Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms

Rogers, Jennifer K.; McMurray, John J.V.; Pocock, Stuart J.; Zannad, Faı̈ez; Krum, Henry; Veldhuisen, Dirk J. van; Swedberg, Karl; Shi, Harry; Vincent, John; Pitt, Bertram

doi:10.1161/circulationaha.112.110536

Cited by 92 publications

(74 citation statements)

References 23 publications

(34 reference statements)

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“…[28][29][30] In the few trials that have reported worsening of symptoms, quality of life, or functional class, active treatments produced a meaningful reduction in the risk of clinical worsening only when missing data were imputed or when patients who died were included in the analysis and assigned the worst possible score. 29,[31][32][33] In contrast, the PARADIGM-HF study is among the first trials to demonstrate a reduction of clinical worsening of surviving patients, which is not only of paramount importance to those afflicted with the disease and their families, but also to the physicians who care for them and the insurers who pay for the intensification of treatments.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

et al. 2015

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Packer et al Angiotensin Neprilysin Inhibition in Heart Failure 55Background-Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results-We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. Conclusions-Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255. (Circulation. 2015;131:54-61.

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Section: Discussionmentioning

confidence: 99%

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

et al. 2015

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“…Various recurrent event methodologies have been proposed [87][88][89][90] and have been tested post hoc in several cardiovascular trials. 91,92 A recurrent event approach that has been vetted with worldwide regulatory authorities is currently being used in a large outcomes trial in heart failure with preserved ejection fraction, 93 and this strategy, which should allow for smaller trials with more disease-specific end points, will likely be used more frequently if shown to be successful.…”

Section: Recurrent Events Analysesmentioning

confidence: 99%

The Future of Clinical Trials in Cardiovascular Medicine

Solomon

Pfeffer

2016

Circulation

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“…[5][6][7] Hence, the relationship between hospitalizations and mortality needs to be taken into account when analyzing the effects of a treatment for HF on hospitalizations especially when the treatment has an effect on the mortality rate. A composite end point of time to first hospitalization or death is often used to simplify the analysis of clinical trials.…”

Section: Clinical Perspective On P 765mentioning

confidence: 99%

“…The randomized cardiac resynchronization trials Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) 5 and Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) 9 were the first HF trials to report a reduction in all hospitalizations for HF using appropriate statistical methods that account for the competing risk of death and correlation of repeated admissions in the same patient. More recently, the SHIFT (Systolic Heart Failure Treatment with the I f inhibitor Ivabradine Trial) 6 and the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) 7 trials found that the pure heart rate-slowing agent ivabradine and the mineralocorticoid receptor antagonist eplerenone reduced all HF hospitalizations.…”

Section: Clinical Perspective On P 765mentioning

confidence: 99%

Effect of Fixed-Dose Combination of Isosorbide Dinitrate and Hydralazine on All Hospitalizations and on 30-Day Readmission Rates in Patients With Heart Failure

Anand

Win

Rector

et al. 2014

Circ: Heart Failure

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Background-Fixed-dose combination of isosorbide dinitrate and hydralazine (FDC-I/H) reduced mortality by 43% and death or first hospitalization for heart failure (HF) by 37% in the African-American Heart Failure Trial (A-HeFT). Reduction in mortality makes it difficult to determine the effect on hospitalizations unless the analysis adjusts for death as a competing risk. Methods and Results-In A-HeFT, 1050 self-identified black patients with moderate to severe HF were randomized to FDC-I/H or placebo. The effects of FDC-I/H on first and all hospitalizations and 30-day readmission rates were analyzed. Deaths as competing risks were adjusted using Fine-Gray regression and joint models of hospitalizations and mortality. There were 558 all-cause and 251 HF hospitalizations in placebo compared with 435 and 173 hospitalizations in the FDC-I/H group. Adjusting for deaths as a competing risk, the effect of FDC-I/H on the first hospitalization for HF, expressed in hazard ratio (95% confidence interval), was 0.61 (0.47-0.80; P<0.001) and 0.88 (0.72-1.06; P=0.18) on the first all-cause hospitalization.The effect of FDC-I/H on all recurrent hospitalizations for HF was 0.66 (0.52-0.83; P=0.0005), similar to the effect on the first hospitalizations for HF, whereas the effect on all hospitalizations for any cause was 0.75 (0.63-0.91; P=0.003). The 30-day all-cause readmission rate after the first hospitalization for HF was 23.6% (29 of 123) in placebo versus 14.8% (12 of 81) in the FDC-I/H group, but the effect (0.59; 0.30-1.16; P=0.12) in this small subgroup was not significant. Conclusions-Treatment with FDC-I/H was associated with a substantial reduction in the first and recurrent HF hospitalizations, and in total all-cause hospitalizations, reducing the total burden of costly and distressing hospitalizations. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047775.(Circ Heart Fail. 2014;7:759-765.)Key Words: heart failure ◼ hospitalization ◼ isosorbide dinitrate Received February 28, 2014; accepted June 13, 2014. 7 trials found that the pure heart rate-slowing agent ivabradine and the mineralocorticoid receptor antagonist eplerenone reduced all HF hospitalizations.Recently, there has been great interest in reducing all-cause readmissions that occur <30 days after a hospitalization for worsening HF. 10,11 These data are used to determine Medicare payments to hospitals for inpatient HF care, and hospitals with above average readmission rates are being financially penalized.1 Whether 30-day readmission rates can be reduced by therapy is unclear, and most clinical trials have not reported the effects of treatments on 30-day all-cause readmission rates. Public measures of 30-day readmission rates count all readmissions, not only those for HF. However, most 30-day readmissions are not because of worsening HF and may not be responsive to treatments for HF. 10,12 We used several statistical methods that take into account the effects of the competing risk of death and correlation of recurrent ...

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Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms

Cited by 92 publications

References 23 publications

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

The Future of Clinical Trials in Cardiovascular Medicine

Effect of Fixed-Dose Combination of Isosorbide Dinitrate and Hydralazine on All Hospitalizations and on 30-Day Readmission Rates in Patients With Heart Failure

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