Background An initial decline in estimated glomerular filtration rate (eGFR) often leads to reluctance to continue life-saving therapies in patients with heart failure (HF). Objectives The goal of this study was to describe the association between initial decline in eGFR and subsequent clinical outcomes in patients randomized to placebo or finerenone. Methods In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure), we examined the association between initial decline in eGFR (≥15%) from randomization to 1 month and subsequent outcomes in patients assigned to finerenone or placebo. The primary outcome was the composite of total HF events and cardiovascular death. Results Among 5,587 patients with an eGFR measurement at both baseline and 1 month, 1,018 (18.2%) experienced a ≥15% decline in eGFR. The proportion of patients experiencing a ≥15% decline in eGFR was 23.0% with finerenone and 13.4% with placebo (OR: 1.95; 95% CI: 1.69-2.24; P < 0.001). After adjustment, an eGFR decline was associated with a higher risk of the primary outcome in patients assigned to placebo (adjusted rate ratio: 1.50; 95% CI: 1.20-1.89) but not in those assigned to finerenone (adjusted rate ratio: 1.07; 95% CI: 0.84-1.35; Pinteraction = 0.04). By contrast, the efficacy of finerenone was consistent across the range of change in eGFR from baseline to 1 month (Pinteraction = 0.50 for percent change in eGFR), and safety, including hyperkalemia, was similar regardless of an early eGFR decline. Conclusions Although an initial decline in eGFR was associated with worse outcomes in patients assigned to placebo, this relationship was not as strong in those treated with finerenone. An early decline in eGFR can be anticipated with finerenone and should not automatically lead to the discontinuation of this disease-modifying therapy (FINEARTS-HF Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [NCT04435626]; A Multicenter, Randomized, Double-Bline, Parallel-Group, Placebo-Controlled Study to Evaluate the efficacy and safety of finerenone on morbidity and mortality in participants With Heart Failure [NYHA II-IV] and left ventricular ejection fraction ≥40% [EudraCT 2020-000306-29]).

BACKGROUND:Little is known about the association between chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) in people with established CVD. Knowing if COPD is associated with a higher risk of cardiovascular events would guide appropriate secondary prevention. OBJECTIVE:To examine the risk of COPD on major adverse cardiac events (MACEs, acute myocardial infarction, stroke and cardiovascular death) in a complete real-world population of a large province, with known CVD. METHODS:We conducted a retrospective population cohort study using health administration, medication, laboratory, electronic medical record and other data from Ontario, Canada. All people with a history of CVD with and without physician-diagnosed COPD as of 2008 were followed until 2016 and cardiac risk factors, sociodemographic factors, comorbidities and other factors were compared. Sequential cause-specific hazard models adjusting for these factors determined the risk of MACE in people with COPD. RESULTS:Of 496 056 individuals with CVD in Ontario on 1 January 2008, 69 161 (13.9%) had COPD. MACE occurred more frequently among those with CVD (45.3 per 1000 person-years) and COPD compared with those with CVD alone (28.6 per 1000 person-years) (HR 1.24, 95% CI 1.21-1.26) after adjustment for cardiac risk factors, comorbidities, socioeconomic status and other factors. People with COPD were less likely to receive preventive CVD medications or see a cardiologist. CONCLUSION:In a large, real-world population of people with established CVD, COPD was associated with a higher rate of cardiovascular events but a lower rate of preventive therapy. Strategies are needed to improve secondary CVD prevention in the COPD population.

Background: The CANVAS (Canagliflozin Cardiovascular Assessment Study) trial provided the opportunity to determine the utility of measuring cardiorenal biomarkers, such as fibroblast growth factor 23 (FGF-23) and high-sensitivity C-reactive protein (hsCRP) levels for determining risk prediction and treatment response to sodium glucose co-transporter 2 inhibitor therapy in patients with type 2 diabetes mellitus. Objectives: The prognostic value of these biomarkers for predicting adverse cardiovascular (CV) outcomes and treatment response was assessed. Methods: Of 4,330, 3,188 (73.6%) participants had available longitudinal biomarker samples. The association between FGF-23 and hsCRP with composite CV death or hospitalization for heart failure (HHF), HHF, CV death, and major adverse CV events were assessed using multivariable Cox proportional hazard models adjusted for clinical risk factors, and markers of cardiac and renal injury. Event rates by randomized treatment assignment were calculated for FGF-23 and hsCRP after assignment to a “low-risk” (quartiles [Q] 1-3) or “high-risk” (Q4) group. Multimarker risk assessment was done by stratifying participants by both FGF-23 and hsCRP quartiles to create 4 risk groups. Results: When compared with Q1, FGF-23 levels in Q4 were significantly associated with CV death/HHF (HR: 1.65; 95% CI: 1.15-2.40; P = 0.008) and HHF (HR: 1.96; 95% CI: 1.04-3.69; P = 0.037) whereas hsCRP levels in Q4 were significantly associated with CV death (HR: 1.78; 95% CI: 1.16-2.73; P = 0.008) and major adverse CV events (HR: 1.35; 95% CI: 1.02-1.78; P = 0.038) in adjusted analyses. There was consistent effect of canagliflozin vs placebo across high- and low-risk groups (P-interactions ≥0.30). Conclusions: FGF-23 and hsCRP are biomarkers associated with increased CV risk, but these markers did not identify participants who preferentially benefited from treatment with canagliflozin.

An initial decline in estimated glomerular filtration rate (eGFR) often leads to reluctance to continue life-saving therapies in patients with heart failure (HF). The goal of this study was to describe the association between initial decline in eGFR and subsequent clinical outcomes in patients randomized to placebo or finerenone. In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure), we examined the association between initial decline in eGFR (≥15%) from randomization to 1 month and subsequent outcomes in patients assigned to finerenone or placebo. The primary outcome was the composite of total HF events and cardiovascular death. Among 5,587 patients with an eGFR measurement at both baseline and 1 month, 1,018 (18.2%) experienced a ≥15% decline in eGFR. The proportion of patients experiencing a ≥15% decline in eGFR was 23.0% with finerenone and 13.4% with placebo (OR: 1.95; 95% CI: 1.69-2.24; P < 0.001). After adjustment, an eGFR decline was associated with a higher risk of the primary outcome in patients assigned to placebo (adjusted rate ratio: 1.50; 95% CI: 1.20-1.89) but not in those assigned to finerenone (adjusted rate ratio: 1.07; 95% CI: 0.84-1.35; Pinteraction = 0.04). By contrast, the efficacy of finerenone was consistent across the range of change in eGFR from baseline to 1 month (Pinteraction = 0.50 for percent change in eGFR), and safety, including hyperkalemia, was similar regardless of an early eGFR decline. Although an initial decline in eGFR was associated with worse outcomes in patients assigned to placebo, this relationship was not as strong in those treated with finerenone. An early decline in eGFR can be anticipated with finerenone and should not automatically lead to the discontinuation of this disease-modifying therapy (FINEARTS-HF Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [NCT04435626]; A Multicenter, Randomized, Double-Bline, Parallel-Group, Placebo-Controlled Study to Evaluate the efficacy and safety of finerenone on morbidity and mortality in participants With Heart Failure [NYHA II-IV] and left ventricular ejection fraction ≥40% [EudraCT 2020-000306-29]).

IMPORTANCE Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) have a spectrum of risk, and the effect of therapies may vary by risk. OBJECTIVES To validate the Prognostic Models for Mortality and Morbidity in HFpEF (PREDICT-HFpEF) in the phase 3 randomized clinical trial Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) and to evaluate the effect of finerenone, compared with placebo, across the spectrum of risk in these patients. DESIGN, SETTING, AND PARTICIPANTS The FINEARTS-HF trial was conducted across 653 sites in 37 countries. Participants were adults 40 years and older with symptomatic HF and left ventricular EF of 40% or greater randomized between September 2020 and January 2023. INTERVENTION Finerenone (titrated to 20 mg or 40 mg) or placebo. MAIN OUTCOMES AND MEASURES The 3 PREDICT-HFpEF risk scores for the composite outcome of cardiovascular death or HF hospitalization, cardiovascular death, and all-cause death, respectively, were calculated. Predicted risk was compared with observed outcomes. Model performance was assessed using the Harrell C statistic. The rates of the predicted outcomes (plus the composite of cardiovascular death and worsening HF events, which was the primary end point in the trial) were examined according to quintiles of risk score, as was the effect of finerenone according to risk quintiles. RESULTS A total of 6001 patients (mean [SD] age, 72 [9.6] years; 3269 male [54.5%]) were randomized in the FINEARTS-HF trial. The C statistics for cardiovascular death or HF hospitalization, cardiovascular death, and all-cause death at 2 years were 0.71 (95% CI, 0.69-0.72), 0.68(95% CI, 0.66-0.71), and 0.69(95% CI, 0.67-0.71), respectively. The risk of the composite outcomes was approximately 8-to 10-fold higher in those in the highest compared with the lowest risk quintile. The relative risk reduction with finerenone compared with placebo was consistent across the spectrum of risk for all outcomes examined (eg, interaction P value for primary outcome = .24). CONCLUSIONS AND RELEVANCE Results of the FINEARTS-HF randomized clinical trial demonstrate that the PREDICT-HFpEF models performed well in terms of calibration and discrimination. Baseline risk did not modify the benefit of finerenone.

BACKGROUND:In the EMPACT-MI trial, empagliflozin did not reduce the primary endpoint of all-cause mortality or hospitalization for heart failure (HHF) following acute myocardial infarction (AMI) but was associated with a risk reduction for HF events. OBJECTIVES:This study aimed to evaluate whether the effect of empagliflozin on HF events is consistent in patients with and without type 2 diabetes and/or chronic kidney disease enrolled in the EMPACT-MI trial. METHODS:Post hoc analysis assessing the effect of empagliflozin on the primary endpoint and on HF events in AMI patients with and without an established recommendation for a sodium-glucose cotransporter-2 inhibitor (SGLT2i) (type 2 diabetes or chronic kidney disease). RESULTS:Of 6522 participants, 3489 (53%) did not have type 2 diabetes and/or chronic kidney disease. Those without these conditions were younger and with fewer comorbidities. No differences were observed for the primary endpoint. Empagliflozin reduced time to first HHF, total HHF, time to adverse event (AE) of HF (including outpatient HF events) and total AEs of HF similarly in patients with and without type 2 diabetes or chronic kidney disease. Total HHFs were 50 and 63 [adjusted event rate 1.74 and 2.31 events per 100 patient-years; rate ratio (RR) 0.75; 95% confidence interval (CI) 0.48, 1.18] in patients without and 98 and 144 (adjusted event rate 3.91 and 6.04 events per 100 patient-years; RR 0.65; 95% CI 0.45, 0.94; P for interaction = 0.61) in those with type 2 diabetes or chronic kidney disease in the empagliflozin and placebo arms, respectively. Any AEs, serious AEs and AEs leading to permanent study drug discontinuation were similar between treatment groups in both subgroups. CONCLUSIONS:Empagliflozin improved HF outcomes similarly in patients after AMI with or without type 2 diabetes or chronic kidney disease.

Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) have a spectrum of risk, and the effect of therapies may vary by risk. To validate the Prognostic Models for Mortality and Morbidity in HFpEF (PREDICT-HFpEF) in the phase 3 randomized clinical trial Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) and to evaluate the effect of finerenone, compared with placebo, across the spectrum of risk in these patients. The FINEARTS-HF trial was conducted across 653 sites in 37 countries. Participants were adults 40 years and older with symptomatic HF and left ventricular EF of 40% or greater randomized between September 2020 and January 2023. Finerenone (titrated to 20 mg or 40 mg) or placebo. The 3 PREDICT-HFpEF risk scores for the composite outcome of cardiovascular death or HF hospitalization, cardiovascular death, and all-cause death, respectively, were calculated. Predicted risk was compared with observed outcomes. Model performance was assessed using the Harrell C statistic. The rates of the predicted outcomes (plus the composite of cardiovascular death and worsening HF events, which was the primary end point in the trial) were examined according to quintiles of risk score, as was the effect of finerenone according to risk quintiles. A total of 6001 patients (mean [SD] age, 72 [9.6] years; 3269 male [54.5%]) were randomized in the FINEARTS-HF trial. The C statistics for cardiovascular death or HF hospitalization, cardiovascular death, and all-cause death at 2 years were 0.71 (95% CI, 0.69-0.72), 0.68 (95% CI, 0.66-0.71), and 0.69 (95% CI, 0.67-0.71), respectively. The risk of the composite outcomes was approximately 8- to 10-fold higher in those in the highest compared with the lowest risk quintile. The relative risk reduction with finerenone compared with placebo was consistent across the spectrum of risk for all outcomes examined (eg, interaction P value for primary outcome = .24). Results of the FINEARTS-HF randomized clinical trial demonstrate that the PREDICT-HFpEF models performed well in terms of calibration and discrimination. Baseline risk did not modify the benefit of finerenone. ClinicalTrials.gov Identifier: NCT04435626.

Introduction People with type 2 diabetes (T2DM) have an elevated risk of adverse outcomes from COVID-19. Dipeptidyl peptidase-4 inhibitors (DPP4is) and glucagon-like peptide-1 receptor agonists (GLP1RAs) might have favorable effects on COVID-19 outcomes.Research design and methods We conducted a population-based cohort study in Ontario, Canada. We compared the risk of both COVID-19 infection as well as adverse outcomes between users of DPP4i or GLP1RA and users of sodium-glucose cotransporter-2 inhibitors (SGLT2is) or sulfonylureas (SUs). The study population was persons ≥66 years with T2DM taking metformin who had ≥1 COVID-19 PCR test between January 2020 and July 2021. We compared (1) COVID-19 infection and (2) adverse outcomes at 30 days among COVID-19 positive patients (major cardiovascular (CV) events, hospitalizations, intensive care unit admission, all-cause mortality, venous thromboembolism, mechanical ventilation). We reported weighted risk differences (RDs) and relative risks (RRs).Results There were 26,485 DPP4i/GLP1RA users (mean age 76, 47% female, 91% DPP4i users) and 14,487 SGLT2i/SU users (mean age 75, 39% female, 65% SGLT2i users). The weighted rate of COVID-19 infection in DPP4i/GLP1RA users was 10.3% compared with 10.4% among SGLT2i/SU users (weighted RD −0.06, 95% CI −0.79 to 0.66; RR 0.99, 95% CI 0.93 to 1.07). Among COVID-19 positive patients, the weighted RD for all-cause hospitalization for DPP4i/GLP1RA users versus SGLT2i/SU users was −6.72% (95% CI −3.02 to −10.4) and the adjusted weighted RR was 0.79 (95% CI 0.70 to 0.89). For major CV events, the weighted RD was −1.91% (95% CI −4.00 to 0.18) and RR 0.73 (95% CI 0.54 to 1.00).Conclusions DPP4i/GLP1RA use was not associated with reduced risk of COVID-19 infection compared with SGLT2i/SU use. DPP4i/GLP1RA use was associated with reduced risk of 30-day hospitalization among COVID-19 positive older adults and a possible trend towards a lower associated risk of CV events.

BACKGROUND:Educational attainment level (EAL) is an indicator of socioeconomic status and has been shown to be inversely related with adverse health outcomes. However, the association between EAL and risk of clinical outcomes in high-risk patients with cardiovascular disease has not been extensively investigated. METHODS:In the INVESTED (Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure) trial, patients with recent heart failure or myocardial infarction hospitalization were randomized 1:1 to high-dose trivalent or standard-dose quadrivalent influenza vaccine from September 2016 to January 2019. We examined the association between EAL and risk of clinical outcomes for each participant across all enrolling seasons using adjusted Cox models stratified by trial entry season. Participants were categorized by EAL (≤high school, post-high school or trade, and ≥college). RESULTS:Of the 4912 participants (mean age: 65.5 years, 28% female, 80% White) with EAL information, 43% had high school, 29% had post-high school or trade, and 28% had ≥college as EAL. Those with higher EAL were more likely to be White or Asian, be married/with long-term partner, have higher left ventricular ejection fraction, have lower New York Heart Association class, and less likely to have comorbidities and risk factors than those with lower EAL. During follow-up (median: 9 months), 1706 (35%) participants experienced the composite of all-cause death or cardiopulmonary hospitalization. Compared with high school, higher EAL was associated with a stepwise decrease in risk (post-high school or trade: hazard ratio [HR], 0.88 [95% CI, 0.79-0.99]; ≥college: HR, 0.71 [95% CI, 0.63-0.81], Ptrend <0.001). CONCLUSIONS:High EAL is significantly associated with a decreased risk of adverse clinical outcomes in patients with high-risk cardiovascular disease after adjustment for other key risk factors, highlighting the need to consider EAL in risk assessment and target additional resources toward those with low EAL to improve prognosis. REGISTRATION:URL: https://clinicaltrials.gov; Unique identifier: NCT02787044.

Background:Comparative effectiveness studies may provide insights into generalizability of the ISCHEMIA trial to real-world patients. We evaluated the long-term effectiveness of revascularization within 90 days after detecting moderate or severe ischemia on myocardial perfusion imaging (MPI) in stable coronary artery disease. Methods:All consecutive patients with moderate or severe ischemia (summed difference score ≥7) on single photon emission computed tomography MPI at a tertiary academic medical center were included (January 2003 to March 2020). Early revascularization (defined as percutaneous coronary intervention or coronary artery bypass grafting within 90 days) after MPI, was compared to those patients treated without early revascularization, excluding those with left main disease, severe chronic kidney disease, severe left ventricular dysfunction, recent acute coronary syndrome or heart failure hospitalization. Primary outcomes were cardiovascular death or the composite of cardiovascular hospitalization or cardiovascular death, and were tracked throughout the provincial healthcare system. Results:1530 patients (mean age: 65 years; 70 % male) were followed for a median of 9.9 years. After inverse-probability treatment weighting, early revascularization was associated with lower risks of cardiovascular death (3.76 % vs 8.93 %; HR 0.54, 95 % CI: 0.31-0.91, p = 0.022) and a reduction in the composite endpoint (33.73 % vs 43.94 %; HR 0.67, 95 % CI: 0.49-0.92, p = 0.013) compared to those treated without early revascularization. Conclusions:Patients with stable coronary artery disease treated with early revascularization after MPI showing moderate or severe ischemia experienced lower risks of cardiovascular death and composite of cardiovascular hospitalization or cardiovascular death compared to those treated without early revascularization.

Data on the cardiovascular–kidney effects and safety of empagliflozin among patients with acute myocardial infarction are limited. EMPACT-MI (Study to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) was a double-blind, multicenter clinical trial that randomized 6,522 patients with acute myocardial infarction and risk for heart failure to empagliflozin or placebo. Here we show in this secondary analysis that the mean estimated glomerular filtration rate at baseline was 76.1 ml min−1 1.73 m−2 (s.d. = 19.9 ml min−1 1.73 m−2), with longitudinal kidney function data available for 1,152 (17.7

BACKGROUND:Non-high-density lipoprotein cholesterol (HDL-C) is increasingly incorporated into guidelines along with low-density lipoprotein cholesterol (LDL-C) to guide lipid-lowering therapy decisions. OBJECTIVES:The purpose of this study was to examine patterns of LDL-C and non-HDL-C levels after statin initiation for primary prevention and their association with incident cardiovascular events. METHODS:This was a population-based cohort study in Ontario, Canada, among persons aged ≥66 years starting a statin for primary prevention between January 1, 2012, and December 31, 2019. We identified those with a lipid panel in the 1-year after starting a statin and categorized individuals based on LDL-C and non-HDL-C thresholds for intensification in the 2021 Canadian Cardiovascular Society dyslipidemia guidelines. We stratified by diabetes/chronic kidney disease (CKD) status. The primary outcome was the composite of all-cause mortality or cardiovascular events, with follow-up to December 31, 2020. We used a Cox proportional hazards model for analysis. RESULTS:Our cohort comprised 125,013 people. The median follow-up was 2.5 years. Compared with those meeting both LDL-C and non-HDL-C thresholds, being above both thresholds was associated with an increased rate of the primary outcome for people without diabetes/CKD (HR: 1.10; 95% CI: 1.05-1.15) and for those with diabetes/CKD (HR: 1.16; 95% CI: 1.09-1.23). Being below the LDL-C threshold but above non-HDL-C threshold was associated with an increased rate of the primary outcome for people with diabetes/CKD (HR: 1.16; 95% CI: 1.03-1.30). CONCLUSIONS:These findings support the residual risk associated with incompletely controlled LDL-C or non-HDL-C levels after statin initiation for primary prevention.

The Cardiac and Renal Endocrine (C.a.R.E) clinic is an interdisciplinary clinic offering integrated care to complex patients with cardiovascular-kidney-metabolic syndrome. Previous data from the clinic demonstrated improvements in clinical parameters but provided limited information on the indicated usage of evidence-based therapies. We aimed to update baseline characteristics and clinical data of the C.a.R.E clinic cohort, with added information on the uptake of therapies and reasons for therapy non-use. We performed a retrospective chart review of patients seen in the C.a.R.E clinic between July 2014 and July 2024 with at least two documented clinic visits. Data from the first and last visits were compared to evaluate treatment uptake and changes in clinical parameters. A total of 125 patients met our inclusion criteria. There were significant improvements in low-density lipoprotein levels (1.61 mmol/L for last visit vs 1.82 mmol/L for first visit), blood pressure (BP) measurements, (median systolic BP of 126 mm Hg vs 130 mm Hg and median diastolic BP of 72 mm Hg vs 76 mm Hg), and proportion of patients achieving BP targets (60.0% vs 44.8%). Uptake of therapies significantly increased, including sodium-glucose cotransporter-2 inhibitors (59.2% vs 24.0%) and glucagon-like peptide-1 receptor agonists (30.4% vs 9.6%). The use of finerenone also increased (22.7% vs 3.0%) among the 66 patients whose last visit occurred after Health Canada approved finerenone. The C.a.R.E clinic demonstrates potential to improve therapy uptake and clinical outcomes in patients with cardiovascular-kidney-metabolic syndrome. However, consistent clinical documentation and innovative strategies are needed to further enhance the adoption of evidence-based therapies.

This Series paper highlights the substantial progress made in understanding and preventing heart failure after acute myocardial infarction. Improving global standards of care for management of acute myocardial infarction with timelier reperfusion has led to stepwise reductions in risk of incident heart failure. Landmark clinical trials have established the role of renin-angiotensin-aldosterone system inhibitors, β blockers, and mineralocorticoid receptor antagonists to specifically reduce the risk of incident heart failure after acute myocardial infarction. However, residual risk of heart failure persists in many individuals, even after revascularisation and standard medical therapies. We review recent epidemiological trends from the past four decades, evolving understanding of the pathological mechanisms underlying incident heart failure, and modern risk stratification tools. We then propose a treatment pathway tailored to individual patient risk and discuss potential future strategies to incrementally improve the risk of development of heart failure after acute myocardial infarction.