Packer, Milton

Abstract Aims To evaluate clinical outcomes, echocardiographic features, and the efficacy and safety of sacubitril/valsartan compared to valsartan across age groups in the PARAGON-HF trial. Methods and results A total of 4796 participants ≥50 years of age with chronic heart failure (HF) and left ventricular ejection fraction (LVEF) ≥45% were divided into three age groups: <65 years (n = 825), 65–74 years (n = 1772), and ≥75 years (n = 2199). Echocardiograms of 1097 patients were analysed in a standardized fashion at a core imaging laboratory. The primary composite outcome was total HF hospitalizations and cardiovascular (CV) death. Older patients were more likely to experience primary composite outcomes (compared to patients <65 years, adjusted rate ratio [aRR] for ≥75 years: 1.39, 95% confidence interval [CI] 1.21–1.61), total HF hospitalization (aRR 1.27, 95% CI 1.09–1.49), and CV death (adjusted hazard ratio [aHR] 2.04, 95% CI 1.44–2.87). Age did not modify the effect of sacubitril/valsartan compared to valsartan on primary composite endpoint (pinteraction = 0.79) in the overall population or in those with LVEF ≤57%. Older adults randomized to sacubitril/valsartan were more likely to develop hypotension compared to those receiving valsartan (pinteraction = 0.026). Older patients had smaller left ventricular chamber sizes, higher LVEF, and were more likely to have abnormal measures of diastolic function. Conclusion Older patients with HF with preserved ejection fraction had higher event rates than younger patients, more adverse events overall, and more hypotension when treated with sacubitril/valsartan; however, the treatment benefits of sacubitril/valsartan were retained in older patients.

Abstract Background Cognitive decline is common in patients with heart failure (HF), but its clinical correlates and prognostic impact are not well understood in this population. Purpose To examine the baseline variables associated with cognitive decline and the associations between cognitive decline and HF outcomes in patients with heart failure and preserved ejection fraction (HFpEF). Methods We analyzed cognitive function, as measured by the Mini-Mental State Examination (MMSE), in 2895 patients with HFpEF enrolled in a pre-specified sub-study of PARAGON-HF. Logistic regression analysis was performed to determine the factors associated with cognitive decline i.e., a decrease in MMSE score of ≥3 points by 48 weeks. Time-updated Cox proportional hazards regressions and semiparametric proportional rates models were used to examine the subsequent risk of clinical outcomes after a decline in MMSE scores of ≥1-, 2- and 3-points during follow-up respectively, adjusted for known prognostic variables including NT-proBNP and baseline MMSE. Results A total of 450 (15.5% of the population) patients experienced a decrease in MMSE score of ≥3 points from baseline, at any follow-up visit. The corresponding number for a decrease in MMSE score of ≥2 points and ≥1 point was 755 (26.1%) and 1231 (42.5%), respectively. Independent predictors of cognitive decline at 48 weeks included older age, living in Latin America or the Asia/Pacific region, ischemic etiology, prior HF hospitalization, history of stroke/TIA, and lower serum albumin level (Figure 1). There was a graded relationship between the size of the decrease in MMSE score from baseline and the subsequent risk of mortality. Notably, a decrease of ≥3 points was associated with a 50% increase in the subsequent risk of death from any cause (adjusted HR 1.53, 95% CI 1.10-2.11) and a 90% elevation in risk of death from cardiovascular causes (1.89, 1.25-2.86), respectively, after extensive adjustment for known prognostic variables and baseline MMSE score. By contrast, cognitive decline during follow-up was not associated with a higher risk of HF hospitalization or the composite of HF hospitalization or CV death (Figure 2). Conclusions In patients with HFpEF, a decline in MMSE score during follow-up is independently associated with a graded increase in the risk for mortality, but not of HF hospitalization.The predictors for cognitive declineRisk of outcomes after a decline in MMSE

Abstract Background NT-proBNP levels are associated with disease severity and outcomes in patients with HF across the spectrum of LVEF. Recently, it has been suggested that the effectiveness of certain treatments may vary by NT-proBNP level with greater benefit from omecamtiv mecarbil, and smaller benefit from vericiguat, in patients with higher NT-proBNP levels. We examined the benefit of sacubitril/valsartan on outcomes across the range of NT-proBNP levels in patients with HFrEF/HFmrEF/HFpEF. Purpose To evaluate clinical outcomes, and the efficacy of sacubitril/valsartan, according to NT-proBNP levels, in patients with HFrEF/HFmrEF/HFpEF, using the pooled dataset of participants in the PARADIGM-HF and PARAGON-HF trials. Methods The PARADIGM-HF (n=8399) and PARAGON-HF (n=4822) trials enrolled patients with HF, functional limitation, and elevated NT-proBNP levels. Patients with LVEF ≤40% were randomized to sacubitril/valsartan 200 mg twice daily or enalapril 10mg twice daily in PARADIGM-HF, and those with LVEF ≥45% to sacubitril/valsartan 200 mg twice daily or valsartan 160mg twice daily in PARAGON-HF. Patients were categorized by quintiles of NT-proBNP level and using NT-proBNP as a continuous variable, analysed using restricted cubic splines. The primary outcome in the present study was the composite of cardiovascular death or HF hospitalization. Results Among the 13195 patients in the pooled PARADIGM-HF and PARAGON-HF dataset, 13142 (99.6%) patients with baseline NT-proBNP were analysed. Patients with higher NT-proBNP levels were more often male, had lower body mass index and LVEF, worse New York Heart Association functional class, worse kidney function, and more atrial fibrillation, while age was similar across NT-proBNP levels. The rate of the primary outcome (per 100 person-years) increased with NT-proBNP level: quintile 1, 5.9 (95%CI 5.3-6.5); quintile 2, 7.5 (95%CI 6.9-8.2); quintile 3, 9.0 (95%CI 8.2-9.7); quintile 4, 12.0 (95%CI 11.1-12.9); and quintile 5, 20.8 (95%CI 19.6-22.2) (Figure 1). Similar trends were observed for other outcomes. The benefit of sacubitril/valsartan was consistent across NT-proBNP levels: the hazard ratio for the primary outcome in NT-proBNP quintile 1 was 0.79 (95%CI 0.65-0.96); quintile 2, 0.87 (95%CI 0.72-1.04); quintile 3, 0.79 (95%CI 0.66-0.93); quintile 4, 0.85 (95%CI 0.73-0.99); and quintile 5, 0.86 (95%CI 0.76-0.97), P-interaction=0.86. The consistent benefit of sacubitril/valsartan was also seen when NT-proBNP was analysed as a continuous variable (Figure 2). The absolute benefit was greatest in quintile 5 of NT-proBNP; the number needed to treat for quintile 5 was 16 versus 37 for the quintile 1 for the primary endpoint. Conclusions Patients with higher NT-proBNP had worse outcomes, but the benefits of sacubitril valsartan were consistent across the range of NT-proBNP levels of participants in PARADIGM-HF and PARAGON-HF.Kaplan-Meier curvesEffect of sac/val across NT-proBNP range

Abstract Background Concerns have been raised about the appropriateness of use and safety of beta-blockers (BBs) in patients with heart failure and mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF). However, randomized trial evidence is still lacking. Purpose To perform an observational analysis of the association between BB use and clinical outcomes in a large dataset of patients with HFmrEF and HFpEF. Methods We pooled individual patient data from four large HFmrEF/HFpEF trials (I-Preserve, TOPCAT, PARAGON-HF, and DELIVER). The associations between baseline BB use and outcomes were analyzed. The primary outcome was the composite of cardiovascular death or HF hospitalization. Results 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 95.1% at 1 year and 93.1% at 2 years (in patients who survived more than 1 and 2 years, respectively). Overall, the hazard ratio (HR) for the primary outcome did not differ between BB users and non-users (HR: 0.98 [95% CI: 0.91-1.05]) but among patients with HFmrEF, BB users had a lower HR (0.84 [95% CI 0.71-0.98]), whereas in HFpEF the HR was similar BB users and non-users (0.99 [95% CI 0.92-1.08]). However, after comprehensive adjustment for known prognostic variables, including NT-proBNP, BB use was associated with a better outcome in the overall cohort (HR 0.81 [0.74-0.88]), and this association was maintained across the range of LVEF (Figure 1). In subgroup analyses, the risk of the primary outcome was similar in BB users and non-users with or without a history of myocardial infarction, with or without a history of hypertension, or with or without 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 (Figure 2). Conclusions Although this is an observational analysis of non-randomized treatment, there was no suggestion that BB use was associated with worse HF outcomes even after extensive adjustment for other prognostic variables. Figure Legends Figure 1. Association between beta-blocker use and outcomes across the range of LVEF. Risk in beta-blocker users versus non-users is shown as an adjusted continuous hazard ratio Figure 2. Association between beta-blocker use and non-use in the overall population and clinically relevant patient subgroups, shown as an adjusted hazard ratio (HR). The outcome analyzed was the composite of CV death or HF hospitalization (primary outcome)Figure 1Figure 2