Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences ...the magnitude of their benefits on heart failure and renal events.
Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes.
Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c HbA1c 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 95% CI, 0.60-0.87 and 0.78 95% CI, 0.64-0.97, respectively,
-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (
-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia.
In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.
The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death.
This study sought to determine ...whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to hospitalization for HF among patients with HF with preserved ejection fraction (HFpEF).
In this post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI Angiotensin Receptor-Neprilysin Inhibitor with ARB Angiotensin Receptor Blocker Global Outcomes in HFpEF), we assessed the risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (≥45%). The primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed by using a semiparametric proportional rates method, stratified by geographic region.
Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31 to 90 days, 435 (9%) within 91 to 180 days, and 694 (14%) after 180 days; 2,490 (52%) were never previously hospitalized. Over a median follow-up of 35 months, risk of total HF hospitalizations and cardiovascular death was inversely and nonlinearly associated with timing from prior HF hospitalization (p < 0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio: 0.73; 95% confidence interval: 0.53 to 0.99) to patients never hospitalized (rate ratio: 1.00; 95% confidence interval: 0.80 to 1.24; trend in relative risk reduction: pinteraction = 0.15). With valsartan alone, the rate of total primary events was 26.7 (≤30 days), 24.2 (31 to 90 days), 20.7 (91 to 180 days), 15.7 (>180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (≤30 days), 4.6% (31 to 90 days), and 3.4% (91 to 180 days), whereas no risk reduction was observed in patients screened >180 days or who were never hospitalized (trend in absolute risk reduction: pinteraction = 0.050).
Recent hospitalization for HFpEF identifies patients at high risk for near-term clinical progression. In the PARAGON-HF trial, the relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrant prospective validation. (PARAGON-HF; NCT01920711)
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ABSTRACT
Aims
EMPEROR‐Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline ...characteristics of the EMPEROR‐Preserved cohort and compares them with patients enrolled in prior HFpEF trials.
Methods and results
EMPEROR‐Preserved is a phase III randomized, international, double‐blind, parallel‐group, placebo‐controlled trial in which 5988 symptomatic HFpEF patients left ventricular ejection fraction (LVEF) >40% with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N‐terminal pro B‐type
natriuretic peptide (NT‐proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalization. Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72 ± 9 years, 45% were women. Almost all patients had New York Heart Association class II or III symptoms (99.6%), and 23% had prior heart failure hospitalization within 12 months. Thirty‐three percent of the patients had baseline LVEF of 41–50%. The mean LVEF (54 ± 9%) was slightly lower while the median NT‐proBNP 974 (499–1731) pg/mL was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor–neprilysin inhibitors (80%) and beta‐blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists.
Conclusion
When compared with prior trials in HFpEF, the EMPEROR‐Preserved cohort has a somewhat higher burden of comorbidities, lower LVEF, higher median NT‐proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR‐Preserved trial will be available in 2021.
Baseline characteristics of patients with heart failure with preserved ejection (HFpEF) in the EMPEROR‐Preserved trial. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; CKD, chronic kidney disease; CV, cardiovascular; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT‐proBNP, N‐terminal pro B‐type natriuretic peptide; NYHA, New York Heart Association; T2DM, type 2 diabetes mellitus.
Abstract
Background
Heart failure (HF) is a global challenge, with lower- and middle-income countries (LMICs) carrying a large share of the burden. Treatment for HF with reduced ejection fraction ...(HFrEF) improves survival but is often underused. Economic factors might have an important effect on the use of medicines.
Methods and results
This analysis assessed prescription rates and doses of renin–angiotensin system (RAS) inhibitors, β-blockers, and mineralocorticoid receptor antagonists at discharge and 6-month follow-up in 8669 patients with HFrEF (1458 from low-, 3363 from middle-, and 3848 from high-income countries) hospitalized for acute HF in 44 countries in the prospective REPORT-HF study. We investigated determinants of guideline-recommended treatments and their association with 1-year mortality, correcting for treatment indication bias.
Only 37% of patients at discharge and 34% of survivors at 6 months were on all three medication classes, with lower proportions in LMICs than high-income countries (19 vs. 41% at discharge and 15 vs. 37% at 6 months). Women and patients without health insurance, or from LMICs, or without a scheduled medical follow-up within 6 months of discharge were least likely to be on guideline-recommended medical therapy at target doses, independent of confounders. Being on ≥50% of guideline-recommended doses of RAS inhibitors, and β-blockers were independently associated with better 1-year survival, regardless of country income level.
Conclusion
Patients with HFrEF in LMICs are less likely to receive guideline-recommended drugs at target doses. Improved access to medications and medical care could reduce international disparities in outcome.
Structured Graphical Abstract
Structured Graphical Abstract
Structured graphical abstract showing a map with percentage of patients on ACEi/ARB/ARNi or Beta blockers at discharge
Heart failure is a global public health problem, affecting a large number of individuals from low-income and middle-income countries. REPORT-HF is, to our knowledge, the first prospective global ...registry collecting information on patient characteristics, management, and prognosis of acute heart failure using a single protocol. The aim of this study was to investigate differences in 1-year post-discharge mortality according to region, country income, and income inequality.
Patients were enrolled during hospitalisation for acute heart failure from 358 centres in 44 countries on six continents. We stratified countries according to a modified WHO regional classification (Latin America, North America, western Europe, eastern Europe, eastern Mediterranean and Africa, southeast Asia, and western Pacific), country income (low, middle, high) and income inequality (according to tertiles of Gini index). Risk factors were identified on the basis of expert opinion and knowledge of the literature.
Of 18 102 patients discharged, 3461 (20%) died within 1 year. Important predictors of 1-year mortality were old age, anaemia, chronic kidney disease, presence of valvular heart disease, left ventricular ejection fraction phenotype (heart failure with reduced ejection fraction HFrEF vs preserved ejection fraction HFpEF), and being on guideline-directed medical treatment (GDMT) at discharge (p<0·0001 for all). Patients from eastern Europe had the lowest 1-year mortality (16%) and patients from eastern Mediterranean and Africa (22%) and Latin America (22%) the highest. Patients from lower-income countries (ie, ≤US$3955 per capita; hazard ratio 1·58, 95% CI 1·41–1·77), or with greater income inequality (ie, from the highest Gini tertile; 1·25, 1·13–1·38) had a higher 1-year mortality compared with patients from regions with higher income (ie, >$12 235 per capita) or lower income inequality (ie, from the lowest Gini tertile). Compared with patients with HFrEF, patients with HFpEF had a lower 1-year mortality with little variation by income level (pinteraction for HFrEF vs HFpEF <0·0001).
Acute heart failure is associated with a high post-discharge mortality, particularly in patients with HFrEF from low-income regions with high income inequality. Regional differences exist in the proportion of eligible patients discharged on GDMT, which was strongly associated with mortality and might reflect lack of access to post-discharge care and prescribing of GDMT.
Novartis Pharma.
Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article ...explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.
Aims
Few prior studies have investigated differences in precipitants leading to hospitalizations for acute heart failure (AHF) in a cohort with global representation.
Methods and results
We analysed ...the prevalence of precipitants and their association with outcomes in 18 553 patients hospitalized for AHF in REPORT‐HF (prospective international REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure) according to left ventricular ejection fraction subtype (reduced HFrEF and preserved ejection fraction HFpEF) and presentation (new‐onset vs. decompensated chronic heart failure DCHF). Patients were enrolled from 358 centres in 44 countries stratified according to Latin America, North America, Western Europe, Eastern Europe, Eastern Mediterranean and Africa, Southeast Asia, and Western Pacific. Precipitants were pre‐with mutually exclusive categories and selected according to the local investigator's discretion. Outcomes included in‐hospital and 1‐year mortality. The median age was 67 (interquartile range 57–77) years, and 39% were women. Acute coronary syndrome (ACS) was the most common precipitant in patients with new‐onset heart failure in all regions except for North America and Western Europe, where uncontrolled hypertension and arrhythmia, respectively, were the most common precipitants, independent of confounders. In patients with DCHF, non‐adherence to diet/medication was the most common precipitant regardless of region. Uncontrolled hypertension was a more likely precipitant in HFpEF, non‐adherence to diet/medication, and ACS were more likely precipitants in HFrEF. Patients admitted due to worsening renal function had the worst in‐hospital (5%) and 1‐year post‐discharge (30%) mortality rates, regardless of region, heart failure subtype and admission type (pinteraction >0.05 for all).
Conclusion
Data on global differences in precipitants for AHF highlight potential regional differences in targets for preventing hospitalization for AHF and identifying those at highest risk for early mortality.
Overview of the methods and results of this study.
Aim
Acute heart failure can be a life‐threatening medical condition. Delaying administration of intravenous furosemide (time‐to‐diuretics) has been postulated to increase mortality, but prior reports ...have been inconclusive. We aimed to evaluate the association between time‐to‐diuretics and mortality in the international REPORT‐HF registry.
Methods and results
We assessed the association of time‐to‐diuretics within the first 24 h with in‐hospital and 30‐day post‐discharge mortality in 15 078 patients from seven world regions in the REPORT‐HF registry. We further tested for effect modification by baseline mortality risk (ADHERE risk score), left ventricular ejection fraction (LVEF) and region. The median time‐to‐diuretics was 67 (25th–75th percentiles 17–190) min. Women, patients with more signs and symptoms of heart failure, and patients from Eastern Europe or Southeast Asia had shorter time‐to‐diuretics. There was no significant association between time‐to‐diuretics and in‐hospital mortality (p > 0.1). The 30‐day mortality risk increased linearly with longer time‐to‐diuretics (administered between hospital arrival and 8 h post‐hospital arrival) (p = 0.016). This increase was more significant in patients with a higher ADHERE risk score (pinteraction = 0.008), and not modified by LVEF or geographic region (pinteraction > 0.1 for both).
Conclusion
In REPORT‐HF, longer time‐to‐diuretics was not associated with higher in‐hospital mortality. However, we did found an association with increased 30‐day mortality, particularly in high‐risk patients, and irrespective of LVEF or geographic region.
Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02595814.
Aims
Recovery of well‐being after hospitalisation for acute heart failure (AHF) is a measure of the success of interventions and the quality of care but has rarely been quantified. Accordingly, we ...measured health status after discharge in an international registry (REPORT‐HF) of AHF.
Methods and results
The analysis included 4606 patients with AHF who survived to hospital discharge, had known vital status at 6 months, and were enrolled in the United States of America, Russian Federation, or Western Europe, where the Kansas City Cardiomyopathy Questionnaire (KCCQ) was administered. Median age was 69 years (quartiles 59–78), 40% were women, and 34% had a left ventricular ejection fraction (LVEF) <40%, and 12% patients died by 6 months. Of 2475 patients with a follow‐up KCCQ, 28% were ‘alive and well’ (KCCQ >75), while 43% had poor health status (KCCQ ≤50). Being ‘alive and well’ was associated with new‐onset AHF, LVEF <40%, younger age, higher baseline KCCQ, country, and race. Associations were similar for increasing health status, with the exception of country and addition of comorbidities.
Conclusion
In this international global registry, health status recovery after AHF hospitalisation was highly variable. Those with the best health status at 6 months were younger, had new‐onset heart failure, and higher baseline KCCQ; nearly one‐third of survivors were ‘alive and well’. Investigating reasons for changes in KCCQ after hospitalisation might identify new therapeutic targets to improve patient‐centred outcomes.
(A) Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ‐OSS) at baseline, 6 months, and 12 months. (B) Forest plot of characteristics associated with being ‘alive and well’ at follow‐up. LVEF, left ventricular ejection fraction; HF, heart failure. *Multivariable logistic regression.
Aim
Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction is ...limited.
Methods and results
We analysed HCRU in relation to left ventricular ejection fraction (LVEF) phenotypes, clinical features and in‐hospital and 12‐month outcomes in 16 943 patients hospitalized for HF in a worldwide registry. HFrEF was more prevalent (53%) than HFmrEF (17%) or HFpEF (30%). Patients with HFmrEF and HFpEF were older, more often women, with milder symptoms and more comorbidities, but differences were not pronounced. HCRU was high in all three groups; two or more in‐ and out‐of‐hospital services were required by 51%, 49% and 52% of patients with HFrEF, HFmrEF and HFpEF, respectively, and intensive care unit by 41%, 41% and 37%, respectively. Hospitalization length was similar (median, 8 days). Discharge prescription of neurohormonal inhibitors was <80% for each agent in HFrEF and only slightly lower in HFmrEF and HFpEF (74% and 67%, respectively, for beta‐blockers). Compared to HFrEF, 12‐month all‐cause and cardiovascular mortality were lower for HFmrEF (adjusted hazard ratios 0.78 95% confidence interval 0.59–0.71 and 0.80 0.70–0.92) and HFpEF (0.64 0.59–0.87 and 0.63 0.56–0.71); 12‐month HF hospitalization was also lower for HFpEF and HFmrEF (21% and 20% vs. 25% for HFrEF). In‐hospital mortality, 12‐month non‐cardiovascular mortality and 12‐month all‐cause hospitalization were similar among groups.
Conclusions
In patients hospitalized for HF, overall HCRU was similarly high across LVEF spectrum, reflecting the subtle clinical differences among LVEF phenotypes during hospitalization. Discharge prescription of neurohormonal inhibitors was suboptimal in HFrEF and lower but significant in patients with HFpEF and HFmrEF, who had better long‐term cardiovascular outcomes than HFrEF, but similar risk for non‐cardiovascular events.
Healthcare resource utilization and outcomes in hospitalized heart failure (HF) patients across left ventricular ejection fraction (LVEF) phenotypes: a REPORT‐HF sub‐analysis. CV, cardiovascular; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.
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