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Aims and Methods: To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE.Results: A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without.Conclusion: ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure and preserved ejection fraction (HFpEF) have a poor prognosis, and no therapies have been proven to improve outcomes. It has been proposed that heart failure, including HFpEF, represents overlapping syndromes that may have different prognoses. We present an exploratory study of patients enrolled in the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) using latent class analysis (LCA) with validation using the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study to identify HFpEF subgroups.Methods and Results: In total, 4113 HFpEF patients randomized to irbesartan or placebo were characterized according to 11 clinical features. The HFpEF subgroups were identified using LCA. Event-free survival and effect of irbesartan on the composite of all-cause mortality and cardiovascular hospitalization were determined for each subgroup. Subgroup definitions were applied to 3203 patients enrolled in CHARM-Preserved to validate observations regarding prognosis and treatment response. Six subgroups were identified with significant differences in event-free survival (P < 0.001). Clinical profiles and prognoses of the six subgroups were similar in CHARM-Preserved. The two subgroups with the worst event-free survival in both studies were characterized by a high prevalence of obesity, hyperlipidaemia, diabetes mellitus, anaemia, and renal insufficiency (Subgroup C) and by female predominance, advanced age, lower body mass index, and high rates of atrial fibrillation, valvular disease, renal insufficiency, and anaemia (Subgroup F).Conclusion: Using a data-driven approach, we identified HFpEF subgroups with significantly different prognoses. Further development of this approach for characterizing HFpEF subgroups is warranted. [ABSTRACT FROM AUTHOR]

Background The impact of depression on outcome in implantable cardioverter defibrillator (ICD) recipients has not been fully appreciated. We assessed the prevalence of depression and its association with heart failure (HF) outcome among veterans with ICDs. Methods and Results Patients enrolled between January 2005 and January 2010 in the Outcomes among Veterans with Implantable Defibrillators Registry were studied. We examined the cross-sectional association of depression with severity of HF functional class as well as the association of depression with the composite outcome of mortality or HF hospitalization over a mean follow-up time of 2.7 years. There were 3,862 patients enrolled. Patients with depression (1,162, 43%) were younger (63.1 ± 9.4 years vs 66.6 ± 9.9 years, P < 0.001), more likely to have a history of tobacco or alcohol abuse (P < 0.0001) or atrial fibrillation (P = 0.05) while having a higher ejection fraction (28.3% vs 27.4%, P = 0.03). Depression was associated with advanced HF class at time of implant; odds ratio (OR; vs class I) for class III: 1.65 (confidence interval [CI] 1.17-2.33), class IV: 1.73 (95% CI 1.08-2.76). Death or HF hospitalization was more likely to occur in patients with depression (35.2% vs 32.0%, HR: 1.15 [95% CI 0.99-1.33]). The predictive value of depression was stronger after multivariable adjustment; HR: 1.25 (95% CI 1.05-1.49). Conclusion Depression was prevalent among veterans with ICDs. Depression was associated with severity of HF. The predictive value of associated depression was significant after multivariable adjustment. [ABSTRACT FROM AUTHOR]

Aims Differences in manifestation, treatment, and outcomes of acute heart failure between men and women have not been well studied. The objective of this analysis was to characterize differences in clinical presentation, and in-hospital and post-discharge outcomes between sexes in acute heart failure patients. Methods and results Clinical profiles, treatment characteristics, and outcomes were compared between sexes in 2033 patients hospitalized for acute heart failure and impaired renal function. Women comprised 33% of the study population and were older, had higher body mass index, LVEF, and systolic blood pressure, and a greater prevalence of diabetes. At baseline, women showed signs and symptoms of congestion comparable with men, but more often had rales, orthopnoea, and worse renal function. Women were less intensively diuresed, as indicated by lower oral and intravenous diuretic doses used, fewer dose increases, and less total weight loss during hospitalization. Furthermore, hospitalization was slightly but significantly prolonged in women (11.04 ± 7.8 vs. 10.65 ± 8.86 days; P = 0.024). Age-adjusted 180-day mortality was lower in women (15.8% vs. 18.5%, hazard ratio 0.74; 95% confidence interval 0.59–0.93, P = 0.010), but multivariable risk-adjusted mortality was similar in both sexes, mainly attributable to lower blood urea nitrogen, higher LVEF, and higher systolic blood pressure in women compared with men. Conclusions Women with acute heart failure present with a clinical profile different from that of men, with more hypertension, diabetes, and depression, and a preserved LVEF. During hospitalization, they were less intensively diuresed. Nevertheless, risk-adjusted 180-day outcome was similar between sexes. [ABSTRACT FROM PUBLISHER]

Heart failure ( HF) care takes place in multiple settings, with a variety of providers, and generally involves patients who have multiple comorbidities. This situation is a 'perfect storm' of factors that predispose patients to medication errors. The goals of this paper are to outline potential roles for clinical pharmacists in a multidisciplinary HF team, to document outcomes associated with interventions by clinical pharmacists, to recommend minimum training for clinical pharmacists engaged in HF care, and to suggest financial strategies to support clinical pharmacy services within a multidisciplinary team. As patients transition from inpatient to outpatient settings and between multiple caregivers, pharmacists can positively affect medication reconciliation and education, assure consistency in management that results in improvements in patient satisfaction and medication adherence, and reduce medication errors. For mechanical circulatory support and heart transplant teams, the Centers for Medicare and Medicaid Services considers the participation of a transplant pharmacology expert (e.g., clinical pharmacist) to be a requirement for accreditation, given the highly specialized and complex drug regimens used. Although reports of outcomes from pharmacist interventions have been mixed owing to differences in study design, benefits such as increased use of evidence-based therapies, decreases in HF hospitalizations and emergency department visits, and decreases in all-cause readmissions have been demonstrated. Clinical pharmacists participating in HF or heart transplant teams should have completed specialized postdoctoral training in the form of residencies and/or fellowships in cardiovascular and/or transplant pharmacotherapy, and board certification is recommended. Financial mechanisms to support pharmacist participation in the HF teams are variable. Positive outcomes associated with clinical pharmacist activities support the value of making this resource available to HF teams. [ABSTRACT FROM AUTHOR]

Aims To examine the characteristics associated with early dyspnoea relief during acute heart failure (HF) hospitalization, and its association with 30-day outcomes. Methods and results ASCEND-HF was a randomized trial of nesiritide vs. placebo in 7141 patients hospitalized with acute HF in which dyspnoea relief at 6 h was measured on a 7-point Likert scale. Patients were classified as having early dyspnoea relief if they experienced moderate or marked dyspnoea improvement at 6 h. We analysed the clinical characteristics, geographical variation, and outcomes (mortality, mortality/HF hospitalization, and mortality/hospitalization at 30 days) associated with early dyspnoea relief. Early dyspnoea relief occurred in 2984 patients (43%). In multivariable analyses, predictors of dyspnoea relief included older age and oedema on chest radiograph; higher systolic blood pressure, respiratory rate, and natriuretic peptide level; and lower serum blood urea nitrogen (BUN), sodium, and haemoglobin (model mean C index = 0.590). Dyspnoea relief varied markedly across countries, with patients enrolled from Central Europe having the lowest risk-adjusted likelihood of improvement. Early dyspnoea relief was associated with lower risk-adjusted 30-day mortality/HF hospitalization [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.68–0.96] and mortality/hospitalization (HR 0.85; 95% CI 0.74–0.99), but similar mortality. Conclusion Clinical characteristics such as respiratory rate, pulmonary oedema, renal function, and natriuretic peptide levels are associated with early dyspnoea relief, and moderate or marked improvement in dyspnoea was associated with a lower risk for 30-day outcomes. [ABSTRACT FROM PUBLISHER]

Aims We examined the prognostic importance of cardiac troponin I (cTnI) in a cohort of patients enrolled in the ASCEND-HF study of nesiritide in acute decompensated heart failure (ADHF). Circulating troponins are a prognostic marker in patients with ADHF. Contemporary assays with greater sensitivity require reassessment of the significance of troponin elevation in HF. Methods and results Cardiac troponin I was measured in a core laboratory in 808 ADHF patients enrolled in the ASCEND-HF biomarkers substudy using a sensitive assay (VITROS Trop I ES, Ortho Clinical Diagnostics) with a lower limit of detection of 0.012 ng/mL and a 99th percentile upper reference limit (URL) of 0.034 ng/mL. Patients with clinical evidence of acute coronary syndrome or troponin >5× the URL were excluded. Multivariable modelling was used to assess the relationship between log(cTnI) and in-hospital and post-discharge outcomes. Baseline cTnI was undetectable in 22% and elevated above the 99th percentile URL in 50% of subjects. cTnI levels did not differ based on HF aetiology. After multivariable adjustment, higher cTnI was associated with worsened in-hospital outcomes such as length of stay (P = 0.01) and worsening HF during the index hospitalization (P = 0.01), but was not associated with worsened post-discharge outcomes at 30 or 180 days. The relationship between cTnI and outcomes was generally linear and there was no evidence of a threshold effect at any particular level of cTnI. Conclusion cTnI is elevated above the 99th percentile URL in 50% of ADHF patients and predicts in-hospital outcome, but is not an independent predictor of long-term outcomes. [ABSTRACT FROM AUTHOR]

Aims In patients with acute heart failure (AHF), early worsening heart failure (WHF) predicts a significant proportion of post-discharge readmissions and mortality. We aimed to identify the predictors of 7-day heart failure events or death in patients hospitalized with AHF. Methods and results A predictive model and risk score for the short-term primary composite endpoint of 7-day death, HF rehospitalization, or WHF was created using variables collected within 24 h of admission from patients with complete data (n = 2015) enrolled in the PROTECT trial of AHF patients. The 7-day composite was experienced by 294 patients (14.6%), with a mortality rate of 1.8% (n = 37), HF rehospitalization rate of 0.5% (n = 9), and WHF rate of 13.1% (n = 264). In multivariable analyses, the strongest predictor of short-term morbidity and mortality was higher blood urea nitrogen (BUN) concentration. Additional independent predictors of a worse outcome were lower serum albumin, cholesterol, and systolic blood pressure, as well as higher heart rate and respiratory rate. Model coefficients were converted to an additive risk score for predicting the 7-day composite endpoint with a total point range of 0–100. The risk score allowed discrimination of a wide spectrum of risk (4.8% risk with score ≤35, to 28.7% risk with score >55). Conclusions Using the PROTECT 7-day risk model and score, the main determinants of an adverse outcome for AHF patients included impaired metabolic status, neurohormonal activation, and reduced cardiac performance, gauged by BUN, serum albumin and cholesterol levels, systolic blood pressure, heart rate, and respiratory rate. [ABSTRACT FROM PUBLISHER]

The article discusses a study on the effects of cardiac troponin T (cTnT) release on outcomes in patients with acute heart failure (AHF). The patients involved in the study were randomized to receive intravenous rolofylline or placebo. Multivariable analysis revealed that positive cTnT at baseline served as an independent predictor of the composite end point of cardiovascular or renal rehospitalization or mortality at 60 days. The cohort group showed a high prevalence of cTnT elevation.

Background: Older patients often receive less guideline-concordant care for heart failure than younger patients.Objective: To determine whether age differences in heart failure care are explained by patient, provider, and health system characteristics and/or by chart-documented reasons for non-adherence to guidelines.Design and Patients: Retrospective cohort study of 2,772 ambulatory veterans with heart failure and left ventricular ejection fraction <40% from a 2004 nationwide medical record review program (the VA External Peer Review Program).Main Measures: Ambulatory use of ACE inhibitors, angiotensin receptor blockers (ARBs), and beta blockers.Results: Among 2,772 patients, mean age was 73 +/- 10 years, 87% received an ACE inhibitor or ARB, and 82% received a beta blocker. When patients with explicit chart-documented reasons for not receiving these drugs were excluded, 95% received an ACE inhibitor or ARB and 89% received a beta blocker. In multivariable analyses controlling for a variety of patient and health system characteristics, the adjusted odds ratio for ACE-inhibitor and ARB use was 0.43 (95% CI 0.24-0.78) for patients age 80 and over vs. those age 50-64 years, and the adjusted odds ratio for beta blocker use was 0.66 (95% CI 0.48-0.93) between the two age groups. The magnitude of these associations was similar but not statistically significant after excluding patients with chart-documented reasons for not prescribing ACE inhibitors or ARBs and beta blockers.Conclusions: A high proportion of veterans receive guideline-recommended medications for heart failure. Older veterans are consistently less likely to receive these drugs, although these differences were no longer significant when accounting for patients with chart-documented reasons for not prescribing these drugs. Closely evaluating reasons for non-prescribing in older adults is essential to assessing whether non-treatment represents good clinical judgment or missed opportunities to improve care. [ABSTRACT FROM AUTHOR]

The article focuses on the benefits of irbesartan in the management of patients with heart failure and preserved ejection fraction. I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Trial) patients' N-terminal pro-brain natriuretic peptide was measured by the authors for their study. They discovered that significant interaction was seen between irbesartan's effect and median split of baseline NT-proBNP, all-cause mortality and the heart failure composite outcome.

Aims The direct effects of adenosine A1 receptor antagonists on haemodynamic parameters in patients with acute heart failure (HF) remain largely unknown. Methods and results We evaluated the haemodynamic effects of the AA1RA rolofylline in 59 HF patients with concomitant renal impairment (estimated creatinine clearance 20–80 mL/min). Placebo or rolofylline 30 mg was administered as a 4 h infusion followed by intravenous (i.v.) loop diuretic administration. Haemodynamic measurements were carried out hourly up to 8 h post-dosing by pulmonary artery catheterization. Urine output, fractional excretion of sodium, potassium, urea, and uric acid, and blood urea nitrogen (BUN) and creatinine levels were also measured. In both groups, the changes from baseline in all haemodynamic indices except mean pulmonary artery pressure (PAP) were not clinically significant. Mean [95% confidence interval (CI)] PAP showed a placebo-adjusted decrease with rolofylline of −1.5 (−4.1, 1.1)mmHg at Hour 4 and −3.5 mmHg (95% CI: −6.2, −0.2) at Hour 8. There was a significant increase with rolofylline in diuresis [placebo-corrected mean (95% CI) change of 68 (20, 116)mL/h at Hour 2–4 and 103 (21, 185)mL/h at Hour 4–8] and in fractional excretion of sodium, potassium, and uric acid. Placebo-corrected changes in plasma levels of creatinine and BUN with rolofylline were non-significant. Conclusion Single administration of rolofylline in patients with HF and impaired renal function produced a slight decrease in mean PAP and consistently increased diuresis and natriuresis without compromising renal function, both before and after administration of i.v. loop diuretics. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate physician-determined worsening heart failure (PD-WHF) in patients admitted with acute heart failure (AHF). Methods: The PROTECT pilot study evaluated rolofylline, an adenosine A1 receptor antagonist, versus placebo in patients with AHF and renal impairment. Signs and symptoms of heart failure (HF) and diuretic administration were prospectively recorded daily for 7 days and patients were followed for 60 days. Patients were categorized into three groups: (A) PD-WHF, based on worsening symptoms and signs of HF and need for additional intravenous (IV) or mechanical therapy (n = 29); (B) increased IV diuretic therapy without PD-WHF (n = 61), and (C) neither PD-WHF nor increase in IV diuretic dose (n = 211). Results: Patients in group A had slower resolution of dyspnea, longer mean (±SD) length of hospitalization (13.8 ± 6.8 vs. 10.5 ± 8.5 and 9.3 ± 5.9 days in groups B and C, respectively; p < 0.05 for both), and higher 60-day death and cardiovascular or renal readmission rates [49.7 (95% confidence interval: 33.1–69.1) vs. 37.3 (26.4–50.9) vs. 19.5% (14.7–25.6) in groups B and C, respectively]. PD-WHF was a strong independent predictor of length of stay and 60-day death and cardiovascular or renal readmission. Conclusions: PD-WHF may be an indicator of short-term risk and treatment efficacy in AHF. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The authors reply to letters written in response to the article "Irbesartan in Patients With Heart Failure and Preserved Ejection Fraction," published in the December 4, 2008 issue.

Background: Approximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome. Methods: We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life. Results: During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes. Conclusions: Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.) N Engl J Med 2008;359:2456-67. [ABSTRACT FROM AUTHOR]

Context: Little randomized evidence is available to guide the in-hospital management of patients with an acute exacerbation of chronic heart failure. Although intravenous inotropic therapy usually produces beneficial hemodynamic effects and is labeled for use in the care of such patients, the effect of such therapy on intermediate-term clinical outcomes is uncertain. Objective: To prospectively test whether a strategy that includes short-term use of milrinone in addition to standard therapy can improve clinical outcomes of patients hospitalized with an exacerbation of chronic heart failure. Design: Prospective, randomized, double-blind, placebo-controlled trial conducted from July 1997 through November 1999. Setting: Seventy-eight community and tertiary care hospitals in the United States. Participants: A total of 951 patients admitted with an exacerbation of systolic heart failure not requiring intravenous inotropic support (mean age, 65 years; 92% with baseline New York Heart Association class III or IV; mean left ventricular ejection fraction, 23%). Intervention: Patients were randomly assigned to receive a 48-hour infusion of either milrinone, 0.5 µg/kg per minute initially (n = 477), or saline placebo (n = 472). Main Outcome Measure: Cumulative days of hospitalization for cardiovascular cause within 60 days following randomization. Results: The median number of days hospitalized for cardiovascular causes within 60 days after randomization did not differ significantly between patients given milrinone (6 days) compared with placebo (7 days; P = .71). Sustained hypotension requiring intervention (10.7% vs 3.2%; P<.001) and new atrial arrhythmias (4.6% vs 1.5%; P = .004) occurred more frequently in patients who received milrinone. The milrinone and placebo groups did not differ significantly in in-hospital mortality (3.8% vs 2.3%; P = .19), 60-day mortality (10.3% vs 8.9%; P = .41), or the composite incidence of death or readmission (35.0% vs 35.3%; P = ... [ABSTRACT FROM AUTHOR]

Objective: A cost-effectiveness analysis of high and low doses of the angiotensin-converting enzyme (ACE) inhibitor lisinopril in the treatment of chronic heart failure.Methods: A cost-effectiveness analysis using data from a randomized controlled trial, ATLAS, where 3164 patients with chronic heart failure were allocated to a high-dose (daily target dose 32.5-35 mg) or low-dose strategy (daily target dose 2.5-5.0 mg) of lisinopril. Differential costs were based on resource use data collected in the trial costed using UK unit costs. Cost-effectiveness analysis related differential costs to differential life-years during a 4-year trial follow-up.Results: The mean total number of hospital in-patient days per patient was 18. 5 in the high dose group and 22.5 in the low dose group. Over the whole duration of the trial, the mean (S.D.) daily dose of lisinopril in the high-dose group was 22.5 mg (15.7 mg) compared to 3.2 mg (2.5 mg) in the low-dose group. The mean difference in cost per patient was pound sterling 397 lower in the high-dose group [95% CI (high-dose-low-dose) - pound sterling 1263 to pound sterling 436]. Mean life-years per patient were 0.085 years higher in the high-dose group [95% CI (high-dose-low-dose) -0.0074 to 0.1706). Based on mean costs and life-years, high-dose therapy dominates low-dose (less costly and more effective). Allowing for uncertainty in mean costs and life-years, the probability of high-dose therapy being less costly than low dose was 82%. If a decision maker is willing to pay at least pound sterling 3600 per life-year gained, the probability of high-dose being more cost-effective was 92%.Conclusions: The ATLAS Study showed that the treatment of heart failure with high-doses of lisinopril has a high probability of being more cost-effective than low-dose therapy. [ABSTRACT FROM AUTHOR]

Background: Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.Methods: After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.Results: After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).Conclusions: In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.). [ABSTRACT FROM AUTHOR]

Background: It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. Methods: We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. Results: The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P=0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P=0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P=0.82). Conclusions: Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized. (Funded by the National Institute of Neurological Disorders and Stroke; WARCEF ClinicalTrials.gov number, NCT00041938.) [ABSTRACT FROM PUBLISHER]