Importance Hyperkalemia is a common complication of taking a renin-angiotensin-aldosterone system inhibitor (RAASi). Post hoc analyses of large randomized clinical trials suggested that the addition of sodium-glucose cotransporter 2 inhibitors (SGLT2i) may attenuate this risk. It is unknown if this observation extends to daily clinical practice. Objective To evaluate the association between SGLT2i initiation and hyperkalemia in individuals receiving RAASi with a background of diabetes, heart failure, or chronic kidney disease. Design, Setting, and Participants This population-based retrospective cohort study was conducted in Ontario, Canada, from July 1, 2015, to June 30, 2021. The cohort comprised adults 66 years and older who were prescribed a RAASi and had a history of diabetes or heart failure, an estimated glomerular filtration rate of less than 45 mL/min/1.73 m 2 , and/or a urine albumin to creatinine ratio of greater than 30 mg/mmol. The data were analyzed between March 28, 2023, and March 22, 2024. Exposure The study exposure was a new prescription of an SGLT2i compared to noninitiation of an SGLT2i. Inverse probability of treatment weighting by a propensity score for the receipt of SGLT2i was used to achieve balance of baseline covariates in both exposure groups. Main Outcomes and Measures The primary study outcome was hyperkalemia, defined as a serum potassium of greater than 5.5 mEq/L or an administrative code for an inpatient or outpatient encounter with hyperkalemia within 1 year of the index date. Results A total of 20 063 individuals who initiated an SGLT2i (mean [SD] age, 76.9 [6.6] years; 12 020 [59.9%] male) were compared to a pseudopopulation of 19 781 nonusers (mean [SD] age, 76.8 [7.0] years; 11 731 [59.3%] male). In the overall cohort, 95% had diabetes, 17% had heart failure, and 32% had stage 3 to 5 chronic kidney disease. SGLT2i initiation was associated with a lower risk of hyperkalemia (hazard ratio, 0.89 [95% CI, 0.82-0.96]). SGLT2i users had a significantly lower rate of RAASi discontinuation compared to nonusers (36% vs 45%; P < .001). Conclusions and Relevance This cohort study demonstrated that, among individuals with diabetes, heart failure, or chronic kidney disease who were receiving a RAASi, SGLT2i initiation was associated with a lower risk of hyperkalemia and RAASi discontinuation.

Atrial Fibrillation (AF) is the most common arrhythmia among patients on hemodialysis (HD), with a prevalence ranging between 15 and 40%. In the general population, AF is associated with cardiac remodeling and structural changes. In patients on HD, AF episodes mostly occur on dialysis days and may specifically be triggered by the HD procedure, when fluid and electrolytes shifts are taking place. Thus, whether AF in patients receiving HD is related to the development of structural changes in the heart remains unclear. Our aim was to study the association between AF and cardiac remodeling in incident HD patients, using echocardiographic parameters. A retrospective, longitudinal, cohort study was conducted. Patients started on maintenance HD at McGill University Health Center in Montreal, Canada between 1/1/2017 and 31/12/2022 were included. They were divided into AF and non-AF groups according to the presence or not of at least one AF episode on file. In the AF group, patients were considered as prevalent if the first AF episode was documented before dialysis initiation, otherwise AF was considered incident. The cohort was limited to patients who had ≥2 transthoracic echocardiograms (TTE), of which at least one before and one after dialysis initiation. For incident AF patients, at least one TTE after the first AF documentation was required. Patients were followed until the date of death, date of kidney transplantation, or September 1, 2024. Two continuous variables were created, AF burden and dialysis vintage. AF burden represents time (in years) since AF onset. For patients with prevalent AF, the date of dialysis initiation was considered as the date of onset. Dialysis vintage was defined as the time between dialysis initiation and AF onset (0 for prevalent AF patients). A complete case analysis was conducted. Linear mixed effects models were used to explore the association of AF burden and dialysis vintage with echocardiographic outcomes of interest, adjusting for use of renin angiotensin inhibitors. Inverse probability treatment weights (derived from propensity scores based on baseline covariates) were applied to reduce confounding. A total of 110 patients (49 with AF) were included in the analysis. Baseline characteristics of the patients with and without AF before and after inverse probability weighting are shown in Table 1. The weighted cohort was well balanced for all baseline characteristics. We found a significant association between AF burden and left ventricular end-diastolic volume index (LVEDVI), with a one-year increase in AF burden being associated with a reduction of 2.70 mL/m2 in LVEDVI (β = −2.70, 95% CI: −4.51 to −0.89, P < 0.01). In addition, dialysis vintage was significantly associated with a drop in LVEDVI (β = −2.08, 95% CI: −3.97 to −0.18, P = 0.03). In contrast, no significant association was found between AF burden or dialysis vintage and left atrial volume index (LAVI; β = 0.79, 95% CI: −1.36 to 2.95, P = 0.47). Furthermore, AF burden was not associated with changes in left ventricular ejection fraction (LVEF; β = −0.04 95% CI: −1.43 to 1.35, P = 0.96), left ventricular mass index (LVMI; β = −0.12, 95% CI: −4.64 to 4.40, P = 0.96), or pulmonary artery systolic pressure (PASP; β = 0.36, 95% CI: −1.57 to 2.28, P = 0.72). A trend towards lower LAVI and PASP was seen with longer dialysis vintage but this trend was not observed with increasing AF burden (Table 2). In this study, both AF burden and dialysis vintage were significantly associated with a reduction in LVEDVI, suggesting potential ventricular remodeling or impaired filling which was more pronounced in patients on HD with AF. A trend towards lower LAVI and PASP was seen with longer dialysis vintage, possibly due to more effective decongestion, but this trend was no longer observed with increased AF burden, suggesting impaired left ventricular filling in patients with AF. No significant associations were observed between AF burden or dialysis vintage and LVMI or LVEF. These findings highlight the impact of AF on left ventricular remodeling in patients on maintenance HD and raise the question of a rhythm control strategy to prevent those changes.

Canagliflozin is an orally active, selective, reversible sodium-glucose cotransport-2 (SGLT-2) inhibitor used in patients with chronic kidney disease (CKD) to prevent cardiovascular (CV) events and CKD progression. Its initiation is currently not recommended in advanced CKD [estimated glomerular filtration rate (eGFR) < 20 mL/min per 1.73 m2], end-stage kidney disease, or in those on kidney replacement therapies due to insufficient clinical and safety data. This study aimed to develop a population pharmacokinetic (popPK) model using data from patients with advanced CKD, including those on maintenance hemodialysis (HD), to characterize the steady-state pharmacokinetics (PK) of canagliflozin at 100 mg and 300 mg doses, and to assess the impact of significant covariates on its PK. PK data were obtained from a single-center, prospective, single-arm, open-label interventional study conducted in two cohorts. The first cohort was a detailed PK sampling done in 10 patients receiving intermittent HD for at least 3 months and the second cohort included sparse PK sampling in 13 patients with advanced CKD, not yet on dialysis. Canagliflozin PK parameters were modeled using nonlinear mixed-effects modeling (NONMEM® version 7.5) with the first-order conditional estimation method with interaction. Model performance was evaluated using goodness of fit plot, bootstrap (n = 1000), and normalized prediction distribution error (NPDE). Model-based simulations were performed using the final model to predict concentration–time profiles at steady state, evaluate the impact of significant covariates on predicted steady-state area under the curve (AUC), and compare PK profiles between patients with non-dialysis CKD and those with hemodialysis. A total of 332 PK observations from 23 patients were analyzed. The mean age of the cohort was 67 ± 15 years with a mean body mass index of 27 ± 5 kg/m2. A two-compartment popPK model of canagliflozin with lag-time, sequential zero- and first-order absorption, and first-order elimination was developed. Age was a significant covariate of the absorption rate constant (Ka), which increased with age. Sex was a significant covariate for the apparent volume of distribution (V/F), which was lower in women (80.7 L in men and 49.1 L in women). Model-based simulations demonstrated that steady-state AUC was 66

Introduction:The goal of this study was to investigate the association between worsening renal function (WRF) and central venous pressure, right ventricular function, and lung fluid overload assessed by point-of-care ultrasound (POCUS) in hospitalized patients with acute heart failure (AHF). Methods:This was a prospective cohort study including AHF adult inpatients, conducted in Geneva University Hospitals from October 2019 to March 2020. The primary outcome was WRF, defined by an increase in creatinine of ≥1.5 times from baseline value or an increase of ≥0.3 mg/dL between admission and day 4 to 6. Expert ultrasonographers used POCUS to examine lungs, inferior vena cava during spontaneous expiration (IVCe), and tricuspid annular plane systolic excursion (TAPSE) at admission. Results:A total of 43 patients were included in the study. A total of 8 patients (19%) developed WRF during the study period (between October 8, 2019 and March 16, 2020), of whom 4 were in the higher quartile of lung fluid overload, 2 had TAPSE <14 mm, and 4 had IVCe ≥ 21 mm. In uni- and multi-variate logistic regression model, neither admission IVCe nor TAPSE was associated with WRF. However, lung congestion, as assessed by the number of B-lines, was significantly associated with WRF (odds ratio [OR] per quartile = 2.47, 95% confidence interval [CI] = 1.01 to 5.86, P = .04). This result remained statistically significant after adjustment for daily diuretic dose in mg/kg (OR = 2.98, 95% CI = 1.11 to 8.00, P = .03). Conclusion:This study showed that lung congestion as assessed by POCUS was associated with WRF in AHF patients, whereas IVCe and TAPSE were not. Due to the small number of participants, our results need to be prospectively validated in future adequately powered clinical trials.

Background Glucagon-like peptide 1 receptor agonists (GLP1RAs) may increase heart rate in patients with heart failure with reduced ejection fraction (HFrEF), which could induce deleterious effects in this population. Information retrieved from implanted cardiac devices may provide more insights into GLP1RA-associated effects on heart rate and arrhythmic events. Objectives This study aims to analyze the effects of GLP1RA on device-related rhythm parameters in patients with HFrEF and implanted cardiac devices. Methods The authors performed a retrospective analysis of outpatients with HFrEF with implanted cardiac devices followed in cardiorenal clinics from a single-center quaternary care hospital in Canada. GLP1RA users were compared with GLP1RA nonusers with similar baseline characteristics for longitudinal changes (1-year follow-up) in heart rate, using data from electrophysiology interrogation reports. Secondary endpoints included relevant arrhythmic events, changes in body mass index (BMI), and laboratory biomarkers. Results Among 253 patients with HFrEF and implanted cardiac devices, 53 new GLP1RA users were compared with 53 GLP1RA nonusers. The mean age was 66 ± 10 years, 81% were men, 93% had diabetes, and 36% had atrial fibrillation. The mean BMI was 31.4 kg/m2, and the mean ejection fraction was 28% ± 10%. After adjustment, GLP1RA use (vs no use) significantly increased heart rate by +7 beats/min (95% CI: 4-10 beats/min; P < 0.01). GLP1RA use (vs no use) was associated with a numeric increase in ventricular tachycardia/fibrillation events (13 vs 2; P = 0.07) and a significant increase in nonsustained ventricular events and total shock/antitachycardia pacing therapies (33 vs 3; P = 0.01). Conclusions In this retrospective analysis of patients with HFrEF and implanted cardiac devices, GLP1RA use was associated with significant increase in heart rate and increased number of nonsustained ventricular events and total shock/antitachycardia pacing therapies. These findings highlight the need for further evaluation of GLP1RA use in HFrEF.

Apixaban is increasingly being used for stroke prevention in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis, but no pharmacostatistical model is available for dosage adjustment. This study aimed to develop a population pharmacokinetic model of apixaban in these patients to characterise its dialytic clearance and determine optimal dosing regimens and discontinuation timing before surgery. Patients received 2.5 mg of apixaban twice daily for 9 days, followed by 5 mg twice daily for 8 days after a 5-day washout period (NCT02672709). Apixaban concentrations were measured on and off dialysis. A population pharmacokinetic model was developed using parametric and non-parametric methods. Simulations were performed to assess plasmatic exposure and the time to reach clinically relevant apixaban concentrations after treatment discontinuation for seven dosing regimens and 13 dialysis schedules. A total of 289 apixaban concentrations were measured, including 85 during haemodialysis. The best model was a two-compartment model with first-order elimination. Dialytic clearance was estimated at 1.20 L/h with high inter-individual variability. Apixaban daily exposure was proportional to the total daily dose, independent of dosing frequency and dialysis timing. The standard discontinuation period of 48–72 h before surgery was insufficient to achieve clinically negligible concentrations in patients undergoing haemodialysis. We propose the first pharmacokinetic model to characterise apixaban clearance in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis. Simulations suggest that dialysis timing is not critical for monitoring apixaban, and the discontinuation period before surgery should be extended beyond current recommendations.

The effect of glucagon-like peptide-1 (GLP-1) receptor agonists-based therapies on cardiovascular and renal outcomes has not been systematically reviewed across baseline kidney function groups. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) with GLP-1 Receptor Agonists (RAs) in patients with and without chronic kidney disease (CKD). We performed a PubMed/Medline search of randomized, placebo-controlled, event-driven outcome trials of GLP-1 RAs versus placebo in patients with and without diabetes from inception to January 2025. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes included hospitalization for heart failure, CKD progression, cardiovascular and all-cause mortality. The relative risk (RR) was estimated using a random-effects model. Nine RCTs were included with a total of 75,088 patients, including 17,568 with eGFR < 60 ml/min/1.73m2. Use of an GLP-1 RA in patients with CKD was associated with a lower incidence of MACE (RR 0.84; 95

Anemia and iron deficiency are common in heart failure (HF) and chronic kidney disease (CKD). These conditions are associated with upregulation of hepcidin, which impairs the enteric absorption of iron, limiting the use of oral iron formulations in these populations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are associated with enhanced erythropoiesis and have been shown to augment the erythropoietic response to intravenous iron. The effect of baseline SGLT2i therapy in the erythropoietic response following oral iron supplementation is currently not known. To compare the erythropoietic response to oral iron supplementation in patients with HF or CKD, using and not using SGLT2i as background therapy. This is a retrospective analysis of ambulatory patients with HF or CKD followed in cardio-kidney-metabolic clinics from a quaternary care hospital in Canada and a tertiary care hospital from Portugal. An age- and sex-matched population of patients using (n = 76) and not using (n = 76) a SGLT2i was compared for changes in hemoglobin and hematocrit following oral iron supplementation. Secondary outcomes included changes in iron biomarkers, natriuretic peptides and kidney function. Overall, the mean age was 75 ± 9 years, 49

Background: Hypertension-mediated organ damage (HMOD) can develop concurrently in the heart, the brain, the kidneys and the vasculature, yet most research still relies on counting the number of affected systems or recording the presence versus absence of multi-organ damage, approaches that overlook the complex, multisystem nature of HMOD. Objective: To identify HMOD profiles in adults with hypertension and to quantify sex-specific differences. Methods: We analyzed 4,787 UK Biobank participants with physician-diagnosed or self-reported hypertension (mean ± SD age 57.4 ± 6.8 years; 41.6 % women). Twenty-two continuous indicators, assessed at baseline or first follow-up and spanning cardiac structure and function, vascular stiffness, brain integrity (white-matter hyperintensity volume and fractional anisotropy), and renal function, were log-transformed and entered into latent profile analysis (LPA). Sex differences in profile membership were subsequently examined. Results: A four-profile solution (entropy = 0.86) best balanced statistical fit with clinical interpretability. The largest profile, comprising 38.0% participants, showed modest arterial stiffness and mild concentric left-ventricular remodeling with largely preserved cerebral and renal integrity; males were more common in this group (17% females vs 53.2% males, p < 0.001). A second profile (37.6%) was marked by heightened autonomic tone, micro-albuminuria and subtle micro-structural brain changes without overt cardiac dysfunction (65.4% females vs 17.6% males, p < 0.001). The third profile (22.1 %) combined QRS prolongation, elevated cystatin-C and albumin-creatinine ratio, and a higher burden of white-matter hyperintensities, indicating a cardio-neuro-renal stress pattern (15.3% females vs 27.1% males, p < 0.001). The smallest profile (2.2 %) exhibited pronounced ventricular dilatation, reduced ejection fraction, rapid ventricular rate and marked QRS widening, consistent with cardiac overload and dysfunction; (2.4 % females vs 2.0% males). Conclusion: LPA identifies four biologically coherent HMOD profiles. Most males fall into a mild vascular–cardiac strain profile, underscoring the need for optimized blood pressure control and arterial stiffness monitoring. Most females cluster in an autonomic–renal–cerebral stress profile with preserved cardiac function, indicating that early renal and neurovascular surveillance should be prioritized for them even when conventional cardiac indices appear normal.

Background: The Canadian Cardiovascular Society recommends that patients with type 2 diabetes (T2D) and cardiovascular disease, renal disease, or multiple cardiovascular risk factors initiate Glucagon-like peptide-1 receptor agonists (GLP-1 RA) or Sodium–glucose cotransporter 2 inhibitors (SGLT2i). Both therapies have demonstrated success reducing deaths, and cardiovascular and renal events for this population but are expensive compared to other T2D treatments. Aims: To assess the cost-effectiveness of SGLT2i and GLP-1 RA in this high-risk population from a Canadian healthcare payer perspective. Methods: We developed a patient-level simulation model to estimate lifetime costs, clinical events, and quality adjusted life years (QALYs) for patients initiating SGLT2i, GLP-1 RA or remaining on “baseline treatment,” i.e., other standard-of-care medications. Simulated patients’ initial laboratory values and demographics were based on 175 Quebec patients referred for GLP-1 RA and/or SGLT2i initiation in 2022–2024. Risk equations and treatment effects were calibrated to endpoints from placebo-controlled cardiovascular outcomes trials. We estimated cost-effectiveness over a patient lifetime horizon using a 3% annual discount rate. Results: Compared to baseline treatment, SGLT2i and GLP-1 RA reduced lifetime rates of cardiovascular and renal events and produced higher net present QALYs (+0.28 SGLT2i; +0.24 GLP-1 RA), but at a higher net present cost (+$4,600 SGLT2i; +$25,560 GLP-1 RA). Per 1000 patient years, the population initiating GLP-1 RA were predicted to have 1.95 fewer renal failure events and 4.22 fewer MACE events compared to baseline treatment. The same population initiating SGLT2i instead were predicted to have 2.29 fewer renal failure events, 3.55 fewer MACE events and 1.42 fewer CHF events compared to baseline treatment. SGLT2i cost $16,440 per QALY gained and were consistently cost-effective in sensitivity analyses at the commonly used threshold of $50,000. GLP-1 RA cost $107,910 per QALY gained and were dominated by SGLT2i in 84% of probabilistic sensitivity analysis iterations. Conclusion: While both treatments improved health outcomes compared to baseline treatment, SGLT2i provided more QALYs at a lower price than GLP-1 RA and are cost-effective at current prices in Canada. The introduction of cheaper generic alternatives and accounting for emerging evidence that these medications impact other clinical outcomes could alter their cost-effectiveness.

BACKGROUND:Diuretic resistance is commonly reported in acute heart failure (AHF), especially in patients presenting with impaired kidney function. Effective treatment strategies for promoting decongestion in this population remain unclear. METHODS:A systematic review using MEDLINE/Cochrane databases was performed from inception to January 2024, identifying randomized clinical trials (RCTs) including patients with diuretic resistance or at risk of diuretic resistance based on the presence of kidney dysfunction at study enrollment. Trials testing different pharmacological or invasive modalities compared to standard of care, placebo or an active comparator were considered. Data on decongestion-related outcomes, safety outcomes, and clinical outcomes up to 90 days were collected. RESULTS:Among the 22 RCTs included, 6 trials involved 529 patients with established diuretic resistance, while 16 trials enrolled 1,913 patients at risk of diuretic resistance. Diuretic resistance was differently defined across studies and most trials focused on interventions targeting different sites of action along the renal tubules. The different treatment strategies demonstrated efficacy in promoting decongestion while being associated with a mild increase in creatinine and cystatin C. The use of appropriately high doses of intravenous loop diuretics was able to promote decongestion across the spectrum of kidney dysfunction. The presence of baseline kidney dysfunction did not identify a population resistant to standard decongestive strategies. CONCLUSIONS:Diuretic resistance is not accurately defined in AHF but is uncommon in patients treated with appropriately high doses of intravenous loop diuretics. The main therapeutic goal in the acute setting should focus on promoting decongestion instead of overemphasizing on mild changes in kidney-related biomarkers.

OBJECTIVE:The study was undertaken because it was unknown whether the duration of type 2 diabetes modifies the effects of sodium-glucose cotransporter 2 inhibitor canagliflozin on cardiovascular (CV) and kidney outcomes. RESEARCH DESIGN AND METHODS:This post hoc analysis of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program (N = 10,142) and Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial (N = 4,401) evaluated hazard ratios and 95% CIs using Cox proportional hazards for the effects of canagliflozin on CV and kidney outcomes, including progression and regression of albuminuria over 5-year intervals of disease duration. RESULTS:Canagliflozin had ranges of benefit across intervals of diabetes duration, with no heterogeneity for major adverse CV events, CV death or heart failure hospitalization, and kidney failure requiring therapy or doubling serum creatinine. Furthermore, canagliflozin reduced albuminuria progression and increased albuminuria regression with no interaction across all diabetes duration subgroups. CONCLUSIONS:Our findings suggest that earlier treatment with canagliflozin confers consistent cardiorenal benefits to individuals with type 2 diabetes.