Proximal versus distal diuretics in congestive heart failure.

Volume overload represents a hallmark clinical feature linked to the development and progression of heart failure (HF). Alleviating signs and symptoms of volume overload represents a foundational HF treatment target that is achieved using loop diuretics in the acute and chronic setting. Recent work has provided evidence to support guideline-directed medical therapies, such as sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor (MR) antagonists, as important adjunct diuretics that may act synergistically when used with background loop diuretics in people with chronic HF. Furthermore, there is growing interest in understanding the role of SGLT2 inhibitors, carbonic anhydrase inhibitors, thiazide diuretics, and MR antagonists in treating volume overload in patients hospitalized for acute HF, particularly in the setting of loop diuretic resistance. Thus, the current review demonstrates that: 1) SGLT2 inhibitors and MR antagonists confer long-term cardioprotection in chronic HF patients but it is unclear if natriuresis or diuresis represents the primary mechanisms for this benefit, 2) SGLT2 inhibitors, carbonic anhydrase inhibitors, and thiazide diuretics increase natriuresis in the acute HF setting, but implications on long-term outcomes remain unclear and warrants further investigation, and 3) a multi-nephron segment approach, using agents that act on distinct segments of the nephron, potentiate diuresis to alleviate signs and symptoms of volume overload in acute HF.

Cardiovascular Risk in Patients With Glomerular Disease: A Narrative Review of the Epidemiology, Mechanisms, Management, and Patient Priorities.

Purpose of review: Cardiovascular (CV) disease is a major cause of morbidity and mortality for patients with glomerular disease. Despite the fact that mechanisms underpinning CV disease risk in this population are likely distinct from other forms of kidney disease, treatment and preventive strategies tend to be extrapolated from studies of patients with undifferentiated chronic kidney disease (CKD). There is an unmet need to delineate the pathophysiology of CV disease in patients with glomerular disease, establish unique risk factors, and identify novel therapeutic targets for disease prevention. The aims of this narrative review are to summarize the existing knowledge regarding the epidemiology, molecular mechanisms, and management of CV disease in patients with common glomerular disease, highlight the patient perspective, and propose specific areas for future study. Sources of information: The literature for this narrative review was accessed using common research search engines, including PubMed, PubMed Central, Medline, and Google Scholar. Information for the patient perspective section was collected through iterative discussions with a patient partner. Methods: We reviewed the epidemiology, molecular mechanisms of disease, management approaches, and the patient perspective in relation to CV disease in patients with glomerulopathies. Throughout, we have highlighted the current knowledge and have discussed future research approaches, both clinical and translational, while integrating the patient perspective. Key findings: Patients with glomerular disease have significant CV disease risk driven by multifactorial, molecular mechanisms originating from their glomerular disease but complicated by existing comorbidities, kidney disease, and medication side effects. The current approach to risk stratification and treatment relies heavily on existing data from CKD patients, but this may not always be appropriate given the unique pathophysiology and mechanisms associated with CV disease risk in patients with glomerular disease. We highlight the need for ongoing glomerular disease-focused studies aimed to better delineate CV disease risk, while integrating the patient perspective. Limitations: This is a narrative review and does not represent a comprehensive and systematic review of the literature.

Motif de la revue: Les maladies cardiovasculaires sont une cause majeure de morbidité et de mortalité chez les patients atteints d'une maladie glomérulaire. Bien que les mécanismes qui sous-tendent le risque de maladie cardiovasculaire dans cette population sont probablement distincts des autres formes de néphropathies, le traitement et les stratégies préventives ont tendance à être extrapolés à partir d'études portant sur des patients atteints d'insuffisance rénale chronique indifférenciée. Il existe ainsi un besoin de délimiter la physiopathologie des maladies cardiovasculaires chez les patients atteints d'une maladie glomérulaire, d'établir les facteurs de risque propres à la maladie glomérulaire et d'identifier de nouvelles cibles thérapeutiques pour la prévenir. Les objectifs de cette revue narrative sont de résumer les connaissances existantes concernant l'épidémiologie, les mécanismes moléculaires et la prise en charge des maladies cardiovasculaires chez les patients atteints d'une maladie glomérulaire commune, de mettre en évidence le point de vue des patients et de proposer des domaines précis pour de futures études. Sources de l'information: La documentation a été consultée par le biais des moteurs de recherche courants, notamment PubMed, PubMed Central, Medline et Google Scholar. Les points de vue des patients ont été recueillis au moyen de discussions itératives avec un patient partenaire. Méthodologie: Nous avons examiné l'épidémiologie et les mécanismes moléculaires de la maladie, les approches de prise en charge et la perspective des patients en lien avec les maladies cardiovasculaires chez les patients atteints d'une maladie glomérulaire. Nous avons fait état des connaissances actuelles et discuté des approches à envisager pour les recherches futures, tant cliniques que translationnelles, tout en intégrant la perspective du patient. Principales observations: Les patients atteints d'une maladie glomérulaire présentent un risque significatif de maladie cardiovasculaire associé à des mécanismes moléculaires multifactoriels provenant de la maladie glomérulaire elle-même. Ce risque est compliqué par les comorbidités existantes, la néphropathie et les effets secondaires des médicaments. L'approche actuelle de stratification du risque et de traitement repose en grande partie sur les données existantes pour les patients atteints d'insuffisance rénale chronique; cette approche pourrait ne pas toujours convenir, compte tenu de la physiopathologie unique et des mécanismes associés au risque de maladie cardiovasculaire chez les patients atteints d'une maladie glomérulaire. Nos résultats mettent en lumière le besoin d'études continues, axées sur les maladies glomérulaires, qui visent à mieux cerner le risque de maladies cardiovasculaires chez ces patients, tout en intègrant leur point de vue. Limites: Il s'agit d'une revue narrative; cette étude ne constitue pas une revue exhaustive et systématique de la littérature.

Sotagliflozin and Kidney Outcomes, Kidney Function, and Albuminuria in Type 2 Diabetes and CKD: A Secondary Analysis of the SCORED Trial.

BACKGROUND: In the initial analysis of the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial, because of early trial termination and suspension of adjudication, reconciliation of eGFR laboratory data and case report forms had not been completed. This resulted in a small number of kidney composite events and a nominal effect of sotagliflozin versus placebo on this outcome. This exploratory analysis uses laboratory eGFR data, regardless of case report form completion, to assess the effects of sotagliflozin on the predefined kidney composite end point in the SCORED trial and additional cardiorenal composite end points. METHODS: SCORED was a multicenter, randomized trial evaluating cardiorenal outcomes with sotagliflozin versus placebo in 10,584 patients with type 2 diabetes and CKD. This exploratory analysis used laboratory data to derive the eGFR components and case report form data for the non-laboratory-defined components that together made up the kidney and cardiorenal composites. AKI was also assessed in this dataset. RESULTS: Using laboratory data, 223 events were identified, and sotagliflozin reduced the risk of the composite of first event of sustained ≥50% decline in eGFR, eGFR <15 ml/min per 1.73 m 2 , dialysis, or kidney transplant with 87 events (1.6%) in the sotagliflozin group and 136 events (2.6%) in the placebo group (hazard ratio [95% confidence interval], 0.62 [0.48 to 0.82]), P < 0.001). Sotagliflozin reduced the risk of a cardiorenal composite end point defined as the abovementioned composite plus cardiovascular or kidney death with 239 events (4.5%) in the sotagliflozin group and 306 events (5.7%) in the placebo group (hazard ratio [95% confidence interval], 0.77 [0.65 to 0.91], P = 0.0023). The results were consistent when using different eGFR decline thresholds and when only including kidney death in composites (all P < 0.01). The incidence of AKI was similar between treatment groups. CONCLUSIONS: In this exploratory analysis using the complete laboratory dataset, sotagliflozin reduced the risk of kidney and cardiorenal composite end points in patients with type 2 diabetes and CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03315143 .

Integrated Care: A Person-Centered and Population Health Strategy for the COVID-19 Pandemic Recovery and Beyond.

The COVID-19 pandemic has mandated a re-imagination of how healthcare is administered and delivered, with a view towards focusing on person-centred care and advancing population health while increasing capacity, access and equity in the healthcare system. These goals can be achieved through healthcare integration. In 2019, the University Health Network (UHN), a consortium of four quaternary care hospitals in Ontario, Canada, established the first stage of a pilot program to increase healthcare integration at the institutional level and vertically with other primary, secondary and tertiary institutions in the Ontario healthcare system. Implementation of the program was accelerated during the COVID-19 pandemic and demonstrated how healthcare integration improves person-centred care and population health; therefore serving as the foundation for a health system response for the COVID-19 pandemic recovery and beyond.

Biology and Clinical Use of Glucagon-Like Peptide-1 Receptor Agonists in Vascular Protection.

Glucagon-like peptide-1 receptor agonists (GLP1RA) are incretin agents initially designed for the treatment of type 2 diabetes mellitus but because of pleiotropic actions are now used to reduce cardiovascular disease in people with type 2 diabetes mellitus and in some instances as approved treatments for obesity. In this review we highlight the biology and pharmacology of GLP1RA. We review the evidence for clinical benefit on major adverse cardiovascular outcomes in addition to modulation of cardiometabolic risk factors including reductions in weight, blood pressure, improvement in lipid profiles, and effects on kidney function. Guidance is provided on indications and potential adverse effects to consider. Finally, we describe the evolving landscape of GLP1RA and including novel glucagon-like peptide-1-based dual/polyagonist therapies that are being evaluated for weight loss, type 2 diabetes mellitus, and cardiorenal benefit.

Reminding Peer Reviewers of Reporting Guideline Items to Improve Completeness in Published Articles: Primary Results of 2 Randomized Trials.

Importance: Numerous studies have shown that adherence to reporting guidelines is suboptimal. Objective: To evaluate whether asking peer reviewers to check if specific reporting guideline items were adequately reported would improve adherence to reporting guidelines in published articles. Design, Setting, and Participants: Two parallel-group, superiority randomized trials were performed using manuscripts submitted to 7 biomedical journals (5 from the BMJ Publishing Group and 2 from the Public Library of Science) as the unit of randomization, with peer reviewers allocated to the intervention or control group. Interventions: The first trial (CONSORT-PR) focused on manuscripts that presented randomized clinical trial (RCT) results and reported following the Consolidated Standards of Reporting Trials (CONSORT) guideline, and the second trial (SPIRIT-PR) focused on manuscripts that presented RCT protocols and reported following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. The CONSORT-PR trial included manuscripts that described RCT primary results (submitted July 2019 to July 2021). The SPIRIT-PR trial included manuscripts that contained RCT protocols (submitted June 2020 to May 2021). Manuscripts in both trials were randomized (1:1) to the intervention or control group; the control group received usual journal practice. In the intervention group of both trials, peer reviewers received an email from the journal that asked them to check whether the 10 most important and poorly reported CONSORT (for CONSORT-PR) or SPIRIT (for SPIRIT-PR) items were adequately reported in the manuscript. Peer reviewers and authors were not informed of the purpose of the study, and outcome assessors were blinded. Main Outcomes and Measures: The difference in the mean proportion of adequately reported 10 CONSORT or SPIRIT items between the intervention and control groups in published articles. Results: In the CONSORT-PR trial, 510 manuscripts were randomized. Of those, 243 were published (122 in the intervention group and 121 in the control group). A mean proportion of 69.3% (95% CI, 66.0%-72.7%) of the 10 CONSORT items were adequately reported in the intervention group and 66.6% (95% CI, 62.5%-70.7%) in the control group (mean difference, 2.7%; 95% CI, -2.6% to 8.0%). In the SPIRIT-PR trial, of the 244 randomized manuscripts, 178 were published (90 in the intervention group and 88 in the control group). A mean proportion of 46.1% (95% CI, 41.8%-50.4%) of the 10 SPIRIT items were adequately reported in the intervention group and 45.6% (95% CI, 41.7% to 49.4%) in the control group (mean difference, 0.5%; 95% CI, -5.2% to 6.3%). Conclusions and Relevance: These 2 randomized trials found that it was not useful to implement the tested intervention to increase reporting completeness in published articles. Other interventions should be assessed and considered in the future. Trial Registration: ClinicalTrials.gov Identifiers: NCT05820971 (CONSORT-PR) and NCT05820984 (SPIRIT-PR).

A longitudinal assessment of trial protocols approved by research ethics committees: The Adherance to SPIrit REcommendations in the UK (ASPIRE-UK) study.

BACKGROUND: To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. METHODS: We had access to RCT study protocols that received ethical approval in the UK in 2012 (n=103) and 2016 (n=108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor. RESULTS: The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6-69.2%) in 2012 to a median of 72.5% (IQR, 65.3-78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1-69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5-67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2-79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6-76.3%). CONCLUSIONS: The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs.

A meta-research study of randomized controlled trials found infrequent and delayed availability of protocols.

OBJECTIVES: Availability of randomized controlled trial (RCT) protocols is essential for the interpretation of trial results and research transparency. STUDY DESIGN AND SETTING: In this study, we determined the availability of RCT protocols approved in Switzerland, Canada, Germany, and the United Kingdom in 2012. For these RCTs, we searched PubMed, Google Scholar, Scopus, and trial registries for publicly available protocols and corresponding full-text publications of results. We determined the proportion of RCTs with (1) publicly available protocols, (2) publications citing the protocol, and (3) registries providing a link to the protocol. A multivariable logistic regression model explored factors associated with protocol availability. RESULTS: Three hundred twenty-six RCTs were included, of which 118 (36.2%) made their protocol publicly available; 56 (47.6% 56 of 118) provided as a peer-reviewed publication and 48 (40.7%, 48 of 118) provided as supplementary material. A total of 90.9% (100 of 110) of the protocols were cited in the main publication, and 55.9% (66 of 118) were linked in the clinical trial registry. Larger sample size (>500; odds ratio [OR] = 5.90, 95% confidence interval [CI], 2.75-13.31) and investigator sponsorship (OR = 1.99, 95% CI, 1.11-3.59) were associated with increased protocol availability. Most protocols were made available shortly before the publication of the main results. CONCLUSION: RCT protocols should be made available at an early stage of the trial.

Reporting quality of clinical trial protocols: a repeated cross-sectional study about the Adherence to SPIrit Recommendations in Switzerland, CAnada and GErmany (ASPIRE-SCAGE).

OBJECTIVES: Comprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist. DESIGN: Repeated cross sectional study. SETTING: Swiss, German and Canadian research ethics committees (RECs). PARTICIPANTS: RCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reported RESULTS: The median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%-79%) in 2012 to 77% (IQR, 68%-82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%-72%) in 2012 to 76% (IQR, 64%-83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%-80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship. CONCLUSIONS: In 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve.

Nonregistration, discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis.

BACKGROUND: We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs. METHODS AND FINDINGS: We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations. CONCLUSIONS: We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research.

Sodium-Glucose Cotransporter-2 Inhibitors and Risk of Diabetic Ketoacidosis Among Adults With Type 2 Diabetes: A Systematic Review and Meta-Analysis.

OBJECTIVES: The magnitude and precision regarding the risk of diabetic ketoacidosis (DKA) with sodium-glucose cotransporter-2 (SGLT2) inhibitors is unclear. Thus, we examined the risk of DKA with SGLT2 inhibitors in both observational studies and large clinical trials. METHODS: Searches were performed in PubMed, Embase, CENTRAL and Google Scholar (from inception to April 15, 2019) without language restrictions, including conference proceedings and reference lists. Study selection consisted of randomized controlled trials and observational studies that quantified the rate of DKA with an SGLT2 inhibitor in comparison to other diabetes medications or placebo. Two independent investigators abstracted the study data and assessed the quality of evidence. Data were pooled using random effects models with the Hartung-Knapp-Sidik-Jonkman method. Absolute event rates and hazard ratios for DKA were extracted from each study. RESULTS: Seven randomized trials encompassing 42,375 participants and 5 cohort studies encompassing 318,636 participants were selected. Among the 7 randomized controlled trials, the absolute rate of DKA among patients randomized to an SGLT2 inhibitor ranged from 0.6 to 2.2 events per 1,000 person years. Four randomized trials were included in the meta-analysis and, compared with placebo or comparator medication, SGLT2 inhibitors had a 2.5-fold higher risk of DKA (relative risk [RR], 2.46; 95% confidence interval [CI], 1.16 to 5.21]; I2=0%; p=0.54). Among the 5 observational studies, the absolute rate of DKA associated with SGLT2 inhibitor use ranged from 0.6 to 4.9 per 1,000 person years and a 1.7-fold higher rate of DKA compared with another diabetes medication (RR, 1.74; 95% CI, 1.07 to 2.83; I2=45%; p=0.12). CONCLUSIONS: In adults with type 2 diabetes, SGLT2 inhibitors were found to increase the risk of DKA in both observational studies and large randomized clinical trials.

Reliability of Trial Information Across Registries for Trials With Multiple Registrations: A Systematic Review.

Importance: Clinical trial registries are important for gaining an overview of ongoing research efforts and for deterring and identifying publication bias and selective outcome reporting. The reliability of the information in trial registries is uncertain. Objective: To assess the reliability of information across registries for trials with multiple registrations. Evidence Review: For this systematic review, 360 protocols of randomized clinical trials (RCTs) approved by research ethics committees in Switzerland, the UK, Canada, and Germany in 2012 were evaluated. Clinical trial registries were searched from March to September 2019 for corresponding registrations of these RCTs. For RCTS that were recorded in more than 1 clinical trial registry, key trial characteristics that should be identical among all trial registries (ie, sponsor, funding source, primary outcome, target sample size, trial status, date of first patient enrollment, results available, and main publication indexed) were extracted in duplicate. Agreement between the different trial registries for these key characteristics was analyzed descriptively. Data analyses were conducted from May 1 to November 30, 2020. Representatives from clinical trial registries were interviewed to discuss the study findings between February 1 and March 31, 2021. Findings: The analysis included 197 RCTs registered in more than 1 trial registry (151 in 2 registries and 46 in 3 registries), with 188 trials in ClinicalTrials.gov, 185 in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), 20 in ISRCTN, and 47 in other registries. The agreement of key information across all registries was as follows: 178 of 197 RCTs (90%; 95% CI, 85%-94%) for sponsor, 18 of 20 (90%; 95% CI, 68%-99%) for funding source (funding was not reported on ClinicalTrials.gov), 154 of 197 (78%; 95% CI, 72%-84%) for primary outcome, 90 of 197 (46%; 95% CI, 39%-53%) for trial status, 122 of 194 (63%; 95% CI, 56%-70%) for target sample size, and 43 of 57 (75%; 95% CI, 62%-86%) for the date of first patient enrollment when the comparison time was increased to 30 days (date of first patient enrollment was not reported on EudraCT). For results availability in trial registries, agreement was 122 of 197 RCTs (62%; 95% CI, 55%-69%) for summary data reported in the registry and 91 of 197 (46%; 95% CI, 39%-53%) for whether a published article with the main results was indexed. Different legal requirements were stated as the main reason for inconsistencies by representatives of clinical trial registries. Conclusions and Relevance: In this systematic review, for a substantial proportion of registered RCTs, information about key trial characteristics was inconsistent across trial registries, raising concerns about the reliability of the information provided in these registries. Further harmonization across clinical trial registries may be necessary to increase their usefulness.

Sodium-Glucose Cotransporter 2 Inhibitors, All-Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta-Analysis and Meta-Regression.

Background This study aimed to assess the effectiveness of sodium-glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta-analysis of randomized controlled trials comparing sodium-glucose cotransporter 2 inhibitors with placebo. We used meta-regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty-three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63-0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69-1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72-1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61-1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63-1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71-1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all-cause and cardiovascular mortality. There was no association between treatment effects for all-cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%-95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause and cardiovascular mortality versus placebo. Treatment effects of sodium-glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.

Efficacy and Safety of Ticagrelor Monotherapy by Clinical Presentation: Pre-Specified Analysis of the GLOBAL LEADERS Trial.

Background The optimal duration of dual antiplatelet therapy after coronary drug-eluting stent placement in adults with stable coronary artery disease (SCAD) versus acute coronary syndromes (ACS) remains uncertain. Methods and Results This was a prespecified subgroup analysis of the GLOBAL LEADERS trial. Participants were randomly assigned 1:1 to the experimental or reference strategy, stratified by ACS (experimental, n=3750; reference, n=3737) versus SCAD (experimental, n=4230; reference, n=4251). The experimental strategy was 75 to 100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy. The reference strategy was 75 to 100 mg aspirin daily plus either 75 mg clopidogrel daily (for SCAD) or 90 mg ticagrelor twice daily (for ACS) for 12 months, followed by aspirin monotherapy for 12 months. The primary end point at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction. The key secondary safety end point was site-reported Bleeding Academic Research Consortium grade 3 or 5 bleeding. The primary end point occurred in 147 (3.92%) versus 169 (4.52%) patients with ACS (rate ratio [RR], 0.86; 95% CI, 0.69-1.08; P=0.189), and in 157 (3.71%) versus 180 (4.23%) patients with SCAD (RR, 0.87; 95% CI, 0.71-1.08; P=0.221) with experimental and reference strategy, respectively (P-interaction=0.926). Bleeding Academic Research Consortium grade 3 or 5 bleeding occurred in 73 (1.95%) versus 100 (2.68%) patients with ACS (RR, 0.73; 95% CI, 0.54-0.98; P=0.037), and in 90 (2.13%) versus 69 (1.62%) patients with SCAD (RR, 1.32; 95% CI, 0.97-1.81; P=0.081; P-interaction=0.007). Conclusions While there was no evidence for differences in efficacy between treatment strategies by subgroup, the experimental strategy appeared to reduce bleeding risk in patients with ACS but not in patients with SCAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01813435.

Reporting quality of trial protocols improved for non-regulated interventions but not regulated interventions: A repeated cross-sectional study.

OBJECTIVES: To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. METHODS: We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions. RESULTS: Overall, 131 (24%) of trial protocols tested non-regulated interventions. In 2012, the median proportion of SPIRIT items reported in these protocols (59%, interquartile range [IQR], 53%-69%) was lower than in protocols with regulated interventions (median, 74%, IQR, 66%-80%). In 2016, the reporting quality of protocols with non-regulated interventions (median, 75%, IQR, 62%-83%) improved to the level of regulated intervention protocols, which had not changed on average. CONCLUSIONS: Reporting of RCT protocols evaluating non-regulated interventions improved between 2012 and 2016, although remained suboptimal. SPIRIT recommendations need to be further endorsed by researchers, ethics committees, funding agencies, and journals to optimize reporting of RCT protocols.

Accuracy of Cardiovascular Trial Outcome Ascertainment and Treatment Effect Estimates from Routine Health Data: A Systematic Review and Meta-Analysis.

BACKGROUND: Registry-based randomized controlled trials allow for outcome ascertainment using routine health data (RHD). While this method provides a potential solution to the rising cost and complexity of clinical trials, comparative analyses of outcome ascertainment by clinical end point committee (CEC) adjudication compared with RHD sources are sparse. Among cardiovascular trials, we set out to systematically compare the incidence of cardiovascular events and estimated randomized treatment effects ascertained from RHD versus traditional clinical evaluation and adjudication. METHODS: We searched MEDLINE (1976 to August 2020) for studies where outcome ascertainment was performed by both RHD and CEC adjudication to compare the incidence of cardiovascular events and treatment effects. We derived ratios of hazard ratios to compare treatment effects from RHD and CEC adjudication. We pooled ratios of hazard ratios using an inverse variance random-effects meta-analysis. RESULTS: Nine studies (1988-2020; 32 156 patients) involving 10 randomized control trials compared outcome ascertainment with RHD and CEC in patients with or at risk of cardiovascular disease. There was a high degree of agreement and interrater reliability between CEC and RHD outcome determination for all-cause mortality (agreement percentage: 98.4%-100% and κ: 0.95-1.0) and cardiovascular mortality (agreement percentage: 97.8%-99.9% and κ: 0.66-0.99). For myocardial infarction, the κ values ranged from 0.67-0.98, and for stroke the values ranged from 0.52-0.89. In contrast, the κ value for peripheral artery disease was low (κ: 0.27). There was little difference in the randomized treatment effect derived from CEC and RHD ascertainment of events based on the ratios of hazard ratio, with pooled ratios of hazard ratios ranging from 0.93 (95% CI, 0.63-1.39) for cardiovascular mortality to 1.27 (95% CI, 0.67-2.41) for stroke. CONCLUSIONS: Clinical outcome ascertainment using retrospectively acquired RHD displayed high levels of agreement with CEC adjudication for identifying all-cause mortality and cardiovascular outcomes. Importantly, cardiovascular treatment effects in randomized control trials determined from RHD and CEC resulted in similar point estimates. Overall, our review supports the use of RHD as a potential alternative source for clinical outcome ascertainment in cardiovascular trials. Validation studies with prospectively planned linkage are warranted.

Cardiorenal Protection in Diabetic Kidney Disease.

Over the last 5 years there have been many new developments in the management of diabetic kidney disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 (SGLT2) inhibitors were initially used for glycemic control, but more recent studies have now shown that their benefits extend to cardiovascular and kidney outcomes. The recent addition of data on the novel mineralocorticoid receptor antagonist (MRA) gives us another approach to further decrease the residual risk of diabetic kidney disease progression. In this review we describe the mechanism of action, key studies, and possible adverse effects related to these three classes of medications. The management of type 2 diabetes now includes an increasing number of medications for the management of comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors, GLP-1 RA and MRAs in patients with type 2 diabetes for heart and kidney protection.