Zile, Michael R.

ABSTRACT Aims In the absence of randomized trial evidence, we performed a large observational analysis of the association between beta-blocker (BB) use and clinical outcomes in patients with heart failure (HF) and mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF). Methods and results We pooled individual patient data from four large HFmrEF/HFpEF trials (I-Preserve, TOPCAT, PARAGON-HF, and DELIVER). The primary outcome was the composite of cardiovascular death or HF hospitalization. Among the 16 951 patients included, the mean left ventricular ejection fraction (LVEF) was 56.8%, and 13 400 (79.1%) had HFpEF (LVEF ≥50%). Overall, 12 812 patients (75.6%) received a BB. The median bisoprolol-equivalent dose of BB was 5.0 (Q1–Q3: 2.5–5.0) mg with BB continuation rates of 93.1% at 2 years (in survivors). The unadjusted hazard ratio (HR) for the primary outcome did not differ between BB users and non-users (HR 0.98, 95% confidence interval [CI] 0.91–1.05), but the adjusted HR was lower in BB users than non-users (0.81, 95% CI 0.74–0.88), and this association was maintained across LVEF (pinteraction = 0.88). In subgroup analyses, the adjusted risk of the primary outcome was similar in BB users and non-users with or without a history of myocardial infarction, hypertension, or a baseline heart rate <70 bpm. By contrast, a better outcome with BB use was seen in patients with atrial fibrillation compared to those without atrial fibrillation (pintreraction = 0.02). Conclusions In this observational analysis of non-randomized BB treatment, there was no suggestion that BB use was associated with worse HF outcomes in HFmrEF/HFpEF, even after extensive adjustment for other prognostic variables.

Background Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Methods and Results We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity–Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β‐2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein–outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), or high‐sensitivity cardiac troponin. Conclusions Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON‐HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. Registration URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0–30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was −0.05 (SE, 0.07); the corresponding change in the valsartan group was −0.04 (0.07). The mean between-treatment difference at week 96 was −0.01 (95% CI, −0.20 to 0.19; P =0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.

Abstract Aims Left ventricular (LV) subclinical impairment has been described in heart failure with preserved ejection fraction (HFpEF). We assessed the relationship between LV myocardial deformation by strain imaging and recurrent hospitalization for heart failure (HF) or cardiovascular death in a large international HFpEF population. Methods and results We assessed two-dimensional speckle-tracking based global longitudinal strain (GLS) in 790 patients (mean age 74 ± 8 years, 54% female) with adequate image quality enrolled in the PARAGON-HF echocardiography study. We examined the relationship of GLS with total HF hospitalizations and cardiovascular death (the primary composite outcome) after accounting for clinical confounders. Approximately 47% of the population had evidence of LV subclinical dysfunction, defined as absolute GLS &lt;16%. Impaired GLS was significantly associated with higher values of circulating baseline N-terminal pro-B-type-natriuretic peptide. After a median follow-up of 3.0 years, there were 407 total HF hospitalizations and cardiovascular deaths. After multivariable adjustment, worse GLS was associated with a greater risk for the primary composite outcome (adjusted hazard ratio per 1% decrease: 1.06; 95% confidence interval 1.02–1.11; p = 0.008). GLS did not modify the treatment effect of sacubitril/valsartan compared with valsartan for the composite outcome (p for interaction &gt;0.1). Conclusions In a large HFpEF population, impaired LV function was observed even among patients with preserved ejection fraction, and was associated with an increased risk of total HF hospitalizations or cardiovascular death, accounting for clinical confounders. These findings highlight the key role of subtle LV systolic impairment in the pathophysiology of HFpEF.

Introduction: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Goal: To identify serum proteins associated with risk for HF hospitalization (HFH) and cardiovascular (CV) death in patients with HFpEF, including proteins with differential associations with clinical outcomes in HFpEF compared to HFrEF. Methods: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF in the PARAGON-HF trial using a modified aptamer proteomic assay. Baseline protein concentrations significantly associated with total HFH and CV death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared to 2515 patients with HFrEF from the PARADIGM-HF and ATMOSPHERE trials. Results: We identified 288 proteins to be robustly associated with the risk of HFH and CV death (335 events over an average of 2.7 years of follow-up) in a HFpEF trial population. Proteins most strongly related to HFpEF outcomes included B2M, TIMP1, SERPINA4, and SVEP1 ( Figure ). Protein-outcome associations in patients with HFpEF did not markedly differ compared to HFrEF. Just 3 proteins (APOE, RTF1, and VWF) were differentially associated with outcomes between the HF subtypes (FDR <0.05). A proteomic risk score derived in HFpEF patients was not superior to a previous proteomic score derived in HFrEF nor to clinical risk factors, NT-proBNP, or high-sensitivity cardiac troponin. Conclusions: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis. SVEP1, a cell adhesion protein recently identified as a HFrEF prognosis biomarker, also strongly predicted risk in HFpEF. Our results demonstrate substantial similarities in serum proteomic risk markers across the EF spectrum.

BACKGROUND: The rate of stroke in patients with heart failure (HF) and preserved ejection fraction but without atrial fibrillation (AF), is uncertain as is whether it is possible to reliably predict the risk of stroke in these patients. METHODS: We validated a previously developed simple risk model for stroke among patients enrolled in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Systolic Function) and PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The risk model consisted of 3 variables: history of previous stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level. RESULTS: Of the 8924 patients included in the pooled trial dataset, 5126 patients did not have AF at baseline. Among patients without AF, 190 (3.7%) experienced a stroke over a median follow-up of 3.6 years (rate 10.5 per 1000 patient-years). The risk for stroke increased with increasing risk score: second tertile hazard ratio, 1.78 (95% CI, 1.17–2.71); third tertile hazard ratio, 3.03 (95% CI, 2.06–4.47), with the first tertile as reference. For patients in the third tertile, the occurrence rate of stroke was 17.7 per 1000 patient-years, similar to that in patients with AF not receiving anticoagulation (20.7 per 1000 patient-years), and those with AF who were receiving anticoagulation (14.5 per 1000 patient-years). Model discrimination was good with a C index of 0.81 (0.68–0.91) and a simple score could be created from the model. CONCLUSIONS: A simple risk model can detect a subset of HF and preserved ejection fraction patients without AF who have a higher risk for stroke. The balance of risk-to-benefit in these individuals may justify the use of prophylactic anticoagulation, but this hypothesis needs to be prospectively evaluated. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00095238 and NCT01920711.

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.

Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P <0.001) and had worse New York Heart Association functional class (class III/IV 24% versus 19%), worse Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (69 versus 76; P <0.001) and more frequent history of heart failure hospitalization (54% versus 47%; P <0.001). The decrement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores with COPD was greater than for other common comorbidities. Patients with COPD had echocardiographic right ventricular enlargement, higher serum creatinine (100 μmol/L versus 96 μmol/L) and neutrophil‐to‐lymphocyte ratio (2.7 versus 2.5), than those without COPD. After multivariable adjustment, COPD was associated with worse outcomes: adjusted rate ratio for the primary outcome 1.51 (95% CI, 1.25–1.83), total heart failure hospitalization 1.54 (95% CI, 1.24–1.90), cardiovascular death (adjusted hazard ratio [HR], 1.42; 95% CI, 1.10–1.82), and all‐cause death (adjusted HR, 1.52; 95% CI, 1.25–1.84). COPD was associated with worse outcomes than other comorbidities and Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores declined more in patients with COPD than in those without. Conclusions Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711 .

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial. Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region. Results: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P >0.05). Conclusions: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.