| 1. |
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| 2. |
- Lumbers, R. T., et al.
(författare)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Tidskriftsartikel (refereegranskat)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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| 3. |
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| 4. |
- Wang, Haidong, et al.
(författare)
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Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1459-1544
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures.METHODS: We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).FINDINGS: Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4-61·9) in 1980 to 71·8 years (71·5-72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7-17·4), to 62·6 years (56·5-70·2). Total deaths increased by 4·1% (2·6-5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8-18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6-16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9-14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1-44·6), malaria (43·1%, 34·7-51·8), neonatal preterm birth complications (29·8%, 24·8-34·9), and maternal disorders (29·1%, 19·3-37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death.INTERPRETATION: At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.
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| 5. |
- O'Connor, C. M., et al.
(författare)
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Effect of nesiritide in patients with acute decompensated heart failure
- 2011
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Ingår i: The New England journal of medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 365:1, s. 32-43
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P
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| 6. |
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| 7. |
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| 8. |
- Cowie, M. R., et al.
(författare)
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New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment
- 2017
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842. ; 19:6, s. 718-727
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Tidskriftsartikel (refereegranskat)abstract
- Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.
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| 9. |
- Dobre, D., et al.
(författare)
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Heart rate: a prognostic factor and therapeutic target in chronic heart failure. The distinct roles of drugs with heart rate-lowering properties
- 2014
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 16:1, s. 76-85
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Tidskriftsartikel (refereegranskat)abstract
- Heart rate not only predicts outcome but may also be a therapeutic target in patients with chronic heart failure. Several classes of pharmacological agents can be used to modulate heart rate, including beta-blockers, ivabradine, digoxin, amiodarone, and verapamil. Choice of agent will depend on heart rhythm, co-morbidities, and disease phenotype. Beneficial and harmful interactions may also exist. The aim of this paper is to summarize the current body of knowledge regarding the relevance of heart rate as a prognostic factor (risk marker) and particularly as a therapeutic target (risk factor) in patients with chronic heart failure, with a special focus on ivabradine, a novel agent that is currently the only available purely bradycardic agent.
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| 10. |
- Shah, S, et al.
(författare)
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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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| 11. |
- Zannad, F., et al.
(författare)
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Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document
- 2013
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 15:10, s. 1082-1094
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Tidskriftsartikel (refereegranskat)abstract
- Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g. all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12-13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.
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| 12. |
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| 13. |
- Kober, L., et al.
(författare)
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Previously known and newly diagnosed atrial fibrillation: a major risk indicator after a myocardial infarction complicated by heart failure or left ventricular dysfunction
- 2006
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Ingår i: European journal of heart failure. - 1388-9842. ; 8:6, s. 591-8
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To characterize the relationship between known and newly diagnosed atrial fibrillation (AF) and the risk of death and major cardiovascular (CV) events in patients with acute myocardial infarction (MI) complicated by heart failure (HF) and/or left ventricular systolic dysfunction (LVSD). METHODS: The VALIANT trial enrolled 14,703 individuals with acute MI complicated by HF and/or LVSD. AF was assessed at presentation and at randomization (median 4.9 days after symptom onset). Primary outcomes were risk of death and major CV events 3 years following acute MI. RESULTS: A total of 1812 with current AF (AF between presentation and randomization), 339 patients with prior AF (history of AF without current AF), and 12,509 without AF were enrolled. Patients with AF were older; had more prior HF, angina, and MI, and received beta-blockers and thrombolytics less often than those without AF. Three-year mortality estimates were 20% in those without AF, 37% with current AF, and 38% with prior AF. Compared with patients without AF, the multivariable adjusted HR of death was 1.25 (1.03-1.52; p=0.03) for prior AF and 1.32 (1.20-1.45; p<0.0001) for current AF. HR for major CV events was 1.15 (0.98-1.35; p=0.08) and 1.21 (1.12-1.31; p<0.0001). CONCLUSION: AF is associated with greater long-term mortality and adverse CV events with acute MI complicated by HF or LVSD.
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| 14. |
- Mc Causland, F. R., et al.
(författare)
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Angiotensin-neprilysin inhibition and renal outcomes across the spectrum of ejection fraction in heart failure
- 2022
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:9, s. 1591-8
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Tidskriftsartikel (refereegranskat)abstract
- 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 m(2) in PARADIGM-HF and 63 +/- 19 ml/min/1.73 m(2) 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 m(2)/year for the sacubitril/valsartan group, compared with -2.4 (95% CI -2.5 to -2.2) ml/min/1.73 m(2)/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.
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| 15. |
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| 16. |
- Shen, L., et al.
(författare)
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Declining Risk of Sudden Death in Heart Failure
- 2017
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 377:1, s. 41-51
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND The risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail. We analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter-defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization. Sudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P = 0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer-standing diagnosis. Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence-based medications on this cause of death. (Funded by the China Scholarship Council and the University of Glasgow.)
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| 17. |
- Shen, L., et al.
(författare)
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Incidence and Outcomes of Pneumonia in Patients With Heart Failure
- 2021
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 77:16, s. 1961-1973
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Tidskriftsartikel (refereegranskat)abstract
- Background: The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Objectives: This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials. Methods: The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro–B-type natriuretic peptide). Results: In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58). Conclusions: The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711) © 2021 The Authors
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| 18. |
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| 19. |
- Teerlink, John R., et al.
(författare)
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Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure
- 2021
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Ingår i: New England Journal of Medicine. - Waltham, MA, United States : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 384:2, s. 105-116
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Tidskriftsartikel (refereegranskat)abstract
- Among patients with heart failure and a reduced ejection fraction, those who received the cardiac myosin activator omecamtiv mecarbil had a lower incidence of a composite of heart-failure events or cardiovascular death at a median of 22 months than those who received placebo. Background The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. Methods We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. Results During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P=0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. Conclusions Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, ; EudraCT number, 2016-002299-28.)
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| 20. |
- Teerlink, John R., et al.
(författare)
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Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC-HF baseline characteristics and comparison with contemporary clinical trials
- 2020
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Ingår i: European Journal of Heart Failure. - : WILEY. - 1388-9842 .- 1879-0844. ; 22:11, s. 2160-2171
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Tidskriftsartikel (refereegranskat)abstract
- Aims The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials. Methods and results Adults with established HFrEF, New York Heart Association (NYHA) functional class >= II, ejection fraction <= 35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m(2) (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594). Conclusions GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation.
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| 21. |
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| 22. |
- Zannad, F., et al.
(författare)
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Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice
- 2012
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 33:22, s. 2782-2795
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Tidskriftsartikel (refereegranskat)abstract
- Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HF-REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifibrotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplerenone and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the drugs, which may be relevant for therapeutic decision making in individual patients. Although serious hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HF-REF.
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| 23. |
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| 24. |
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| 25. |
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| 26. |
- Ambrosy, A. P., et al.
(författare)
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Changes in Dyspnea Status During Hospitalization and Postdischarge Health-Related Quality of Life in Patients Hospitalized for Heart Failure: Findings From the EVEREST Trial
- 2016
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Ingår i: Circulation-Heart Failure. - : Ovid Technologies (Wolters Kluwer Health). - 1941-3289 .- 1941-3297. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- Background-Dyspnea is the most common symptom among hospitalized patients with heart failure and represents a therapeutic target. However, the association between short-term dyspnea relief and postdischarge clinical outcomes and health-related quality of life (HRQOL) remains uncertain. Methods and Results-A post hoc analysis was performed of the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial, which enrolled 4133 patients within 48 hours of admission for heart failure with an ejection fraction <= 40%. Physician-assessed dyspnea was recorded on a daily basis from baseline until discharge or day 7 as none, seldom, frequent, or continuous. Patient-reported dyspnea was measured using a 7-point Likert scale, and patients experiencing moderate or marked dyspnea improvement on day 1 were classified as early responders. The Kansas City Cardiomyopathy Questionnaire summary score, which ranges from 0 to 100, was collected postdischarge at week 1. The primary outcome was unfavorable HRQOL, defined a priori as a Kansas City Cardiomyopathy Questionnaire score <45. Secondary outcomes included 30-day all-cause mortality, and all-cause and cause-specific hospitalizations. The final analytic cohort included 1567 patients discharged alive with complete HRQOL data. Patients were 66.0 +/- 12.7 years old and had a mean ejection fraction of 25 +/- 8%. Physician-assessed dyspnea was rated as frequent or continuous in 1399 patients (90%) at baseline, which decreased to 250 patients (16%) by discharge, whereas patient-reported early dyspnea relief was reported by 610 patients (40%). The median Kansas City Cardiomyopathy Questionnaire score at week 1 was 50 (35, 65). All-cause mortality was 3.0%, and all-cause hospitalization was 20.5% within 30 days of discharge. Physician-assessed and patient-reported dyspnea was not independently associated with HRQOL, all-cause mortality, or all-cause or cause-specific hospitalization. Conclusions-In-hospital physician-assessed, and patient-reported dyspnea was not independently associated with postdischarge HRQOL, survival, or readmissions. Although dyspnea relief remains a goal of therapy for hospitalized patients with heart failure with reduced ejection fraction, this measure may not be a reliable surrogate for long-term patient-centered or hard clinical outcomes.
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| 27. |
- Ambrosy, A. P., et al.
(författare)
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Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: findings from the EVEREST trial
- 2013
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 34:11, s. 835-43
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Tidskriftsartikel (refereegranskat)abstract
- Aims Signs and symptoms of congestion are the most common cause for hospitalization for heart failure (HHF). The clinical course and prognostic value of congestion during HHF has not been systemically characterized. Methods and results A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 h of admission (median approximately 24 h) for worsening HF with an EF 3. B-type natriuretic peptide (BNP) and amino terminal-proBNP, respectively, decreased from 734 (313, 1523) pg/mL and 4857 (2251, 9642) pg/mL at baseline to 477 (199, 1079) pg/mL, and 2834 (1218, 6075) pg/mL at discharge/Day 7. A CCS at discharge was associated with increased risk (HR/point CCS, 95% CI) for a subset of endpoints at 30 days (HHF: 1.06, 0.95-1.19; ACM: 1.34, 1.14-1.58; and ACM + HHF: 1.13, 1.03-1.25) and all outcomes for the overall study period (HHF: 1.07, 1.01-1.14; ACM: 1.16, 1.09-1.24; and ACM + HHF 1.11, 1.06-1.17). Patients with a CCS of 0 at discharge experienced HHF of 26.2% and ACM of 19.1% during the follow-up. Conclusion Among patients admitted for worsening signs and symptoms of HF and reduced EF, congestion improves substantially during hospitalization in response to standard therapy alone. However, patients with absent or minimal resting signs and symptoms at discharge still experienced a high mortality and readmission rate.
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| 28. |
- Ambrosy, A. P., et al.
(författare)
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Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial
- 2012
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Ingår i: European journal of heart failure. - : Wiley. - 1879-0844 .- 1388-9842. ; 14:3, s. 302-311
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Abnormal liver function tests (LFTs) are common in ambulatory heart failure (HF). The aim of this study was to characterize abnormal LFTs during index hospitalization. METHODS AND RESULTS: A post-hoc analysis was carried out of the placebo group of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial, which enrolled patients hospitalized for HF with an ejection fraction (EF) 34 IU/L), alanine transaminase (ALT, >34 IU/L), alkaline phosphatase (AP, >123 IU/L),gamma-glutamyl transferase (GGT, >50 IU/L), and total bilirubin (T Bili, >1.2 mg/dL) were measured at baseline, discharge/day 7, and post-discharge. Co-primary endpoints were all-cause mortality (ACM) and cardiovascular mortality or first HF hospitalization (CVM + HFH). Study participants had a mean age of 65.6 +/-12.0 years, were mostly male, reported high prevalences of medical co-morbidities, and were well treated with evidence-based therapies. Baseline LFT abnormalities were common (ALB 17%, AST 21%, ALT 21%, AP 23%, GGT 62%, and T Bili 26%). Abnormal T Bili was the only marker to decrease substantially from baseline (26%) to discharge/day 7 (19%). All LFTs, except AP, improved post-discharge. Lower baseline ALB and elevated T Bili were associated with higher rates of ACM, and in-hospital decreases in ALB and increases in T Bili were associated with higher rates of both ACM and CVM + HFH. CONCLUSION: LFT abnormalities are common during hospitalization for HF in patients with reduced EF and were persistent at discharge. Baseline and in-hospital changes in ALB and T Bili provide additional prognostic value.
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| 29. |
- Blair, J. E., et al.
(författare)
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Changes in renal function during hospitalization and soon after discharge in patients admitted for worsening heart failure in the placebo group of the EVEREST trial
- 2011
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 32:20, s. 2563-2572
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Tidskriftsartikel (refereegranskat)abstract
- Aim To provide an in-depth clinical characterization and analysis of outcomes of the patients hospitalized for heart failure (HF) who subsequently develop worsening renal function (WRF) during hospitalization or soon after discharge. Methods and results Of the 4133 patients hospitalized with worsening HF and reduced left ventricular ejection fraction (LVEF) (/=0.3 mg/dL during the in-hospital (randomization to discharge or Day 7) and post-discharge (discharge or Day 7 to 4 weeks post-discharge) periods. Blood pressure (BP), body weight (BW), natriuretic peptides (NPs), and congestion score were correlated with WRF. The prognostic value of baseline renal function at admission and WRF during hospitalization and post-discharge on long-term outcomes were assessed using a Cox proportional hazards model adjusted for other baseline covariates. At randomization, 53.2% of patients had moderately or severely reduced estimated glomerular filtration rate (eGFR) (<60.0 mL/min/1.73 m(2)). Worsening renal function was observed in 13.8% in-hospital and 11.9% post-discharge. Worsening renal function during hospitalization and post-discharge was associated with greater reductions in BP, BW, and NPs. Baseline renal dysfunction as well as in-hospital and post-discharge WRF were predictive of a composite endpoint of cardiovascular (CV) mortality/HF rehospitalization. Conclusion The prevalence of renal dysfunction is high in patients hospitalized for HF with reduced LVEF. Worsening renal function may occur not only during hospitalization, but also in the early post-discharge period. Since worsening renal function during hospitalization is associated with a significant decrease in signs and symptoms of congestion, body weight and natriuretic peptides, which are good prognostic indicators, worsening renal function during hospitalization as an endpoint in clinical trials should be re-evaluated.
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| 30. |
- Butler, J., et al.
(författare)
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Relationship Between Clinical Trial Site Enrollment With Participant Characteristics, Protocol Completion, and Outcomes Insights From the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) Trial
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 61:5, s. 571-579
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes. Background Whether and how site enrollment volume affects clinical trials is not known. Methods A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization). Results Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for <10, 61.7% for 11 to 30, and 68.4% for sites enrolling >30 participants; p < 0.001). Conclusions Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics. (J Am Coll Cardiol 2013; 61: 571-9) (C) 2013 by the American College of Cardiology Foundation
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| 31. |
- Cannon, J. A., et al.
(författare)
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Clinical outcomes according to QRS duration and morphology in the Eplerenone in Mild Patients: Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF)
- 2015
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842. ; 17:7, s. 707-716
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Tidskriftsartikel (refereegranskat)abstract
- AimsWe examined the relationship between different degrees of QRS prolongation and different QRS morphologies and clinical outcomes in patients with heart failure, reduced ejection fraction (HF-REF), and mild symptoms in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). We also evaluated the effect of eplerenone in these patients according to QRS duration/morphology. Methods and resultsPatients were categorized as: QRS duration (ms) (i) <120 (n = 1375); (ii) 120-149 (n = 517); and (iii) 150 (n = 383), and QRS morphology (i) normal (n = 1252); (ii) left bundle branch block (BBB) (n = 608); and (iii) right BBB/intraventricular conduction defect (IVCD) (n = 415). The outcomes examined were the composite of cardiovascular death or heart failure hospitalization and all-cause mortality. Both abnormal QRS duration and QRS morphology were associated with higher risk, e.g. the rates of the composite outcome were: 10.2, 17.6, and 15.5 per 100 patient-years in the <120, 120-149, and 150ms groups, respectively. Eplerenone reduced the risk of the primary outcome and mortality, compared with placebo, consistently across the QRS duration/morphology subgroups. ConclusionWe found that even moderate prolongation of QRS duration and right BBB/IVCD were associated with a high risk of adverse outcomes in HF-REF. Eplerenone was similarly effective, irrespective of QRS duration/morphology.
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| 32. |
- Chin, K. L., et al.
(författare)
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Aspirin does not reduce the clinical benefits of the mineralocorticoid receptor antagonist eplerenone in patients with systolic heart failure and mild symptoms: an analysis of the EMPHASIS-HF study
- 2016
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 18:9, s. 1175-1181
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: It is not known whether concomitant use of aspirin might attenuate the beneficial effects of mineralocorticoid receptor antagonists (MRAs). The purpose of this subgroup analysis was to explore the interaction between baseline aspirin treatment and the effect of eplerenone on the primary efficacy outcomes (composite of hospitalization for heart failure or cardiovascular mortality), its components, and safety markers [estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP), and serum potassium >5.5 mmol/L] in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). METHODS AND RESULTS: Patients with chronic heart failure, reduced ejection fraction (HFREF), and mild symptoms were enrolled in EMPHASIS-HF. We evaluated baseline characteristics according to aspirin use. We explored the interaction between aspirin and eplerenone, using Cox proportional hazards models providing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) and P-values for interaction. Of the 2737 patients randomized, 1605 patients (58.6%) were taking aspirin. The beneficial effects of eplerenone on the primary endpoint were similar in patients not treated (adjusted HR 0.59, 95% CI 0.46-0.75) or treated (adjusted HR 0.71, 95% CI 0.59-0.87) with aspirin at baseline (interaction P-value = 0.19). We did not observe any significant modification of the safety markers by aspirin that was clinically meaningful. CONCLUSION: Aspirin use in patients with chronic systolic heart failure and mild symptoms did not substantially reduce the overall beneficial effects of the MRA eplerenone contrary to what has been described in some studies with ACE inhibitors.
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| 33. |
- Chin, K. L., et al.
(författare)
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Impact of eplerenone on major cardiovascular outcomes in patients with systolic heart failure according to baseline heart rate
- 2019
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Ingår i: Clinical Research in Cardiology. - : Springer Science and Business Media LLC. - 1861-0684 .- 1861-0692. ; 108:7, s. 806-814
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIncreased resting heart rate is a risk factor for cardiovascular mortality and morbidity. Mineralocorticoid receptor antagonists (MRAs) have been shown to improve cardiac sympathetic nerve activity, reduce heart rate and attenuate left ventricular remodelling. Whether or not the beneficial effects of MRA are affected by heart rate in heart failure patients with reduced ejection fraction (HFREF) is unclear.MethodsWe undertook a secondary analysis of data from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study to assess if clinical outcomes, as well as the efficacy of eplerenone, varied according to heart rate at baseline.ResultsHigh resting heart rate of 80bpm and above predisposed patients to greater risk of all outcomes in the trial, regardless of treatment allocation. The beneficial effects of eplerenone were observed across all categories of heart rate. Eplerenone reduced the risk of primary endpoint, the composite of cardiovascular death and hospitalisation for heart failure, by 30% (aHR 0.70; 95% CI 0.54-0.91) in subjects with heart rate80bpm, and by 48% (aHR 0.52; 95% CI 0.33-0.81) in subjects with heart rate60bpm. Eplerenone also reduced the risks of hospitalisation for heart failure, cardiovascular deaths and all-cause deaths independently of baseline heart rate.ConclusionsBaseline heart rate appears to be an important predictor of major clinical outcome events in patients with HFREF, as has been previously reported. The benefits of eplerenone were preserved across all categories of baseline heart rate, without observed heterogeneity in the responses.
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| 34. |
- Coiro, S., et al.
(författare)
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Diuretic therapy as prognostic enrichment factor for clinical trials in patients with heart failure with reduced ejection fraction
- 2021
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Ingår i: Clinical Research in Cardiology. - : Springer Science and Business Media LLC. - 1861-0684 .- 1861-0692. ; 110, s. 1308-1320
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Tidskriftsartikel (refereegranskat)abstract
- Background Loop diuretics are the mainstay of congestion treatment in patients with heart failure (HF). We assessed the association between baseline loop diuretic use and outcome. We also compared the increment in risk related to diuretic dose with conventional prognostic enrichment criteria used in the EMPHASIS-HF trial, which included patients with systolic HF and mild symptoms, such as prior hospitalization and elevated natriuretic peptides. Methods Individual analyses were performed according to baseline loop diuretic usage (furosemide-equivalent dose > 40 mg, 1-40 mg, and no furosemide), and according to enrichment criteria adopted in the trial [i.e. recent hospitalization (< 30 days or 30 to 180 days prior to randomization) due to HF or other cardiovascular cause, or elevated natriuretic peptides]. The primary endpoint was a composite of cardiovascular death or HF hospitalization. Results Loop diuretic usage at baseline (HR for > 40 mg furosemide-equivalent dose = 3.16, 95% CI 2.43-4.11; HR for 1-40 mg = 2.06, 95% CI 1.60-2.65) was significantly associated with a higher risk for the primary endpoint in a stepwise manner when compared to no baseline loop diuretic usage. In contrast, the differences in outcome rates were more modest when using history of hospitalization and/or BNP: all HR ranged from 1 (reference, non-HF related CV hospitalization > 30 days) to 2.04 (HF hospitalization < 30 days). The effect of eplerenone on the primary endpoint was consistent across subgroups in both analyses (P for interaction >= 0.2 for all). Conclusions Loop diuretic usage (especially at doses > 40 mg) identified patients at higher risk than history of HF hospitalization and/or high BNP blood concentrations. Graphic abstract
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| 35. |
- Collier, T. J., et al.
(författare)
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The impact of eplerenone at different levels of risk in patients with systolic heart failure and mild symptoms: insight from a novel risk score for prognosis derived from the EMPHASIS-HF trial
- 2013
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 34:36, s. 2823-2829
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Our objective was to create a simple prognostic risk score for patients with systolic heart failure and mild symptoms. We then assessed the efficacy of eplerenone across different categories of risk. METHODS AND RESULTS: The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure trial (EMPHASIS-HF) was an international randomized trial, comparing eplerenone with placebo in 2737 patients with systolic heart failure and mild symptoms. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure, over a median 2.1 years follow-up. Using multivariable Cox modelling age, sex, systolic blood pressure, estimated glomerular filtration rate, diabetes, BMI, haemoglobin, prior heart failure (HF) hospitalization, prior myocardial infarction/coronary artery bypass surgery (CABG), and heart rate were identified as strong independent risk factors. Estimates from the model were converted into a simple integer risk score which was categorized into three groups of low-, medium-, and high risk. In placebo patients, the rates (per 100 patient-years) for the primary outcome were 7.6, 19.0, and 39.4 in the low-, medium-, and high-risk groups, respectively. On eplerenone, these rates were reduced to 5.6, 12.2, and 24.2, respectively. Eplerenone was beneficial across all risk categories and the hazard ratios were similar. The absolute treatment benefit was greatest among those at highest risk. Similar patterns emerged for all-cause mortality and for all HF hospitalizations. CONCLUSION: This easy-to-use integer risk score should be of value in quantifying individual patient risk in patients with systolic HF and mild symptoms. The relative benefits of eplerenone appeared consistent across the whole spectrum of risk, including those at lower risk.
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| 36. |
- Cook, T. D., et al.
(författare)
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Temporal Changes in Postdischarge Mortality Risk After Hospitalization for Heart Failure (from the EVEREST Trial)
- 2016
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 117:4, s. 611-616
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Tidskriftsartikel (refereegranskat)abstract
- In observational studies of patients hospitalized for heart failure (HHF), risk of death is highest immediately after discharge and decreases over time. It is unclear whether this population risk trajectory reflects (1) lowering of individual patient mortality risk with increasing time from index hospitalization or (2) temporal changes in population case-mix with earlier postdischarge death for "sicker" patients. Survival rate and longitudinal models were used to estimate temporal changes in postdischarge all-cause mortality risk in 3,993 HHF patients discharged alive in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with, Tolvaptan (EVEREST) trial. After median 'follow-up of 9.9 months, 971 patients died (24.2%). Predicted mortality rate decreased from 15.9 per 100 patient-years immediately after discharge to 13.4 at 30 days and 12.8 at 90 days; mortality rate increased steadily thereafter. Risk variation between quintiles of risk was considerably larger than the temporal variation within risk strata. In a longitudinal model serially reassessing predicted patient mortality risk after each follow-up visit using data collected at these visits, predicted mortality risk increased during the 90 days preceding subsequent heart failure readmission and then followed' a postdischarge trajectory similar to the index admission. In conclusion, although there is transiently elevated individual patient risk in the 90 days before and after discharge, the patient's individual risk profile, rather than temporal change in risk relative to hospitalization, remains the main determinant of mortality. For purposes of reducing all-cause mortality in HF patients, preventative and therapeutic measures may be best implemented as long-term interventions for high mortality risk patients based on serial risk assessments, irrespective of recent hospitalization. (C) 2016 Elsevier Inc. All rights reserved.
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| 37. |
- Dewan, P., et al.
(författare)
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Income Inequality and Outcomes in Heart Failure A Global Between-Country Analysis
- 2019
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Ingår i: Jacc-Heart Failure. - : Elsevier BV. - 2213-1779. ; 7:4, s. 336-346
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES This study examined the relationship between income inequality and heart failure outcomes. BACKGROUND The income inequality hypothesis postulates that population health is influenced by income distribution within a society, with greater inequality associated with worse outcomes. METHODS This study analyzed heart failure outcomes in 2 large trials conducted in 54 countries. Countries were divided by tertiles of Gini coefficients (where 0% represented absolute income equality and 100% represented absolute income inequality), and heart failure outcomes were adjusted for standard prognostic variables, country per capita income, education index, hospital bed density, and health worker density. RESULTS Of the 15,126 patients studied, 5,320 patients lived in Gini coefficient tertile 1 countries (coefficient: <33%), 6,124 patients lived in tertile 2 countries (33% to 41%), and 3,772 patients lived in tertile 3 countries (>41%). Patients in tertile 3 were younger than tertile 1 patients, were more often women, and had less comorbidity and several indicators of less severe heart failure, yet the tertile 3-to-1 hazard ratios (HRs) for the primary composite outcome of cardiovascular death or heart failure hospitalization were 1.57 (95% confidence interval [CI]: 1.38 to 1.79) and 1.48 for all-cause death (95% CI: 1.29 to 1.71) after adjustment for recognized prognostic variables. After additional adjustments were made for per capita income, education index, hospital bed density, and health worker density, these HRs were 1.46 (95% CI: 1.25 to 1.70) and 1.30 (95% CI: 1.10 to 1.53), respectively. CONCLUSIONS Greater income inequality was associated with worse heart failure outcomes, with an impact similar to those of major comorbidities. Better understanding of the societal and personal bases of these findings may suggest approaches to improve heart failure outcomes. (C) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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| 38. |
- Eschalier, R., et al.
(författare)
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Safety and efficacy of eplerenone in patients at high-risk for hyperkalemia and/or worsening renal function: Analyses of EMPHASIS-HF study subgroups
- 2013
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 62:17, s. 1585-1593
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We investigated the safety and efficacy of eplerenone in patients at high-risk for hyperkalemia or worsening renal function (WRF) in EMPHASIS-HF, a trial which enrolled patients aged at least 55 years with heart failure and reduced ejection fraction (HF-REF), in NYHA functional class II and with an eGFR>30ml/min/1.73m2 and serum potassium <5.0 mmol/l. Patients were receiving optimal therapy and most had been hospitalized for a cardiovascular reason within 180 days of inclusion. BACKGROUND: Underuse of eplerenone in patients with HF-REF may be due to fear of inducing hyperkalemia or WRF in high-risk patients. METHODS: This was a pre-specified analysis of subgroups of patients at high-risk of hyperkalemia or WRF (patients >/=75years, with diabetes, with eGFR<60ml/min/1.73m2, and with systolic blood pressure 5.5, >6.0 and <3.5mmol/l; hyperkalemia leading to study-drug discontinuation or hospitalization; and hospitalization for WRF) as well as the primary outcome (hospitalization for HF or cardiovascular mortality). RESULTS: In all high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5mmol/l but not of potassium >6.0mmol/l, and of hospitalization for hyperkalemia or discontinuation of study medication due to adverse events. Eplerenone was effective in reducing the primary composite endpoint in all sub-groups. CONCLUSIONS: In patients with chronic HF-REF, in NYHA class II and meeting specific inclusion and exclusion criteria, including an eGFR >30ml/min/1.73m2 and potassium <5.0 mmol/l, eplerenone was both efficacious and safe when carefully monitored, even in subgroups at high-risk of developing hyperkalemia or WRF.
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| 39. |
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| 40. |
- Ferreira, J. P., et al.
(författare)
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Impact of Insulin Treatment on the Effect of Eplerenone: Insights From the EMPHASIS-HF Trial
- 2021
-
Ingår i: Circulation-Heart Failure. - : Ovid Technologies (Wolters Kluwer Health). - 1941-3289 .- 1941-3297. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and insulin-treated diabetes have a high risk of cardiovascular complications. Mineralocorticoid receptor antagonists may mitigate this risk. We aim to explore the effect of eplerenone on cardiovascular outcomes and all-cause mortality in HFrEF patients with diabetes, including those treated with insulin in the EMPHASIS-HF trial (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms). METHODS: The primary outcome was the composite of heart failure hospitalization or cardiovascular death. Cox models with treatment-by-diabetes subgroup interaction terms were used. RESULTS: The median follow-up was 21 (10-33) months. Of the 2737 patients included, 623 (23%) had non-insulin-treated diabetes, 236 (9%) had insulin-treated diabetes and 1878 did not have diabetes. Patients with insulin-treated diabetes were younger, more often women, with higher body mass index, waist circumference, more frequent ischemic heart failure cause, impaired kidney function, and longer diabetes duration. Compared with patients without diabetes, those with insulintreated diabetes had a 2-fold higher risk of having a primary outcome event. The hazard ratio (95% CI) for the effect of eplerenone, compared with placebo, on the primary outcome was 0.31 (0.19-0.50) in insulin-treated diabetes, 0.69 (0.500.93) in non-insulin-treated diabetes, and 0.72 (0.58-0.88) in patients without diabetes; interaction P=0.007. The annualized number needed-to-treat-to-benefit with regards to the primary outcome was 3 (95% CI, 3-4) in patients with insulin-treated diabetes, 16 (13-19) in patients with diabetes not receiving insulin, and 26 (24-28) in patients without diabetes. CONCLUSIONS: Patients with insulin-treated diabetes experienced a greater benefit from eplerenone than those with diabetes not treated with insulin and people without diabetes.
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| 41. |
- Ferreira, J. P., et al.
(författare)
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Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial
- 2019
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 21:3, s. 345-351
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Tidskriftsartikel (refereegranskat)abstract
- Background Current heart failure guidelines recommend target eplerenone dose of 50 mg/day. We have examined the effect of different eplerenone doses based on pre-specified renal function stratification in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Methods and results In EMPHASIS-HF, the target dose of eplerenone/placebo was stratified at randomization according to estimated glomerular filtration rate (eGFR): 50 mg/day if eGFR >= 50 mL/min/1.73m(2) and <= 25 mg/day if eGFR 30-49mL/min/1.73m(2). Patients remained within these dose ranges during the trial (as per stratification). The primary outcome was a composite of heart failure hospitalization or cardiovascular mortality. Eplerenone was superior to placebo within each respective eGFR stratum [eplerenone vs. placebo in the eGFR >= 50 mL/min/1.73m2 stratum: hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.45-0.74; and eplerenone vs. placebo in the eGFR 30-49mL/min/1.73m(2) stratum: HR 0.62, 95% CI 0.49-0.78; P-interaction = 0.89]. Despite receiving lower eplerenone doses, patients in the eGFR 30-49mL/min/1.73m(2) stratum more often had hyperkalaemia, renal failure events, and drug discontinuation. Conclusion In EMPHASIS-HF the eplerenone dose was stratified according to renal function and the treatment effect was not influenced by renal function: 25 mg/day in patients with eGFR 30-49mL/min/1.73m(2) was as effective as 50 mg/day in patients with eGFR> = 50 mL/min/1.73m(2). However, patients with impaired renal function experienced more adverse events, despite reveiving lower eplerenone doses. Current guidelines do not recommend tailoring the dose of eplereone according to renal function but the current data suggest they should.
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| 42. |
- Gheorghiade, M., et al.
(författare)
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Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST)
- 2005
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Ingår i: Journal of cardiac failure. - 1071-9164. ; 11:4, s. 260-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hospitalizations for worsening heart failure due to fluid overload (congestion) are common. Agents that treat congestion without causing electrolyte abnormalities or worsening renal function are needed. Tolvaptan is an oral vasopressin (V 2 ) antagonist that decreases body weight and increases urine volume without inducing renal dysfunction or hypokalemia. The Efficacy of Vasopressin antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial is evaluating mortality, morbidity, and patient-assessed global clinical status in patients treated with tolvaptan compared with standard care. METHODS AND RESULTS: Patients are eligible for inclusion if they have a reduced left ventricular ejection fraction and are hospitalized for worsening heart failure with evidence of systemic congestion. Patients are randomized 1:1 to tolvaptan 30 mg/day or matching placebo for a minimum of 60 days. Time to all-cause mortality and time to cardiovascular mortality or heart failure hospitalization are the coprimary end points. Patient-assessed global clinical status and quality of life are also evaluated. EVEREST will be continued until 1065 deaths occur. As of April 18, 2005, 2260 patients have been enrolled. CONCLUSION: Tolvaptan has been shown to reduce body weight in patients with worsening heart failure without inducing renal dysfunction or causing hypokalemia. The results of EVEREST will determine whether these effects translate into improved clinical outcomes.
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| 43. |
- Gheorghiade, M., et al.
(författare)
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Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials
- 2007
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Ingår i: JAMA. - 1538-3598. ; 297:12, s. 1332-43
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Heart failure causes more than 1 million US hospitalizations yearly, mostly related to congestion. Tolvaptan, an oral, nonpeptide, selective vasopressin V2-receptor antagonist, shows promise in this condition. OBJECTIVE: To evaluate short-term effects of tolvaptan when added to standard therapy in patients hospitalized with heart failure. DESIGN, SETTING, AND PATIENTS: Two identical prospective, randomized, double-blind, placebo-controlled trials at 359 sites in North America, South America, and Europe were conducted during the inpatient period of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) between October 7, 2003, and February 3, 2006. A total of 2048 (trial A) and 2085 (trial B) patients hospitalized with heart failure and congestion were studied. INTERVENTION: Patients were randomized to receive either tolvaptan (30 mg/d) or matching placebo, within 48 hours of admission. MAIN OUTCOME MEASURES: Primary end point was a composite of changes in global clinical status based on a visual analog scale and body weight at day 7 or discharge if earlier. Secondary end points included dyspnea (day 1), global clinical status (day 7 or discharge), body weight (days 1 and 7 or discharge), and peripheral edema (day 7 or discharge). RESULTS: Rank sum analysis of the composite primary end point showed greater improvement with tolvaptan vs placebo (trial A, mean [SD], 1.06 [0.43] vs 0.99 [0.44]; and trial B, 1.07 [0.42] vs 0.97 [0.43]; both trials P<.001). Mean (SD) body weight reduction was greater with tolvaptan on day 1 (trial A, 1.71 [1.80] vs 0.99 [1.83] kg; P<.001; and trial B, 1.82 [2.01] vs 0.95 [1.85] kg; P<.001) and day 7 or discharge (trial A, 3.35 [3.27] vs 2.73 [3.34] kg; P<.001; and trial B, 3.77 [3.59] vs 2.79 [3.46] kg; P<.001), whereas improvements in global clinical status were not different between groups. More patients receiving tolvaptan (684 [76.7%] and 678 [72.1%] for trial A and trial B, respectively) vs patients receiving placebo (646 [70.6%] and 597 [65.3%], respectively) reported improvement in dyspnea at day 1 (both trials P<.001). Edema at day 7 or discharge improved significantly with tolvaptan in trial B (P = .02) but did not reach significance in trial A (P = .07). Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension. CONCLUSION: In patients hospitalized with heart failure, oral tolvaptan in addition to standard therapy including diuretics improved many, though not all, heart failure signs and symptoms, without serious adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00071331
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| 44. |
- Girerd, N., et al.
(författare)
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Clinical benefits of eplerenone in patients with systolic heart failure and mild symptoms when initiated shortly after hospital discharge: analysis from the EMPHASIS-HF trial
- 2015
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 36:34, s. 2310-2317
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Tidskriftsartikel (refereegranskat)abstract
- Aims Cardiovascular hospitalization (CVH) in patients with heart failure (HF) is associated with a high post-discharge rate of early re-admission and CV death. Eplerenone might be effective in reducing the incidence of these adverse clinical outcomes during this period. Methods and results The EMPHASIS-HF trial compared eplerenone with placebo added to standard therapy in 2737 patients with New York Heart Association class II HF and left ventricular ejection fraction <= 35%. We conducted a post hoc analysis in the 2338 patients randomized within 180 days of a CVH. The interaction between the time from the qualifying CVH to randomization and the primary outcome of CV death or hospitalization for HF (HHF), as well as other secondary outcomes, was assessed in Cox survival models. Most of the qualifying CVHs were HHF (N = 1496, 64.0%), acute coronary syndromes (N = 390, 16.7%), and arrhythmias (N = 197, 7.2%). The median time of study drug initiation from qualifying CVH was 42 days. The relative rate reductions in CV death/HHF, HHF, and all-cause mortality were similar (P for interaction = 0.65, 0.44, and 0.40, respectively) whether the treatment was initiated <42 or 42+ days after qualifying CVH. Absolute rate reductions were -5.61 [-8.67, -2.55] events per 100 patient x years in the <42 days group and -3.58 [-6.37, -0.79] in the 42+ days group. The adverse effects of eplerenone were also unaffected by the time from the qualifying CVH. Conclusion Eplerenone is safe, improves survival, and may prevent re-admission when initiated soon after a hospitalization for HF or acute coronary syndromes in patients with systolic HF and mild symptoms.
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| 45. |
- Girerd, N., et al.
(författare)
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Serum aldosterone is associated with mortality and re-hospitalization in patients with reduced ejection fraction hospitalized for acute heart failure: analysis from the EVEREST trial
- 2013
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842. ; 15:11, s. 1228-1235
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Post-discharge morbidity and mortality for acute heart failure (AHF) patients remains high. Although the adverse effects of neurohormonal activation are well known in chronic HF, the prognostic significance of serum aldosterone in patients hospitalized for AHF has not been well studied. METHODS AND RESULTS: A secondary analysis was carried out of the placebo arm (n = 1850) from the EVEREST trial which had aldosterone measured at baseline. All patients were hospitalized for worsening HF and had an LVEF <40%. The median follow-up was 9.9 months. The association between serum aldosterone levels at baseline and the independently adjudicated outcomes [all-cause mortality (ACM) and the combined outcome of cardiovascular mortality (CVM) and HF re-hospitalization] were explored with multivariable Cox models. Median aldosterone levels increased during the hospital stay from 11 ng/dL at baseline to 15 ng/dL at discharge (P < 0.001) and remained increased after discharge (16 ng/dL at 24 weeks, P < 0.001). After adjusting for potential confounders, higher baseline aldosterone levels were associated with an increased risk for ACM and CVM or HF re-hospitalization [hazard ratio (HR) 1.49, 95% confidence intrerval (CI) 1.11-1.99; and HR 1.40, 95% CI 1.11-1.78, respectively, in the highest quartile when compared with the lowest]. CONCLUSION: In patients with LVEF <40% hospitalized for AHF and receiving standard therapy, serum aldosterone levels correlated with worse post-discharge outcomes. Aldosterone levels increase during AHF hospitalization and remain increased long after discharge. These results suggest that further modulation of the renin-angiotensin-aldosterone system in patients admitted with worsening HF might favourably improve post-discharge outcomes.
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| 46. |
- Greene, S. J., et al.
(författare)
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Prognostic Value of Monocyte Count in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction (from the EVEREST Trial)
- 2012
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Ingår i: The American journal of cardiology. - : Elsevier BV. - 1879-1913 .- 0002-9149. ; 110:11, s. 1657-1662
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Tidskriftsartikel (refereegranskat)abstract
- Monocytes play a critical role in the pathophysiology of heart failure (HF), but few studies have evaluated the prognostic implications of an increased monocyte count in patients with HF and reduced ejection fraction (EF). The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) examined the effects of tolvaptan in patients with worsening HF and EF /=800/mul. Patients with increased monocyte count tended to have an increased EF and were less likely to have a history of diabetes mellitus, hypercholesterolemia, or coronary revascularization but were more likely to have higher HF functional class and to be taking HF therapies such as diuretics, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and digoxin (p <0.05 for all comparisons). At median follow-up of 9.9 months, increased monocyte count was predictive of all-cause mortality (hazard ratio 1.27, 95% confidence interval 1.003 to 1.60, p = 0.047) but was not associated with cardiovascular mortality or HF hospitalization (hazard ratio 1.06, 95% confidence interval 0.87 to 1.30, p = 0.55). Similar results were seen when monocyte count was analyzed as a continuous variable. However, after adjustment for baseline clinical risk factors, monocyte count was not predictive of either primary end point. In conclusion, increased monocyte count occurs in a minority of patients hospitalized with HF and is associated with poor postdischarge prognosis. However, it does not contribute prognostic value above other more traditional risk factors.
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| 47. |
- Greene, S. J., et al.
(författare)
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The Prognostic Significance of Heart Rate in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction in Sinus Rhythm. Insights From the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) Trial
- 2013
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Ingår i: JACC: Heart Failure. - : Elsevier BV. - 2213-1779. ; 1:6, s. 488-496
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The purpose of this study was to characterize the relationship between heart rate and post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction (EF) in sinus rhythm. Background: A reduction in heart rate improves clinical outcomes in patients with chronic heart failure and in sinus rhythm, but the association between heart rate and post-discharge outcomes in patients with HHF is presently unclear. Methods: This post-hoc analysis of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial examined 1,947 patients with HHF and EF≤40% not in atrial fibrillation/flutter or pacemaker dependent. Results: The median follow-up period was 9.9 months. At baseline, patients with a higher heart rate tended to be younger with lower EF and were more likely to have worse New York Heart Association functional class and higher natriuretic peptide levels. After adjustment for clinical risk factors, baseline heart rate was not predictive of all-cause mortality (p≥ 0.066). However, at≥70 beats/min, every 5-beat increase in 1-week post-discharge heart rate was independently associated with increased all-cause mortality (hazard ratio: 1.13 [95% confidence interval: 1.05 to 1.22]; p= 0.002). Similarly, every 5-beat increase≥70 beats/min in 4-week post-discharge heart rate was predictive of all-cause mortality (hazard ratio: 1.12 [95% confidence interval: 1.05 to 1.19]; p= 0.001). Conclusions: In this large cohort of patients with HHF with reduced EF and in sinus rhythm, baseline heart rate did not correlate with all-cause mortality. In contrast, at≥70 beats/min, higher heart rate in the early post-discharge period was independently predictive of death during subsequent follow-up. Further study of post-discharge heart rate as a potential therapeutic target in this high-risk population is encouraged. © 2013 American College of Cardiology Foundation.
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| 48. |
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| 49. |
- Haffner, S. M., et al.
(författare)
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Metabolic syndrome, new onset diabetes, and new end points in cardiovascular trials
- 2006
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Ingår i: J Cardiovasc Pharmacol. - 0160-2446. ; 47:3, s. 469-75
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic syndrome affects approximately 44% of the US population over the age of 50 years. Although conflicting definitions exist, the syndrome is typically characterized by abdominal obesity, dyslipidemia, hypertension, and insulin resistance. Thus, it is a major risk factor for both coronary heart disease and type 2 diabetes. Furthermore, the risk of cardiovascular (CV) death is significantly increased in patients with diabetes and/or the metabolic syndrome. Although very few studies exist in patients with the metabolic syndrome, lifestyle changes and drug intervention targeted at the individual components have been shown to reduce the risk of developing diabetes and the incidence of CV disease in high-risk patients. Because many of the conventional antihypertensive drugs may affect the development of new onset diabetes, both positively and negatively, the choice of therapy is particularly important in this population. However, the long-term clinical trials to date have either not included new onset diabetes as a protocol end point or used various different criteria, making comparisons difficult. This review assesses the need for future research into metabolic syndrome and discusses whether clinical surrogates for CV end points, such as new onset diabetes, should be included in clinical trials of new drugs, new regimens, or new indications.
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| 50. |
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