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1.
Circ Heart Fail ; 3(3): 347-53, 2010 May.
Article in English | MEDLINE | ID: mdl-20299607

ABSTRACT

BACKGROUND: Aldosterone antagonism has been studied in patients with advanced heart failure (HF) and also in patients with post-myocardial infarction and left ventricular (LV) dysfunction with HF symptoms. Few data are available on effects of aldosterone antagonism in patients with mild-to-moderate HF. METHODS AND RESULTS: In a multicenter, randomized, double-blind, placebo-controlled study in patients with mild-to-moderate HF and LV systolic dysfunction, patients with New York Heart Association class II/III HF and LV ejection fraction (EF) < or =35% were randomly assigned to receive eplerenone 50 mg/d versus placebo in addition to contemporary background therapy. Quantitative radionuclide ventriculograms to assess LV volumes and ejection fraction were performed at baseline and again after 9 months of double-blind treatment and were analyzed in a central core laboratory, blinded to treatment. The primary efficacy analysis was the between-group comparison of the change in LV end-diastolic volume index. Secondary analyses examined changes in LV end-systolic volume index and ejection fraction as well as markers of collagen turnover. Of the total 226 patients enrolled, 117 were randomly assigned to receive eplerenone and 109 to receive placebo. There was high use of contemporary background therapy at baseline, with > 90% use of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers and > 90% use of beta-blockers. Over 36 weeks of treatment, there was no apparent between-group difference in the changes in end-diastolic volume index or end-systolic volume index. There was a reduction in the collagen turnover marker procollagen type I N-terminal propeptide and plasma B-type natriuretic peptide in the eplerenone group compared with placebo (P=0.01 and P=0.04, respectively). There was no change in symptom status or quality-of-life measures. CONCLUSIONS: In a clinically stable, well-treated population of patients with mild-to-moderate HF symptoms and LV dysfunction, 36 weeks of treatment of aldosterone antagonism with eplerenone at a dose of 50 mg daily had no detectable effect on parameters of LV remodeling.


Subject(s)
Heart Failure/physiopathology , Mineralocorticoid Receptor Antagonists/therapeutic use , Spironolactone/analogs & derivatives , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/physiopathology , Ventricular Remodeling/drug effects , Aged , Cohort Studies , Double-Blind Method , Eplerenone , Female , Gated Blood-Pool Imaging , Heart Failure/drug therapy , Heart Failure/pathology , Humans , Male , Middle Aged , Mineralocorticoid Receptor Antagonists/pharmacology , Natriuretic Peptide, Brain/blood , Procollagen/blood , Quality of Life , Spironolactone/pharmacology , Spironolactone/therapeutic use , Stroke Volume , Treatment Outcome , Ventricular Dysfunction, Left/diagnostic imaging
2.
Am Heart J ; 158(3): 437-43, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19699868

ABSTRACT

BACKGROUND: Heart failure (HF) with reduced left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) is associated with increased readmission rates. This study evaluated the effects of eplerenone, a selective aldosterone blocking agent, on the duration of subsequent hospitalizations for HF in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). METHODS: The EPHESUS study included 6,632 patients post-AMI with LVEF < or =40% and clinical HF or diabetes, receiving standard therapy, randomized to either eplerenone 25 mg, titrated to 50 mg daily, or placebo, with a mean follow-up of 16 months. Analyses of the length of stay and total number of days of HF hospitalizations per patient were conducted on a subgroup of 828 patients with subsequent HF hospitalizations, overall and across 5 distinct geographic regions. RESULTS: Eplerenone was associated with a 1.6-day reduction in the mean length of HF hospitalization (9.2 vs 10.8 days with placebo; P = .019) and 3.6-day reduction in the total days spent in the hospital for HF (13.3 vs 16.9 days with placebo; P = .0006). These benefits were observed in all geographic regions. CONCLUSIONS: In patients post-AMI with reduced LVEF and HF or diabetes, eplerenone added to standard therapy reduced the mean length and total days of HF hospitalizations compared to placebo in all regions. Given the high cost of hospital care for HF, these findings may translate into an economic benefit to health care worldwide.


Subject(s)
Heart Failure/drug therapy , Mineralocorticoid Receptor Antagonists/therapeutic use , Myocardial Infarction/complications , Spironolactone/analogs & derivatives , Ventricular Dysfunction, Left/drug therapy , Aged , Double-Blind Method , Eplerenone , Female , Heart Failure/etiology , Hospitalization , Humans , Length of Stay , Male , Middle Aged , Spironolactone/therapeutic use , Ventricular Dysfunction, Left/etiology
3.
Circulation ; 118(16): 1643-50, 2008 Oct 14.
Article in English | MEDLINE | ID: mdl-18824643

ABSTRACT

BACKGROUND: Aldosterone blockade is recommended for patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction; however, the perceived risk of hyperkalemia may limit implementation of this therapeutic approach. This subanalysis examined the relationship between eplerenone, serum potassium (K(+)), and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). METHODS AND RESULTS: Hospitalized patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction (left ventricular ejection fraction < or =40%) treated with standard therapy were randomized 3 to 14 days after the acute myocardial infarction to additional treatment with eplerenone (25 to 50 mg/d; n=3319) or placebo (n=3313). Patients were excluded if baseline K(+) was >5.0 mEq/L or serum creatinine was >2.5 mg/dL. In patients receiving standard therapy, the addition of eplerenone resulted in a 4.4% absolute increase in the incidence of K(+) >5.5 mEq/L, a 1.6% increase of K(+) > or =6.0 mEq/L, and a 4.7% absolute decrease in hypokalemia (K(+) <3.5 mEq/L). Four independent baseline predictors of hyperkalemia (defined as > or =6.0 mEq/L) were identified: potassium (K(+) greater than the median; 4.3 mEq/L), estimated glomerular filtration rate (< or =60 mL . min(-1) . 1.73 m(-2)), history of diabetes mellitus, and prior use of antiarrhythmic agents. None of these independent baseline risk factors significantly impacted the cardiovascular benefit of eplerenone for reducing all-cause mortality. CONCLUSIONS: Use of selective aldosterone blockade with eplerenone within the dose range of 25 to 50 mg/d in post-acute myocardial infarction patients with heart failure and left ventricular systolic dysfunction who are treated with standard therapy improves outcomes without an excess of risk of hyperkalemia (> or =6.0 mEq/L) when periodic monitoring of serum K(+) is instituted.


Subject(s)
Hyperkalemia/chemically induced , Hyperkalemia/mortality , Mineralocorticoid Receptor Antagonists/adverse effects , Myocardial Infarction/drug therapy , Myocardial Infarction/mortality , Spironolactone/analogs & derivatives , Aged , Eplerenone , Female , Heart Failure/drug therapy , Heart Failure/mortality , Humans , Hyperkalemia/blood , Incidence , Logistic Models , Male , Potassium/blood , Predictive Value of Tests , Risk Factors , Spironolactone/adverse effects , Treatment Outcome , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/mortality
4.
Eur J Heart Fail ; 8(3): 295-301, 2006 May.
Article in English | MEDLINE | ID: mdl-16504579

ABSTRACT

AIMS: Because of the prognostic importance of LV dysfunction following an AMI and the increasing use of electrical and/or mechanical interventions in patients with LV systolic dysfunction, this retrospective analysis of EPHESUS patients with LVEF

Subject(s)
Heart Failure/drug therapy , Myocardial Infarction/complications , Spironolactone/analogs & derivatives , Stroke Volume/drug effects , Ventricular Function, Left/drug effects , Adult , Aged , Eplerenone , Female , Heart Failure/physiopathology , Humans , Male , Middle Aged , Spironolactone/adverse effects , Spironolactone/therapeutic use
5.
Clin J Am Soc Nephrol ; 1(5): 940-51, 2006 Sep.
Article in English | MEDLINE | ID: mdl-17699311

ABSTRACT

Previous studies have shown that the selective aldosterone blocker eplerenone, in doses of up to 200 mg/d, reduces albuminuria in patients with type 2 diabetes. This study was conducted to ascertain whether lower doses of eplerenone (50 or 100 mg/d) co-administered with the angiotensin-converting enzyme (ACE) inhibitor enalapril would produce a similar antialbuminuric effect while obviating the hyperkalemia observed previously. After open-label run-in with enalapril 20 mg/d, patients with diabetes and a urinary albumin:creatinine ratio (UACR) > or = 50 mg/g were randomly assigned to receive enalapril plus one of three double-blind daily treatments for 12 wk: placebo, eplerenone 50 mg (EPL50), or eplerenone 100 mg (EPL100). After week 4, amlodipine 2.5 to 10 mg/d was allowed for BP control (systolic/diastolic BP < or = 130/80 mmHg). The primary study end points were the percentage change from baseline at week 12 in UACR and the incidence of hyperkalemia. Secondary end points included percentage changes from baseline in UACR at weeks 4 and 8 and changes from baseline in systolic and diastolic BP. Treatment with EPL50 or EPL100 but not placebo significantly reduced albuminuria from baseline. By week 12, UACR was reduced by 7.4% in the placebo group, by 41.0% in the EPL50 group, and by 48.4% in the EPL100 group (both eplerenone groups, P < 0.001 versus placebo). The incidences of sustained and severe hyperkalemia were not significantly different in any of the three treatment arms and did not differ on the basis of quartile of estimated GFR (all NS). For the secondary end points, both eplerenone treatment groups significantly reduced albuminuria from baseline as early as week 4 (P < 0.001), whereas placebo treatment (including enalapril) did not result in any significant decreases in UACR. Systolic BP decreased significantly in all treatment groups at all time points, but, generally, all treatment groups experienced similar decreases in BP. Co-administration of EPL50 or EPL100 with an ACE inhibitor as compared with an ACE inhibitor alone significantly reduces albuminuria in patients with diabetes without producing significant increases in hyperkalemia.


Subject(s)
Albuminuria/drug therapy , Diabetes Mellitus, Type 2/complications , Mineralocorticoid Receptor Antagonists/therapeutic use , Spironolactone/analogs & derivatives , Aged , Albuminuria/blood , Albuminuria/etiology , Albuminuria/physiopathology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Blood Pressure/drug effects , Creatinine/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/physiopathology , Dose-Response Relationship, Drug , Double-Blind Method , Drug Therapy, Combination , Enalapril/pharmacology , Enalapril/therapeutic use , Eplerenone , Female , Glomerular Filtration Rate/drug effects , Humans , Hyperkalemia/blood , Hyperkalemia/epidemiology , Hyperkalemia/etiology , Incidence , Male , Middle Aged , Mineralocorticoid Receptor Antagonists/administration & dosage , Mineralocorticoid Receptor Antagonists/adverse effects , Potassium/blood , Spironolactone/administration & dosage , Spironolactone/adverse effects , Spironolactone/therapeutic use , Treatment Outcome , United States
6.
J Am Coll Cardiol ; 46(3): 425-31, 2005 Aug 02.
Article in English | MEDLINE | ID: mdl-16053953

ABSTRACT

OBJECTIVES: This study sought to assess the impact of the selective aldosterone blocker eplerenone on mortality 30 days after randomization in patients after acute myocardial infarction (AMI) with a left ventricular ejection fraction (LVEF) < or =40% and clinical signs of heart failure. BACKGROUND: In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), eplerenone reduced all-cause mortality by 15% (p = 0.008) over a mean follow-up of 16 months when used with standard therapy in patients after AMI with an LVEF < or =40% and clinical signs of heart failure. METHODS: We analyzed the effect of eplerenone 25 mg/day initiated 3 to 14 days after AMI (mean, 7.3 days) on the co-primary end points of time to death from any cause and the composite end point of time to death from cardiovascular (CV) causes or hospitalization for CV events, and the secondary end points of CV mortality, sudden cardiac death, and fatal/nonfatal hospitalization for heart failure, after 30 days of therapy in the EPHESUS trial. RESULTS: At 30 days after randomization, eplerenone reduced the risk of all-cause mortality by 31% (3.2% vs. 4.6% in eplerenone and placebo-treated patients, respectively; p = 0.004) and reduced the risk of CV mortality/CV hospitalization by 13% (8.6% vs. 9.9% in eplerenone and placebo-treated patients, respectively; p = 0.074). Eplerenone also reduced the risk of CV mortality by 32% (p = 0.003) and the risk of sudden cardiac death by 37% (p = 0.051). CONCLUSIONS: Eplerenone 25 mg/day significantly reduced all-cause mortality 30 days after randomization (when initiated at a mean of 7.3 days after AMI) in addition to conventional therapy in patients with an LVEF < or =40% and signs of heart failure. Based on its early survival benefit, eplerenone should be administered in the hospital after AMI.


Subject(s)
Heart Failure/mortality , Myocardial Infarction/drug therapy , Myocardial Infarction/mortality , Spironolactone/analogs & derivatives , Ventricular Dysfunction, Left/mortality , Aged , Coronary Angiography , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Eplerenone , Female , Follow-Up Studies , Heart Failure/complications , Heart Failure/diagnosis , Heart Function Tests , Humans , Male , Middle Aged , Myocardial Infarction/complications , Myocardial Infarction/diagnostic imaging , Probability , Proportional Hazards Models , Reference Values , Severity of Illness Index , Spironolactone/administration & dosage , Treatment Outcome , Ventricular Dysfunction, Left/complications , Ventricular Dysfunction, Left/diagnosis
7.
J Clin Hypertens (Greenwich) ; 6(11): 614-20, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15538094

ABSTRACT

Patients with severe hypertension are at high risk for cardiovascular events. The authors hypothesized that initial treatment with a combination angiotensin receptor blocker/diuretic agent would be safe and more effective than initial treatment with a single agent for these patients. In this 6-week, double-blind trial, 585 patients were randomized to losartan/hydrochlorothiazide or losartan as monotherapy and titrated as needed at 2-week intervals to reach goal blood pressure (<90 mm Hg). Almost twice as many patients achieved goal at the primary end point of 4 weeks on 50 mg losartan/12.5 mg hydrochlorothiazide vs. the losartan regimen (50-100 mg; p=0.002). Additionally, almost three times as many patients achieved goal blood pressures at 6 weeks (p<0.001). Adverse experiences on losartan/hydrochlorothiazide (43%) were significantly less than with the angiotensin receptor blocker alone (52.6%). This study confirmed the efficacy and tolerability of initial use of a fixed combination of losartan/hydrochlorothiazide vs. losartan without a thiazide.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Hypertension/drug therapy , Losartan/therapeutic use , Sodium Chloride Symporter Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Diuretics , Drug Therapy, Combination , Female , Humans , Hydrochlorothiazide/therapeutic use , Male , Middle Aged , Prospective Studies , Treatment Outcome
8.
JAMA ; 292(11): 1307-16, 2004 Sep 15.
Article in English | MEDLINE | ID: mdl-15337732

ABSTRACT

CONTEXT: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. OBJECTIVE: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. DESIGN, SETTING, AND PARTICIPANTS: International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. MAIN OUTCOME MEASURE: The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke. Follow-up was for at least 6 months and up to 24 months. RESULTS: Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95% confidence interval [CI] 0.76-1.04; P =.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) patients in the 2 groups (HR, 0.75; 95% CI, 0.57-1.00; P =.05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95% CI, 0.83-1.25; P =.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR, 0.75; 95% CI, 0.60-0.95; P =.02). Myopathy (creatine kinase >10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P =.02). CONCLUSIONS: The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.


Subject(s)
Angina Pectoris/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypolipidemic Agents/therapeutic use , Simvastatin/therapeutic use , Aged , Angina Pectoris/blood , Double-Blind Method , Drug Administration Schedule , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hypolipidemic Agents/administration & dosage , Lipids/blood , Male , Middle Aged , Myocardial Ischemia/blood , Myocardial Ischemia/drug therapy , Proportional Hazards Models , Simvastatin/administration & dosage , Treatment Outcome
9.
Am Heart J ; 144(3): 470-7, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12228784

ABSTRACT

BACKGROUND: In comparison with treatment with unfractionated heparin (UFH) and aspirin (ASA), both tirofiban administered with UFH and ASA, and enoxaparin plus ASA have shown superiority in reducing cardiac ischemic events in patients with unstable angina and non-ST-segment elevation myocardial infarction. Replacing UFH with enoxaparin when tirofiban is administered to patients may offer further therapeutic benefit, but could also increase bleeding. OBJECTIVE: Our objective was to provide estimates of the frequency of bleeding complications, as defined by means of the Thrombolysis In Myocardial Infarction(TIMI) group, and collect data on clinical efficacy of the combination of tirofiban with enoxaparin plus ASA. METHODS: Five hundred twenty-five patients with UA/NSTEMI were treated with tirofiban coadministered with ASA and randomized to receive either UFH (n = 210) or enoxaparin (n = 315). Therapy was administered for 24 to 96 hours. Bleeding incidences were assessed until 24 hours after trial therapy was discontinued; other clinical outcomes were assessed for as long as 30 days. RESULTS: The total bleeding rate (TIMI major + minor + loss-no-site) for the UFH group versus the enoxaparin group was 4.8% vs 3.5% (odds ratio [OR] 1.4, CI 0.6-3.4). The TIMI major and minor bleeding rates for the UFH versus the enoxaparin groups were 1.0% versus 0.3% (OR 3.0, CI 0.3-33.8) and 4.3% versus 2.5% (OR 1.7, CI 0.7-4.6). There was an increase in nuisance cutaneous and oral bleeds (<50 mL of blood loss) in the enoxaparin group. Death or myocardial infarction occurred with similar frequency in the 2 groups (9.0% vs 9.2%). However, refractory ischemia requiring urgent revascularization and rehospitalization because of unstable angina occurred more frequently in the UFH group (4.3% vs 0.6% and 7.1% vs 1.6%, respectively). CONCLUSIONS: Combination therapy with tirofiban plus enoxaparin appears safe, relative to therapy with tirofiban plus UFH.


Subject(s)
Aspirin/therapeutic use , Coronary Disease/drug therapy , Electrocardiography/statistics & numerical data , Enoxaparin/therapeutic use , Fibrinolytic Agents/therapeutic use , Hemorrhage/chemically induced , Heparin/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex/therapeutic use , Tyrosine/analogs & derivatives , Tyrosine/therapeutic use , Adult , Aged , Aged, 80 and over , Aspirin/adverse effects , Coronary Disease/diagnosis , Double-Blind Method , Drug Therapy, Combination , Female , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/adverse effects , Heparin/adverse effects , Humans , Infusions, Intravenous , Male , Middle Aged , Platelet Glycoprotein GPIIb-IIIa Complex/adverse effects , Tirofiban , Treatment Outcome , Tyrosine/adverse effects
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