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Aims: Cardiovascular‐kidney‐metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown. Methods and results: In this PARAGON‐HF post‐hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end‐stage kidney disease, or kidney‐related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33–4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (pinteraction = 0.75), CV death (pinteraction = 0.82), total HF hospitalizations (pinteraction = 0.67), and the composite kidney endpoint (pinteraction = 0.99). Conclusions: Cardiovascular‐kidney‐metabolic multimorbidity was common in PARAGON‐HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden. Clinical Trial Registration: ClinicalTrials.gov NCT01920711. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does the benefit of renin-angiotensin system (RAS) blockers in patients with heart failure and reduced ejection fraction differ between Black and non-Black patients? Findings: In this meta-analysis involving more than 16 000 patients from 5 randomized trials, the mortality benefit from RAS blockade was similar in Black and non-Black patients. Although the relative risk reduction in hospitalizations for heart failure was smaller in Black patients, the absolute benefit was comparable in the 2 groups given the greater incidence of hospitalization in Black patients. Meaning: RAS blockers are effective at improving cardiovascular outcomes in Black and non-Black patients with heart failure. Importance: Concerns have arisen that renin-angiotensin system (RAS) blockers are less effective in Black patients than non-Black patients with heart failure and reduced ejection fraction (HFrEF). Objective: To determine whether the effects of RAS blockers on cardiovascular outcomes differ between Black patients and non-Black patients with HFrEF. Data Sources: MEDLINE and Embase databases through December 31, 2023. Study Selection: Randomized trials investigating the effect of RAS blockers on cardiovascular outcomes in adults with HFrEF that enrolled Black and non-Black patients. Data Extraction and Synthesis: Individual-participant data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-analyses Independent Personal Data (PRISMA-IPD) reporting guidelines. Effects were estimated using a mixed-effects model using a 1-stage approach. Main Outcome and Measure: The primary outcome was first hospitalization for HF or cardiovascular death. Results: The primary analysis, based on the 3 placebo-controlled RAS inhibitor monotherapy trials, included 8825 patients (9.9% Black). Rates of death and hospitalization for HF were substantially higher in Black than non-Black patients. The hazard ratio (HR) for RAS blockade vs placebo for the primary composite was 0.84 (95% CI, 0.69-1.03) in Black patients and 0.73 (95% CI, 0.67-0.79) in non-Black patients (P for interaction =.14). The HR for first HF hospitalization was 0.89 (95% CI, 0.70-1.13) in Black patients and 0.62 (95% CI, 0.56-0.69) in non-Black patients (P for interaction =.006). Conversely, the corresponding HRs for cardiovascular death were 0.83 (95% CI, 0.65-1.07) and 0.84 (95% CI, 0.77-0.93), respectively (P for interaction =.99). For total hospitalizations for HF and cardiovascular deaths, the corresponding rate ratios were 0.82 (95% CI, 0.66-1.02) and 0.72 (95% CI, 0.66-0.80), respectively (P for interaction =.27). The supportive analyses including the 2 trials adding an angiotensin receptor blocker to background angiotensin-converting enzyme inhibitor treatment (n = 16 383) gave consistent findings. Conclusions and Relevance: The mortality benefit from RAS blockade was similar in Black and non-Black patients. Despite the smaller relative risk reduction in hospitalization for HF with RAS blockade in Black patients, the absolute benefit in Black patients was comparable with non-Black patients because of the greater incidence of this outcome in Black patients. This meta-analysis assesses whether Black patients with heart failure and reduced ejection fraction respond differently than patients of other races to renin-angiotensin system (RAS) blockade by examining individual patient data from randomized clinical trials. [ABSTRACT FROM AUTHOR]

Aims: Red cell distribution width (RDW) is a strong prognostic marker in patients with heart failure (HF) and reduced ejection fraction and other conditions. However, very little is known about its prognostic significance in HF with preserved ejection fraction. We examined the relationship between RDW and outcomes and the effect of sacubitril/valsartan, compared with valsartan, on RDW and clinical outcomes in PARAGON‐HF. Methods and results: PARAGON‐HF enrolled patients with a left ventricular ejection fraction of ≥45%, structural heart disease, and elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). The primary endpoint was a composite of total HF hospitalizations and cardiovascular deaths. Median RDW at randomization was 14.1% (interquartile range 13.5–15.0%). Patients with higher RDW levels were more often men and had more comorbidity, a higher heart rate and NT‐proBNP concentration, more advanced New York Heart Association class, and worse Kansas City Cardiomyopathy Questionnaire scores. There was a graded relationship between quartiles of RDW at randomization and the primary endpoint, with a significantly higher risk associated with increasing RDW, even after adjustment for NT‐proBNP and other prognostic variables {Quartile 1, reference; Quartile 2, rate ratio 1.03 [95% confidence interval (CI) 0.83 to 1.28]; Quartile 3, 1.25 [1.01 to 1.54]; Quartile 4, 1.70 [1.39 to 2.08]}. This association was seen for each of the secondary outcomes, including cardiovascular and all‐cause death. Compared with valsartan, sacubitril/valsartan reduced RDW at 48 weeks [mean change −0.09 (95% CI −0.15 to −0.02)]. The effect of sacubitril/valsartan vs. valsartan was not significantly modified by RDW levels at randomization. Conclusions: RDW, a routinely available and inexpensive biomarker, provides incremental prognostic information when added to established predictors. Compared with valsartan, sacubitril/valsartan led to a small reduction in RDW. [ABSTRACT FROM AUTHOR]

Large-scale clinical trials are essential in cardiology and require rapid, accurate publication, and dissemination. Whereas conference presentations, press releases, and social media disseminate information quickly and often receive considerable coverage by mainstream and healthcare media, they lack detail, may emphasize selected data, and can be open to misinterpretation. Preprint servers speed access to research manuscripts while awaiting acceptance for publication by a journal, but these articles are not formally peer-reviewed and sometimes overstate the findings. Publication of trial results in a major journal is very demanding but the use of existing checklists can help accelerate the process. In case of rejection, procedures such as easing formatting requirements and possibly carrying over peer-review to other journals could speed resubmission. Secondary publications can help maximize benefits from clinical trials; publications of secondary endpoints and subgroup analyses further define treatment effects and the patient populations most likely to benefit. These rely on data access, and although data sharing is becoming more common, many challenges remain. Beyond publication in medical journals, there is a need for wider knowledge dissemination to maximize impact on clinical practice. This might be facilitated through plain language summary publications. Social media, websites, mainstream news outlets, and other publications, although not peer-reviewed, are important sources of medical information for both the public and for clinicians. This underscores the importance of ensuring that the information is understandable, accessible, balanced, and trustworthy. This report is based on discussions held on December 2021, at the 18th Global Cardiovascular Clinical Trialists meeting, involving a panel of editors of some of the top medical journals, as well as members of the lay press, industry, and clinical trialists. [ABSTRACT FROM AUTHOR]

Aims Stroke is an important problem in patients with heart failure (HF), but the intersection between the two conditions is poorly studied across the range of ejection fraction. The prevalence of history of stroke and related outcomes were investigated in patients with HF. Methods and results Individual patient meta-analysis of seven clinical trials enrolling patients with HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Of the 20 159 patients with HFrEF, 1683 (8.3%) had a history of stroke, and of the 13 252 patients with HFpEF, 1287 (9.7%) had a history of stroke. Regardless of ejection fraction, patients with a history of stroke had more vascular comorbidity and worse HF. Among those with HFrEF, the incidence of the composite of cardiovascular death, HF hospitalization, stroke, or myocardial infarction was 18.23 (16.81–19.77) per 100 person-years in those with prior stroke vs. 13.12 (12.77–13.48) in those without [hazard ratio 1.37 (1.26–1.49), P < 0.001]. The corresponding rates in patients with HFpEF were 14.16 (12.96–15.48) and 9.37 (9.06–9.70) [hazard ratio 1.49 (1.36–1.64), P < 0.001]. Each component of the composite was more frequent in patients with stroke history, and the risk of future stroke was doubled in patients with prior stroke. Among patients with prior stroke, 30% with concomitant atrial fibrillation were not anticoagulated, and 29% with arterial disease were not taking statins; 17% with HFrEF and 38% with HFpEF had uncontrolled systolic blood pressure (≥140 mmHg). Conclusion Heart failure patients with a history of stroke are at high risk of subsequent cardiovascular events, and targeting underutilization of guideline-recommended treatments might be a way to improve outcomes in this high-risk population. [ABSTRACT FROM AUTHOR]

Aim: Mortality from acute myocardial infarction (AMI) has declined, increasing the pool of survivors at risk of later development of heart failure (HF). However, coronary reperfusion limits infarct size and secondary prevention therapies have improved. In light of these competing influences, we examined long‐term trends in the risk of HF hospitalization (HFH) following a first AMI occurring in Scotland over 25 years. Methods and results: All patients in Scotland discharged alive after a first AMI between 1991 and 2015 were followed until a first HFH or death until the end of 2016 (minimum follow‐up 1 year, maximum 26 years). A total of 175 672 people with no prior history of HF were discharged alive after a first AMI during the period of study. A total of 21 445 (12.2%) patients had a first HFH during a median follow‐up of 6.7 years. Incidence of HFH (per 1000 person‐years) at 1 year following discharge from a first AMI decreased from 59.3 (95% confidence interval [CI] 54.2–64.7) in 1991 to 31.3 (95% CI 27.3–35.8) in 2015, with consistent trends seen for HF occurring within 5 and 10 years. Accounting for the competing risk of death, the adjusted risk of HFH at 1 year after discharge decreased by 53% (95% CI 45–60%), with similar decreases at 5 and 10 years. Conclusion: The incidence of HFH following AMI in Scotland has decreased since 1991. These trends suggest that better treatment of AMI and secondary prevention are having an impact on the risk of HF at a population level. [ABSTRACT FROM AUTHOR]

Keywords: GLP-1 receptor agonists; lixisentatide; natriuretic peptides; randomized controlled trial EN GLP-1 receptor agonists lixisentatide natriuretic peptides randomized controlled trial 1125 1129 5 03/08/23 20230401 NES 230401 BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) lower glucose, weight and blood pressure, and reduce cardiovascular and kidney outcomes in people with type 2 diabetes (T2D).[1], [2], [3] Although mechanisms for their effects remain unclear, small recent studies have reported that they may reduce natriuretic peptides.[4] B-type natriuretic peptide (BNP) and its inactive precursor N-terminal-pro BNP (NT-proBNP) were measured at baseline and follow-up in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial. GLP-1 receptor agonists, lixisentatide, natriuretic peptides, randomized controlled trial 2 Abbreviation: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; NT-proBNP, N terminal, pro-hormone B-type natriuretic peptide. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. [Extracted from the article]

Aims: Several patients with heart failure and reduced ejection fraction (HFrEF) do not receive renin–angiotensin–aldosterone system (RAAS) inhibitors at the recommended dose or at all, frequently due to actual or feared hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is an orally administered non‐absorbed intestinal potassium binder proven to lower serum potassium concentrations. Methods and results: PRIORITIZE‐HF was an international, multicentre, parallel‐group, randomized, double‐blind, placebo‐controlled study to evaluate the benefits and risks of using SZC to intensify RAAS inhibitor therapy. Patients with symptomatic HFrEF were eligible and randomly assigned to receive SZC 5 g or placebo once daily for 12 weeks. Doses of study medication and RAAS inhibitors were titrated during the treatment period. The primary endpoint was the proportion of patients at 12 weeks in the following categories: (i) any RAAS inhibitor at less than target dose, and no MRA; (ii) any RAAS inhibitor at target dose and no MRA; (ii) MRA at less than target dose; and (iv) MRA at target dose. Due to challenges in participant management related to the COVID‐19 pandemic, the study was prematurely terminated with 182 randomized patients. There was no statistically significant difference in the distribution of patients by RAAS inhibitor treatment categories at 3 months (P = 0.43). The proportion of patients at target MRA dose was numerically higher in the SZC group (56.4%) compared with the placebo group (47.0%). Overall, SZC was well tolerated. Conclusions: PRIORITIZE‐HF was terminated prematurely due to COVID‐19 and did not demonstrate a statistically significant increase in the intensity of RAAS inhibitor therapies with the potassium‐reducing agent SZC compared with placebo. [ABSTRACT FROM AUTHOR]

Aims Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown. Methods and results An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200–1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17–1.31 and HR: 1.16, 95% CI: 1.05–1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90–1.06 and HR: 0.87, 95% CI: 0.39–1.92, respectively). Conclusion Growth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS. [ABSTRACT FROM AUTHOR]

Aims: Spironolactone is currently used in a large proportion of patients with heart failure and preserved ejection fraction (HFpEF), yet its effect on cardiac structure and function in a large population has not been well established. The aim of this study was to evaluate the impact of spironolactone on key echocardiographic parameters in HFpEF. Methods and results: An individual‐patient‐data meta‐analysis of three randomized trials (HOMAGE, Aldo‐DHF, and TOPCAT) was performed comparing spironolactone (9–12 month exposure) to placebo (or control) for the changes in left atrial volume index (LAVi), left ventricular mass index (LVMi), interventricular septum (IVS) thickness, E/e′ ratio, and left ventricular ejection fraction (LVEF) among patients with stage B (HOMAGE) or C (Aldo‐DHF and TOPCAT) HFpEF. Analysis of covariance was used to test the effect of spironolactone on echocardiographic changes. A total of 984 patients were included in this analysis: 452 (45.9%) from HOMAGE, 398 (40.4%) from Aldo‐DHF, and 134 (13.6%) from TOPCAT. The pooled‐cohort patient's median age was 71 (66–77) years and 39% were women. Median LAVi was 29 (24–35) ml/m2, LVMi 100 (84–118) g/m2, IVS thickness 12 (10–13) mm, E/e′ ratio 11 (9–13), and LVEF 64 (59–69)%. Spironolactone reduced LAVi by −1.1 (−2.0 to −0.1) ml/m2 (p = 0.03); LVMi by −3.6 (−6.4 to −0.8) g/m2 (p = 0.01); IVS thickness by −0.2 (−0.3 to −0.1) mm (p = 0.01); E/e′ ratio by −1.3 (−2.4 to −0.2) (p = 0.02); and increased LVEF by 1.7 (0.8–2.6)% (p < 0.01). No treatment‐by‐study heterogeneity was found except for E/e′ ratio with a larger effect in Aldo‐DHF and TOPCAT (interaction p < 0.01). Conclusions: Spironolactone improved cardiac structure and function of patients with HFpEF. [ABSTRACT FROM AUTHOR]

Aims: As sacubitril/valsartan may potentiate early natriuresis, expert consensus documents recommend diuretic dose reduction on first initiation. However, there are limited data on the effects of sacubitril/valsartan on the background of varying diuretic regimens or on diuretic requirements over time in heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results: In this post hoc analysis of PARAGON‐HF, of the 4796 patients, background diuretic therapy was distributed as follows: 341 (7%) on no diuretic, 698 (15%) on non‐loop diuretic, and 3757 (78%) were on loop diuretics (1255, 1589, and 913 were on <40, 40 and >40 mg furosemide equivalent doses, respectively). The primary composite outcome of total HF hospitalizations and cardiovascular death was analysed using semiparametric proportional rates methods. The cumulative incidence of the primary composite outcome (first events) was lowest in patients on no diuretic and highest in those on >40 mg of loop diuretic (p < 0.001). The effects of sacubitril/valsartan (vs. valsartan) on the primary composite outcome (recurrent events) did not significantly vary by baseline diuretic use (pinteraction = 0.65). Treatment effects on safety outcomes were similar across diuretic categories. Sacubitril/valsartan reduced new loop diuretic initiations over the course of the trial (hazard ratio 0.83; 95% confidence interval 0.68–1.00, p = 0.055), with similar mean loop diuretic dose and rates of diuretic discontinuation between treatment groups in follow‐up. Patients randomized to sacubitril/valsartan experienced a slight early reduction in diuretic initiation or dose escalation at 30 days after initiation (net reduction 1.7%, p = 0.02), but these differences were not sustained beyond this timepoint. Conclusions: Patients with HFpEF on higher baseline diuretic doses were at heightened risk of HF events, but similarly benefited from sacubitril/valsartan with a consistent safety profile across a range of diuretic doses. Initiation of sacubitril/valsartan was associated with modestly lower new loop diuretic requirement in follow‐up. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is associated with poor health‐related quality of life (HRQL). Patients with HF with preserved ejection fraction (HFpEF) have similar HRQL impairment as those with reduced ejection fraction. This study describes the impact of sacubitril/valsartan on HRQL in patients with HFpEF enrolled in the PARAGON‐HF trial. Methods and results: Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol (EQ‐5D) at randomization, 4, 8 months, and annually thereafter. Changes in HRQL scores were evaluated using repeated measures models adjusted for treatment, baseline values and region. The pre‐specified principal efficacy assessment was at 8 months at which time patients randomized to sacubitril/valsartan had borderline higher KCCQ clinical summary score (CSS) with least squares mean (LSM) adjusted difference of 1.0 (95% confidence interval [CI] 0.0, 2.1; p = 0.051). Including all visits up to 36 months, the LSM difference in KCCQ‐CSS favoured sacubitril/valsartan with average adjusted difference of 1.1 (95% CI 0.1, 2.0; p = 0.034). Patients treated with sacubitril/valsartan had greater odds of clinically meaningful improvement (≥5‐point increase) in KCCQ‐CSS (odds ratio 1.31; 95% CI 1.06, 1.61) at 8 months. At 8 months, there was no significant difference in the EQ visual analogue scale between the treatment arms, but sacubitril/valsartan was associated with higher EQ‐5D utility score (US‐based) with LSM adjusted difference of 0.01 (95% CI 0.00, 0.02; p = 0.019). Conclusion: Compared with valsartan, sacubitril/valsartan had a borderline benefit on KCCQ‐CSS at 8 months in patients with HFpEF. This benefit became more significant when data from all visits up to 36 months were included. This modest overall benefit was also supported by greater odds of patients reporting a clinically meaningful improvement in HRQL with sacubitril/valsartan. [ABSTRACT FROM AUTHOR]

Aims In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. Methods and results dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1–3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75–1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65–0.96) for myocardial infarction, 0.92 (95% CI 0.64–1.33) for stroke, 1.21 (95% CI 0.91–1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60–9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70–0.98). Conclusion Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. Clinical Trial Registration Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939 [ABSTRACT FROM AUTHOR]

Aims: Worsening renal function may impact long-term outcomes in heart failure (HF). However, little is known about the longitudinal trajectories in renal function in relation to HF hospitalization or how this high-risk clinical event impacts renal outcomes.Methods and Results: In PARAGON-HF, we evaluated the association between recency of prior HF hospitalization (occurring pre-randomization) and subsequent first renal composite outcome: (i) time to ≥50% decline in estimated glomerular filtration rate (eGFR); (ii) development of end-stage renal disease; or (iii) death attributable to renal causes. A total of 2306 (48.1%) patients had a history of prior HF hospitalization. Incident rates of the renal outcome were highest in those most recently hospitalized and decreased with longer time from last hospitalization. Treatment effect on the renal outcome of sacubitril/valsartan versus valsartan was similar between patients with (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.24-0.76) and without (HR 0.63; 95% CI: 0.33-1.18; pinteraction  = 0.39) a prior history of HF hospitalization and appeared consistent regardless of timing of prior hospitalization for HF (pinteraction  = 0.39). Serial eGFR measurements leading up to and after a HF hospitalization (occurring during the study period) and estimated eGFR trajectories using repeated measures regression models with restricted cubic splines were also examined. Patients experiencing a post-randomization HF hospitalization had a significant decline in eGFR prior to hospitalization while patients without HF hospitalization experienced a relatively stable eGFR trajectory (p < 0.001). A change in the rate of decline of eGFR trajectory was observed 12 months preceding a HF hospitalization, and continued in the post-discharge window to 12 months following hospitalization.Conclusions: Heart failure hospitalization denotes increased risk for kidney disease progression which continues following recovery from HF decompensation in patients with HF with preserved ejection fraction.Clinical Trial Registration: PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction), ClinicalTrials.gov NCT01920711. [ABSTRACT FROM AUTHOR]

Aim: The win ratio can incorporate different types of outcomes and enhance statistical power, making it a useful method for analysing composite outcomes in cardiovascular trials. The application of this approach to the PARADISE‐MI trial provides an additional perspective into understanding the effects of sacubitril/valsartan in patients with acute myocardial infarction. Methods and results: We conducted a post‐hoc analysis of the PARADISE‐MI trial, which randomly assigned patients with acute myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril/valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to guideline‐recommended therapy. The principal composite outcome was analysed in the hierarchical order of death due to cardiovascular causes, first hospitalization for heart failure, and first outpatient episode of symptomatic heart failure. We included events confirmed by the clinical events classification (CEC) committee as well as events identified by investigators that did not meet study definitions. Results were analysed by the unmatched win‐ratio method. A win ratio that exceeds 1.00 reflects a better outcome. A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril/valsartan and 2831 to receive ramipril. The hierarchical analysis of the principal composite outcome demonstrated a larger number of wins (1 265 767 [15.7%]) than losses (1 079 502 [13.4%]) in the sacubitril/valsartan group (win ratio of 1.17, 95% confidence interval [CI] 1.03–1.33; p = 0.015). Sensitivity analyses using alternative definitions of the composite outcome showed results similar to those of the principal analysis, except for analysis restricted to events that met CEC definitions (win ratio of 1.11, 95% CI 0.96–1.30; p = 0.16). Conclusion: In this post‐hoc analysis of the PARADISE‐MI trial using the win ratio and including investigator‐identified events not having CEC confirmation, sacubitril/valsartan was superior to ramipril among high‐risk survivors of acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Aims: Steroidal mineralocorticoid receptor antagonists (MRAs) form a cornerstone of the management of heart failure (HF), but little is known about the long-term effects of MRA therapy on kidney function. We evaluated acute and chronic estimated glomerular function (eGFR) slopes in the two largest completed trials testing steroidal MRAs in chronic HF.Methods and Results: We conducted parallel post hoc eGFR slope analyses in two multinational, double-blind randomized, placebo-controlled trials of steroidal MRAs in chronic HF with reduced ejection fraction (EMPHASIS-HF) and preserved ejection fraction (TOPCAT Americas region). GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. Annual slopes of eGFR were assessed by generalized random coefficient models. Least square mean differences in eGFR slopes between steroidal MRA and placebo arms were assessed. Median follow-up was 1.8 years (EMPHASIS-HF) and 3.3 years (TOPCAT Americas). From baseline to month 4-6 ('acute eGFR slope'), compared to placebo, MRA treatment led to an acute decline in eGFR of -2.4 ml/min/1.73 m2 (95% confidence interval [CI] -3.4 to -1.4; p < 0.001) and -2.0 ml/min/1.73 m2 (95% CI -3.0 to -1.8; p < 0.001) in EMPHASIS-HF and TOPCAT Americas, respectively. From month 4-6 to end of study, there was no difference in 'chronic eGFR slope' between MRA and placebo arms (-0.3 ml/min/1.73 m2 /year [95% CI -1.3 to 0.7; p = 0.53] and 0.1 ml/min/1.73 m2 /year [95% CI -1.4 to 1.7; p = 0.86]) in EMPHASIS-HF and TOPCAT Americas, respectively.Conclusions: Steroidal MRAs result in acute declines in eGFR but do not modify long-term kidney disease trajectories in chronic HF with reduced or preserved ejection fraction.Clinical Trial Registration: EMPHASIS-HF (ClinicalTrials.gov NCT00232180) and TOPCAT (ClinicalTrials.gov NCT00094302). [ABSTRACT FROM AUTHOR]

Aims: Patients with heart failure are at higher risk of progression to end‐stage renal disease (ESRD), regardless of ejection fraction (EF). We assessed the renal effects of angiotensin–neprilysin inhibition in a pooled analysis of 13 195 patients with heart failure with reduced and preserved EF. Methods and results: We combined data from PARADIGM‐HF (EF ≤40%; n = 8399) and PARAGON‐HF (EF ≥45%; n = 4796) in a pre‐specified pooled analysis. We assessed the effect of treatment (sacubitril/valsartan vs. enalapril or valsartan) on a composite of either ≥50% reduction in estimated glomerular filtration rate (eGFR), ESRD, or death from renal causes, in addition to changes in eGFR slope. We assessed whether baseline renal function or EF modified the effect of therapy on renal outcomes. At randomization, eGFR was 68 ± 20 ml/min/1.73 m2 in PARADIGM‐HF and 63 ± 19 ml/min/1.73 m2 in PARAGON‐HF. The composite renal outcome occurred in 70 of 6594 patients (1.1%) in the sacubitril/valsartan group and in 123 of 6601 patients (1.9%) in the valsartan or enalapril group (hazard ratio 0.56, 95% confidence interval [CI] 0.42–0.75; p < 0.001). The mean eGFR change was −1.8 (95% CI −1.9 to −1.7) ml/min/1.73 m2/year for the sacubitril/valsartan group, compared with −2.4 (95% CI −2.5 to −2.2) ml/min/1.73 m2/year for the valsartan or enalapril group. The treatment effect on the composite renal endpoint was not modified by categories of baseline eGFR (p‐interaction = 0.64), but was most pronounced in those with baseline EF between 30% and 60% (p‐interaction = 0.001). Conclusions: In patients with heart failure, sacubitril/valsartan reduced the risk of serious adverse renal outcomes and slowed decline in eGFR, compared with valsartan or enalapril, independent of baseline renal function. [ABSTRACT FROM AUTHOR]

Objective: To use protein biomarkers to identify people with type 2 diabetes at high risk of cardiovascular outcomes and death.Research Design and Methods: Biobanked serum from 4,957 ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial participants was analyzed. Forward-selection Cox models identified independent protein risk factors for major adverse cardiovascular events (MACE) and death that were compared with a previously validated biomarker panel.Results: NT-proBNP and osteoprotegerin predicted both outcomes. In addition, trefoil factor 3 predicted MACE, and angiopoietin-2 predicted death (C = 0.70 and 0.79, respectively, compared with 0.63 and 0.66 for clinical variables alone). These proteins had all previously been identified and validated. Notably, C statistics for just NT-proBNP plus clinical risk factors were 0.69 and 0.78 for MACE and death, respectively.Conclusions: NT-proBNP and other proteins independently predict cardiovascular outcomes in people with type 2 diabetes following acute coronary syndrome. Adding other biomarkers only marginally increased NT-proBNP's prognostic value. [ABSTRACT FROM AUTHOR]

Background: Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. Methods: We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. Results: Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: − 0.24%, 95% CI − 0.33 to − 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62–1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05–2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (Pinteraction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63–0.89, P = 0.001), compared with enalapril or valsartan. Conclusions: Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711 [ABSTRACT FROM AUTHOR]

Aims: Diabetes is associated with a faster rate of renal function decline in patients with heart failure (HF). Sacubitril/valsartan attenuates the deterioration of renal function to a greater extent in patients with diabetes and HF with reduced ejection fraction compared with renin–angiotensin system inhibitors alone. We assessed whether the same may be true in HF with preserved ejection fraction (HFpEF). Methods and results: In the PARAGON‐HF trial in patients with HF and left ventricular ejection fraction of ≥45% (n = 4796), we characterized the effects of sacubitril/valsartan on changes in estimated glomerular filtration rate (eGFR) over a period of 192 weeks, and on the pre‐specified renal composite outcome (eGFR reduction of ≥50%, end‐stage renal disease, or death attributable to renal causes) in patients with (n = 2388) and without diabetes (n = 2408). The decline in eGFR was greater in patients with diabetes than in those without (−2.6 vs. −1.7 ml/min/1.73 m2 per year, p < 0.001), regardless of treatment assignment. Sacubitril/valsartan attenuated decline in eGFR similarly in patients with (−2.2 vs. −2.9 ml/min/1.73 m2 per year, p = 0.001) and without diabetes (−1.5 vs. −2.0 ml/min/1.73 m2 per year, p = 0.006) (pinteraction for difference in eGFR slopes = 0.40). Compared with valsartan, sacubitril/valsartan reduced the renal composite outcome similarly in patients without diabetes (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.19–0.91) and those with diabetes (HR 0.54, 95% CI 0.33–0.89; pinteraction = 0.59), as well as across a range of baseline glycated haemoglobin (pinteraction = 0.71). Conclusion: Sacubitril/valsartan, compared with valsartan, attenuates the decline of eGFR and reduces clinically relevant kidney events similarly among patients with HFpEF with and without diabetes. [ABSTRACT FROM AUTHOR]

Background: Weight loss has been associated with poor outcomes in patients with heart failure (HF). However, few data are available for patients with heart failure with preserved ejection fraction (HFpEF). The impact of weight gain on outcomes has not been frequently reported either. Aims: To study post-randomization weight changes and how these could impact outcomes and the effect of spironolactone in patients with HFpEF enrolled in the TOPCAT-Americas trial (N = 1767). Methods: Mixed-effects regressions and time-updated Cox models to assess the factors associated with weight changes and their impact on subsequent outcomes. Results: Over a median follow-up of 3 years, 824 (47%) patients experienced weight loss ≥ 5% and 390 (22%) experienced weight loss ≥ 10%. Patients experiencing weight loss were older and more frequently women with severe HF symptoms. Spironolactone slightly reduced body weight before 12 months of follow-up: β = − 0.55 (− 0.82 to − 0.29) kg, without effect on weight afterwards: β = 0.01 (− 0.66 to 0.68) kg; treatment-by-time interaction P = 0.0015. Spironolactone did not increase the odds of weight loss but reduced the odds of weight gain. Weight loss ≥ 5% was associated with a higher risk of cardiovascular and all-cause death irrespective of baseline body mass index: HR = 1.47, 95%CI = 1.07–2.01 and HR = 1.84, 95%CI = 1.46–2.31, respectively. Weight gain was not associated with an increased risk of any outcome. Conclusion: Weight loss ≥ 5% was frequent and independently associated with an increased risk of subsequent mortality. Spironolactone induced only slight body weight reductions early after its introduction and up to a maximum of 8–12 months of follow-up. Association between body weight changes and subsequent death. Legend: HR, hazard ratio from time-updated Cox models. Model adjusted on age, sex, race, NYHA class, systolic blood pressure, diabetes, atrial fibrillation, previous myocardial infarction, previous heart failure hospitalization, estimated glomerular filtration rate, diuretic use, and baseline weight. [ABSTRACT FROM AUTHOR]

Aims: We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia Methods and results: Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23–1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38–2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin. Conclusions: In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients. [ABSTRACT FROM AUTHOR]

Aim: Natriuretic peptides (NPs) are now routinely incorporated as key inclusion criteria in clinical trials of heart failure with preserved ejection fraction (HFpEF) as objective measures of risk. An early amendment in PARAGON‐HF required all participants to have elevated NP concentrations, but some were enrolled pre‐amendment, providing a unique opportunity to understand the influence of enrolment pathway in HFpEF clinical trials. Methods and results: Among 4796 participants in PARAGON‐HF, 193 (4.0%) did not meet the final NP‐based enrolment criteria (N‐terminal pro‐B‐type natriuretic peptide >300 pg/ml for patients in sinus rhythm or >900 pg/ml for patients in atrial fibrillation/flutter). These patients had lower rates of the primary endpoint of total heart failure hospitalizations and cardiovascular death as compared with patients meeting final enrolment criteria (8.6 [6.7–11.2] events per 100 patient‐years vs. 14.0 [13.4–14.7] events per 100 patient‐years; p = 0.01). The rate ratio for the treatment effect comparing sacubitril/valsartan with valsartan was 0.85 (95% confidence interval 0.74–0.99; p = 0.04) in those who met final criteria. Conclusions: Natriuretic peptides are an important tool in HFpEF clinical trials to objectively affirm diagnoses and enrich clinical event rates. [ABSTRACT FROM AUTHOR]

Aim There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre-diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre-diabetes in PARAGON-HF. Methods and results Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, <6.0%; (ii) pre-diabetes, 6.0%-6.4%; (iii) diabetes, ≥6.5% or history of diabetes. The primary outcome was a composite of cardiovascular (CV) death and total heart failure hospitalizations (HFH). Of 4796 patients, 50% had diabetes and 18% had pre-diabetes. Compared to patients with normal HbA1c, patients with pre-diabetes and diabetes more often were obese, had a history of myocardial infarction and had lower Kansas City Cardiomyopathy Questionnaire scores, while patients with diabetes had more clinical evidence of congestion, but similar NT-proBNP concentrations. The risks of the primary composite outcome (rate ratio [RR] 1.59, 95% confidence interval [CI] 1.35-1.88), total HFH (RR 1.67, 95% CI 1.39-2.02) and CV death (hazard ratio [HR] 1.35, 95% CI 1.07-1.71) were higher among patients with diabetes, compared to those with normal HbA1c. Patients with pre-diabetes had a higher risk (which was intermediate between that of patients with diabetes and those with normal HbA1c) of the primary outcome (HR 1.27, 95% CI 1.00-1.60) and HFH (HR 1.35, 95% CI 1.03-1.77), but not of CV death (HR 1.02, 95% CI 0.75-1.40). Patients with diabetes treated with insulin had worse outcomes than those not, and those with 'lean diabetes' had similar mortality rates to those with a higher body mass index, but lower rates of HFH. Conclusion Pre-diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01920711. [ABSTRACT FROM AUTHOR]

Aim: There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre‐diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre‐diabetes in PARAGON‐HF. Methods and results: Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, <6.0%; (ii) pre‐diabetes, 6.0%–6.4%; (iii) diabetes, ≥6.5% or history of diabetes. The primary outcome was a composite of cardiovascular (CV) death and total heart failure hospitalizations (HFH). Of 4796 patients, 50% had diabetes and 18% had pre‐diabetes. Compared to patients with normal HbA1c, patients with pre‐diabetes and diabetes more often were obese, had a history of myocardial infarction and had lower Kansas City Cardiomyopathy Questionnaire scores, while patients with diabetes had more clinical evidence of congestion, but similar NT‐proBNP concentrations. The risks of the primary composite outcome (rate ratio [RR] 1.59, 95% confidence interval [CI] 1.35–1.88), total HFH (RR 1.67, 95% CI 1.39–2.02) and CV death (hazard ratio [HR] 1.35, 95% CI 1.07–1.71) were higher among patients with diabetes, compared to those with normal HbA1c. Patients with pre‐diabetes had a higher risk (which was intermediate between that of patients with diabetes and those with normal HbA1c) of the primary outcome (HR 1.27, 95% CI 1.00–1.60) and HFH (HR 1.35, 95% CI 1.03–1.77), but not of CV death (HR 1.02, 95% CI 0.75–1.40). Patients with diabetes treated with insulin had worse outcomes than those not, and those with 'lean diabetes' had similar mortality rates to those with a higher body mass index, but lower rates of HFH. Conclusion: Pre‐diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01920711. [ABSTRACT FROM AUTHOR]

Aims Outpatient treatment for the worsening of signs and symptoms of heart failure (HF) is usually not incorporated in the main outcomes of HF trials. Patients with HF and a preserved ejection fraction (HFpEF) may experience frequent episodes of outpatient worsening HF. The aim of this study was to evaluate the frequency, prognostic impact, and the effect of spironolactone on outpatient diuretic intensification (ODI), among 1767 patients enrolled in TOPCAT-Americas. Methods and results Time-updated Cox models and win ratio analysis. ODI was defined by a post-randomization loop diuretic dose increase or new initiation. The median follow-up was 2.9 years. At baseline, 1362 (77%) patients were taking loop diuretics. During the follow-up, 685 (38.8%) patients experienced ODI, which was associated with a higher risk of subsequent cardiovascular events and death [adjusted hazard ratio (HR) for HF hospitalization or cardiovascular death 1.67, 95% confidence interval (CI) 1.36-2.04; HR for cardiovascular death 2.17, 95% CI 1.64-2.87); and HR for all-cause mortality 1.75, 95% CI 1.41-2.16] (p <0.001 for all outcomes). Adding ODI to the composite of HF hospitalization or cardiovascular death increased the event rate by three-fold in the placebo group (from 10.4 to 29.9 events per 100 person-years). Spironolactone treatment led to a 26% relative reduction of the extended composite of ODI or HF hospitalization or cardiovascular death (HR 0.74, 95% CI 0.65-0.85; p <0.001) compared with a 16% relative reduction of HF hospitalization or cardiovascular death (HR 0.84, 95% CI 0.70-0.99; p =0.044). Using win ratio provided similar estimates. Conclusion In HFpEF, ODI was frequent and independently associated with subsequent cardiovascular events. Spironolactone significantly reduced an extended composite outcome incorporating ODI. [ABSTRACT FROM AUTHOR]

Aims: Outpatient treatment for the worsening of signs and symptoms of heart failure (HF) is usually not incorporated in the main outcomes of HF trials. Patients with HF and a preserved ejection fraction (HFpEF) may experience frequent episodes of outpatient worsening HF. The aim of this study was to evaluate the frequency, prognostic impact, and the effect of spironolactone on outpatient diuretic intensification (ODI), among 1767 patients enrolled in TOPCAT‐Americas. Methods and results: Time‐updated Cox models and win ratio analysis. ODI was defined by a post‐randomization loop diuretic dose increase or new initiation. The median follow‐up was 2.9 years. At baseline, 1362 (77%) patients were taking loop diuretics. During the follow‐up, 685 (38.8%) patients experienced ODI, which was associated with a higher risk of subsequent cardiovascular events and death [adjusted hazard ratio (HR) for HF hospitalization or cardiovascular death 1.67, 95% confidence interval (CI) 1.36–2.04; HR for cardiovascular death 2.17, 95% CI 1.64–2.87); and HR for all‐cause mortality 1.75, 95% CI 1.41–2.16] (p < 0.001 for all outcomes). Adding ODI to the composite of HF hospitalization or cardiovascular death increased the event rate by three‐fold in the placebo group (from 10.4 to 29.9 events per 100 person‐years). Spironolactone treatment led to a 26% relative reduction of the extended composite of ODI or HF hospitalization or cardiovascular death (HR 0.74, 95% CI 0.65–0.85; p < 0.001) compared with a 16% relative reduction of HF hospitalization or cardiovascular death (HR 0.84, 95% CI 0.70–0.99; p = 0.044). Using win ratio provided similar estimates. Conclusion: In HFpEF, ODI was frequent and independently associated with subsequent cardiovascular events. Spironolactone significantly reduced an extended composite outcome incorporating ODI. [ABSTRACT FROM AUTHOR]

Aims: The 4822 patients randomized in the PARAGON‐HF trial were a subset of 5746 initially eligible patients who entered sequential run‐in periods. We identified patient factors associated with study discontinuation during the run‐in period and estimated the implications of these discontinuations for the overall study result. Methods and results: We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run‐in period. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run‐in population was estimated by weighting randomized patients according to the inverse probability of run‐in completion. A total of 924 (16.1%) subjects failed to complete the run‐in period. In multivariable models, non‐completion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower haemoglobin, lower estimated glomerular filtration rate, higher N‐terminal pro‐B‐type natriuretic peptide, higher New York Heart Association functional class, prior heart failure (HF) hospitalization, and lack of prior use of renin–angiotensin system inhibitors or beta‐blocker. In repeat analysis of the effect of randomized treatment in PARAGON‐HF giving greater weight to participants resembling those who failed to complete the run‐in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio 0.86; 95% confidence interval 0.74–1.00). Conclusion: Patients with more advanced HF were at higher risk for non‐completion of the run‐in period in PARAGON‐HF. Re‐analysis of study outcomes accounting for the effect of run‐in non‐completion did not alter the estimated treatment effects of sacubitril/valsartan vs. valsartan. [ABSTRACT FROM AUTHOR]

Recent guidelines restricted aspirin (ASA) in primary prevention of cardiovascular disease (CVD) to patients <70 years old and more recent guidance to <60. In the most comprehensive prior meta-analysis, the Antithrombotic Trialists Collaboration reported a significant 12% reduction in CVD with similar benefit-risk ratios at older ages. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, four trials were added to an updated meta-analysis. ASA produced a statistically significant 13% reduction in CVD with 95% confidence limits (0.83 to 0.92) with similar benefits at older ages in each of the trials. Primary care providers should make individual decisions whether to prescribe ASA based on benefit-risk ratio, not simply age. When the absolute risk of CVD is >10%, benefits of ASA will generally outweigh risks of significant bleeding. ASA should be considered only after implementation of therapeutic lifestyle changes and other drugs of proven benefit such as statins, which are, at the very least, additive to ASA. Our perspective is that individual clinical judgements by primary care providers about prescription of ASA in primary prevention of CVD should be based on our evidence-based solution of weighing all the absolute benefits and risks rather than age. This strategy would do far more good for far more patients as well as far more good than harm in both developed and developing countries. This new and novel strategy for primary care providers to consider in prescribing ASA in primary prevention of CVD is the same as the general approach suggested by Professor Geoffrey Rose decades ago. [ABSTRACT FROM AUTHOR]

Aims Patients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on 'apparent resistant hypertension' in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril–valsartan with valsartan. Methods and results In this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n  = 4795). 'Apparent resistant hypertension' was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. 'Apparent mineralocorticoid receptor antagonist (MRA)-resistant' hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril–valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6–19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7–14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05–1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril–valsartan vs. valsartan in patients with apparent resistant hypertension [−4.8 (−7.0 to −2.5) and 3.9 (−6.6 to −1.3) mmHg] and apparent MRA-resistant hypertension [−8.8 (−14.0 to −3.5) and −6.3 (−12.5 to −0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril–valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30–2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18–5.89). Conclusion Sacubitril–valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA. Clinical trial registration PARAGON-HF: ClinicalTrials.gov Identifier NCT01920711. [ABSTRACT FROM AUTHOR]

Background: Sudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF. Methods: Models were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials. Results: The clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell's C of 0.71 (95% CI 0.68–0.75) and 0.78 (95% CI 0.75–0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination. Conclusions: The clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials. Clinical trial registration: I-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712. [ABSTRACT FROM AUTHOR]

Debate articles that appraise the value of a universal definition of heart failure (HF) based on the determination of circulating natriuretic peptide (NP) levels are presented. Topics covered include difficulties in diagnosing and treating HF with preserved ejection fraction (HFpEF), caveats precluding the introduction of NP elevation for HF diagnosis, and congestion due to cardiac dysfunction.

Aims: Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial.Methods and Results: PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate <60 mL/min/1.73 m2 , diabetes, prior myocardial infarction, atrial fibrillation, LVEF <30%, Killip class ≥III, ST-elevation myocardial infarction without reperfusion) were required for inclusion. PARADISE-MI was event-driven targeting 708 primary endpoints (cardiovascular death, HF hospitalization or outpatient development of HF). Randomization of 5669 patients occurred 4.3 ± 1.8 days from presentation with index AMI. The mean age was 64 ± 12 years, 24% were women. The majority (76%) qualified with ST-segment elevation myocardial infarction; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ± 9% and 58% were in Killip class ≥II.Conclusions: Baseline therapies in PARADISE-MI reflect advances in contemporary evidence-based care. With enrollment complete PARADISE-MI is poised to determine whether sacubitril/valsartan is more effective than a proven ACE inhibitor in preventing development of HF and cardiovascular death following AMI. [ABSTRACT FROM AUTHOR]

Aims: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well‐established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON‐HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan. Methods and results: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo‐, normo‐, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4–5 mmol/L and >5 mmol/L, respectively. Both screening and time‐updated potassium (categorical and continuous spline‐transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time‐updated (but not screening) hypo‐ and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30–1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02–1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all‐cause, cardiovascular and non‐cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all‐cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow‐up. Conclusions: Both hypo‐ and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non‐cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death. [ABSTRACT FROM AUTHOR]