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: (i) SGLT2 inhibitors and MR antagonists confer long-term cardioprotection in chronic HF patients but it is unclear whether natriuresis or diuresis represents the primary mechanisms for this benefit, (ii) 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 (iii) 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.

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1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up.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.

Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction (BIOSTEMI): a single-blind, prospective, randomised superiority trial.

BACKGROUND: Newer-generation drug-eluting stents that combine ultrathin strut metallic platforms with biodegradable polymers might facilitate vascular healing and improve clinical outcomes in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention (PCI) compared with contemporary thin strut second-generation drug-eluting stents. We did a randomised clinical trial to investigate the safety and efficacy of ultrathin strut biodegradable polymer sirolimus-eluting stents versus thin strut durable polymer everolimus-eluting stents in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. METHODS: The BIOSTEMI trial was an investigator-initiated, multicentre, prospective, single-blind, randomised superiority trial at ten hospitals in Switzerland. Patients aged 18 years or older with acute STEMI who were referred for primary PCI were eligible to participate. Patients were randomly allocated (1:1) to either biodegradable polymer sirolimus-eluting stents or durable polymer everolimus-eluting stents. Central randomisation was done based on a computer-generated allocation sequence with variable block sizes of 2, 4, and 6, which was stratified by centre, diabetes status, and presence or absence of multivessel coronary artery disease, and concealed using a secure web-based system. Patients and treating physicians were aware of group allocations, whereas outcome assessors were masked to the allocated stent. The experimental stent (Orsiro; Biotronik; Bülach, Switzerland) consisted of an ultrathin strut cobalt-chromium metallic stent platform releasing sirolimus from a biodegradable polymer. The control stent (Xience Xpedition/Alpine; Abbott Vascular, Abbott Park, IL, USA) consisted of a thin strut cobalt-chromium stent platform that releases everolimus from a durable polymer. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial reinfarction (Q-wave and non-Q-wave), and clinically-indicated target lesion revascularisation, within 12 months of the index procedure. All analyses were done with the individual participant as the unit of analysis and according to the intention-to-treat principle. The trial was registered with ClinicalTrials.gov, number NCT02579031. FINDINGS: Between April 26, 2016, and March 9, 2018, we randomly assigned 1300 patients (1623 lesions) with acute myocardial infarction to treatment with biodegradable polymer sirolimus-eluting stents (649 patients and 816 lesions) or durable polymer everolimus-eluting stents (651 patients and 806 lesions). At 12 months, follow-up data were available for 614 (95%) patients treated with biodegradable polymer sirolimus-eluting stents and 626 (96%) patients treated with durable polymer everolimus-eluting stents. The primary composite endpoint of target lesion failure occurred in 25 (4%) of 649 patients treated with biodegradable polymer sirolimus-eluting stents and 36 (6%) of 651 patients treated with durable polymer everolimus-eluting stents (difference -1·6 percentage points; rate ratio 0·59, 95% Bayesian credibility interval 0·37-0·94; posterior probability of superiority 0·986). Cardiac death, target vessel myocardial reinfarction, clinically-indicated target lesion revascularisation, and definite stent thrombosis were similar between the two treatment groups in the 12 months of follow-up. INTERPRETATION: In patients with acute STEMI undergoing primary PCI, biodegradable polymer sirolimus-eluting stents were superior to durable polymer everolimus-eluting stents with respect to target lesion failure at 1 year. This difference was driven by reduced ischaemia-driven target lesion revascularisation in patients treated with biodegradable polymer sirolimus-eluting stents compared with durable polymer everolimus-eluting stents. FUNDING: Biotronik.

Association of acute kidney injury and bleeding events with mortality after radial or femoral access in patients with acute coronary syndrome undergoing invasive management: secondary analysis of a randomized clinical trial.

AIMS: In the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) trial, adults with acute coronary syndrome undergoing coronary intervention who were allocated to radial access had a lower risk of bleeding, acute kidney injury (AKI), and all-cause mortality, as compared with those allocated to femoral access. The mechanism of the mortality benefit of radial access remained unclear. METHODS AND RESULTS: We used multistate and competing risk models to determine the effects of radial and femoral access on bleeding, AKI and all-cause mortality in the MATRIX trial and to disentangle the relationship between these different types of events. There were large relative risk reductions in mortality for radial compared with femoral access for the transition from AKI to death [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.31-0.97] and for the pathway from coronary intervention to AKI to death (HR 0.49, 95% CI 0.26-0.92). Conversely, there was little evidence for a difference between radial and femoral groups for the transition from bleeding to death (HR 1.05, 95% CI 0.42-2.64) and the pathway from coronary intervention to bleeding to death (HR 0.84, 95% CI 0.28-2.49). CONCLUSION: The prevention of AKI appeared predominantly responsible for the mortality benefit of radial as compared with femoral access in the MATRIX trial. There was little evidence for an equally important, independent role of bleeding.

AKI and Long-Term Risk for Cardiovascular Events and Mortality.

AKI associates with increased long-term risk of mortality, but the prognostic significance of AKI in terms of long-term cardiovascular disease remains unconfirmed. We conducted a systematic review and meta-analysis to assess whether AKI associates with long-term cardiovascular disease. We included cohort studies that examined adults with and without AKI and reported a multivariable-adjusted relative risk (RR) for the association between AKI and cardiovascular mortality, major cardiovascular events, and disease-specific events: congestive heart failure, acute myocardial infarction, and stroke. Twenty-five studies involving 254,408 adults (55,150 with AKI) were included. AKI associated with an 86% and a 38% increased risk of cardiovascular mortality and major cardiovascular events, respectively ([RR 1.86; 95% confidence interval (95% CI), 1.72 to 2.01] and [RR 1.38; 95% CI, 1.23 to 1.55], respectively). For disease-specific events, AKI associated with a 58% increased risk of heart failure (RR 1.58; 95% CI, 1.46 to 1.72) and a 40% increased risk of acute myocardial infarction (RR 1.40; 95% CI, 1.23 to 1.59). The elevated risk of heart failure and acute myocardial infarction persisted in subgroup analyses on the basis of AKI severity and the proportion of adults with baseline ischemic heart disease. Finally, AKI was associated with a 15% increased risk of stroke (RR 1.15; 95% CI, 1.03 to 1.28). In conclusion, AKI associates with an elevated risk of cardiovascular mortality and major cardiovascular events, particularly heart failure and acute myocardial infarction.

Prognostic Importance of Atrial Fibrillation Timing and Pattern in Adults With Congestive Heart Failure: A Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) is common among adults with congestive heart failure (CHF). We conducted a meta-analysis to summarize the risk of mortality and cardiovascular disease associated with AF in CHF and stratified our analyses by AF timing and pattern. METHODS: We searched MEDLINE and EMBASE for observational studies examining the association of AF with cardiovascular disease and death. Eligible studies had a minimum of 50 participants with AF and 50 participants without AF, and a median follow-up of 6 months. RESULTS: Thirty-three studies involving 114,204 adults (43,549 with AF) were included in this meta-analysis. AF was associated with an increased risk of mortality and this risk varied between incident and prevalent AF (relative risk 2.21, 95% confidence interval 1.96-2.49 vs relative risk 1.19, 95% confidence interval 1.03-1.38, respectively; P < .001 for interaction). The risk of mortality associated with incident AF was consistent in adults with CHF with reduced and preserved ejection fraction. The relative risk of mortality did not vary between paroxysmal and chronic AF. Finally, AF was associated with an increased risk of cardiovascular mortality and stroke. LIMITATION: Use of anticoagulation was infrequently reported in included studies. CONCLUSIONS: AF was associated with an increased risk of cardiovascular disease and death and, notably, the risk of mortality varied by AF timing.

Prevalence of Albuminuria in a General Population Cohort of Patients With Established Chronic Heart Failure.

BACKGROUND: Numerous studies have reported an association between albuminuria and adverse outcomes in adults with chronic heart failure (CHF). However, the prevalence of albuminuria in adults with established CHF remains unclear. METHODS AND RESULTS: This study was a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) 1999-2012. Adults aged ≥18 years were included, and diagnosis of CHF was based on participant self-report. The primary outcome was the prevalence of microalbuminuria (albumin-to-creatinine ratio 30-300 mg/g) and macroalbuminuria (albumin-to-creatinine ratio >300 mg/g) in adults with CHF. The secondary outcome was the adjusted odds ratio of any albuminuria in adults with and without CHF. During the study period, 37,961 adults did not have CHF and 1,214 adults had CHF. In adults with CHF, 22.1% (95% confidence interval [CI] 19.6%-24.7%) had microalbuminuria and 10.4% (95% CI 8.1%-12.7%) macroalbuminuria. In adjusted analyses, the odds of albuminuria in adults with CHF was 1.89-fold higher (95% CI 1.59-2.26; P < .001) than in adults without CHF. CONCLUSIONS: Taken together, albuminuria is more common in adults with CHF than in those without CHF, even after adjustment for important demographic and clinical confounders.

Transdermal contraception and the renin-angiotensin-aldosterone system in premenopausal women.

The oral contraceptive pill (OCP) activates the renin-angiotensin-aldosterone system (RAAS) through first-pass hepatic metabolism. Although usually benign, RAAS activation may have detrimental effects on renal and hemodynamic function in some women. Since combined hormonal contraception with the transdermal patch (EVRA) does not undergo first-pass hepatic metabolism, we hypothesized that the RAAS response would be different from that of OCP subjects. Thirty-five nonsmoking, premenopausal women (15 control subjects, 10 OCP subjects, and 10 contraceptive patch subjects) without evidence of cardiovascular disease, renal disease, or diabetes were studied. Baseline angiotensinogen, renin, angiotensin II, aldosterone, and plasma renin activity were assessed along with hormonal and hemodynamic responses to simulated orthostatic stress using incremental lower body negative pressure (LBNP; -15, -25, and -40 mmHg). Baseline levels of angiotensinogen, angiotensin II, and plasma renin activity were significantly higher in OCP subjects compared with normotensive control and contraceptive patch subjects (P < 0.05), whereas aldosterone was significantly higher in OCP versus control subjects only (P < 0.05). Plasma renin levels were significantly lower at baseline in contraceptive patch subjects compared with normotensive control and OCP subjects (P < 0.05). In response to LBNP, increases in renin, angiotensin II, and aldosterone were attenuated in contraceptive patch subjects in conjunction with an exaggerated decline in mean arterial pressure (P < 0.05 vs. control and OCP subjects). The contraceptive patch in healthy premenopausal women is associated with an impaired ability to maintain blood pressure in response to LBNP, possibly due to insensitivity of the endogenous RAAS. Further evaluation may be beneficial in women with kidney disease.

Intensive hemodialysis associates with improved pregnancy outcomes: a Canadian and United States cohort comparison.

Pregnancy is rare in women with ESRD and when it occurs, it is often accompanied by significant maternal and fetal morbidity and even mortality. Preliminary data from the Toronto Nocturnal Hemodialysis Program suggested that increased clearance of uremic toxins by intensified hemodialysis improves pregnancy outcomes, but small numbers and the absence of a comparator group limited widespread applicability of these findings. We compared pregnancy outcomes from 22 pregnancies in the Toronto Pregnancy and Kidney Disease Clinic and Registry (2000-2013) with outcomes from 70 pregnancies in the American Registry for Pregnancy in Dialysis Patients (1990-2011). The primary outcome was the live birth rate and secondary outcomes included gestational age and birth weight. The live birth rate in the Canadian cohort (86.4%) was significantly higher than the rate in the American cohort (61.4%; P=0.03). Among patients with established ESRD, the median duration of pregnancy in the more intensively dialyzed Toronto cohort was 36 weeks (interquartile range, 32-37) compared with 27 weeks (interquartile range, 21-35) in the American cohort (P=0.002). Furthermore, a dose response between dialysis intensity and pregnancy outcomes emerged, with live birth rates of 48% in women dialyzed ≤20 hours per week and 85% in women dialyzed >36 hours per week (P=0.02), with a longer gestational age and greater infant birth weight for women dialyzed more intensively. Pregnancy complications were few and manageable. We conclude that pregnancy may be safe and feasible in women with ESRD receiving intensive hemodialysis.

A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar® Gel) in nephrotic syndrome due to idiopathic membranous nephropathy.

BACKGROUND: H.P. Acthar(®) Gel is currently the only Food and Drug Administration therapy approved for the treatment of nephrotic syndrome. Active drug ingredients include structurally related melanocortin peptides that bind to cell surface G-protein-coupled receptors known as melanocortin receptors, which are expressed in glomerular podocytes. In animal models of membranous nephropathy, stimulation has been demonstrated to reduce podocyte injury and loss. We hypothesized that H.P. Acthar(®) Gel would improve symptoms of the nephrotic syndrome in patients with idiopathic membranous nephropathy. METHODS: Twenty patients received a subcutaneous dose of 40 or 80 IU twice weekly. Changes in proteinuria, albumin, cholesterol profile, estimated glomerular filtration rate and serum anti-PLA2R antibodies were assessed at baseline and in response to treatment along with tolerance and safety. RESULTS: Baseline characteristics included mean proteinuria (9.1 ± 3.4 g/day), albumin (2.7 ± 0.8 g/dL), estimated glomerular filtration rate (77 ± 30 mL/min) along with elevated total and low-density lipoprotein (LDL) cholesterol. By 12 months of follow-up, there was a significant improvement in proteinuria in the entire cohort, decreasing to 3.87 ± 4.24 g/day (P < 0.001) with significant improvements in serum albumin, total and LDL cholesterol. A >50% decrease in proteinuria was noted in 65% of the patients with a trend toward better outcomes among patients who received greater cumulative doses. No significant adverse effects were documented. Clearing of serum anti-PLA2R antibodies prior to or in parallel with proteinuria improvement was noted in some, but not all patients. CONCLUSIONS: H.P. Acthar(®) Gel is a potential therapy for nephrotic syndrome secondary to idiopathic membranous nephropathy that deserves further study.

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 .

Effect of Qualifying Atherosclerotic Cardiovascular Disease Diagnosis Proximity on Cardiovascular Risk and Benefit of Empagliflozin in the EMPA-REG OUTCOME Trial.

Background: In patients with type 2 diabetes mellitus (T2DM), a history of an ischemic event is associated with increased risk for cardiovascular (CV) disease. Whether patients with T2DM and a recent atherothrombotic diagnosis benefit from early intervention with a sodium-glucose co-transporter 2 inhibitor is unknown. Methods: This study is a secondary analysis of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), which compared empagliflozin to placebo in adults with T2DM and atherosclerotic CV disease (ASCVD). Participants were categorized based on the time since their last qualifying ASCVD diagnosis (≤ 1 year vs > 1 year). Qualifying ASCVD diagnoses included ischemic or hemorrhagic stroke, myocardial infarction, coronary artery disease, and peripheral artery disease. The primary outcome was a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Results: A total of 6796 participants (n = 4547 empagliflozin, n = 2249 placebo) were included. Median time since the last qualifying ASCVD diagnosis was 3.8 years (quartile 1-quartile 3: 1.5-7.6), and most qualifying diagnoses occurred > 1 year before randomization (≤ 1 year, n = 1214; > 1 year, n = 5582). Empagliflozin reduced the incidence of the primary outcome irrespective of the time since the last qualifying ASCVD diagnosis (≤ 1 year: hazard ratio 0.82, 95% confidence interval: 0.57-1.16; vs > 1 year: hazard ratio 0.85, 95% confidence interval: 0.72-1.00; P for interaction = 0.84). Results were similar for the composite of CV death or hospitalization for heart failure. Conclusions: Empagliflozin improved CV outcomes in participants with T2DM, irrespective of the time since the last qualifying ASCVD diagnosis at randomization. Prospective trials are necessary to investigate the use of sodium-glucose co-transporter 2 inhibitors at the time of an acute ASCVD event. Trial Registration: EMPA-REG OUTCOME (Clinicaltrials.gov identifier: NCT01131676).

Contexte: Chez les patients atteints de diabète de type 2 (DT2), des antécédents d'accidents ischémiques sont associés à un risque accru de maladie cardiovasculaire (CV). On ignore si une intervention précoce par un inhibiteur du cotransporteur sodium-glucose de type 2 pourrait être bénéfique pour les patients atteints de DT2 ayant récemment reçu un diagnostic d'athérothrombose. Méthodologie: Cette étude est une analyse secondaire de l'essai EMPA-REG OUTCOME ( Empa gliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients­ R emoving E xcess G lucose), qui visait à comparer l'empagliflozine à un placebo chez des adultes atteints de DT2 et d'une maladie CV athéroscléreuse. Les participants ont été répartis selon le temps écoulé depuis leur plus récent diagnostic de maladie CV athéroscléreuse admissible (≤ 1 an vs > 1 an). Les diagnostics de maladies CV athéroscléreuses admissibles comprenaient un accident vasculaire cérébral ischémique ou hémorragique, un infarctus du myocarde, une coronaropathie et une artériopathie périphérique. Le critère d'évaluation principal était composé des décès d'origine CV, des infarctus du myocarde non mortels et des accident vasculaire cérébral non mortels. Résultats: Au total, 6796 participants (n = 4547 pour l'empagliflozine, n = 2249 pour le placebo) ont été inclus. Le temps écoulé médian depuis le diagnostic le plus récent de maladie CV athéroscléreuse admissible était de 3,8 ans (quartile 1-quartile 3 : 1,5-7,6). La plupart des diagnostics admissibles avaient été posés plus de 1 an avant la répartition aléatoire (≤ 1 an, n = 1214; > 1 an, n = 5582). L'empagliflozine a réduit la fréquence des événements constituant le critère d'évaluation principal, sans égard au temps écoulé depuis le plus récent diagnostic de maladie CV athéroscléreuse admissible (≤ 1 an : rapport des risques instantanés 0,82, intervalle de confiance à 95 % : 0,57-1,16; vs > 1 an : rapport des risques instantanés 0,85, intervalle de confiance à 95 % : 0,72-1,00; p pour l'interaction = 0,84). Les résultats étaient comparables à ceux observés pour le critère composé des décès d'origine CV et des hospitalisations pour insuffisance cardiaque. Conclusions: L'empagliflozine a amélioré les issues CV chez les patients atteints de DT2 sans égard au temps écoulé depuis le plus récent diagnostic de maladie CV admissible au moment de la répartition aléatoire. Des essais prospectifs sont nécessaires pour étudier l'utilisation des inhibiteurs du cotransporteur sodium-glucose de type 2 lorsqu'une manifestation de maladie CV athéroscléreuse aiguë survient. Inscription de l'essai: EMPA-REG OUTCOME (numéro d'identification dans clinicaltrials.gov : NCT01131676).

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.

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.

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).

Cystatin C and acute changes in glomerular filtration rate.

The identification of an effective marker of acutely changing kidney function is a priority in clinical nephrology. While serum creatinine is the most widely used surrogate for glomerular filtration rate (GFR), its vulnerability to non-glomerular clearance results in biased estimates of GFR and may delay the identification of acute changes. Alternatively, cystatin C (CysC) has been recognized as a promising marker of GFR. Controlled physiological studies in diabetes, protein-induced glomerular hyperfiltration and extreme exercise demonstrated that acute changes in CysC provide a better approximation of GFR than serum creatinine. Clinical studies examining contrast induced nephropathy, acute kidney injury, and kidney transplantation have also demonstrated several possible advantages of CysC with respect to accurately measuring GFR and early diagnosis of renal dysfunction. CysC measurements also provide ancillary benefits such as improved prediction of patient outcomes and prognosis. Our aim was to review the literature on short-term changes in CysC over days, weeks and months to explore the clinical utility of CysC in the acute setting. Based on existing evidence, CysC may improve clinicians' ability to detect acute changes in kidney function.

Epidemiology of acute kidney injury in Canadian critical care units: a prospective cohort study.

PURPOSE: We undertook this study to characterize the epidemiology of acute kidney injury (AKI) in Canadian critical care units. We aimed to identify predictors of mortality for patients diagnosed with AKI. METHODS: We conducted a prospective cohort study of consecutive patients admitted to critical care units at five Canadian hospitals over a 30-day period. Each patient was followed until hospital discharge or for a maximum of 30 days. The serum creatinine criteria for the Acute Kidney Injury Network (AKIN-SCr) system were used to identify, classify, and characterize patients who developed AKI. We used multivariable logistic regression to predict 30-day mortality among patients with AKI. RESULTS: We identified 603 patients, 161 (26.7%) of whom developed AKI. Compared to patients without AKI, those with AKI were more likely to die (29.2% vs 8.6%, P < 0.001). The risk of death increased with increasing AKIN-SCr stage (P < 0.001). In all, 19 patients (11.8% of those with AKI) commenced dialysis a median of one day (interquartile range, one to two days) after AKI diagnosis. At AKI diagnosis, the blood urea nitrogen (BUN) level (adjusted odds ratio [OR] 1.68, 95% confidence interval [CI] 1.01 to 2.79/10 mmol·L(-1)) and serum bicarbonate (adjusted OR 0.88, 95% CI 0.81 to 0.95/1 mmol·L(-1)) were associated with 30-day mortality and predicted death with an area under the receiver-operating characteristic curve of 0.79 (95% CI 0.71 to 0.86). CONCLUSIONS: Acute kidney injury is a common complication of critical illness in Canada. The development of even the mildest stage of AKI is associated with a substantially higher risk of death. At AKI diagnosis, routine clinical data may be helpful for predicting adverse outcomes.