and molecule-specific analyses were conducted at a limited number of sites. CONCLUSION: SGLT-2 inhibitors were associated with an almost 3-fold increased risk for DKA, with molecule-specific analyses suggesting a class effect. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Transcranial Magnetic Stimulation for the Treatment of Concussion: A Systematic Review.

BACKGROUND: Post-concussive symptoms (PCSs) are common, disabling, and challenging to manage. Evolving models of concussion pathophysiology suggest evidence of brain network dysfunction that may be amenable to neuromodulation. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential novel treatment option for PCSs. OBJECTIVES: To systematically review rTMS trials for the treatment of symptoms following concussion/mild traumatic brain injury (mTBI). MATERIALS AND METHODS: We conducted a systematic review of Pubmed/Medline, Embase, and PsychINFO databases were searched up to May 19, 2020. Studies were included if they were prospective rTMS treatment studies of patients with mTBI/concussion. Variables including patient demographics, study design, rTMS protocol parameters, primary outcome measures, and efficacy data were extracted and qualitatively synthesized. rTMS methodology and study quality were also evaluated. RESULTS: Of the 342 studies identified, 11 met eligibility criteria and were included for synthesis. Forty-one percent of patients were female and age ranged from 18 to 65 (average age = 38.5 years). Post-concussive depression (seven studies) and headache (four studies) were the most commonly investigated symptoms. The majority of trials were sham-controlled with randomized control trial (RCT) designs, but all were small pilot samples (n < 30). Methodological heterogeneity and a low number of identified trials precluded quantitative meta-analysis. Regarding rTMS for post-concussive depression, positive results were found in two out of four studies with depression as a primary outcome, and all three studies that assessed depression as a secondary outcome. All four rTMS studies for post-concussive headache reported positive results. CONCLUSIONS: rTMS for the treatment of concussion/mTBI shows promising preliminary results for post-concussive depression and headache, symptoms that otherwise have limited effective treatment options. More studies with larger sample sizes are needed to further establish potential efficacy.

Sodium-glucose co-transporter-2 inhibitors and the risk of urosepsis: A multi-site, prevalent new-user cohort study.

AIM: To compare urosepsis rates in patients with type 2 diabetes treated using sodium-glucose co-transporter-2 inhibitors (SGLT2i) with dipeptidyl peptidase-4 inhibitors (DPP4i) in a real-world setting. METHODS: We conducted a matched cohort study using a prevalent new-user design with time-conditional propensity scores. New users of SGLT2i from seven Canadian provinces and the UK were matched to DPP4i users. The primary outcome was hospitalization with a diagnosis of urosepsis and the secondary outcome was Fournier's gangrene. Site-specific hazard ratios for urosepsis comparing SGLT2i with DPP4i were estimated using Cox proportional hazards models and pooled using a random effects meta-analysis. RESULTS: We included 208 244 users of SGLT2i and 208 244 users of DPP4i. Among SGLT2i users, 42% initiated canagliflozin, 31% dapagliflozin and 27% empagliflozin. During a mean follow-up of 0.9 years, patients initiating SGLT2i had a lower rate of urosepsis compared with those receiving DPP4i. The pooled adjusted hazard ratio was 0.58 (95% confidence interval [CI]: 0.42-0.80). The incidence rates of Fournier's gangrene were numerically similar in SGLT2i (0.08 per 1000 person-years; 95% CI: 0.05-0.13) and DPP4i users (0.14; 95% CI: 0.09-0.21). CONCLUSIONS: In this large, multi-site study, we did not observe an increased risk for urosepsis associated with SGLT2i compared with DPP4i among patients with type 2 diabetes in a real-world setting.

Using Data From Routine Care to Estimate the Effectiveness and Potential Limitations of Outcomes-Based Contracts for Diabetes Medications.

OBJECTIVES: Outcomes-based contracts tie rebates and discounts for expensive drugs to outcomes. The objective was to estimate the utility of outcomes-based contracts for diabetes medications using real-world data and to identify methodologic limitations of this approach. METHODS: A population-based cohort study of adults newly prescribed a medication for diabetes with a publicly announced outcomes-based contract (ie, exenatide microspheres ["exenatide"], dulaglutide, or sitagliptin) was conducted. The comparison group included patients receiving canagliflozin or glipizide. The primary outcome was announced in the outcomes-based contract: the percentage of adults with a follow-up hemoglobin A1C <8% up to 1 year later. Secondary outcomes included the percentage of patients diagnosed with hypoglycemia and the cost of a 1-month supply. RESULTS: Thousands of adults newly filled prescriptions for exenatide (n = 5079), dulaglutide (n = 6966), sitagliptin (n = 40 752), canagliflozin (n = 16 404), or glipizide (n = 59 985). The percentage of adults subsequently achieving a hemoglobin A1C below 8% ranged from 83% (dulaglutide, sitagliptin) to 71% (canagliflozin). The rate of hypoglycemia was 25 per 1000 person-years for exenatide, 37 per 1000 person-years for dulaglutide, 28 per 1000 person-years for sitagliptin, 18 per 1000 person-years for canagliflozin, and 34 per 1000 person-years for glipizide. The cash price for a 1-month supply was $847 for exenatide, $859 for dulaglutide, $550 for sitagliptin, $608 for canagliflozin, and $14 for glipizide. CONCLUSION: Outcomes-based pricing of diabetes medications has the potential to lower the cost of medications, but using outcomes such as hemoglobin A1C may not be clinically meaningful because similar changes in A1C can be achieved with generic medications at a far lower cost.