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| 2. |
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| 3. |
- Kotecha, D., et al.
(författare)
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Effect of age and sex on efficacy and tolerability of beta blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis
- 2016
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Ingår i: Bmj-British Medical Journal. - : BMJ. - 1756-1833. ; 353
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES To determine the efficacy and tolerability of beta blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials. Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction < 0.45. The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model. Compared with placebo, beta blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by beta blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give beta blockers, 15.6% in those receiving placebo). Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive beta blockers to reduce the risk of death and admission to hospital.
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| 4. |
- 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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| 5. |
- Zannad, F., et al.
(författare)
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Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF)
- 2010
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Ingår i: European Journal of Heart Failure. - 1388-9842. ; 12:6, s. 617-622
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: In chronic heart failure (HF), aldosterone antagonists have been shown to improve survival in patients with low ejection fraction and moderate-to-severe symptoms [New York Heart Association (NYHA) classes III and IV]. Efficacy of these agents was also shown when they were administered to patients with left ventricular dysfunction and signs and symptoms of CHF early after acute myocardial infarction. It is not known whether the selective aldosterone antagonist eplerenone can improve outcomes in mildly symptomatic patients. The Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF) was designed to evaluate the effect of eplerenone on mortality and morbidity in patients with chronic systolic HF in NYHA class II. Methods Approximately 3100 patients with ejection fraction < or =30% and estimated glomerular filtration rate > or =30 mL/min/1.73 m(2) will be recruited. Patients are randomized 1:1 to double-blind eplerenone or placebo in addition to standard chronic HF therapy. Doses are adjusted from 25 mg every other day to 50 mg daily, depending on serum potassium. The primary endpoint is a composite of time to cardiovascular death or first hospital admission for worsening HF, whichever occurs first. CONCLUSION: The study will be complete when approximately 813 subjects experience a primary endpoint. Clinical Trials.gov. NCT00232180.
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| 6. |
- Amzaleg, Y., et al.
(författare)
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Estrogens and selective estrogen receptor modulators differentially antagonize Runx2 in ST2 mesenchymal progenitor cells
- 2018
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 183, s. 10-17
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens attenuate bone turnover by inhibiting both osteoclasts and osteoblasts, in part through antagonizing Runx2. Apparently conflicting, stimulatory effects in osteoblast lineage cells, however, sway the balance between bone resorption and bone formation in favor of the latter. Consistent with this dualism, 17 beta-estradiol (E2) both stimulates and inhibits Runx2 in a locus-specific manner, and here we provide evidence for such locus specific regulation of Runx2 by E2 in vivo. We also demonstrate dual, negative and positive, regulation of Runx2-driven alkaline phosphatase (ALP) activity by increasing E2 concentrations in ST2 osteoblast progenitor cells. We further compared the effects of E2 to those of the Selective Estrogen Receptor Modulators (SERMs) raloxifene (ral) and lasofoxifene (las) and the phytoestrogen puerarin. We found that E2 at the physiological concentrations of 0.1-1 nM, as well as ral and las, but not puerarin, antagonize Runx2-driven ALP activity. At >= 10 nM, E2 and puerarin, but not ral or las, stimulate ALP relative to the activity measured at 0.1-1 nM. Contrasting the difference between E2 and SERMs in ST2 cells, they all shared a similar dose-response profile when inhibiting preosteoclast proliferation. That ral and las poorly mimic the locus-and concentration-dependent effects of E2 in mesenchymal progenitor cells may help explain their limited clinical efficacy.
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| 7. |
- 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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| 8. |
- 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
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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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| 9. |
- Ferrari, Pietro, et al.
(författare)
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Dietary fiber intake and risk of hormonal receptor-defined breast cancer in the European Prospective Investigation into Cancer and Nutrition study
- 2013
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 97:2, s. 344-353
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Tidskriftsartikel (refereegranskat)abstract
- Background: Limited scientific evidence has characterized the association between dietary fiber intake and risk of breast cancer (BC) by menopausal status and hormone receptor expression in tumors. ' Objective: We investigated the relation between total dietary fiber and its main food sources (vegetables, fruit, cereals, and legumes) and BC risk by using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). Design: A total of 11,576 invasive BC cases in 334,849 EPIC women mostly aged 35-70 y at baseline were identified over a median follow-up of 11.5 y. Dietary fiber was estimated from country-specific dietary questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk with energy adjustment by using the residual method. Subgroup analyses were performed by menopausal status and estrogen receptor (ER) and progesterone receptor (PR) expression in tumors. Results: BC risk was inversely associated with intakes of total dietary fiber [hazard ratio comparing fifth quintile to first quintile (HRQ5-Q1): 0.95; 95% CI: 0.89, 1.01; P-trend = 0.03] and fiber from vegetables (0.90; 0.84, 0.96; P-trend < 0.01) but not with fiber from fruit, cereals, or legumes. Overall, associations were homogeneous by menopausal status and ER and PR expression in tumors. For vegetable fiber, stronger associations were observed for estrogen receptor-negative and progesterone receptor-negative (HRQ5-Q1: 0.74; 95% CI: 0.59, 0.93; P-trend = 0.01) than for estrogen receptor-positive and progesterone receptor-positive tumors (0.92: 0.81, 1.03; P-trend = 0.05), with P-heterogeneity = 0.09. Conclusion: Diets rich in dietary fiber and, particularly, fiber from vegetables may be associated with a small reduction in risk of BC, independently of menopausal status.
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| 10. |
- Hopper, I., et al.
(författare)
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Sympathetic Response and Outcomes Following Renal Denervation in Patients With Chronic Heart Failure: 12-Month Outcomes From the Symplicity HF Feasibility Study
- 2017
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Ingår i: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164. ; 23:9, s. 702-707
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heart failure (HF) is associated with chronic sympathetic activation. Renal denervation (RDN) aims to reduce sympathetic activity by ablating the renal sympathetic nerves. We investigated the effect of RDN in patients with chronic HF and concurrent renal dysfunction in a prospective, multicenter, single-arm feasibility study. Methods and Results: Thirty-nine patients with chronic systolic HF (left ventricular ejection fraction [LVEF] <40%, New York Heart Association class II-III,) and renal impairment (estimated glomerular filtration rate [eGFR; assessed with the use of the Modification of Diet in Renal Disease equation] < 75 mL . min(-1) . 1.73 m(-2)) on stable medical therapy were enrolled. Mean age was 65 +/- 11 years; 62% had ischemic HF. The average number of ablations per patient was 13 +/- 3. No protocol-defined safety events were associated with the procedure. One subject experienced a renal artery occlusion that was possibly related to the denervation procedure. Statistically significant reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP; 1530 +/- 1228 vs 1428 +/- 1844 ng/mL; P = .006) and 120-minute glucose tolerance test (11.2 +/- 5.1 vs 9.9 +/- 3.6; P = .026) were seen at 12 months, but there was no significant change in LVEF (28 +/- 9% vs 29 +/- 11%; P = .536), 6-minute walk test (384 +/- 96 vs 391 +/- 97 m; P = .584), or eGFR (52.6 +/- 15.3 vs 52.3 +/- 18.5 mL . min(-1) . 1.73 m(-2); P = .700). Conclusions: RDN was associated with reductions in NT-proBNP and 120-minute glucose tolerance test in HF patients 12 months after RDN treatment. There was no deterioration in other indices of cardiac and renal function in this small feasibility study.
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| 11. |
- Krum, H., et al.
(författare)
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Clinical Benefit of Eplerenone in Patients With Mild Symptoms of Systolic Heart Failure Already Receiving Optimal Best Practice Background Drug Therapy: Analysis of the EMPHASIS-HF Study
- 2013
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Ingår i: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 6:4, s. 711-8
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Tidskriftsartikel (refereegranskat)abstract
- Background- In EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), eplerenone significantly reduced major cardiovascular events versus placebo in 2737 patients with mild symptoms of heart failure and an ejection fraction of <35%, in addition to recommended therapy. However, it is not known whether such benefits were preserved in patients receiving optimal background drug therapy, that is, high doses of angiotensin-converting enzyme inhibitor (ACEi, or angiotensin receptor blocker), beta-blocker, or both drug classes. Methods and Results- We further analyzed EMPHASIS-HF according to the use and dose of these BACKGROUND: value for interaction 0.80, 0.15, and 0.53, respectively), as well as for all-cause mortality. There were no major safety issues, except a borderline increased risk of hypotension with eplerenone in those on high-dose ACEi or ACEi/beta-blocker. Conclusions- Eplerenone provides substantial benefit on major events (with an acceptable safety profile) in patients with mild symptoms of systolic heart failure, even in those already receiving high doses of standard background therapies. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00232180.
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| 12. |
- Krum, H., et al.
(författare)
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Prognostic benefit of beta-blockers in patients not receiving ACE-Inhibitors
- 2005
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Ingår i: Eur Heart J. - : Oxford University Press (OUP). - 0195-668X. ; 26:20, s. 2154-8
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Beta-blockers (BBs) confer significant prognostic benefit in patients (pts) with systolic chronic heart failure (CHF). However, major trials have thus far studied BBs mainly in addition to ACE-Inhibitors or angiotensin receptor blockers (ARBs) as background therapy. The magnitude of the prognostic benefit of BBs in the absence of ACE-I or ARB has not as yet been determined. METHODS AND RESULTS: We performed a meta-analysis of all placebo-controlled BB studies in patients with CHF (n>200). Trials were identified via Medline literature searches, meeting abstracts, and contact with study organizations. Results for all-cause mortality and death or heart failure hospitalization were pooled using the Mantel-Haenszel (fixed effects) method. The impact of BB therapy on all-cause mortality in CHF, in the absence (4.8%) and presence (95.2%) of ACE-I (or ARB), was determined from six trials of 13 370 patients. The risk ratio (RR) for BBs vs. placebo was 0.73 [95% confidence interval (CI) 0.53-1.02] in the absence of ACE-I or ARB at baseline, compared with a RR of 0.76 (95% CI 0.71-0.83) in the presence of these agents. When ACE-Inhibitors were analysed in the same way (pre-BB), a RR of 0.89 (0.80-0.99) vs. placebo was observed in studies of >90 days. The impact of BB therapy on death or HF hospitalization in systolic CHF, in the absence and presence of ACE-I, was determined from three trials of 8988 patients. The RR for BBs vs. placebo was 0.81 (95% CI 0.61-1.08) in the absence of ACE-I or ARB at baseline, compared with a RR of 0.78 (95% CI 0.74-0.83) in the presence of these agents. When ACE-Is were analysed in the same way (pre-BB), a RR of 0.85 (95% CI 0.78-0.93) vs. placebo was observed in studies of >90 days. CONCLUSION: The magnitude of the prognostic benefit conferred by BBs in the absence of ACE-I appears to be similar to those of ACE-Is in systolic CHF. These data therefore suggest that either ACE-Is or BBs could be used as first-line neurohormonal therapy in patients with systolic CHF. Prospective studies directly comparing these agents are required to definitively address this issue.
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| 13. |
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| 15. |
- Mann, D. L., et al.
(författare)
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Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL)
- 2004
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Ingår i: Circulation. - 1524-4539. ; 109:13, s. 1594-602
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure. METHODS AND RESULTS: Patients with New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction < or =0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375) or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per week (n=308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE (P=0.17) or RECOVER (P=0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, P=0.33). CONCLUSIONS: The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.
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| 16. |
- Preiss, D., et al.
(författare)
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Eplerenone and new-onset diabetes in patients with mild heart failure: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)
- 2012
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 14:8, s. 909-915
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Tidskriftsartikel (refereegranskat)abstract
- No studies have examined the effect of mineralocorticoid receptor antagonist therapy on new-onset diabetes. In addition, though the combination of diabetes and chronic heart failure (CHF) carries a poor prognosis, few studies have examined predictors of new-onset diabetes in those with CHF. In patients with symptomatically mild CHF who participated in the placebo-controlled Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, we examined the effect of the aldosterone antagonist, eplerenone, on physician-diagnosed diabetes using univariate Cox proportional hazard analysis. To identify predictors of new-onset diabetes (measures of glycaemia were not available), data from trial arms were combined and multivariate Cox proportional hazard analyses and receiver operating characteristic curve analyses were conducted. At baseline, the mean age of 1846 initially non-diabetic patients was 69 years and mean left ventricular ejection fraction was 26. Over 21 months, 69 (3.7) developed diabetes (33 on eplerenone, 36 on placebo). Eplerenone had no effect on new-onset diabetes [hazard ratio (HR) 0.94, 95 confidence interval (CI) 0.591.52] and no effect on the composite of new-onset diabetes or mortality (HR 0.80, 95 CI 0.641.01). Independent predictors of new-onset diabetes included digoxin therapy, higher serum alanine aminotransferase, longer duration of heart failure, current or previous smoker, higher waist circumference, lower age, and higher systolic blood pressure with a combined c-statistic of 0.74. Eplerenone had no effect on new-onset diabetes in patients with CHF, but further large-scale studies are required to address this question comprehensively. Commonly recorded parameters provided useful information for predicting new-onset diabetes.
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| 17. |
- Ritte, Rebecca, et al.
(författare)
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Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer : A cohort study
- 2013
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Ingår i: International Journal of Cancer. - : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 132:11, s. 2619-2629
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Tidskriftsartikel (refereegranskat)abstract
- Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospective Investigation into Cancer and Nutrition cohort, Cox proportional hazards models were used to describe the relationships of adult height, leg length and sitting height and age at menarche with risk of estrogen and progesterone receptor negative (ER-PR-) (n = 990) and ER+PR+ (n = 3,524) breast tumors. Height as a single risk factor was compared to a model combining leg length and sitting height. The possible interactions of height, leg length and sitting height with menarche were also analyzed. Risk of both ER-PR- and ER+PR+ malignancies was positively associated with standing height, leg length and sitting height and inversely associated with increasing age at menarche. For ER+PR+ disease, sitting height (hazard ratios: 1.14[95% confidence interval: 1.081.20]) had a stronger risk association than leg length (1.05[1.001.11]). In comparison, for ER-PR- disease, no distinct differences were observed between leg length and sitting height. Women who were tall and had an early menarche (13 years) showed an almost twofold increase in risk of ER+PR+ tumors but no such increase in risk was observed for ER-PR- disease. Indicators of exposures during rapid growth periods were associated with risks of both HR-defined breast cancers. Exposures during childhood promoting faster development may establish risk associations for both HR-positive and negative malignancies. The stronger associations of the components of height with ER+PR+ tumors among older women suggest possible hormonal links that could be specific for postmenopausal women.
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| 18. |
- Rogers, J. K., et al.
(författare)
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Eplerenone in patients with systolic heart failure and mild symptoms: analysis of repeat hospitalizations
- 2012
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Ingår i: Circulation. - 1524-4539. ; 126:19, s. 2317-23
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Eplerenone is known to reduce time to first hospitalization for heart failure or cardiovascular death in patients with heart failure and mild symptoms. In chronic diseases such as heart failure, characterized by repeat hospitalizations, analyzing all heart failure hospitalizations, not just the first, should give a more complete picture of treatment benefits. METHODS AND RESULTS: The Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF) trial compared eplerenone with placebo in 2737 patients with mild heart failure, followed for a median 2.08 years (interquartile range, 1.08-3.10 years). Data were collected on all hospitalizations, with a focus on those due to heart failure. Heart failure hospitalization rates in the eplerenone and placebo groups were 10.70 and 16.99 per 100 patient-years, respectively. Allowing for skewness in the frequency of hospitalizations by using the negative binomial generalized linear model, the rate ratio (eplerenone versus placebo) was 0.53 (95% confidence interval, 0.42-0.66; P<0.0001). A plot of cumulative hospitalization rates over time revealed that most of the reduced risk on eplerenone occurred in the first year of follow-up. Several baseline variables strongly predicted the risk of hospitalization. More complex statistical methods, adjusting for mortality (as informative censoring), made a negligible difference in these findings. CONCLUSIONS: Eplerenone markedly reduces the risk of heart failure hospitalizations in patients with heart failure and mild symptoms to a greater extent than is captured by only studying the time to first hospitalization. Future clinical trials in heart failure would gain from incorporating repeat hospitalizations into their primary evaluation of treatment effects. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00232180.
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| 19. |
- Rossignol, P., et al.
(författare)
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Incidence, Determinants, and Prognostic Significance of Hyperkalemia and Worsening Renal Function in Patients with Heart Failure Receiving the Mineralocorticoid Receptor Antagonist Eplerenone or Placebo Additional to Optimal Medical Therapy: Results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)
- 2014
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Ingår i: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 7:1, s. 51-58
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: -Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with systolic heart failure (HF), but may induce a worsening of renal function (WRF) and/or hyperkalemia (HK). We assessed the risk factors for MRA-related WRF and for HK, as well as the association between HK and WRF with clinical outcomes in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) METHODS AND RESULTS: -Serial changes in estimated glomerular filtration rate (eGFR) and in serum potassium were available in 2737 patients during a median 21-month follow-up. HK variably defined as serum K>4.5, 5 or 5.5 mmol/L occurred in 74.7 %, 32.5 %, and 8.9 % of EMPHASIS-HF patients, respectively. WRF defined as a decrease in eGFR > 20% or >30% from baseline occurred in 27% and 14% of patients, respectively. Patients assigned eplerenone displayed modest and early but significant and persistent i) rise in serum potassium, and ii) reduction in eGFR compared with placebo. In multivariate analyses, eplerenone was associated with a higher incidence of WRF and HK, which were interrelated and also associated with baseline patient characteristics (e.g. age >/=75 years, hypertension, diabetes, non-white race, ejection fraction <30%, and treatment with an antiarrythmics drug or loop diuretic). Eplerenone retained its survival benefits, without any significant interaction with the association between HK >5.5 mmol/l only and WRF and worse outcomes. CONCLUSIONS: -In HF patients receiving optimal therapy, WRF and HK were more frequent when eplerenone was added, but their occurence did not eliminate the survival benefit of eplerenone. Clinical Trial Registration-URL: http://www.ClinicalTrials.gov number. Unique identifier: NCT00232180.
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| 20. |
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| 21. |
- Zannad, F., et al.
(författare)
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Eplerenone in patients with systolic heart failure and mild symptoms
- 2011
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Ingår i: The New England journal of medicine. - 0028-4793. ; 364:1, s. 11-21
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms. METHODS: In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001). CONCLUSIONS: Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).
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| 22. |
- Bakris, George L, et al.
(författare)
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Divergent results using clinic and ambulatory blood pressures report of a darusentan-resistant hypertension trial
- 2010
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 56:5, s. 824-830
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Tidskriftsartikel (refereegranskat)abstract
- Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving ≥3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist darusentan, placebo, or the central α-2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for darusentan (−15±14 mm Hg) were greater than for guanfacine (−12±13 mm Hg; P<0.05) but not greater than placebo (−14±14 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (−9±12 mm Hg) more than placebo (−2±12 mm Hg) or guanfacine (−4±12 mm Hg) after 14 weeks of treatment (P<0.001 for each comparison). The most frequent adverse event associated with darusentan was fluid retention/edema at 28% versus 12% in each of the other groups. More patients withdrew because of adverse events on darusentan as compared with placebo or guanfacine. We conclude that darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies.
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| 23. |
- 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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| 24. |
- 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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| 25. |
- 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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