ABSTRACT
Background: Adult congenital heart disease (ACHD) patients have significant morbidity and rise in cardiac admissions. Their outcome with high-dose influenza vaccination is unknown in comparison to those without ACHD. Objectives: The purpose of this study was to compare all-cause mortality or cardiopulmonary hospitalizations in self-identified ACHD versus non-ACHD patients receiving high- or low-dose influenza vaccination within the INfluenza Vaccine to Effectively Stop cardioThoracic Events and Decompensated heart failure trial. Methods: We prospectively included ACHD patients in the INVESTED (INfluenza Vaccine to Effectively Stop cardioThoracic Events and Decompensated heart failure) trial. The primary endpoint was all-cause death or hospitalization for cardiovascular or pulmonary causes. Results: Of the 272 ACHD patients, 132 were randomly assigned to receive high-dose trivalent and 140 to standard-dose quadrivalent influenza vaccine. Compared to the non-ACHD cohort (n = 4,988), ACHD patients were more likely to be younger, women, smokers, have atrial fibrillation, and have a qualifying event of heart failure. The primary outcome was 49.8 events versus 42.8 events per 100 person-years (adjusted HR: 1.17; 95% CI: 0.95-1.45; P = 0.144) in the ACHD group and non-ACHD group, respectively. The interaction between ACHD status and randomized treatment effect was not significant for the primary outcome (P = 0.858). Vaccine-related adverse events were similar in both groups. Conclusions: Patients who self-identify as being ACHD had similar primary outcome of all-cause death or hospitalization for cardiovascular or pulmonary causes compared to non-ACHD cohort. High-dose influenza vaccination was similar to standard-dose influenza vaccination on the primary outcome in patients who self-identify as ACHD.
ABSTRACT
BACKGROUND: Little is known regarding differences in cause-specific costs between heart failure (HF) with ejection fraction (EF) ≤40% vs >40%, and potential cost implications of sodium glucose co-transporter 2 inhibitor (SGLT2i) therapy. OBJECTIVES: This study sought to compare cause-specific health care costs following hospitalization for HF with EF ≤40% vs >40% and estimate the cost offset with implementation of SGLT2i therapy. METHODS: This study examined Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-Heart Failure registry from 2016 to 2020. Mean per-patient total (excluding drug costs) and cause-specific costs from discharge through 1-year follow-up were calculated and compared between EF ≤40% vs >40%. Next, risk reductions on total all-cause and HF hospitalizations were estimated in a trial-level meta-analysis of 5 pivotal trials of SGLT2is in HF. Finally, these relative treatment effects were applied to Medicare beneficiaries eligible for SGLT2i therapy to estimate the projected cost offset with implementation of SGLT2i, excluding drug costs. RESULTS: Among 146,003 patients, 50,598 (34.7%) had EF ≤40% and 95,405 (65.3%) had EF >40%. Mean total cost through 1 year was $40,557. Total costs were similar between EF groups overall but were higher for EF ≤40% among patients surviving the 1-year follow-up period. Patients with EF >40% had higher costs caused by non-HF and noncardiovascular hospitalizations, and skilled nursing facilities (all P < 0.001). Trial-level meta-analysis of the 5 SGLT2i clinical trials estimated 11% (rate ratio: 0.89; 95% CI: 0.84-0.93; P < 0.001) and 29% (rate ratio: 0.71; 95% CI: 0.66-0.76; P < 0.001) relative reductions in rates of total all-cause and HF hospitalizations, respectively, regardless of EF. Reductions in all-cause and HF hospitalizations were projected to reduce annual costs of readmission by $2,451 to $2,668 per patient with EF ≤40% and $1,439 to $2,410 per patient with EF >40%. CONCLUSIONS: In this large cohort of older U.S. adults hospitalized for HF, cause-specific costs of care differed among patients with EF ≤40% vs >40%. SGLT2i significantly reduced the rate of HF and all-cause hospitalizations irrespective of EF in clinical trials, and implementation of SGLT2i therapy in clinical practice is projected to reduce costs by $1,439 to $2,668 per patient over the 1 year post-discharge, excluding drug costs.
Subject(s)
Health Care Costs , Heart Failure , Hospitalization , Medicare , Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/economics , Heart Failure/economics , Heart Failure/therapy , Heart Failure/drug therapy , Hospitalization/economics , Aged , Female , Male , United States , Health Care Costs/statistics & numerical data , Medicare/economics , Stroke Volume/physiology , Aged, 80 and over , RegistriesABSTRACT
AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.
Subject(s)
Heart Failure , Mineralocorticoid Receptor Antagonists , Naphthyridines , Stroke Volume , Humans , Heart Failure/physiopathology , Heart Failure/drug therapy , Stroke Volume/physiology , Female , Male , Aged , Mineralocorticoid Receptor Antagonists/therapeutic use , Naphthyridines/therapeutic use , Double-Blind Method , Ventricular Function, Left/physiology , Ventricular Function, Left/drug effects , Middle Aged , Treatment Outcome , Glomerular Filtration Rate/physiology , Natriuretic Peptide, Brain/bloodABSTRACT
OBJECTIVES: To summarize current evidence of high-dose influenza vaccine (HD-IV) vs standard-dose (SD-IV) regarding severe clinical outcomes. METHODS: A prespecified meta-analysis was conducted to assess relative vaccine effectiveness (rVE) of HD-IV vs SD-IV in reducing the rates of (1) pneumonia and influenza (P&I) hospitalization, (2) all hospitalizations, and (3) all-cause death in adults ≥ 65 years in randomized controlled trials. Pooled effect sizes were estimated using fixed-effects models with the inverse variance method. RESULTS: Five randomized trials were included encompassing 105,685 individuals. HD-IV vs SD-IV reduced P&I hospitalizations (rVE: 23.5 %, [95 %CI: 12.3 to 33.2]). HD-IV vs SD-IV also reduced rate of all-cause hospitalizations (rVE: 7.3 %, [95 %CI: 4.5 to 10.0]). No significant differences were observed in death rates (rVE = 1.6 % ([95 %CI: -2.0 to 5.0]) in HD-IV vs SD-IV. Sensitivity analyses omitting trials with participants sharing the same comorbidity, trials with ≥ 100 events, and random-effects models provided comparable estimates for all outcomes. CONCLUSIONS: HD-IV reduced the incidence of P&I and all-cause hospitalization vs SD-IV in adults ≥ 65 years in randomized trials, through no significant difference was observed in all-cause death rates. These findings, supported by evidence from several randomized studies, can benefit from replication in a fully powered, individually randomized trial.
Subject(s)
Hospitalization , Influenza Vaccines , Influenza, Human , Randomized Controlled Trials as Topic , Humans , Hospitalization/statistics & numerical data , Influenza Vaccines/administration & dosage , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Influenza, Human/mortality , Aged , Vaccine Efficacy , Pneumonia/prevention & control , Pneumonia/mortality , Male , Aged, 80 and over , FemaleABSTRACT
Importance: Kidney health has received increasing focus as part of comprehensive heart failure (HF) treatment efforts. However, the occurrence of clinically relevant kidney outcomes in contemporary populations with HF has not been well studied. Objective: To examine rates of incident dialysis and acute kidney injury (AKI) among Medicare beneficiaries after HF hospitalization. Design, Setting, and Participants: This retrospective cohort study evaluated adults aged 65 years or older who were hospitalized for HF across 372 sites in the Get With The Guidelines-Heart Failure registry in the US between January 1, 2014, and December 31, 2018. Patients younger than 65 years or requiring dialysis either during or prior to hospitalization were excluded. Data were analyzed from May 4, 2021, to March 8, 2024. Main Outcomes and Measures: The primary outcome was inpatient dialysis initiation in the year after HF hospitalization and was ascertained via linkage with Medicare claims data. Other all-cause and cause-specific hospitalizations were also evaluated. The covariate-adjusted association between discharge estimated glomerular filtration rate (eGFR) and 1-year postdischarge outcomes was examined using Cox proportional hazards regression models. Results: Overall, among 85â¯298 patients included in the analysis (mean [SD] age, 80 [9] years; 53% women) mean (SD) left ventricular ejection fraction was 47% (16%) and mean (SD) eGFR was 53 (29) mL/min per 1.73 m2; 54â¯010 (63%) had an eGFR less than 60 mL/min per 1.73 m2. By 1 year after HF hospitalization, 6% had progressed to dialysis, 7% had progressed to dialysis or end-stage kidney disease, and 7% had been readmitted for AKI. Incident dialysis increased steeply with lower discharge eGFR category: compared with patients with an eGFR of 60 mL/min per 1.73 m2 or more, individuals with an eGFR of 45 to less than 60 and of less than 30 mL/min per 1.73 m2 had higher rates of dialysis readmission (45 to <60: adjusted hazard ratio [AHR], 2.16 [95% CI, 1.86-2.51]; <30: AHR, 28.46 [95% CI, 25.25-32.08]). Lower discharge eGFR (per 10 mL/min per 1.73 m2 decrease) was independently associated with a higher rate of readmission for dialysis (AHR, 2.23; 95% CI, 2.14-2.32), dialysis or end-stage kidney disease (AHR, 2.34; 95% CI, 2.24-2.44), and AKI (AHR, 1.25; 95% CI, 1.23-1.27), with similar findings for all-cause mortality, all-cause readmission, and HF readmission. Baseline left ventricular ejection fraction did not modify the covariate-adjusted association between lower discharge eGFR and kidney outcomes. Conclusions and Relevance: In this study, older adults with HF had substantial risk of kidney complications, with an estimated 6% progressing to dialysis in the year after HF hospitalization. These findings emphasize the need for health care approaches prioritizing kidney health in this high-risk population.
Subject(s)
Acute Kidney Injury , Glomerular Filtration Rate , Heart Failure , Hospitalization , Medicare , Humans , Heart Failure/therapy , Heart Failure/epidemiology , Male , Female , United States/epidemiology , Aged , Hospitalization/statistics & numerical data , Retrospective Studies , Aged, 80 and over , Acute Kidney Injury/therapy , Acute Kidney Injury/epidemiology , Renal Dialysis/statistics & numerical data , RegistriesABSTRACT
Importance: High-dose trivalent compared with standard-dose quadrivalent influenza vaccine did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations in patients with high-risk cardiovascular disease in the INVESTED trial. Whether humoral immune response to influenza vaccine is associated with clinical outcomes is unknown. Objective: To examine the antibody response to high-dose trivalent compared with standard-dose quadrivalent inactivated influenza vaccine and its associations with clinical outcomes. Design, Setting, and Participants: This secondary analysis is a prespecified analysis of the immune response substudy of the randomized, double-blind, active-controlled INVESTED trial, which was conducted at 157 sites in the United States and Canada over 3 influenza seasons between September 2016 and January 2019. Antibody titers were determined by hemagglutination inhibition assays at randomization and 4 weeks during the 2017-2018 and 2018-2019 seasons. Eligibility criteria included recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor. Data were analyzed from February 2023 to June 2023. Main Outcomes and Measures: Mean antibody titer change, seroprotection (antibody titer level ≥1:40) and seroconversion (≥4-fold increase in titer) at 4 weeks, and the association between seroconversion status and the risk for adverse clinical outcomes. Interventions: High-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine, with revaccination up to 3 seasons. Results: Antibody data were available for 658 of 5260 randomized participants (12.5%; mean [SD] age, 66.2 [11.4] years; 507 male [77.1%], 151 female [22.9%]; 348 with heart failure [52.9%]). High-dose vaccine was associated with an increased magnitude in antibody titers for A/H1N1, A/H3N2, and B-type antigens compared with standard dose. More than 92% of all participants achieved seroprotection for each of the contained antigens, while seroconversion rates were higher in participants who received high-dose vaccine. Seroconversion for any antigen was not associated with the risk for cardiopulmonary hospitalizations or all-cause mortality (hazard ratio, 1.09; 95% CI, 0.79-1.53; P = .59), irrespective of randomized treatment (P = .38 for interaction). Conclusions and Relevance: High-dose vaccine elicited a more robust humoral response in patients with heart failure or prior myocardial infarction enrolled in the INVESTED trial, with no association between seroconversion status and the risk for cardiopulmonary hospitalizations or all-cause mortality. Vaccination to prevent influenza remains critical in high-risk populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.
Subject(s)
Influenza Vaccines , Influenza, Human , Humans , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage , Male , Female , Aged , Influenza, Human/prevention & control , Influenza, Human/immunology , Double-Blind Method , Middle Aged , Cardiovascular Diseases/immunology , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/mortality , Antibodies, Viral/blood , Hospitalization/statistics & numerical data , Hemagglutination Inhibition Tests/methods , Myocardial Infarction/immunology , Heart Failure/immunologyABSTRACT
AIMS: Patients with heart failure (HF) and preserved ejection fraction (HFpEF) have a particularly high prevalence of comorbidities, often necessitating treatment with many medications. The aim of this study was to evaluate the association between polypharmacy status and outcomes in PARAGON-HF. METHODS AND RESULTS: In this post hoc analysis, baseline medication status was available in 4793 of 4796 patients included in the primary analysis of PARAGON-HF. The effects of sacubitril/valsartan, compared with valsartan, were assessed according to the number of medications at baseline: 683 non-polypharmacy (<5 medications); 2750 polypharmacy (5-9 medications), and 1360 hyper-polypharmacy (≥10 medications). The primary outcome was total HF hospitalizations and cardiovascular deaths. Patients with hyper-polypharmacy were older, had more severe limitations due to HF (worse New York Heart Association class and Kansas City Cardiomyopathy Questionnaire scores), and had greater comorbidity. The non-adjusted risk of the primary outcome was significantly higher in patients taking more medications, and similar trends were seen for HF hospitalization and cardiovascular and all-cause death. The effect of sacubitril/valsartan versus valsartan on the primary outcome from the lowest to highest polypharmacy category was (as a rate ratio): 1.19 (0.76-1.85), 0.94 (0.77-1.15), and 0.77 (0.61-0.96) (pinteraction = 0.16). Treatment-related adverse events were more common in patients in the higher polypharmacy categories but not more common with sacubitril/valsartan, versus valsartan, in any polypharmacy category. CONCLUSIONS: Polypharmacy is very common in patients with HFpEF, and those with polypharmacy have worse clinical status and a higher rate of non-fatal and fatal outcomes. The benefit of sacubitril/valsartan was not diminished in patients taking a larger number of medications at baseline.
Subject(s)
Aminobutyrates , Angiotensin Receptor Antagonists , Biphenyl Compounds , Drug Combinations , Heart Failure , Polypharmacy , Stroke Volume , Tetrazoles , Valsartan , Humans , Aminobutyrates/therapeutic use , Heart Failure/drug therapy , Heart Failure/physiopathology , Male , Female , Aged , Angiotensin Receptor Antagonists/therapeutic use , Tetrazoles/therapeutic use , Stroke Volume/physiology , Treatment Outcome , Hospitalization/statistics & numerical data , Middle AgedSubject(s)
Heart Failure , Stroke Volume , Humans , Heart Failure/physiopathology , Heart Failure/therapy , Heart Failure/drug therapy , Stroke Volume/physiology , Female , Male , Sex Factors , Aged , Middle AgedABSTRACT
BACKGROUND: Inadequate inclusion in clinical trial enrollment may contribute to health inequities by evaluating interventions in cohorts that do not fully represent target populations. OBJECTIVES: The aim of this study was to determine if characteristics of patients with heart failure (HF) enrolled in a pivotal trial are associated with who receives an intervention after approval. METHODS: Demographics from 2,017,107 Medicare patients hospitalized for HF were compared with those of the first 10,631 Medicare beneficiaries who received implantable pulmonary artery pressure sensors. Characteristics of the population studied in the pivotal CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) clinical trial (n = 550) were compared with those of both groups. All demographic data were analyzed nationally and in 4 U.S. regions. RESULTS: The Medicare HF cohort included 80.9% White, 13.3% African American, 1.9% Hispanic, 1.3% Asian, and 51.5% female patients. Medicare patients <65 years of age were more likely to be African American (33%) and male (58%), whereas older patients were mostly White (84%) and female (53%). Forty-one percent of U.S. HF hospitalizations occurred in the South; demographic characteristics varied significantly across all U.S. regions. The CHAMPION trial adequately represented African Americans (23% overall, 35% <65 years of age), Hispanic Americans (2%), and Asian Americans (1%) but underrepresented women (27%). The trial's population characteristics were similar to those of the first patients who received pulmonary artery sensors (82% White, 13% African American, 1% Asian, 1% Hispanic, and 29% female). CONCLUSIONS: Demographics of Centers for Medicare and Medicaid Services beneficiaries hospitalized with HF vary regionally and by age, which should be considered when defining "adequate" representation in clinical studies. Enrollment diversity in clinical trials may affect who receives early application of recently approved innovations.
Subject(s)
Clinical Trials as Topic , Heart Failure , Medicare , Humans , Male , Female , Heart Failure/therapy , Aged , United States , Middle Aged , Patient Selection , Aged, 80 and over , Hospitalization/statistics & numerical dataABSTRACT
BACKGROUND: Hypotension is a potential adverse effect of sacubitril/valsartan, but there are limited data regarding the predictors and implications of treatment-related hypotension in heart failure (HF) with mildly reduced and preserved ejection fraction. OBJECTIVES: We investigated predictors of treatment-associated hypotension, clinical outcomes after hypotension, and the relationship between left ventricular ejection fraction (LVEF) and incidence of hypotension in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial. METHODS: PARAGON-HF randomized patients with chronic HF (≥45%) to sacubitril/valsartan or valsartan. Following randomization, hypotension was defined as investigator-reported hypotension with a systolic blood pressure <100 mm Hg. Predictors of hypotension were assessed using multivariable Cox models. Associations between hypotension and clinical outcomes were evaluated in time-updated Cox models. The relationship among treatment, LVEF, and incident rates of hypotension and clinical outcomes was estimated using Poisson regression models. RESULTS: Of 4,796 patients in PARAGON-HF, 637 (13%) experienced hypotension, more frequently in the sacubitril/valsartan arm (P < 0.001). Following documented hypotension, patients had higher risk of cardiovascular death and total HF hospitalizations (adjusted RR: 1.63; 95% CI: 1.27-2.09; P < 0.001) and all-cause death (adjusted HR: 1.62; 95% CI: 1.28-2.05; P < 0.001). LVEF modified the association between sacubitril/valsartan and risk of hypotension (Pinteraction = 0.019) such that patients with LVEF ≥60% experienced substantially higher treatment-related risks of hypotension. CONCLUSIONS: In PARAGON-HF, a higher LVEF was associated with an increased risk of hypotension in patients treated with sacubitril/valsartan compared with valsartan. Because these subjects are also less likely to derive clinical benefit from sacubitril/valsartan, our data reinforce that the benefit/risk ratio favors the use of sacubitril/valsartan in patients with LVEF below normal, but not at higher LVEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
Subject(s)
Aminobutyrates , Angiotensin Receptor Antagonists , Biphenyl Compounds , Drug Combinations , Heart Failure , Hypotension , Stroke Volume , Valsartan , Humans , Valsartan/adverse effects , Hypotension/chemically induced , Hypotension/epidemiology , Hypotension/physiopathology , Heart Failure/physiopathology , Heart Failure/drug therapy , Heart Failure/epidemiology , Aminobutyrates/adverse effects , Male , Female , Stroke Volume/drug effects , Stroke Volume/physiology , Aged , Angiotensin Receptor Antagonists/adverse effects , Angiotensin Receptor Antagonists/administration & dosage , Middle Aged , Tetrazoles/adverse effects , Prospective StudiesABSTRACT
BACKGROUND: The sodium glucose cotransporter-2 inhibitors are guideline-recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter-2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking. METHODS AND RESULTS: We conducted a US-based cost-effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3-state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were obtained from published sources, including published rebates in dapagliflozin cost. Adding dapagliflozin to standard of care was estimated to produce an additional 0.53 quality-adjusted life years (QALYs) compared with standard of care alone. Incremental cost effectiveness ratios were $85 554/QALY when using the publicly reported full (undiscounted) Medicare cost ($515/month) and $40 081/QALY, at a published nearly 50% rebate ($263/month). The addition of dapagliflozin to standard of care would be of at least intermediate value (<$150 000/QALY) at a cost of <$872.58/month, of high value (<$50 000/QALY) at <$317.66/month, and cost saving at <$40.25/month. Dapagliflozin was of at least intermediate value in 92% of simulations when using the full (undiscounted) Medicare list cost in probabilistic sensitivity analyses. Cost effectiveness was most sensitive to the dapagliflozin cost and the effect on cardiovascular death. CONCLUSIONS: The addition of dapagliflozin to standard of care in patients with heart failure across the spectrum of ejection fraction was at least of intermediate value at the undiscounted Medicare cost and may be potentially of higher value on the basis of the level of discount, rebates, and price negotiations offered. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01035255 & NCT01920711.
Subject(s)
Glucosides , Heart Failure , Sodium-Glucose Transporter 2 Inhibitors , Aged , Humans , Benzhydryl Compounds/therapeutic use , Cost-Benefit Analysis , Cost-Effectiveness Analysis , Heart Failure/drug therapy , Medicare , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Stroke Volume , United States , Ventricular Function, Left , Clinical Trials as TopicABSTRACT
Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular conditions that frequently coexist. Among patients with HF, more than one-half also have AF. Both are associated with significant morbidity and mortality. Moreover, the prevalence of each is increasing globally, and this trend is expected to continue owing to an aging population and increased life expectancy. Diagnosis of AF in a patient with HF is associated with greater symptom burden, more frequent hospitalizations, and a worse prognosis. Guideline-directed medical therapy (GDMT) for HF can affect the incidence of AF. Once present, AF can influence the efficacy of some components of GDMT for HF. In this review, we discuss the effect of GDMT for HF across the spectrum of ejection fraction on prevention of AF as well as the benefit of GDMT in patients with vs without AF.
Subject(s)
Atrial Fibrillation , Heart Failure , Humans , Aged , Atrial Fibrillation/complications , Atrial Fibrillation/epidemiology , Atrial Fibrillation/therapy , Stroke Volume , Prognosis , Hospitalization , Heart Failure/epidemiology , Heart Failure/therapy , Heart Failure/diagnosisABSTRACT
AIM: Inhibition of microRNA (miR)-132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR-132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment. METHODS: The HF-REVERT (Phase 2, multicenter, randomized, parallel, 3-arm, placebo-controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post-acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N-terminal pro-B-type natriuretic peptide. The study consists of a 6-month double-blinded treatment period with the primary endpoint LV end-systolic volume index and relevant secondary endpoints, followed by a 6-month open-label observation period. CONCLUSION: The HF-REVERT trial may underpin the concept of miR-132 inhibition to prevent or reverse cardiac remodelling in post-MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF.
Subject(s)
Myocardial Infarction , Stroke Volume , Humans , Myocardial Infarction/drug therapy , Myocardial Infarction/physiopathology , Myocardial Infarction/complications , Stroke Volume/physiology , Male , Female , Heart Failure/drug therapy , Heart Failure/physiopathology , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/etiology , Treatment Outcome , MicroRNAs , Ventricular Remodeling/drug effects , Middle Aged , Aged , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides, Antisense/administration & dosage , Double-Blind Method , Ventricular Function, Left/physiology , Ventricular Function, Left/drug effectsABSTRACT
Importance: Heart failure with improved ejection fraction (HFimpEF), defined as prior left ventricular ejection fraction (LVEF) 40% or lower that has increased to greater than 40%, is understudied. Objective: To examine mode of death and the association of dapagliflozin with reductions in cause-specific death in patients with HFimpEF. Design, Setting, and Participants: This was a post hoc analysis from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) randomized clinical trial, conducted from August 2018 to December 2020. The trial randomly assigned patients with HF with LVEF greater than 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The presence of HFimpEF was captured through study case report forms. The primary outcome was a composite of worsening HF events (hospitalization or urgent HF visits) or cardiovascular death. Clinical outcomes were adjudicated by a blinded clinical end points committee. Data were analyzed from May 2022 to August 2023. Intervention: Dapagliflozin vs placebo. Main Outcomes and Measures: The mode of death in relation to HFimpEF status was examined, as well as the association of randomized treatment with cause-specific death in Cox regression models. Results: Of 1151 patients with HFimpEF in DELIVER, 190 (16.5%) died, compared with 833 patients (16.3%) of 5112 with LVEF consistently greater than 40%. The overall distribution of mode of death was similar in those with HFimpEF compared with those with LVEF consistently greater than 40% (noncardiovascular death: 103 of 190 [54%] vs 428 of 833 [51%]; cardiovascular death: 87 of 190 [46%] vs 405 of 833 [49%], respectively). Most deaths in individuals with HFimpEF were noncardiovascular (103 of 180 [54%]). For cardiovascular deaths, sudden deaths were most common (36 of 190 events [19%]), followed by HF-related (29 of 190 events [15%]). Among patients with HFimpEF, treatment with dapagliflozin was associated with lower rates of cardiovascular death relative to placebo, a difference primarily due to lower rates of sudden death (hazard ratio, 0.38; 95% CI, 0.18-0.79; P for interaction = .01). Conclusions and Relevance: The findings in this study support current guideline recommendations for use of sodium-glucose transport protein 2 inhibitor therapy, and further suggest that the addition of a sodium-glucose transport protein 2 inhibitor therapy to other guideline-directed medical therapies may help reduce cardiovascular mortality in patients with HFimpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.
Subject(s)
Benzhydryl Compounds , Glucosides , Heart Failure , Ventricular Function, Left , Humans , Stroke Volume , Sodium-Glucose Transport Proteins/therapeutic useABSTRACT
BACKGROUND: Patients hospitalized with heart failure (HF) and diabetes mellitus (DM) are at risk for worsening clinical status. Little is known about the frequency of therapeutic changes during hospitalization. We characterized the use of medical therapies before, during and after hospitalization in patients with HF and DM. METHODS: We identified Medicare beneficiaries in Get With The Guidelines-Heart Failure (GWTG-HF) hospitalized between July 2014 and September 2019 with Part D prescription coverage. We evaluated trends in the use of 7 classes of antihyperglycemic therapies (metformin, sulfonylureas, GLP-1RA, SGLT2-inhibitors, DPP-4 inhibitors, thiazolidinediones, and insulins) and 4 classes of HF therapies (evidence-based ß-blockers, ACEi or ARB, MRA, and ARNI). Medication fills were assessed at 6 and 3 months before hospitalization, at hospital discharge and at 3 months post-discharge. RESULTS: Among 35,165 Medicare beneficiaries, the median age was 77 years, 54% were women, and 76% were white; 11,660 (33%) had HFrEF (LVEF ≤ 40%), 3700 (11%) had HFmrEF (LVEF 41%-49%), and 19,805 (56%) had HFpEF (LVEF ≥ 50%). Overall, insulin was the most commonly prescribed antihyperglycemic after HF hospitalization (nâ¯=â¯12,919, 37%), followed by metformin (nâ¯=â¯7460, 21%) and sulfonylureas (nâ¯=â¯7030, 20%). GLP-1RA (nâ¯=â¯700, 2.0%) and SGLT2i (nâ¯=â¯287, 1.0%) use was low and did not improve over time. In patients with HFrEF, evidence-based beta-blocker, RASi, MRA, and ARNI fills during the 6 months preceding HF hospitalization were 63%, 62%, 19%, and 4%, respectively. Fills initially declined prior to hospitalization, but then rose from 3 months before hospitalization to discharge (beta-blocker: 56%-82%; RASi: 51%-57%, MRA: 15%-28%, ARNI: 3%-6%, triple therapy: 8%-20%; P < 0.01 for all). Prescription rates 3 months after hospitalization were similar to those at hospital discharge. CONCLUSIONS: In-hospital optimization of medical therapy in patients with HF and DM is common in participating hospitals of a large US quality improvement registry.
Subject(s)
Diabetes Mellitus , Heart Failure , Metformin , Humans , Female , Aged , United States/epidemiology , Male , Heart Failure/drug therapy , Heart Failure/epidemiology , Angiotensin Receptor Antagonists/therapeutic use , Aftercare , Patient Discharge , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Stroke Volume , Medicare , Diabetes Mellitus/drug therapy , Diabetes Mellitus/epidemiology , Hospitalization , Adrenergic beta-Antagonists/therapeutic use , Hypoglycemic Agents/therapeutic use , Registries , Metformin/therapeutic useABSTRACT
The INVESTED trial did not show benefits of high-dose (HD) vaccine vs. standard-dose (SD) for a primary composite outcome of cardiopulmonary hospitalization or all-cause mortality (hazard ratio (HR) = 1.05, 95% confidence interval (CI) = 0.96-1.15) and its components (all-cause mortality HR = 1.01, 95% CI = 0.84-1.21, cardiopulmonary hospitalization HR = 1.05, 95% CI = 0.96-1.16) during three influenza seasons (2016-2019) among participants with recent myocardial infarction or hospitalization for heart failure (HHF). We emulated INVESTED using Medicare claims data to assess whether the real-world evidence (RWE) study reached similar conclusions. We identified 1:1 propensity score (PS)-matched trial-eligible Medicare beneficiaries aged > 65 years and with prior HHF who received an HD or SD vaccine for the 2016-2019 seasons. We also re-analyzed the INVESTED trial data restricting to participants > 65 years with prior HHF to align eligibility criteria more closely with the RWE study. We compared HRs from the trial and RWE study for the main outcomes. Among 53,393 pairs of PS-matched Medicare beneficiaries, the HD vaccine group showed lower risk of the primary composite outcome (HR = 0.96, 95% CI = 0.95-0.98) and all-cause mortality (HR = 0.93, 95% CI = 0.91-0.95), and similar risk of cardiopulmonary hospitalization (HR = 0.98, 95% CI = 0.96-1.00), compared with SD. The RWE and trial results were closely concordant after the trial population was limited to participants > 65 years with prior HHF: trial-based results for the primary composite outcome (HR = 1.02, 95% CI = 0.89-1.17), all-cause mortality (HR = 0.92, 95% CI = 0.72-1.16), and cardiopulmonary hospitalization (HR = 1.02, 95% CI = 0.88-1.18). Although similar to the main trial results, the RWE was closer to the results from trial participants with aligned eligibility criteria. This study affirms the importance of considering different distributions of baseline patient characteristics when comparing trial findings to RWE.
Subject(s)
Heart Failure , Influenza Vaccines , Humans , Aged , United States , Medicare , Heart Failure/therapy , HospitalizationABSTRACT
BACKGROUND: Although beta-blockers are not recommended for the treatment of heart failure with preserved ejection fraction (HFpEF) according to the latest European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers may adversely influence clinical outcomes by limiting chronotropic response in HFpEF. OBJECTIVES: This study sought to examine the contemporary use and implications of beta-blockers in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF. METHODS: In the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, a total of 6,263 patients with symptomatic heart failure (HF) with a left ventricular ejection fraction (LVEF) >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF. RESULTS: Overall, beta-blockers were used in 5,177 patients (83%), with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR: 0.70; 95% CI: 0.60-0.83). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR: 0.82; 95% CI: 0.72-0.94) and in patients not taking beta-blockers (HR: 0.79; 95% CI: 0.61-1.03; Pinteraction = 0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use. CONCLUSIONS: In patients with HFmrEF or HFpEF who were enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).