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1.	Dicker, D, et al. (author) Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017 2018 In: Lancet (London, England). - 1474-547X .- 0140-6736. ; 392:10159, s. 1684-1735 Journal article (peer-reviewed)
2.	James, SL, et al. (author) Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017 2018 In: Lancet (London, England). - 1474-547X .- 0140-6736. ; 392:10159, s. 1789-1858 Journal article (peer-reviewed)
3.	Kyu, HH, et al. (author) Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017 2018 In: Lancet (London, England). - 1474-547X .- 0140-6736. ; 392:10159, s. 1859-1922 Journal article (peer-reviewed)
4.	Roth, GA, et al. (author) Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017 2018 In: Lancet (London, England). - 1474-547X .- 0140-6736. ; 392:10159, s. 1736-1788 Journal article (peer-reviewed)
5.	Lozano, Rafael, et al. (author) Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017 2018 In: The Lancet. - : Elsevier. - 1474-547X .- 0140-6736. ; 392:10159, s. 2091-2138 Journal article (peer-reviewed)abstract Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030.
6.	Murray, Christopher J. L., et al. (author) Population and fertility by age and sex for 195 countries and territories, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017 2018 In: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1995-2051 Journal article (peer-reviewed)abstract Background: Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. Methods: We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10–54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10–14 years and 50–54 years was estimated from data on fertility in women aged 15–19 years and 45–49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. Findings: From 1950 to 2017, TFRs decreased by 49·4% (95% uncertainty interval [UI] 46·4–52·0). The TFR decreased from 4·7 livebirths (4·5–4·9) to 2·4 livebirths (2·2–2·5), and the ASFR of mothers aged 10–19 years decreased from 37 livebirths (34–40) to 22 livebirths (19–24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83·8 million people per year since 1985. The global population increased by 197·2% (193·3–200·8) since 1950, from 2·6 billion (2·5–2·6) to 7·6 billion (7·4–7·9) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2·0%; this rate then remained nearly constant until 1970 and then decreased to 1·1% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2·5% in 1963 to 0·7% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2·7%. The global average age increased from 26·6 years in 1950 to 32·1 years in 2017, and the proportion of the population that is of working age (age 15–64 years) increased from 59·9% to 65·3%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1·0 livebirths (95% UI 0·9–1·2) in Cyprus to a high of 7·1 livebirths (6·8–7·4) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0·08 livebirths (0·07–0·09) in South Korea to 2·4 livebirths (2·2–2·6) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0·3 livebirths (0·3–0·4) in Puerto Rico to a high of 3·1 livebirths (3·0–3·2) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2·0% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. Interpretation: Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress. Funding: Bill & Melinda Gates Foundation.
7.	Stanaway, Jeffrey D., et al. (author) Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017 2018 In: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994 Journal article (peer-reviewed)abstract Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
8.	Johnson, CO, et al. (author) Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016 2019 In: The Lancet. Neurology. - 1474-4465 .- 1474-4422. ; 18:5, s. 439-458 Journal article (peer-reviewed)
9.	Inciardi, RM, et al. (author) OPTImal PHARMacological therapy for patients with heart failure: Rationale and design of the OPTIPHARM-HF registry 2024 In: European journal of heart failure. - 1879-0844. ; 26:8, s. 1707-1714 Journal article (peer-reviewed)
10.	Mc Causland, F. R., et al. (author) Angiotensin-neprilysin inhibition and renal outcomes across the spectrum of ejection fraction in heart failure 2022 In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:9, s. 1591-8 Journal article (peer-reviewed)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.
11.	Mentz, R. J., et al. (author) Atrial fibrillation or flutter on initial electrocardiogram is associated with worse outcomes in patients admitted for worsening heart failure with reduced ejection fraction: Findings from the EVEREST Trial 2012 In: American Heart Journal. - : Elsevier BV. - 0002-8703. ; 164:6 Journal article (peer-reviewed)abstract Background Heart failure (HF) complicated by atrial fibrillation/flutter (AF/AFL) is associated with worse outcomes. However, the clinical profile and outcomes of patients following hospitalization for HF with AF/AFL on initial electrocardiogram (ECG) has not been well studied. Methods EVEREST was a randomized trial of vasopressin-2 receptor blockade, in addition to standard therapy, in 4133 patients hospitalized with HF with ejection fraction <= 40%. A post hoc analysis was performed comparing the clinical characteristics and outcomes [all-cause mortality and cardiovascular mortality/HF hospitalization] of patients with AF/AFL versus sinus rhythm (SR) on baseline ECG, which were centrally analyzed. Times to events were compared using log-rank tests and Cox regression models. Results Of the 4133 patients, 1195 (29%) were classified with AF/AFL and 2071(50%) with SR. The remaining patients (21%) were excluded because ECGs were unavailable (n = 106), rhythm was paced (n = 727), or junctional/other supraventricular (n = 34). AF/AFL patients were older, with increased weight, faster heart rate, higher blood urea nitrogen, and natriuretic peptide levels compared to SR patients. Anticoagulation was prescribed in 67% of AF/AFL patients on discharge. AF/AFL patients were less likely to receive beta-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (all P < .05). After risk adjustment, AF/AFL was associated with increased mortality (hazard ratio 1.23; 95% CI, 1.04-1.46) and cardiovascular mortality/HF hospitalization (hazard ratio 1.26; 95% CI, 1.07-1.47). Conclusion AF/AFL on initial ECG in patients hospitalized with HF with reduced ejection fraction is associated with lower use of evidence-based therapies and increased mortality and rehospitalization compared to patients in SR. (Am Heart J 2012;164:884-892.e2.)
12.	Vaduganathan, M., et al. (author) Relation of Serum Uric Acid Levels and Outcomes Among Patients Hospitalized for Worsening Heart Failure With Reduced Ejection Fraction (from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan Trial) 2014 In: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 114:11, s. 1713-21 Journal article (peer-reviewed)abstract We investigated the clinical profiles associated with serum uric acid (sUA) levels in a large cohort of patients hospitalized for worsening chronic heart failure with ejection fraction (EF) /=30 ml/min/1.73 m(2), sUA was strongly associated with increased all-cause mortality (hazard ratio 1.44, 95% confidence interval 1.22 to 1.69, p <0.001) and the composite end point (hazard ratio 1.44, 95% confidence interval 1.26 to 1.64, p <0.001). However, in patients with estimated glomerular filtration rate <30 ml/min/1.73 m(2), sUA was not related with either end point (both p >0.4). Adjusted interaction analyses for gender, race, and admission allopurinol use were not significant. In conclusion, sUA is commonly elevated in patients hospitalized for worsening chronic heart failure and reduced EF, especially in men and blacks. The prognostic use of sUA differs by baseline renal function, suggesting different biologic and pathophysiologic significance of sUA among those with and without significant renal dysfunction.
13.	Ambrosy, A. P., et al. (author) 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 In: European journal of heart failure. - : Wiley. - 1879-0844 .- 1388-9842. ; 14:3, s. 302-311 Journal article (peer-reviewed)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.
14.	Mentz, R. J., et al. (author) Influence of documented history of coronary artery disease on outcomes in patients admitted for worsening heart failure with reduced ejection fraction in the EVEREST trial 2013 In: European journal of heart failure. - : Wiley. - 1879-0844 .- 1388-9842. ; 15:1, s. 61-68 Journal article (peer-reviewed)abstract AIMS: Data on the prognosis of heart failure (HF) patients with coronary artery disease (CAD) have been conflicting. We describe the clinical characteristics and mode-specific outcomes of HF patients with reduced ejection fraction (EF) and documented CAD in a large randomized trial. METHODS AND RESULTS: EVEREST was a prospective, randomized trial of vasopressin-2 receptor blockade, in addition to standard therapy, in 4133 patients hospitalized with worsening HF and reduced EF. Patients were classified as having CAD based on patient-reported myocardial infarction (MI) or coronary revascularization. We analysed the characteristics and outcomes [all-cause mortality and cardiovascular (CV) mortality/HF hospitalization] of patients with and without documented CAD. All events were centrally adjudicated. Documented CAD was present in 2353 patients (57%). Patients with CAD were older and had more co-morbidities compared with those without CAD. Patients with CAD were more likely to receive a beta-blocker, but less likely to receive an angiotensin-converting enzyme (ACE) inhibitor or aldosterone antagonist (P < 0.01). After risk adjustment, patients with documented CAD had similar mortality [hazard ratio (HR) 1.12, 95% confidence interval (CI) 0.97-1.30], but were at an increased risk for CV mortality/HF hospitalization (HR 1.25, 95% CI 1.12-1.41) due to an increased risk for HF hospitalization (HR 1.26, 95% CI 1.10-1.44). Patients with CAD had increased HF- and MI-related events, but similar rates of sudden cardiac death. CONCLUSION: Documented CAD in patients hospitalized for worsening HF with reduced EF was associated with a higher burden of co-morbidities, lower use of HF therapies (except beta-blockers), and increased HF hospitalization, while all-cause mortality was similar.
15.	Wijkman, Magnus, et al. (author) Effects of sacubitril/valsartan on glycemia in patients with diabetes and heart failure: the PARAGON-HF and PARADIGM-HF trials 2022 In: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 21:1 Journal article (peer-reviewed)abstract Background Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. Methods We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. Results Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: - 0.24%, 95% CI - 0.33 to - 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62-1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05-2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (P-interaction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63-0.89, P = 0.001), compared with enalapril or valsartan. Conclusions Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711
16.	Bhatt, A. S., et al. (author) Effect of sacubitril/valsartan vs. enalapril on changes in heart failure therapies over time: the PARADIGM-HF trial 2021 In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:9, s. 1518-1524 Journal article (peer-reviewed)abstract Aims Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing of other elements of guideline-directed medical therapy for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on beta-blocker and mineralocorticoid receptor antagonist (MRA) use and dosing in a large randomized clinical trial. Methods and results Patients with full data on medication use were included. We examined beta-blocker and MRA use in patients randomized to sacubitril/valsartan vs. enalapril through 12-month follow-up. New initiations and discontinuations of beta-blocker and MRA were compared between treatment groups. Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of beta-blocker and MRA at any dose was 87% and 56%, respectively. Mean doses of beta-blocker and MRA were similar between treatment groups at baseline and at 6-month and 12-month follow-up. New initiations through 12-month follow-up were infrequent and similar in the sacubitril/valsartan and enalapril groups for beta-blockers [37 (9.0%) vs. 42 (10.2%), P = 0.56] and MRA [127 (7.6%) vs. 143 (9.2%), P = 0.10]. Among patients on MRA therapy at baseline, there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12 months [125 (6.2%) vs. 187 (9.0%), P = 0.001]. Discontinuations of beta-blockers were not significantly different between groups in follow-up (2.2% vs. 2.6%, P = 0.26). Conclusions Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose down-titration of other key guideline-directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow-up.
17.	Fudim, M, et al. (author) Prognosis for patients with heart failure and reduced ejection fraction with and without diabetes: A 7 year nationwide veteran administration analysis 2022 In: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 346, s. 30-34 Journal article (peer-reviewed)
18.	Greene, S. J., et al. (author) Prognostic Value of Monocyte Count in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction (from the EVEREST Trial) 2012 In: The American journal of cardiology. - : Elsevier BV. - 1879-1913 .- 0002-9149. ; 110:11, s. 1657-1662 Journal article (peer-reviewed)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.
19.	Greene, S. J., et al. (author) 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 In: JACC: Heart Failure. - : Elsevier BV. - 2213-1779. ; 1:6, s. 488-496 Journal article (peer-reviewed)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.
20.	Khan, M. S., et al. (author) Natriuretic peptide plasma concentrations and risk of cardiovascular versus non-cardiovascular events in heart failure with reduced ejection fraction: Insights from the PARADIGM-HF and ATMOSPHERE trials 2021 In: American Heart Journal. - : Elsevier BV. - 0002-8703. ; 237, s. 45-53 Journal article (peer-reviewed)abstract Background : N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known. Objective : To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations. Methods : In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels ( <400, 400-999, 1000-1999, 2000-2999, and >3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors. Results : A total of 14,737 patients with mean age of 62 +/- 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the <= 400 pg/mL group to 142.3 in the >= 3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months. Conclusions : The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.
21.	Khan, S. S., et al. (author) Changes in Serum Potassium Levels During Hospitalization in Patients With Worsening Heart Failure and Reduced Ejection Fraction (from the EVEREST Trial) 2015 In: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 115:6, s. 790-796 Journal article (peer-reviewed)abstract Both hyperkalemia and hypokalemia may be related to heart failure (HF) therapy and are associated with adverse outcomes. Abnormalities in serum potassium levels in hospitalized patients with HF and reduced ejection fraction (EF) have not been previously investigated. A post hoc analysis was performed in 1,907 hospitalized patients with worsening HF and reduced EF in the placebo arm of the Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan (EVEREST) trial. Serum potassium was measured at randomization and at discharge or day 7. The co-primary end points were all-cause mortality (ACM) and cardiovascular mortality or the first HF hospitalization (CVM + HFH). The association between inhospital change in potassium levels and time to outcomes was evaluated using multivariate Cox regression models. Study participants had a mean age of 65.6 +/- 12.0 years and were on optimal guideline-directed medical therapies, including beta blockers (77%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (85%), and aldosterone antagonists (55%). Baseline potassium concentration was 4.3 +/- 0.6 mEq/l, and hyperkalemia or hypokalemia was seen in 6.5% of the participants. On average, serum potassium level increased by 0.21 +/- 0.66 mEq/l, p < 0.0001, during hospitalization. Inhospital potassium change was not associated with either the primary or the secondary end point over a median follow-up of 9.9 months. In conclusion, in patients with reduced EF hospitalized for worsening HF, serum potassium abnormalities are common at baseline (within 48 hours of admission) and potassium levels increase during hospitalization, despite aggressive diuretic therapy. However, they are not associated with all-cause or CVM or HFH. Inhospital changes in potassium may limit the implementation of evidence-based therapies such as mineralocorticoid receptor antagonists. (C) 2015 Elsevier Inc. All rights reserved.
22.	Rohde, L. E., et al. (author) Associations Between New York Heart Association Classification, Objective Measures, and Long-term Prognosis in Mild Heart Failure A Secondary Analysis of the PARADIGM-HF Trial 2023 In: Jama Cardiology. - : American Medical Association (AMA). - 2380-6583. ; 8:2, s. 150-158 Journal article (peer-reviewed)abstract Importance Heart failure (HF) treatment recommendations are centered on New York Heart Association (NYHA) classification, such that most apparently asymptomatic patients are not eligible for disease-modifying therapies.Objectives To assess within-patient variation in NYHA classification over time, the association between NYHA class and an objective measure of HF severity (N-terminal pro-B-type natriuretic peptide [NT-proBNP] level), and their association with long-term prognosis in the PARADIGM-HF trial.Design, Setting, and Participants All patients in PARADIGM-HF were in NYHA class II or higher at baseline and were treated with sacubitril-valsartan during a 6- to 10-week run-in period before randomization. Patients classified as NYHA class I, II, and III in PARADIGM-HF were compared at randomization.Exposures NYHA class at randomization after 6 to 10 weeks of the run-in period.Main Outcomes and Measures Primary outcome was cardiovascular death or first HF hospitalization. Logistic regression models, areas under the receiver operating characteristic curve (AUC), kernel density estimation overlaps, and Cox proportional hazards models were used.Results The analysis included 8326 patients with known NYHA classification at randomization. Of 389 patients in NYHA class I, 228 (58%) changed functional class during the first year after randomization. Level of NT-proBNP was a poor discriminator of NYHA classification: for NYHA class I vs II, the AUC was 0.51 (95% CI, 0.48-0.54). For NT-proBNP level, estimated kernel density overlap was 93% between NYHA class I vs II, 79% between NYHA I vs III, and 83% between NYHA II vs III. Patients classified as NYHA III displayed a distinctively higher rate of cardiovascular events (NYHA III vs I, hazard ratio [HR], 1.84; 95% CI, 1.44-2.37; NYHA III vs II, HR, 1.49; 95% CI, 1.35-1.64). Patients in NYHA class I and II revealed lower event rates (NYHA II vs I, HR, 1.24; 95% CI, 0.97-1.58). Stratification by NT-proBNP level (< 1600 pg/mL or >= 1600 pg/mL) identified subgroups with distinctive risk, such that NYHA class I patients with high NT-proBNP levels (n = 175) had a numerically higher event rate than patients with low NT-proBNP levels from any NYHA class (vs I, HR, 3.43; 95% CI, 2.03-5.87; vs II, HR, 2.12; 95% CI, 1.58-2.86; vs III, HR, 1.37; 95% CI, 1.00-1.88).Conclusions and Relevance In this study, patients in NYHA class I and II overlapped substantially in objective measures and long-term prognosis. Physician-defined "asymptomatic " functional class concealed patients who were at substantial risk for adverse outcomes. NYHA classification might be limited to differentiate mild forms of HF.
23.	Rohde, L. E., et al. (author) Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death in heart failure with reduced ejection fraction: a PARADIGM-HF analysis 2021 In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:8, s. 1346-1356 Journal article (peer-reviewed)abstract Aims Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment. Methods and results We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1 year prior to the event (P-interaction < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square = 46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05). Conclusions Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.
24.	Rohde, L. E., et al. (author) Sacubitril/Valsartan and Sudden Cardiac Death According to Implantable Cardioverter-Defibrillator Use and Heart Failure Cause: A PARADIGM-HF Analysis 2020 In: Jacc-Heart Failure. - : Elsevier BV. - 2213-1779. ; 8:10, s. 844-855 Journal article (peer-reviewed)abstract OBJECTIVES The purpose of this study was to investigate the effect of sacubitril/valsartan therapy on sudden cardiac death (SCD) according to the use of and eligibility for an implantable cardioverter-defibrillator (ICD), stratified by heart failure cause. BACKGROUND SCD still accounts for a significant proportion of overall mortality in heart failure with reduced ejection fraction (HFrEF). METHODS Patients enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial (n = 8,399) were evaluated to assess patterns of ICD implantation and eligibility according to clinical guidelines. The impact of ICD (adjusted for propensity of ICD implantation) and sacubitril/valsartan therapy on SCD was evaluated by using cause-specific Cox models and competing risk analysis. RESULTS At baseline, of the 7,145 patients (85%) eligible for ICD implantation, only 1,243 (15%) had an ICD. Use of ICD varied by region with the highest rates in North America (56%) and lowest in Asia-Pacific (1.7%). In a propensity score-adjusted analysis, use of an ICD was associated with a 56% lower risk of SCD in ICD-eligible patients, in both patients with ischemic (p < 0.001) and nonischemic cardiomyopathy (p = 0.02). Sacubitril/valsartan reduced SCD risk in patients with an ICD (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.25 to 0.99) and in those who were eligible for but did not receive an ICD (HR: 0.81; 95% CI: 0.67 to 0.98). This effect was particularly evident in nonischemic cardiomyopathy (p < 0.05), although interaction with the cause of HF was not significant (p = 0.11 in subjects using an ICD and p = 0.25 in eligible nonusers). CONCLUSIONS Use of an ICD was associated with lower rates of SCD, regardless of HF cause but was underused in most regions of the world in the PARADIGM-HF study. Sacubitril/valsartan reduced SCD risk regardless of use of an ICD or eligibility, particularly in ICD users and nonischemic cardiomyopathy. (c) 2020 Published by Elsevier on behalf of the American College of Cardiology Foundation.
25.	Selvaraj, S., et al. (author) Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients With Heart Failure and Reduced Ejection Fraction PARADIGM-HF 2019 In: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 140:17, s. 1369-1379 Journal article (peer-reviewed)abstract Abstract Background: The contemporary prognostic value of the physical examination— beyond traditional risk factors including natriuretic peptides, risk scores, and symptoms—in heart failure (HF) with reduced ejection fraction is unknown. We aimed to determine the association between physical signs of congestion at baseline and during study follow-up with quality of life and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion. Methods: We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and third heart sound) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up and whether improvement in congestion is related to changes in clinical outcomes and quality of life, assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores. Results: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2% of patients, respectively. Patients with baseline congestion were older, more often female, had higher MAGGIC risk scores (Meta-Analysis Global Group in Chronic Heart Failure) and lower Kansas City Cardiomyopathy Questionnaire overall summary scores (P<0.05). After adjusting for baseline natriuretic peptides, time-updated Meta-Analysis Global Group in Chronic Heart Failure score, and time-updated New York Heart Association class, increasing time-updated congestion was associated with all outcomes (P<0.001). Sacubitril/valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline (P=0.16 for interaction), and treatment with the drug improved congestion to a greater extent than did enalapril (P=0.011). Each 1-sign reduction was independently associated with a 5.1 (95% CI, 4.7–5.5) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary scores. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (P<0.001). Conclusions: In HF with reduced ejection fraction, the physical exam continues to provide significant independent prognostic value even beyond symptoms, natriuretic peptides, and Meta-Analysis Global Group in Chronic Heart Failure risk score. Sacubitril/valsartan improved congestion to a greater extent than did enalapril. Reducing congestion in the outpatient setting is independently associated with improved quality of life and reduced cardiovascular events, including mortality.
26.	Shen, L., et al. (author) Incidence and Outcomes of Pneumonia in Patients With Heart Failure 2021 In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 77:16, s. 1961-1973 Journal article (peer-reviewed)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
27.	Tolomeo, P., et al. (author) Importance of cystatin C in estimating glomerular filtration rate: the PARADIGM-HF trial 2023 In: European Heart Journal. - 0195-668X .- 1522-9645. ; 44:24, s. 2202-2212 Journal article (peer-reviewed)abstract Aims The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation combining creatinine and cystatin C provides a better estimation of glomerular filtration rate (GFR) compared to the creatinine-only equation.Methods and results CKD-EPI creatinine-cystatin C equation (creatinine-cystatin) was compared to creatinine-only (creatinine) equation in a subpopulation of Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF). Patients were categorized according to difference in eGFR using the two equations: Group 1 (<-10 mL/min/1.73 m(2), i.e. creatinine-cystatin more than 10 mL/min lower than creatinine), Group 2 (>-10 and <10 mL/min/1.73 m(2)), and Group 3 (>10 mL/min/1.73 m(2), i.e. creatinine-cystatin more than 10 mL/min higher than creatinine). Cystatin C and creatinine were available in 1966 patients at randomization. Median (interquartile range) eGFR difference was -0.7 (-6.4-4.8) mL/min/1.73 m(2). Compared to creatinine, creatinine-cystatin led to a substantial reclassification of chronic kidney disease stages. Overall, 212 (11%) and 355 (18%) patients were reallocated to a better and worse eGFR category, respectively. Compared to patients in Group 2, those in Group 1 (lower eGFR with creatinine-cystatin) had higher mortality and those in Group 3 (higher eGFR with creatinine-cystatin) had lower mortality. Increasing difference in eGFR (due to lower eGFR with creatinine-cystatin compared to creatinine) was associated with increasing elevation of biomarkers (including N-terminal pro-B-type natriuretic peptide and troponin) and worsening Kansas City Cardiomyopathy Questionnaire clinical summary score. The reason why the equations diverged with increasing severity of heart failure was that creatinine did not rise as steeply as cystatin C.Conclusion The CKD-EPI creatinine-only equation may overestimate GFR in sicker patients.
28.	Ambrosy, A. P., et al. (author) 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 In: Circulation-Heart Failure. - : Ovid Technologies (Wolters Kluwer Health). - 1941-3289 .- 1941-3297. ; 9:5 Journal article (peer-reviewed)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.
29.	Ambrosy, A. P., et al. (author) Clinical profile and prognostic value of low systolic blood pressure in patients hospitalized for heart failure with reduced ejection fraction: insights from the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial 2013 In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 165:2, s. 216-25 Journal article (peer-reviewed)abstract BACKGROUND: Systolic blood pressure (SBP) is related to the pathophysiologic development and progression of heart failure (HF) and is inversely associated with adverse outcomes during hospitalization for HF (HHF). The prognostic value of SBP after initiating inhospital therapy and the mode of death and etiology of cardiovascular readmissions based on SBP have not been well characterized in HHF. METHODS: A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 hours of admission for worsening HF with an ejection fraction (EF) /=90 mm Hg, for a median follow-up of 9.9 months. Systolic blood pressure was measured at baseline, daily during hospitalization, and at discharge/day 7. Patients were divided into the following quartiles by SBP at baseline: /=131 mm Hg. Outcomes were all-cause mortality (ACM) and the composite of cardiovascular mortality or HHF (CVM + HHF). The associations between baseline, discharge, and inhospital change in SBP and ACM and CVM + HHF were assessed using multivariable Cox proportional hazards regression models adjusted for known covariates. RESULTS: Median (25th, 75th) SBP at baseline was 120 (105, 130) mm Hg and ranged from 82 to 202 mm Hg. Patients with a lower SBP were younger and more likely to be male; had a higher prevalence of prior revascularization and ventricular arrhythmias; had a lower EF, worse renal function, higher natriuretic peptide concentrations, and wider QRS durations; and were more likely to require intravenous inotropes during hospitalization. Lower SBP was associated with increased mortality, driven by HF and sudden cardiac death, and cardiovascular hospitalization, primarily caused by HHF. After adjusting for potential confounders, SBP was inversely associated with risk of the coprimary end points both at baseline (ACM: hazard ratio [HR]/10-mm Hg decrease 1.15, 95% CI1.08-1.22; CVM + HHF: HR 1.09/10-mm Hg decrease, 95% CI 1.04-1.14) and at the time of discharge/day 7 (ACM: HR 1.15/10-mm Hg decrease, 95% CI 1.08-1.22; CVM + HHF: HR 1.07/10-mm Hg decrease, 95% CI 1.02-1.13), but the association with inhospital SBP change was not significant. CONCLUSION: Systolic blood pressure is an independent clinical predictor of morbidity and mortality after initial therapy during HHF with reduced EF.
30.	Butler, J., et al. (author) 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 In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 61:5, s. 571-579 Journal article (peer-reviewed)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
31.	Cunningham, J. W., et al. (author) Myocardial Infarction in Heart Failure With Preserved Ejection Fraction Pooled Analysis of 3 Clinical Trials 2020 In: Jacc-Heart Failure. - : Elsevier BV. - 2213-1779. ; 8:8, s. 618-626 Journal article (peer-reviewed)abstract OBJECTIVES The authors investigated the relationship between past or incident myocardial infarction (MI) and car-diovascular (CV) events in heart failure with preserved ejection fraction (HFpEF). BACKGROUND MI and HFpEF share some common risk factors. The prognostic significance of MI in patients with HFpEF is uncertain. METHODS The authors pooled data from 3 trials-CHARM Preserved (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity), I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function), and the Americas region of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) (N 1/4 8,916)-and examined whether MI before or following enrollment independently predicted CV death and heart failure (HF) hospitalization. RESULTS At baseline, 2,668 patients (30%) had history of MI. Prior MI was independently associated with greater risk of CV death (4.7 vs. 3.5 events/100 patient-years [py], adjusted hazard ratio [HR]: 1.42 [95% confidence interval (CI): 1.23 to 1.64]; p < 0.001). Excess sudden death drove this difference (1.9 vs. 1.2 events/100 py, adjusted HR: 1.55 [95% CI: 1.23 to 1.97]; p < 0.001). There was no difference in HF hospitalization (5.9 vs. 5.5 events/100 py, adjusted HR: 1.05, 95% CI: 0.92 to 1.19) or HF death by prior MI. During follow-up, MI occurred in 336 patients (3.8%). Risk of CV death increased 31-fold in the first 30 days after first post-enrollment MI, and remained 58% higher beyond 1 year after MI. Risk of first or recurrent HF hospitalization increased 2.4-fold after MI. CONCLUSIONS Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes. Patients with HFpEF who experience MI are at high risk of subsequent CV death and HF hospitalization. These data highlight the importance of primary and secondary prevention of MI in patients with HFpEF. (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve]; NCT00095238; and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302) (J Am Coll Cardiol HF 2020;8:618-26) (c) 2020 by the American College of Cardiology Foundation.
32.	Vaduganathan, M., et al. (author) Efficacy of oral tolvaptan in acute heart failure patients with hypotension and renal impairment 2012 In: Journal of Cardiovascular Medicine. - 1558-2027. ; 13:7, s. 415-422 Journal article (peer-reviewed)
33.	Vaduganathan, M., et al. (author) Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure 2018 In: Jacc-Heart Failure. - : Elsevier BV. - 2213-1779. ; 6:7, s. 564-569 Journal article (peer-reviewed)abstract OBJECTIVES This study sought to determine whether treatment-related changes in natriuretic peptides (NPs) predict longer-term therapeutic effects in clinical trials of heart failure (HF). BACKGROUND The lack of reliable predictors of efficacy of drugs and devices in HF has presented a major hurdle to the development and evaluation of novel therapies. METHODS The study conducted a trial-level analysis of 16 phase III chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. Weighted Pearson correlation coefficients were calculated between average control-or placebo-corrected changes in NPs and longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios). RESULTS Median follow-up for clinical endpoints was 28 (25th to 75th percentile range: 18 to 36) months. NPs were available in a median of 748 (25th to 75th percentile range: 270 to 1,868) patients and measured at a median of 4 (25th to 75th percentile range: 3 to 6) months after randomization. Treatment-related changes in NPs were not correlated with longer-term treatment effects on all-cause mortality (r = 0.12; p = 0.63), but were correlated with HF hospitalization (r = 0.63; p = 0.008). Correlation with HF hospitalization improved when analyses were restricted to trials completed in the last decade (>2010; r = 0.92; p = 0.0095), using N-terminal pro-B-type NP assays (r = 0.65; p = 0.06), and evaluating inhibitors of the renin-angiotensin-aldosterone system (r = 0.97; p = 0.0002). CONCLUSIONS When examining a broad range of interventions, therapy-related changes in NPs appeared modestly correlated with longer-term therapeutic effects on hospitalization for HF, but not with effects on all-cause mortality. These observations raise important caveats regarding the use of NPs in phase II trials for decision making regarding phase III trials. (C) 2018 by the American College of Cardiology Foundation.
34.	Vaduganathan, M., et al. (author) Predictive Value of Low Relative Lymphocyte Count in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction: Insights from the EVEREST Trial 2012 In: Circulation. Heart failure. - 1941-3297. ; 5:6, s. 750-758 Journal article (peer-reviewed)abstract Background- Low lymphocyte count has been shown to be an independent prognostic marker in heart failure (HF) in the outpatient setting. Limited data exist regarding whether relative lymphocyte count correlates with postdischarge outcomes in patients hospitalized for HF. Methods and Results- We performed a post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, which randomized 4133 patients hospitalized for worsening HF with an ejection fraction
35.	Vaduganathan, M., et al. (author) Predictive Value of Low Relative Lymphocyte Count in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction Insights from the EVEREST Trial 2012 In: Circulation-Heart Failure. - : Ovid Technologies (Wolters Kluwer Health). - 1941-3289 .- 1941-3297. ; 5:6, s. 750-758 Journal article (peer-reviewed)abstract Background—Low lymphocyte count has been shown to be an independent prognostic marker in heart failure (HF) in the outpatient setting. Limited data exist regarding whether relative lymphocyte count correlates with postdischarge outcomes in patients hospitalized for HF. Methods and Results—We performed a post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, which randomized 4133 patients hospitalized for worsening HF with an ejection fraction ≤40% within 48 hours of admission to tolvaptan or placebo for a median follow-up of 9.9 months. The primary end points of all-cause mortality and cardiovascular mortality or HF hospitalization were analyzed in patients with available baseline complete blood counts (n=3717). Lymphocyte percentage was analyzed as a continuous variable. Times to events were compared using log-rank tests and multivariable Cox regression models. Patients with low lymphocyte percentage tended to be older and had higher rates of comorbid disease (diabetes mellitus, atrial fibrillation, and renal insufficiency). Low lymphocyte counts were associated with wide QRS duration, high natriuretic peptides, and low ejection fraction, blood pressure, and serum sodium. These patients were less likely to receive evidence-based HF medications. After adjusting for 22 known clinical risk factors, a 10% decrease in lymphocytes was associated with an increased hazard of all-cause mortality (adjusted hazard ratio 1.31 [95% CI: 1.14–1.150], P<0.001) and cardiovascular mortality or HF hospitalization (adjusted hazard ratio 1.14 [95% CI: 1.04–1.25], P=0.007) in the first 100 days postdischarge. Lymphopenia during hospitalization normalizes in majority of patients in the early postdischarge period. Conclusions—Low relative lymphocyte count during hospitalization for HF is an independent predictor of poor outcomes in the early postdischarge period, beyond traditional prognostic indicators.
36.	Yadgir, S, et al. (author) Global, Regional, and National Burden of Calcific Aortic Valve and Degenerative Mitral Valve Diseases, 1990-2017 2020 In: Circulation. - 1524-4539. ; 141:21, s. 1670-1680 Journal article (peer-reviewed)
37.	Mentz, R. J., et al. (author) Clinical Profile and Prognostic Value of Anemia at the Time of Admission and Discharge Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction: Findings From the EVEREST Trial 2014 In: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 7:3, s. 401-8 Journal article (peer-reviewed)abstract BACKGROUND: Anemia has been associated with worse outcomes in patients with chronic heart failure (HF). We aimed to characterize the clinical profile and postdischarge outcomes of hospitalized HF patients with anemia at admission or discharge. METHODS AND RESULTS: An analysis was performed on 3731 (90%) of 4133 hospitalized HF patients with ejection fraction 100 days) on adjusted analysis (both P>0.1). CONCLUSIONS: Among hospitalized HF patients with reduced ejection fraction, modest anemia at discharge but not baseline was associated with increased all-cause mortality and short-term cardiovascular mortality plus HF hospitalization. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00071331.
38.	Vaduganathan, M, et al. (author) Sudden Death After Hospitalization for Heart Failure With Reduced Ejection Fraction (from the EVEREST Trial) 2018 In: Am J Cardiol. - : Elsevier BV. - 1879-1913. ; 122:2, s. 255-260 Journal article (peer-reviewed)abstract Patients with chronic heart failure with reduced ejection fraction (HFrEF) benefit from medical and device therapies targeting sudden cardiac death (SCD). Contemporary estimates of SCD risk after hospitalization for heart failure are limited. We describe the incidence, timing, and clinical predictors of SCD after hospitalization for HFrEF (30 baseline covariates (including treatment randomization, demographics, comorbid conditions, natriuretic peptides, ejection fraction, and medical and device therapies) to identify predictors of 1-year SCD. Of the 4,024 trial patients discharged alive (97%), there were 268 who experienced SCD (7%) and 703 who experienced non-SCD (17%) during median follow-up of 9.9 months. Implantable cardioverter defibrillator use at baseline was 14.5%. Estimates of SCD at 1, 3, 6, and 12 months were 0.8%, 2.3%, 4.1%, and 7.4%, respectively. Most patients were readmitted before SCD (n = 147, 55%). Male gender, black race, diabetes mellitus, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were potential predictors of 1-year SCD after hospitalization for HFrEF (all p <0.10); however, this final model demonstrated poor discrimination (C-statistic 0.57). In conclusion, in the EVEREST trial, patients hospitalized for HFrEF faced risks of 1-year postdischarge SCD of 7%, which accrued gradually over time, and were balanced with high competing risks of nonsudden death (17%). Traditional clinical characteristics fail to adequately predict SCD risk. Further data are needed to identify patients at greatest relative risk for SCD (compared with non-SCD) after hospitalization for HFrEF.
39.	Cunningham, Jonathan W., et al. (author) Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction. 2022 In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 80:14, s. 1302-1310 Journal article (peer-reviewed)abstract BACKGROUND: Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death. OBJECTIVES: The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization. METHODS: The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF $>$40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death. RESULTS: Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P $<$ 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients. CONCLUSIONS: Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
40.	Khan, Muhammad Shahzeb, et al. (author) Leveraging electronic health records to streamline the conduct of cardiovascular clinical trials 2023 In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 44:21, s. 1890-1909 Research review (peer-reviewed)abstract Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. Trial recruitment, participation, and data collection can burden participants and research personnel. In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication. Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. Importantly, the data collection infrastructure should be reusable to support multiple cardiovascular RCTs over time. Systems, processes, and policies will need to have sufficient flexibility to allow interoperability between different sources of data acquisition. Clinical research guidelines, ethics oversight, and regulatory requirements also need to evolve. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. There is a particular focus on methods to utilize routinely generated data for trials while complying with regional data protection laws. The discussion is supported with examples of cardiovascular outcome trials that have successfully leveraged the electronic health record, web-enabled devices or administrative databases to conduct randomized trials.
41.	Ostrominski, John W., et al. (author) Dapagliflozin and New York Heart Association Functional Class in Heart Failure with Mildly Reduced or Preserved Ejection Fraction : The DELIVER Trial. 2022 In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:10, s. 1892-1901 Journal article (peer-reviewed)abstract AIMS: This pre-specified analysis of the DELIVER trial examined whether clinical benefits of dapagliflozin in heart failure (HF) with left ventricular ejection fraction (LVEF) $>$40% varied by baseline New York Heart Association (NYHA) class and examined the treatment effects on NYHA class over time. METHODS AND RESULTS: Treatment effects of dapagliflozin by baseline NYHA class II (n = 4713) versus III/IV (n = 1549) were examined on the primary endpoint (cardiovascular death or worsening HF event) and key secondary endpoints. Effects of dapagliflozin on change in NYHA class at 4, 16, and 32 weeks were also evaluated. Higher baseline NYHA class was associated with older age, female sex, greater comorbidity burden, lower LVEF, and higher natriuretic peptide levels. Participants with baseline NYHA class III/IV, as compared with II, were independently more likely to experience the primary endpoint (adjusted hazard ratio [HR] 1.16 [95% confidence interval, 1.02-1.33]) and all-cause death (adjusted HR 1.22 [1.06-1.40]). Dapagliflozin consistently reduced the risk of the primary endpoint compared with placebo, irrespective of baseline NYHA class (HR 0.81 [0.70-0.94] for NYHA class II vs. HR 0.80 [0.65-0.98] for NYHA class III/IV; pinteraction = 0.921). Participants with NYHA class III/IV had greater improvement in Kansas City Cardiomyopathy Questionnaire total symptom scores between baseline and 32 weeks (+4.8 [2.5-7.1]) versus NYHA class II (+1.8 [0.7-2.9]; pinteraction = 0.011). Dapagliflozin was associated with higher odds of any improvement in NYHA class (odds ratio [OR] 1.32 [1.16-1.51]), as well as improvement to NYHA class I (OR 1.43 [1.17-1.75]), versus placebo at 32 weeks, with benefits seen as early as 4 weeks. CONCLUSIONS: Among symptomatic patients with HF and LVEF $>$40%, treatment with dapagliflozin provided clinical benefit irrespective of baseline NYHA class and was associated with early and sustained improvements in NYHA class over time.
42.	Pareek, Manan, et al. (author) Single and multiple cardiovascular biomarkers in subjects without a previous cardiovascular event 2017 In: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4881 .- 2047-4873. ; , s. 1648-1659 Journal article (peer-reviewed)abstract Aims To assess the incremental value of biomarkers, including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), growth differentiation factor 15 (GDF-15), and procollagen type 1 N-terminal propeptide (P1NP), in predicting incident cardiovascular events and mortality among asymptomatic individuals from the general population, beyond traditional risk factors, including fasting glucose and renal function (cystatin C), medication use, and echocardiographic measures. Methods and results Prospective population-based cohort study of 1324 subjects without a previous cardiovascular event, who underwent baseline echocardiography and biomarker assessment between 2002 and 2006. The clinical endpoint was the composite of myocardial infarction, invasively treated stable/unstable ischemic heart disease, heart failure, stroke, or all-cause mortality. Predictive capabilities were evaluated using Cox proportional-hazards regression, Harrell's concordance index (C-index), and net reclassification improvement. Median age was 66 (interquartile range: 60-70) years, and 413 (31%) were female. During median 8.6 (interquartile range: 8.1-9.2) follow-up years, 368 (28%) composite events occurred. NT-proBNP, hs-TnT, GDF-15, and IL-6 were significantly associated with outcome, independently of traditional risk factors, medications, and echocardiography ( p < 0.05 for all). Separate addition of NT-proBNP and GDF-15 to traditional risk factors, medications, and echocardiographic measurements provided significant improvements in discriminative ability (NT-proBNP: C-index 0.714 vs. 0.703, p = 0.03; GDF-15: C-index 0.721 vs. 0.703, p = 0.02). Both biomarkers remained significant predictors of outcome upon inclusion in the same model ( p < 0.05 for both). Conclusions NT-proBNP and GDF-15 each enhance prognostication beyond traditional risk factors, glucose levels, renal function, and echocardiography in individuals without known cardiovascular disease.
43.	Vaduganathan, Muthiah, et al. (author) Dronedarone for the treatment of atrial fibrillation with concomitant heart failure with preserved and mildly reduced ejection fraction : a post-hoc analysis of the ATHENA trial 2022 In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:6, s. 1094-1101 Journal article (peer-reviewed)abstract Aims: Limited therapeutic options are available for the management of atrial fibrillation/flutter (AF/AFL) with concomitant heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF). Dronedarone reduces the risk of cardiovascular events in patients with AF, but sparse data are available examining its role in patients with AF complicated by HFpEF and HFmrEF. Methods and results: ATHENA was an international, multicentre trial that randomized 4628 patients with paroxysmal or persistent AF/AFL and cardiovascular risk factors to dronedarone 400 mg twice daily versus placebo. We evaluated patients with (i) symptomatic HFpEF and HFmrEF (defined as left ventricular ejection fraction [LVEF] >40%, evidence of structural heart disease, and New York Heart Association class II/III or diuretic use), (ii) HF with reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVEF ≤40%), and (iii) those without HF. We assessed effects of dronedarone versus placebo on death or cardiovascular hospitalization (primary endpoint), other key efficacy endpoints, and safety. Overall, 534 (12%) had HFpEF or HFmrEF, 422 (9%) had HFrEF or left ventricular dysfunction, and 3672 (79%) did not have HF. Patients with HFpEF and HFmrEF had a mean age of 73 ± 9 years, 37% were women, and had a mean LVEF of 57 ± 9%. Over a mean follow-up of 21 ± 5 months, dronedarone consistently reduced risk of death or cardiovascular hospitalization (hazard ratio 0.76; 95% confidence interval 0.69–0.84) without heterogeneity based on HF status (pinteraction >0.10). This risk reduction in the primary endpoint was consistent across the range of LVEF (as a continuous function) in HF without heterogeneity (pinteraction = 0.71). Rates of death, cardiovascular hospitalization, and HF hospitalization each directionally favoured dronedarone versus placebo in HFpEF and HFmrEF, but these treatment effects were not statistically significant in this subgroup. Conclusions: Dronedarone is associated with reduced cardiovascular events in patients with paroxysmal or persistent AF/AFL and HF across the spectrum of LVEF, including among those with HFpEF and HFmrEF. These data support a rationale for a future dedicated and powered clinical trial to affirm the net clinical benefit of dronedarone in this population.
44.	Vaduganathan, Muthiah, et al. (author) Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction : A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial. 2022 In: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 7:12, s. 1259-1263 Journal article (peer-reviewed)abstract Importance: Dapagliflozin was recently shown to reduce cardiovascular death or worsening heart failure (HF) events in patients with HF with mildly reduced or preserved ejection fraction in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. Objective: To evaluate the time course of benefits of dapagliflozin on clinically relevant outcomes in this population. Design, Setting, and Participants: The DELIVER trial was a global phase 3 clinical trial that randomized patients with HF with mildly reduced or preserved ejection fraction to dapagliflozin or matching placebo. Inclusion criteria included symptomatic HF, left ventricular ejection fraction greater than 40%, elevated natriuretic peptide levels, and evidence of structural heart disease. In this prespecified secondary analysis of the DELIVER trial, to examine the timeline to onset of clinical benefit with dapagliflozin, hazard ratios (HR) and 95% CIs were iteratively estimated for the primary composite end point and worsening HF events alone with truncated data at every day postrandomization. Time to first and sustained statistical significance of dapagliflozin for these end points were then examined. Participants were enrolled from August 2018 to December 2020, and for this secondary analysis, data were analyzed from April to September 2022. Interventions: Dapagliflozin, 10 mg, once daily or matching placebo. Main Outcomes and Measures: The primary outcome was time to first occurrence of cardiovascular death or worsening HF (hospitalization for HF or urgent HF visit requiring intravenous HF therapies). Results: Overall, 6263 patients were randomized across 350 centers in 20 countries. Of 6263 included patients, 2747 (43.9%) were women, and the mean (SD) age was 71.7 (9.6) years. During a median (IQR) of 2.3 (1.7-2.8) years’ follow- up, 1122 primary end point events occurred, with an incidence rate per 100 patient-years of 8.7 (95% CI, 8.2-9.2). Time to first nominal statistical significance for the primary end point was 13 days (HR, 0.45; 95% CI, 0.20-0.99; P = .046), and significance was sustained from day 15 onwards. First and sustained statistical significance was reached for worsening HF events (HR, 0.45; 95% CI, 0.21-0.96; P = .04) by day 16 after randomization. Significant benefits for the primary end point and worsening HF events were sustained at 30 days, 90 days, 6 months, 1 year, 2 years, and final follow-up (primary end point: HR, 0.82; 95% CI, 0.73-0.92; worsening HF events: HR, 0.79; 95% CI, 0.69-0.91). Conclusions and Relevance: In the DELIVER trial, dapagliflozin led to early and sustained reductions in clinical events in patients with HF with mildly reduced or preserved ejection fraction with statistically significant reductions observed within 2 weeks of treatment initiation. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.
45.	Wijkman, Magnus, 1978-, et al. (author) Importance of NT-proBNP and conventional risk factors for prediction of death in older adults with and without diabetes mellitus- A report from the Atherosclerosis Risk in Communities (ARIC) study. 2022 In: Diabetes Research and Clinical Practice. - : Elsevier. - 0168-8227 .- 1872-8227. ; 194 Journal article (peer-reviewed)abstract In this community-based cohort of 5861 individuals followed for median 7.2 years, the discriminatory ability of NT-proBNP alone in predicting mortality was similar to that of multiple conventional markers of risk in people without diabetes. In people with diabetes, NT-proBNP alone discriminated risk of mortality better than conventional risk factors.

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Research subject (UKÄ/SCB): Medical and Health Sciences (42); Natural sciences (1); Social Sciences (1)

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