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Abstract Despite significant advances in the last 30 years in reducing morbidity and mortality from heart failure with reduced ejection fraction (HFrEF) with pharmacological and device-based therapies, patients remain at a high risk of adverse cardiovascular outcomes. Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitors (ARNI), has been shown to reduce the risk of cardiovascular death or heart failure hospitalisation and improve symptoms in patients with chronic, ambulatory, symptomatic HFrEF in a large, phase 3, multicentre, international, randomised controlled trial, PARADIGM-HF, when compared to the gold-standard angiotensin converting enzyme inhibitor, enalapril. This article will review the development of sacubitril/valsartan, the evidence for its use and its current and future role in the management of HFrEF. Highlights • Natriuretic peptides have protective properties in heart failure with reduced ejection fraction. • Neprilysin degrades natriuretic peptides as well as other vasoactive peptides. • Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor. • Sacubitril/valsartan reduces mortality, the risk of heart failure hospitalisation and symptoms in patients with heart failure compared with the ACE-inhibitor, enalapril. [ABSTRACT FROM AUTHOR]

This paper tackles several statistical controversies that are commonly faced when reporting a major clinical trial. Topics covered include: multiplicity of data, interpreting secondary endpoints and composite endpoints, the value of covariate adjustment, the traumas of subgroup analysis, assessing individual benefits and risks, alternatives to analysis by intention to treat, interpreting surprise findings (good and bad), and the overall quality of clinical trial reports. All is put in the context of topical cardiology trial examples and is geared to help trialists steer a wise course in their statistical reporting, thereby giving readers a balanced account of trial findings. [ABSTRACT FROM AUTHOR]

This paper is a practical guide to the essentials of statistical analysis and reporting of randomized clinical trials (RCTs). It is the first in a series of 4 educational papers on statistical issues for RCTs, which will also include statistical controversies in RCT reporting and interpretation, the fundamentals of design for RCTs, and statistical challenges in the design and monitoring of RCTs. Here, we concentrate on displaying results in tables and figures, estimating treatment effects, expressing uncertainty using confidence intervals, and using p values wisely to assess the strength of evidence for a treatment difference. The various methods and their interpretation are illustrated by recent, topical cardiology trial results. [ABSTRACT FROM AUTHOR]

Objectives: The study sought to investigate the safety and efficacy of eplerenone in patients at high risk for hyperkalemia or worsening renal function (WRF) in EMPHASIS-HF, a trial that enrolled patients at least 55 years old with heart failure and reduced ejection fraction (HF-REF), in New York Heart Association (NYHA) functional class II and with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2 and serum potassium <5.0 mmol/l. Patients were receiving optimal therapy and most had been hospitalized for a cardiovascular reason within 180 days of inclusion. Background: Underuse of eplerenone in patients with HF-REF may be due to fear of inducing hyperkalemia or WRF in high-risk patients. Methods: This was a pre-specified analysis of subgroups of patients at high risk of hyperkalemia or WRF (patients ≥75 years of age, with diabetes, with eGFR <60 ml/min/1.73 m2, and with systolic blood pressure < median of 123 mm Hg), examining the major safety measures (potassium >5.5, >6.0, and <3.5 mmol/l; hyperkalemia leading to study-drug discontinuation or hospitalization; and hospitalization for WRF) as well as the primary outcome (hospitalization for HF or cardiovascular mortality). Results: In all high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5 mmol/l but not of potassium >6.0 mmol/l, and of hospitalization for hyperkalemia or discontinuation of study medication due to adverse events. Eplerenone was effective in reducing the primary composite endpoint in all subgroups. Conclusions: In patients with chronic HF-REF, in NYHA functional class II, and meeting specific inclusion and exclusion criteria, including an eGFR >30 ml/min/1.73 m2 and potassium <5.0 mmol/l, eplerenone was both efficacious and safe when carefully monitored, even in subgroups at high risk of developing hyperkalemia or WRF. (A Comparison Of Outcomes In Patients In New York Heart Association [NYHA] Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines [EMPHASIS-HF Study]; NCT00232180) [Copyright &y& Elsevier]

Objectives: The purpose of this study was to determine whether coenzyme Q10 is an independent predictor of prognosis in heart failure. Background: Blood and tissue concentrations of the essential cofactor coenzyme Q10 are decreased by statins, and this could be harmful in patients with heart failure. Methods: We measured serum coenzyme Q10 in 1,191 patients with ischemic systolic heart failure enrolled in CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) and related this to clinical outcomes. Results: Patients with lower coenzyme Q10 concentrations were older and had more advanced heart failure. Mortality was significantly higher among patients in the lowest compared to the highest coenzyme Q10 tertile in a univariate analysis (hazard ratio: 1.50, 95% confidence interval: 1.04 to 2.6, p = 0.03) but not in a multivariable analysis. Coenzyme Q10 was not an independent predictor of any other clinical outcome. Rosuvastatin reduced coenzyme Q10 but there was no interaction between coenzyme Q10 and the effect of rosuvastatin. Conclusions: Coenzyme Q10 is not an independent prognostic variable in heart failure. Rosuvastatin reduced coenzyme Q10, but even in patients with a low baseline coenzyme Q10, rosuvastatin treatment was not associated with a significantly worse outcome. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310) [ABSTRACT FROM AUTHOR]

Objectives: We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective. Background: Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile. Methods: In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke. Results: Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin. Conclusions: Patients with heart failure due to ischemic heart disease who have NT-proBNP values <103 pmol/l (868 pg/ml) may benefit from rosuvastatin. [Copyright &y& Elsevier]

With an increasing burden of cardiovascular disease and many promising novel treatments in development, the need for efficient systems to evaluate treatments has never been greater. To understand whether a treatment should be used in practice, we need to know whether it makes patients live longer, feel better, prevents adverse events, or does these things with better tolerability or lower cost. But therapeutic development is expensive, inefficient, and is generally focused on short-term treatment effects, rather than on prevention and on long-term impact. Could measures of disease progression, combined with trends on clinical outcomes and post-marketing surveillance to assess safety, serve as the foundation for therapeutic development? Experience and principles of clinical research tell us no. Especially in the field of heart failure, numerous treatments have appeared promising based on disease markers, yet caused harm when tested in studies that assessed clinical outcomes. The intersection of complex human disease, intended and unintended targets of therapy, and overall risk and benefit make it impossible to accurately predict the effect on clinical outcomes based on impact on a disease marker. While reliable measures of disease progression are important to guide which treatments to study in trials, clinical outcome trials must remain the basis for informing clinicians on which treatments improve clinical outcomes. Improved reliability and capacity require the development of more efficient clinical trial methods, streamlined regulatory processes, rational use of privacy protection, leveraging of electronic medical records, and recruitment of a larger proportion of the clinical community to participate in clinical trials. [Copyright &y& Elsevier]

The development of heart failure and/or left ventricular systolic dysfunction (LVSD) in the setting of acute myocardial infarction (AMI) results in significant risk far above that of AMI independently. In patients admitted to the hospital for AMI, concomitant heart failure and/or LVSD on hospital admission or development of either or both of these conditions during admission are among the strongest predictors of inhospital death and are associated with significant increases in inhospital, 30-day, and long-term mortality and rehospitalization rates. Given the high risks in this population, aggressive treatment, comprising early initiation and sustained use of evidence-based treatments, is essential for improving prognosis. [Copyright &y& Elsevier]

Abstract: Background: The aim of this study was to determine the effects of carvedilol on the costs related to the treatment of severe chronic heart failure (CHF). Methods: Costs for the treatment for heart failure within the National Health Service (NHS) in the United Kingdom (UK) were applied to resource utilisation data prospectively collected in all patients randomized into the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study. Unit-specific, per diem (hospital bed day) costs were used to calculate expenditures due to hospitalizations. We also included costs of carvedilol treatment, general practitioner surgery/office visits, hospital out-patient clinic visits and nursing home care based on estimates derived from validated patterns of clinical practice in the UK. Results: The estimated cost of carvedilol therapy and related ambulatory care for the 1156 patients assigned to active treatment was £530,771 (£44.89 per patient/month of follow-up). However, patients assigned to carvedilol were hospitalised less often and accumulated fewer and less expensive days of admission. Consequently, the total estimated cost of hospital care was £3.49 million in the carvedilol group compared with £4.24 million for the 1133 patients in the placebo arm. The cost of post-discharge care was also less in the carvedilol than in the placebo group (£479,200 vs. £548,300). Overall, the cost per patient treated in the carvedilol group was £3948 compared to £4279 in the placebo group. This equated to a cost of £385.98 vs. £434.18, respectively, per patient/month of follow-up: an 11.1% reduction in health care costs in favour of carvedilol. Conclusions: These findings suggest that not only can carvedilol treatment increase survival and reduce hospital admissions in patients with severe CHF but that it can also cut costs in the process. [Copyright &y& Elsevier]

Impaired endothelial function in isolated human uremic resistance arteries. Background. Patients with chronic renal failure (CRF) face a markedly increased risk of cardiovascular death. CRF is frequently complicated by hypertension and changes in both the heart (left ventricular hypertrophy) and the vasculature (endothelial dysfunction and accelerated atherosclerosis). The mechanisms underlying changes in vascular function and specifically endothelial dysfunction are unclear. This present study therefore examined subcutaneous resistance artery function in vitro, comparing adult uremic patients and controls using wire myography. Methods. Subcutaneous fat biopsies were obtained from 12 patients with CRF (median serum creatinine 735 μmol/L) at the time of renal transplantation or peritoneal dialysis catheter insertion, and from eight controls without renal disease at the time of abdominal surgery. Resistance arteries were mounted on a wire myograph. Their contractile ability was tested with high potassium depolarization, and endothelial integrity was tested by relaxation to acetylcholine. Cumulative concentration-response curves were then constructed for norepinephrine, endothelin-1, acetylcholine, and sodium nitroprusside (SNP). Results. Following preconstriction with norepinephrine, vessels from uremic patients vasodilated less well to acetylcholine compared with vessels from controls [maximum % relaxation 77% (range 41, 97) vs. 98% (78, 100), P < 0.001]. The vasodilation to SNP was similar [95% (63, 100) vs. 94% (71, 100), P = 0.751]. There was a trend toward increased maximum pressure (kPa) achieved with both norepinephrine and endothelin-1 in vessels from uremic patients, and the contractions to both of these agents were more prolonged in the uremic vessels. Conclusions. The pattern of normal vasodilation to SNP but reduced vasodilation to acetylcholine is consistent with endothelial dysfunction due to impaired nitric oxide (NO) production in uremic... [ABSTRACT FROM AUTHOR]

Endothelial dysfunction in renal transplant recipients maintained on cyclosporine. Background. Hypertension is almost universal following renal transplantation and may contribute to the already poor cardiovascular prognosis of this group. Cyclosporine-induced hypertension is a particular problem and has variously been attributed to increased sympathetic nerve activity, salt and water retention, and increased circulating endothelin levels. However, the effects of cyclosporine on the l-arginine/nitric oxide (NO) system in vivo in humans are unknown. In this present study, we examined basal and stimulated NO production from the vascular endothelium in cyclosporine-treated renal transplant recipients using the technique of forearm venous plethysmography. Methods. In study 1, stimulated NO production was assessed in 9 cyclosporine-treated renal transplant recipients (CsA), 7 azathioprine-treated renal transplant recipients (AZA), and 12 controls, using carbachol (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). In study 2, basal NO production was assessed in 9 cyclosporine-treated patients and 11 controls using l-NMMA (inhibits NO synthase), with norepinephrine as a control vasoconstrictor. Drugs were infused into the nondominant forearm through a sterile 27-gauge needle, and changes in forearm blood flow (FBF) were measured using venous occlusion plethysmography. Results. In study 1, sodium nitroprusside caused a similar dose-dependent increase in FBF in all groups. However, the median (range) percentage increase FBF to carbachol (3 μg/min) was markedly reduced in the CsA patients (188.8; 72.5 to 385.1) compared with AZA patients (378.1; 124.0 to 548.9; P = 0.042) and to controls (303.8; 124.8 to 813.3; P = 0.028). In study 2, the maximum percentage reduction in FBF to l-NMMA (4 μmol/min) was less pronounced in CsA patients (-19.5; -4.7 to -63.1) compared with controls (- 39.5; -15.7 to -52.8; P =... [ABSTRACT FROM AUTHOR]

Kidney dysfunction often leads to reluctance to start or continue life-saving heart failure (HF) therapy. This study sought to examine the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with HF with reduced ejection fraction experiencing significant kidney dysfunction. We pooled individual patient data from the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. The association between MRA treatment and outcomes was assessed according to whether the estimated glomerular filtration rate (eGFR) declined to <30 mL/min/1.73 m2 or not. The primary outcome was cardiovascular death or HF hospitalization. Among 4,355 patients included, 295 (6.8%) experienced a deterioration of eGFR after randomization to <30 mL/min/1.73 m2. These patients had more impaired baseline cardiac and kidney function (eGFR 47.3 ± 13.4 mL/min/1.73 m2 vs 70.5 ± 21.8 mL/min/1.73 m2) and had a higher risk of the primary outcome than patients without eGFR deterioration (HR: 2.49; 95% CI: 2.01-3.08; P < 0.001). However, the risk reduction in the primary outcome with MRA therapy was similar in those who experienced a decrease in eGFR to <30 mL/min/1.73 m2 (HR: 0.65; 95% CI: 0.43-0.99) compared with those who did not (HR: 0.63; 95% CI: 0.56-0.71) (P interaction = 0.87). In patients with a decrease in eGFR to <30 mL/min/1.73 m2, 21 fewer individuals (per 100 person-years) experienced the primary outcome with MRA treatment, vs placebo, compared with an excess of 3 more patients with severe hyperkalemia (>6.0 mmol/L). Because patients experiencing a decrease in eGFR to <30 mL/min/1.73 m2 are at very high risk, the absolute risk reduction with an MRA in these patients is large and this decline in eGFR should not automatically lead to treatment discontinuation. [Display omitted] [ABSTRACT FROM AUTHOR]

The Kidney Disease Improving Global Outcomes (KDIGO) classification integrates both estimated glomerular filtration rate and urine-albumin-creatinine ratio to stratify risk more comprehensively in patients with chronic kidney disease. There are limited data assessing whether this classification system is associated with prognosis and treatment response in heart failure populations. The aim of this study was to evaluate the relative treatment effects of sacubitril/valsartan across the KDIGO risk categories in patients with HFrEF. PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) was a global randomized controlled trial evaluating sacubitril/valsartan vs enalapril in patients with heart failure with reduced ejection fraction (HFrEF). Patients were classified according to low, moderate, and high/very high KDIGO risk. Treatment responses were assessed according to baseline KDIGO risk. The primary outcome was a composite of cardiovascular (CV) death or heart failure hospitalization. A renal composite outcome was defined as sustained decline in estimated glomerular filtration rate by ≥40% or end-stage kidney disease. Among 1,910 (23% of total) participants with available data, 42%, 32%, and 26% were classified as low, moderate, and high/very high KDIGO risk, respectively. Patients in the highest KDIGO risk categories experienced the highest rates of the primary composite outcome (7.6 per 100 person-years [95% CI: 6.5-9.0 per 100 person-years], 9.4 per 100 person-years [95% CI: 7.9-11.2 per 100 person-years], and 14.9 per 100 person-years [95% CI: 12.7-17.6 per 100 person-years]; P < 0.001). Sacubitril/valsartan had a similar safety profile and demonstrated consistent effects on the risk of both the primary outcome (P Interaction = 0.31) and the renal composite outcome (P Interaction = 0.50) across the spectrum of KDIGO risk. One in 4 patients with HFrEF were classified as at least high KDIGO kidney risk; these individuals faced concordantly the highest risks of CV events. Sacubitril/valsartan exhibited consistent CV and kidney protective benefits as well as safety across the spectrum of baseline kidney risk. These data further support initiation of sacubitril/valsartan in HFrEF across a broad range of kidney risk. (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF]; NCT01035255) [Display omitted] [ABSTRACT FROM AUTHOR]

Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (−3.8 days [95% CI: −6.6 to −1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire–overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization −0.9 days [−0.7%] at 120 days, −2.3 days [−1.0%] at 240 days, and −4.8 days [−1.3%] at 360 days). Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124) [Display omitted] [ABSTRACT FROM AUTHOR]

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. 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. 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. 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 (P interaction = 0.019) such that patients with LVEF ≥60% experienced substantially higher treatment-related risks of hypotension. 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) [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: Heart failure is a fatal complication of type 2 diabetes but little is known about its incidence in people with impaired glucose tolerance (IGT). We used Acarbose Cardiovascular Evaluation (ACE) trial data to identify predictors of hospitalisation for heart failure (hHF) or cardiovascular (CV) death in patients with coronary heart disease (CHD) and IGT randomised to acarbose or placebo.Methods: Independent hHF/CV death risk factors were determined using Cox proportional hazards models, with participants censored at first hHF event, CV death, or end of follow-up.Results: During median 5-year follow-up, the composite outcome of hHF/CV death occurred in 393 (6.0%) participants. Significant hHF/CV death multivariate predictors were higher age and plasma creatinine, and prior heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF) and stroke. Acarbose, compared with placebo, did not reduce hHF/CV death (hazard ratio [HR] 0.89, 95% CI 0.64-1.24, P = 0.48) or hHF (HR 0.90, 95% CI 0.74-1.10, P = 0.32).Conclusions: Patients with CHD and IGT at greater risk of hHF/CV death were older with higher plasma creatinine, prior HF, MI, AF or stroke. Addition of acarbose to optimised CV therapy to reduce post-prandial glucose excursions did not reduce the risk of hHF/CV death or hHF.Clinical Trial Registration: ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513. [ABSTRACT FROM AUTHOR]

Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non–ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients. The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI. The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type. Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53). Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727) [Display omitted] [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline recommended in the management of heart failure (HF). Although these therapies can be initiated even in patients with comorbid chronic kidney disease, some patients may face deterioration of kidney function over time. In this study, the authors sought to examine the safety and efficacy of continuing SGLT2 inhibitors in HF when the estimated glomerular filtration rate (eGFR) falls below thresholds for initiation. Associations between a deterioration of eGFR to <25 mL/min/1.73 m2, efficacy, and safety outcomes and treatment with dapagliflozin were evaluated in time-updated Cox proportional hazard models in a participant-level pooled analysis of the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. Among 11,007 patients, 347 (3.2%) experienced a deterioration of eGFR to <25 mL/min/1.73 m2 at least once in follow-up. These patients had a higher risk of the primary composite outcome (HR: 1.87; 95% CI: 1.48-2.35; P < 0.001). The risk of the primary outcome was lower with dapagliflozin compared with placebo among patients who did (HR: 0.53; 95% CI: 0.33-0.83) as well as did not (HR: 0.78; 95% CI: 0.72-0.86) experience deterioration of eGFR to <25 mL/min/1.73 m2 (P interaction = 0.17). The risk of safety outcomes, including drug discontinuation, was higher among patients with deterioration of eGFR to <25 mL/min/1.73 m2; however, rates remained similar between treatment groups including among those who remained on study drug. Patients with deterioration of eGFR to <25 mL/min/1.73 m2 had elevated risks of cardiovascular outcomes yet appeared to benefit from continuation of dapagliflozin with no excess in safety outcomes between treatment groups. The benefit-to-risk ratio may favor continuation of dapagliflozin treatment in patients with HF experiencing deterioration of kidney function. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124 ; and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213) [Display omitted] [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists (GLP-1 RAs) reduce adverse cardiovascular outcomes in type 2 diabetes (T2D). However, the efficacy of combination therapy is unclear. The aim of this study was to evaluate the effects of GLP-1 RAs on cardiovascular outcomes in patients with T2D treated with or without SGLT2 inhibitors. Post hoc analysis of Harmony Outcomes (Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease) evaluating the effect of albiglutide in T2D with cardiovascular disease by background SGLT2 inhibitor use. Additionally, a trial-level meta-analysis of Harmony Outcomes and AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes), which evaluated T2D with cardiovascular or renal disease, was performed, combining the treatment effect estimates according to SGLT2 inhibitor use. Of the 9,462 participants in Harmony Outcomes, 575 (6.1%) were treated with SGLT2 inhibitors at baseline. The effect of albiglutide on reducing the composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events) was consistent with or without SGLT2 inhibitors (P interaction = 0.70). The effect of albiglutide on secondary outcomes and adverse events was not modified by SGLT2 inhibitors. A meta-analysis of Harmony Outcomes and AMPLITUDE-O included 13,538 patients, of whom 1,193 (8.8%) used SGLT2 inhibitors. Compared to placebo, GLP1-RAs reduced major adverse cardiovascular events without effect modification by SGLT2 inhibitor use (HR: 0.77; 95% CI: 0.68-0.87 without SGLT2 inhibitors; and HR: 0.78; 95% CI: 0.49-1.24 with SGLT2 inhibitors) (P for interaction = 0.95) and reduced heart failure hospitalization (HR: 0.72; 95% CI: 0.55-0.92 vs HR: 0.34; 95% CI: 0.12-0.96) (P for interaction = 0.18). In patients with T2D and cardiovascular disease, GLP-1 RAs reduced cardiovascular events independently of SGLT2 inhibitor use. These findings suggest that the combination of GLP-1 RAs with SGLT2 inhibitors may further reduce cardiovascular risk. Clinical trials with combination therapy are needed. [Display omitted] [ABSTRACT FROM AUTHOR]

Limited data exist to characterize novel measures of right ventricular (RV) function and the coupling to pulmonary circulation in patients with heart failure and preserved left ventricular ejection fraction (HFpEF). This study sought to assess the clinical implications of RV function, the association with N-terminal pro–B-type natriuretic peptide, and the risk for adverse events among patients with HFpEF. This study analyzed measures of RV function by assessing absolute RV free wall longitudinal strain (RVFWLS) and its ratio to estimated pulmonary artery systolic pressure (PASP) (RVFWLS/PASP ratio) in 528 patients (mean age 74 ± 8 years, 56% female) with adequate echocardiographic images quality enrolled in the PARAGON-HF trial. Associations with baseline N-terminal pro–B-type natriuretic peptide and with total HF hospitalizations and cardiovascular death were assessed, after accounting for confounders. Overall, 311 patients (58%) had evidence of RV dysfunction, defined as absolute RVFWLS <20%, and among the 388 patients (73%) with normal tricuspid annular planar systolic excursion and RV fractional area change, more than one-half showed impaired RV function. Lower values of RVFWLS and RVFWLS/PASP ratios were significantly associated with higher circulating N-terminal pro–B-type natriuretic peptide. With a median follow-up of 2.8 years, there were 277 total HF hospitalizations and cardiovascular deaths. Both absolute RVFWLS (HR: 1.39; 95% CI: 1.05-1.83; P = 0.018) and RVFWLS/PASP ratio (HR: 1.43; 95% CI: 1.13-1.80; P = 0.002) were significantly associated with the composite outcome. Treatment effect of sacubitril/valsartan was not modified by measures of RV function. Worsening RV function and its ratio to pulmonary pressure is common and significantly associated with an increased risk of HF hospitalizations and cardiovascular death in patients with HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711) [Display omitted] [ABSTRACT FROM AUTHOR]

Some patients with heart failure may experience transient changes in kidney function upon transition to sacubitril/valsartan. Whether such changes portend adverse outcomes or influence long-term treatment benefits with sacubitril/valsartan continuation is unknown. This investigation aimed to evaluate the association between the occurrence of moderate estimated glomerular filtration rate (eGFR) decline (>15%) after initial exposure to sacubitril/valsartan and subsequent cardiovascular outcomes and its treatment benefits in PARADIGM-HF and PARAGON-HF. In sequential run-in phases, patients were titrated to enalapril 10 mg twice daily and then sacubitril/valsartan 97 mg/103 mg twice daily (in PARADIGM-HF) or valsartan 80 mg twice daily and then sacubitril/valsartan 49 mg/51 mg twice daily (in PARAGON-HF). Among randomized participants, 11% in PARADIGM-HF and 10% in PARAGON-HF experienced eGFR decline (>15%) during sacubitril/valsartan run-in. eGFR partially recovered (from nadir to postrandomization week 16) regardless of sacubitril/valsartan continuation or switch to renin-angiotensin system inhibitor (RASi) postrandomization. Initial eGFR decline was not consistently associated with clinical outcomes in either trial. Treatment benefits of sacubitril/valsartan vs RASi on primary outcomes were similar irrespective of run-in eGFR decline in PARADIGM-HF (eGFR decline, HR: 0.69; 95% CI: 0.53-0.90; and no eGFR decline, HR: 0.80; 95% CI: 0.73-0.88; P interaction = 0.32) and PARAGON-HF (eGFR decline, rate ratio [RR]: 0.84; 95% CI: 0.52-1.36 and no eGFR decline, RR: 0.87; 95% CI: 0.75-1.02, P interaction = 0.92). The treatment effect of sacubitril/valsartan remained consistent across a range of eGFR declines. Moderate eGFR decline when transitioning from RASi to sacubitril/valsartan is not consistently associated with adverse outcomes, and its long-term benefits are retained in heart failure across a broad range of eGFR declines. Early eGFR changes should not deter continuation of sacubitril/valsartan or stall uptitration. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711 ; Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitors with Angiotensin-Converting Enzyme Inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Recent guidelines support consideration of sodium-glucose cotransporter-2 inhibitors in the long-term management of heart failure (HF) with mildly reduced or preserved ejection fraction. Patients and clinicians may be interested in the expected lifetime benefits of sodium-glucose cotransporter-2 inhibitors in this population.Objectives: This study aimed to estimate event-free survival gains from long-term use of dapagliflozin in patients with HF with mildly reduced or preserved ejection fraction overall and in clinically relevant subgroups.Methods: In this prespecified analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we applied validated nonparametric age-based methods to extrapolate potential gains in survival free from the primary endpoint (cardiovascular death or worsening HF event) from long-term use of dapagliflozin. Eligible participants had symptomatic HF, left ventricular ejection fraction >40%, elevated natriuretic peptide levels, and structural heart disease. For every year between the ages of 55 and 85 years, we estimated event-free survival using age at randomization rather than time from randomization as the time horizon. Residual lifespan free from a primary endpoint was estimated based on area under the survival curve in each arm.Results: Among 6,263 participants, mean survival free from the primary endpoint for a 65-year-old participant was 12.1 years (95% CI: 11.0-13.2 years) with dapagliflozin and 9.7 years (95% CI: 8.8-10.7 years) with placebo, representing a 2.3-year (95% CI: 0.9-3.8 years) event-free survival gain (P = 0.002). Treatment gains in survival free from the primary endpoint ranged from 2.0 years (95% CI: -0.6 to 4.6 years) in a 55-year-old to 1.2 years (95% CI: -0.1 to 2.4 years) in a 75-year-old patient. Mean event-free survival was greater with dapagliflozin than with placebo across all 14 subgroups.Conclusions: Treatment with dapagliflozin is projected to extend event-free survival by up to 2.0 to 2.5 years among middle-aged and older individuals with HF with mildly reduced or preserved ejection fraction. (DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure]; NCT03619213). [ABSTRACT FROM AUTHOR]

Background: Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure.Objectives: This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF).Methods: Patients admitted for AHF with left ventricular ejection fraction ≤40%, dyspnea, and elevated plasma concentrations of natriuretic peptides were randomized to receive a double-blind, 48-h intravenous infusion of placebo or OM in 3 sequential, escalating-dose cohorts.Results: In 606 patients, OM did not improve the primary endpoint of dyspnea relief (3 OM dose groups and pooled placebo: placebo, 41%; OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; p = 0.33) or any of the secondary outcomes studied. In supplemental, pre-specified analyses, OM resulted in greater dyspnea relief at 48 h (placebo, 37% vs. OM, 51%; p = 0.034) and through 5 days (p = 0.038) in the high-dose cohort. OM exerted plasma concentration-related increases in left ventricular systolic ejection time (p < 0.0001) and decreases in end-systolic dimension (p < 0.05). The adverse event profile and tolerability of OM were similar to those of placebo, without increases in ventricular or supraventricular tachyarrhythmias. Plasma troponin concentrations were higher in OM-treated patients compared with placebo (median difference at 48 h, 0.004 ng/ml), but with no obvious relationship with OM concentration (p = 0.95).Conclusions: In patients with AHF, intravenous OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group. (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure [ATOMIC-AHF]; NCT01300013). [ABSTRACT FROM AUTHOR]

Predischarge risk stratification of patients with acute heart failure (AHF) could facilitate tailored treatment and follow-up, however, simple scores to predict short-term risk for HF readmission or death are lacking. We sought to develop a congestion-focused risk score using data from a prospective, two-center observational study in adults hospitalized for AHF. Laboratory data were collected on admission. Patients underwent physical examination, 4-zone, and in a subset 8-zone, lung ultrasound (LUS), and echocardiography at baseline. A second LUS was performed before discharge in a subset of patients. The primary endpoint was the composite of HF hospitalization or all-cause death. Among 350 patients (median age 75 years, 43% women), 88 participants (25%) were hospitalized or died within 90 days after discharge. A stepwise Cox regression model selected four significant independent predictors of the composite outcome, and each was assigned points proportional to its regression coefficient: NT-proBNP ≥2000 pg/mL (admission) (3 points), systolic blood pressure < 120 mmHg (baseline) (2 points), left atrial volume index ≥60 mL/m2 (baseline) (1 point) and ≥ 9 B-lines on predischarge 4-zone LUS (3 points). This risk score provided adequate risk discrimination for the composite outcome (HR 1.48 per 1 point increase, 95% confidence interval: 1.32–1.67, p < 0.001, C-statistic: 0.70). In a subset of patients with 8-zone LUS data (n = 176), results were similar (C-statistic: 0.72). A four-variable risk score integrating clinical, laboratory and ultrasound data may provide a simple approach for risk discrimination for 90-day adverse outcomes in patients with AHF if validated in future investigations. [Display omitted] • We identified key predictors of 90-day heart failure readmission and death in patients with acute heart failure. • Risk predictors included admission NT-proBNP, baseline systolic blood pressure, baseline left atrial size and B-lines predischarge. • We developed a 4-variable score to predict the risk of the 90-day composite outcome. [ABSTRACT FROM AUTHOR]

With the current landscape of approved therapies for heart failure (HF), there is a need to determine the role of a standard background therapy against which novel therapies are studied. The Heart Failure Collaboratory convened a multistakeholder group of clinical investigators, clinicians, patients, government representatives including U.S. Food and Drug Administration and National Institutes of Health participants, payers, and industry in March 2021 to discuss whether standardization of background drug therapy is necessary in clinical trials in patients with HF. The current paper summarizes the discussion and provides potential conceptual approaches, with a focus on therapies indicated for HF with reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Abstract: Background: Atrial fibrillation (AF) represents an increasing public health challenge with profound social and economic implications. Methods: A comprehensive synthesis and review of the AF literature was performed. Overall, key findings from 182 studies were used to describe the indicative scope and impact of AF from an individual to population perspective. Results: There are many pathways to AF including advancing age, cardiovascular disease and increased levels of obesity/metabolic disorders. The reported population prevalence of AF ranges from 2.3%–3.4% and historical trends reflect increased AF incidence. Estimated life-time risk of AF is around 1 in 4. Primary care contacts reflect whole population trends: AF-related case-presentations increase from less than 0.5% in those aged 40years or less to 6–12% for those aged 85years or more. Globally, AF-related hospitalisations (primary or secondary diagnosis) showed an upward trend (from ~35 to over 100 admissions/10,000 persons) during 1996 to 2006. The estimated cost of AF is greater than 1% of health care expenditure and rising with hospitalisations the largest contributor. For affected individuals, quality of life indices are poor and AF confers an independent 1.5 to 2.0-fold probability of death in the longer-term. AF is also closely linked to ischaemic stroke (3- to 5-fold risk), chronic heart failure (up to 50% develop AF) and acute coronary syndromes (up to 25% develop AF) with consistently worse outcomes reported with concurrent AF. Future projections predict at least a doubling of AF cases by 2050. Summary: AF represents an evolving, global epidemic providing considerable challenges to minimise its impact from an individual to whole society perspective. [Copyright &y& Elsevier]