Ferric carboxymaltose in patients with heart failure and iron deficiency.

BACKGROUND: Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia. METHODS: We enrolled 459 patients with chronic heart failure of New York Heart Association (NYHA) functional class II or III, a left ventricular ejection fraction of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level <100 microg per liter or between 100 and 299 microg per liter, if the transferrin saturation was <20%), and a hemoglobin level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of intravenous iron (ferric carboxymaltose) or saline (placebo). The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at week 24. Secondary end points included the distance walked in 6 minutes and the health-related quality of life. RESULTS: Among the patients receiving ferric carboxymaltose, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% confidence interval [CI], 1.75 to 3.61). Among the patients assigned to ferric carboxymaltose, 47% had an NYHA functional class I or II at week 24, as compared with 30% of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups. CONCLUSIONS: Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile is acceptable. (ClinicalTrials.gov number, NCT00520780).

Diuretics for heart failure.

BACKGROUND: Chronic heart failure is a major cause of morbidity and mortality worldwide. Diuretics are regarded as the first-line treatment for patients with congestive heart failure since they provide symptomatic relief. The effects of diuretics on disease progression and survival remain unclear. OBJECTIVES: To assess the harms and benefits of diuretics for chronic heart failure SEARCH METHODS: Updated searches were run in the Cochrane Central Register of Controlled Trials in The Cochrane Library (CENTRAL Issue 1 of 4, 2011), MEDLINE (1966 to 22 February 2011), EMBASE (1980 to 2011 Week 07) and HERDIN database (1990 to February 2011). We hand searched pertinent journals and reference lists of papers were inspected. We also contacted manufacturers and researchers in the field. No language restrictions were applied. SELECTION CRITERIA: Double-blinded randomised controlled trials of diuretic therapy comparing one diuretic with placebo, or one diuretic with another active agent (e.g. ACE inhibitors, digoxin) in patients with chronic heart failure. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted the data and assessed the eligibility and methodological quality of each trial. Extracted data were analysed by determining the odds ratio for dichotomous data, and difference in means for continuous data, of the treated group compared with controls. The likelihood of heterogeneity of the study population was assessed by the Chi-square test. If there was no evidence of statistical heterogeneity and pooling of results was clinically appropriate, a combined estimate was obtained using the fixed-effects model. MAIN RESULTS: This update has not identified any new studies for inclusion. The review includes 14 trials (525 participants), 7 were placebo-controlled, and 7 compared diuretics against other agents such as ACE inhibitors or digoxin. We analysed the data for mortality and for worsening heart failure. Mortality data were available in 3 of the placebo-controlled trials (202 participants). Mortality was lower for participants treated with diuretics than for placebo, odds ratio (OR) for death 0.24, 95% confidence interval (CI) 0.07 to 0.83; P = 0.02. Admission for worsening heart failure was reduced in those taking diuretics in two trials (169 participants), OR 0.07 (95% CI 0.01 to 0.52; P = 0.01). In four trials comparing diuretics to active control (91 participants), diuretics improved exercise capacity in participants with CHF, difference in means WMD 0.72 , 95% CI 0.40 to 1.04; P < 0.0001. AUTHORS' CONCLUSIONS: The available data from several small trials show that in patients with chronic heart failure, conventional diuretics appear to reduce the risk of death and worsening heart failure compared to placebo. Compared to active control, diuretics appear to improve exercise capacity.

Hyponatraemia: A strong predictor of mortality in adults with congenital heart disease.

AIMS: We studied the prevalence of hyponatraemia and its prognostic implications in a large population of adult patients with congenital heart disease (ACHD). METHODS AND RESULTS: A total of 1004 ACHD patients were retrospectively entered in this study (mean age 36.2 +/- 14.4 years, 48.7% male). Cox regression was used to estimate mortality associated with hyponatraemia, adjusted for potential confounders using both multivariable regression and propensity score matching. Mean sodium concentration in this ACHD cohort was 137.6 +/- 2.6 mmol/L. The overall prevalence of hyponatraemia in this cohort was 15.5% and was highest in congenitally corrected transposition (33.3%), after Fontan operation (29.6%), and in patients with Eisenmenger syndrome (22.0%). Predictors of hyponatraemia were worse functional class, cyanosis, higher serum creatinine levels, and treatment with diuretics. Patients were followed for a median of 4.1 years, during which there were 96 deaths. Hyponatraemia was a strong predictor of death, independent of age, previous surgery, functional class, systemic ventricular function, creatinine levels, and the use of diuretics (adjusted HR 2.82, 95% CI: 1.72-4.63, P < 0.0001). CONCLUSION: Hyponatraemia is relatively common in ACHD. Hyponatraemia carries a three-fold higher risk of death in ACHD and is a simple, cheap but powerful marker of mortality.

Maximizing survival benefit with primary prevention implantable cardioverter-defibrillator therapy in a heart failure population.

BACKGROUND: Although implantable cardioverter-defibrillator (ICD) therapy reduces mortality in moderately symptomatic heart failure patients with an ejection fraction 20%), no benefit of ICD treatment was seen. Projected over each patient's predicted lifespan, ICD treatment added 6.3, 4.1, 3.0, 1.9, and 0.2 additional years of life in the lowest- to highest-risk groups, respectively. CONCLUSIONS: A clinical risk prediction model identified subsets of moderately symptomatic heart failure patients in SCD-HeFT in whom single-lead ICD therapy was of no benefit and other subsets in which benefit was substantial.

Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

BACKGROUND: Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. METHODS: This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259. FINDINGS: Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group. INTERPRETATION: Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit. FUNDING: Merck (USA).

Prevalence, predictors, and prognostic value of renal dysfunction in adults with congenital heart disease.

BACKGROUND: Renal insufficiency in patients with ischemic heart disease and acquired heart failure is associated with higher mortality and morbidity. We studied the prevalence of renal dysfunction in adult patients with congenital heart disease (ACHD) and its relation to outcome. METHODS AND RESULTS: A total of 1102 adult patients with congenital heart disease (age 36.0+/-14.2 years) attending our institution between 1999 and 2006 had creatinine concentration measured. Glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease equation. Patients were divided into groups of normal GFR (> or =90 mL . min(-1) . 1.73 m(-2)), mildly impaired GFR (60 to 89 mL . min(-1) . 1.73 m(-2)), and moderately/severely impaired GFR (<60 mL . min(-1) . 1.73 m(-2)). Survival was compared between GFR groups by Cox regression. Median follow-up was 4.1 years, during which 103 patients died. Renal dysfunction was mild in 41% of patients and moderate or severe in 9%. A decrease in GFR was more common among patients with Eisenmenger physiology, of whom 72% had reduced GFR (<90 mL . min(-1) . 1.73 m(-2), P<0.0001 compared with the remainder), and in 18%, this was moderate or severe (P=0.007). Renal dysfunction had a substantial impact on mortality (propensity score-weighted hazard ratio 3.25, 95% CI 1.54 to 6.86, P=0.002 for moderately or severely impaired versus normal GFR). CONCLUSIONS: Deranged physiology in adult patients with congenital heart disease is not limited to the heart but also affects the kidney. Mortality is 3-fold higher than normal in the 1 in 11 patients who have moderate or severe GFR reduction.

Reduction in circulating testosterone relates to exercise capacity in men with chronic heart failure.

BACKGROUND: We investigated whether anabolic deficiency was linked to exercise intolerance in men with chronic heart failure (CHF). Anabolic hormones (testosterone, dehydroepiandrosterone sulfate, insulin-like growth factor 1 [IGF1]) contribute to exercise capacity in healthy men. This issue remains unclear in CHF. METHODS AND RESULTS: We studied 205 men with CHF (age 60 +/- 11 years, New York Heart Association [NYHA] Class I/II/III/IV: 37/95/65/8; LVEF [left ventricular ejection fraction]: 31 +/- 8%). Exercise capacity was expressed as peak oxygen consumption (peak VO(2)), peak O(2) pulse, and ventilatory response to exercise (VE-VCO(2) slope). In multivariable models, reduced peak VO(2) (and reduced peak O(2) pulse) was associated with diminished serum total testosterone (TT) (P < .01) and free testosterone (eFT; estimated from TT and sex hormone globulin levels) (P < .01), which was independent of NYHA Class, plasma N-terminal pro-brain natriuretic peptide, and age. These associations remained significant even after adjustment for an amount of leg lean tissue. In multivariable models, high VE-VCO(2) slope was related to reduced serum IGF1 (P < .05), advanced NYHA Class (P < .05), increased plasma NT-proBNP (P < .0001), and borderline low LVEF (P = .07). In 44 men, reassessed after 2.3 +/- 0.4 years, a reduction in peak VO(2) (and peak O(2) pulse) was accompanied by a decrease in TT (P < .01) and eFT (P

Bone mineral status and bone loss over time in men with chronic systolic heart failure and their clinical and hormonal determinants.

AIMS: Bone status has not been comprehensively studied in chronic heart failure (CHF). In CHF men, we evaluated bone status, bone loss over time, and their clinical and hormonal determinants. METHODS AND RESULTS: Bone mineral content (BMC) and bone mineral density (BMD) of arms, legs, trunk, and total body were examined using dual-energy X-ray absorptiometry in 187 men with CHF [age: 60+/-11 years, left ventricular ejection fraction (LVEF): 32+/-7%, New York Heart Association (NYHA) class (I/II/III/IV): 20/76/76/15] and in 21 age-matched male controls without CHF. Men with CHF had reduced BMD and BMC compared with controls (P < 0.05). Reduced BMD and BMC were independently determined by CHF severity (high NYHA class and impaired LVEF), reduced lean tissue mass, low serum dehydroepiandrosterone sulphate, total testosterone (TT), and estimated free testosterone (eFT) (all P < 0.05). Bone status was reassessed in 60 patients who survived >2 years from the initial evaluation. Significant bone loss over time (a reduction in BMC total > or = 1%/year) occurred in 35% of CHF men. Advanced NYHA class (P < 0.05) and reduced serum TT and eFT (P < 0.0001) at baseline predicted augmented bone loss. CONCLUSION: In CHF men, reduced BMD and BMC constitute an element of generalized body wasting, determined mainly by advanced heart failure and androgen deficiencies. Significant bone loss over time frequently occurs in CHF men and is related to testosterone depletion and disease severity.

Years-needed-to-treat to add 1 year of life: a new metric to estimate treatment effects in randomized trials.

AIMS: A standard metric to estimate absolute treatment effects is numbers-needed-to-treat (NNT), which implicitly assumes that all benefits reverse at trial-end. However, in-trial survival benefits typically do not reverse until long after trial-end, so that NNT will substantially underestimate lifetime benefits. METHODS AND RESULTS: We developed a new concept, years-needed-to-treat (YNT) to add 1 year of life, that quantifies the expected average life expectancy for two treatments including the estimated years of life remaining post-trial. Numbers-needed-to-treat and YNT were calculated in the COMET trial, in which carvedilol vs. metoprolol tartrate resulted in 17% lower mortality over 4.8 years. A multivariate Cox model was used to predict survival. Remaining years of life were estimated using the mortality-life-table method. At trial-end, survival was 9% higher in the carvedilol arm. Assuming that patients remained on the same therapy post-trial, the average total years of life for carvedilol vs. metoprolol were 10.63 +/- 0.19 vs. 9.48 +/- 0.18 (P < 0.0001) or 1.15 (95% confidence interval 0.64-1.66) additional years of life. The YNT was 9.2, indicating that 9.2 person-years of treatment added 1 person-year of life, compared with NNT of 59. CONCLUSION: Compared with NNT, the YNT method more accurately accounts for potential long-term benefits of interventions in randomized trials.

C-type natriuretic peptide production by the human kidney is blunted in chronic heart failure.

CNP (C-type natriuretic peptide) is a vasodilatory peptide produced by vascular endothelium and the human heart with a short half-life. CNP has been identified within the human kidney; however, few results are available on whether the human kidney is a systemic source of CNP. The aim of the present study was to establish whether CNP is secreted by the human kidney and if synthesis is blunted in CHF (chronic heart failure). A total of 20 male subjects (age, 57+/-2 years; mean+/-S.E.M.) undergoing CHF assessment (n=13) or investigation of paroxysmal supraventricular arrhythmia (normal left ventricular function in sinus rhythm during procedure) (n=7) were recruited. Renal CNP production was determined from concomitant plasma concentrations in the aorta and renal vein. When considering all subjects, a significant step-up in plasma CNP was found from the aorta to renal vein (3.0+/-0.3 compared with 8.3+/-2.4 pg/ml respectively; P=0.0045). The mean increase in CNP was 5.3+/-2.4 pg/ml (range, -0.9 to +45.3 pg/ml). In patients with CHF, the aortic concentration was 3.3+/-0.4 pg/ml compared with a renal vein concentration of 4.3+/-0.6 pg/ml (P=0.11). In those with normal left ventricular function, the respective values were 2.5+/-0.5 and 15.7+/-6.0 pg/ml (P=0.01). In conclusion, CNP is synthesized and secreted into the circulation by the normal human kidney, where it may have paracrine actions. Net renal secretion of CNP appears to be blunted in patients with CHF.

Age-dependent impairment of endothelial progenitor cells is corrected by growth-hormone-mediated increase of insulin-like growth-factor-1.

Aging is associated with an increased risk for atherosclerosis. A possible cause is low numbers and dysfunction of endothelial progenitor cells (EPC) which insufficiently repair damaged vascular walls. We hypothesized that decreased levels of insulin-like growth factor-1 (IGF-1) during age contribute to dysfunctional EPC. We measured the effect of growth hormone (GH), which increases endogenous IGF-1 levels, on EPC in mice and human subjects. We compared EPC number and function in healthy middle-aged male volunteers (57.4+/-1.4 years) before and after a 10 day treatment with recombinant GH (0.4 mg/d) with that of younger and elderly male subjects (27.5+/-0.9 and 74.1+/-0.9 years). Middle-aged and elderly subjects had lower circulating CD133(+)/VEGFR-2(+) EPC with impaired function and increased senescence. GH treatment in middle-aged subjects elevated IGF-1 levels (126.0+/-7.2 ng/mL versus 241.1+/-13.8 ng/mL; P<0.0001), increased circulating EPC with improved colony forming and migratory capacity, enhanced incorporation into tube-like structures, and augmented endothelial nitric oxide synthase expression in EPC comparable to that of the younger group. EPC senescence was attenuated, whereas telomerase activity was increased after GH treatment. Treatment of aged mice with GH (7 days) or IGF-1 increased IGF-1 and EPC levels and improved EPC function, whereas a two day GH treatment did not alter IGF-1 or EPC levels. Ex vivo treatment of EPC from elderly individuals with IGF-1 improved function and attenuated cellular senescence. IGF-1 stimulated EPC differentiation, migratory capacity and the ability to incorporate into forming vascular networks in vitro via the IGF-1 receptor. IGF-1 increased telomerase activity, endothelial nitric oxide synthase expression, phosphorylation and activity in EPC in a phosphoinositide-3-kinase/Akt dependent manner. Small interference RNA-mediated knockdown of endothelial nitric oxide synthase in EPC abolished the IGF-1 effects. Growth hormone-mediated increase in IGF-1 reverses age-related EPC dysfunction and may be a novel therapeutic strategy against vascular disorders with impairment of EPC.

Circulating estradiol and mortality in men with systolic chronic heart failure.

CONTEXT: Androgen deficiency is common in men with chronic heart failure (HF) and is associated with increased morbidity and mortality. Estrogens are formed by the aromatization of androgens; therefore, abnormal estrogen metabolism would be anticipated in HF. OBJECTIVE: To examine the relationship between serum concentration of estradiol and mortality in men with chronic HF and reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study at 2 tertiary cardiology centers (Wroclaw and Zabrze, Poland) of 501 men (mean [SD] age, 58 [12] years) with chronic HF, LVEF of 28% (SD, 8%), and New York Heart Association [NYHA] classes 1, 2, 3, and 4 of 52, 231, 181, and 37, respectively, who were recruited between January 1, 2002, and May 31, 2006. Cohort was divided into quintiles of serum estradiol (quintile 1, < 12.90 pg/mL; quintile 2, 12.90-21.79 pg/mL; quintile 3, 21.80-30.11 pg/mL; quintile 4, 30.12-37.39 pg/mL; and quintile 5, > or = 37.40 pg/mL). Quintile 3 was considered prospectively as the reference group. MAIN OUTCOME MEASURES: Serum concentrations of estradiol and androgens (total testosterone and dehydroepiandrosterone sulfate [DHEA-S]) were measured using immunoassays. RESULTS: Among 501 men with chronic HF, 171 deaths (34%) occurred during the 3-year follow-up. Compared with quintile 3, men in the lowest and highest estradiol quintiles had increased mortality (adjusted hazard ratio [HR], 4.17; 95% confidence interval [CI], 2.33-7.45 and HR, 2.33; 95% CI, 1.30-4.18; respectively; P < .001). These 2 quintiles had different clinical characteristics (quintile 1: increased serum total testosterone, decreased serum DHEA-S, advanced NYHA class, impaired renal function, and decreased total fat tissue mass; and quintile 5: increased serum bilirubin and liver enzymes, and decreased serum sodium; all P < .05 vs quintile 3). For increasing estradiol quintiles, 3-year survival rates adjusted for clinical variables and androgens were 44.6% (95% CI, 24.4%-63.0%), 65.8% (95% CI, 47.3%-79.2%), 82.4% (95% CI, 69.4%-90.2%), 79.0% (95% CI, 65.5%-87.6%), and 63.6% (95% CI, 46.6%-76.5%); respectively (P < .001). CONCLUSION: Among men with chronic HF and reduced LVEF, high and low concentrations of estradiol compared with the middle quintile of estradiol are related to an increased mortality.

Prediction of mode of death in heart failure: the Seattle Heart Failure Model.

BACKGROUND: Prognosis and mode of death in heart failure patients are highly variable in that some patients die suddenly (often from ventricular arrhythmia) and others die of progressive failure of cardiac function (pump failure). Prediction of mode of death may facilitate decisions about specific medications or devices. METHODS AND RESULTS: We used the Seattle Heart Failure Model (SHFM), a validated prediction model for total mortality in heart failure, to assess the mode of death in 10,538 ambulatory patients with New York Heart Association class II to IV heart failure and predominantly systolic dysfunction enrolled in 6 randomized trials or registries. During 16,735 person-years of follow-up, 2014 deaths occurred, which included 1014 sudden deaths and 684 pump-failure deaths. Compared with a SHFM score of 0, patients with a score of 1 had a 50% higher risk of sudden death, patients with a score of 2 had a nearly 3-fold higher risk, and patients with a score of 3 or 4 had a nearly 7-fold higher risk (P<0.001 for all comparisons; 1-year area under the receiver operating curve, 0.68). Stratification of risk of pump-failure death was even more pronounced, with a 4-fold higher risk with a score of 1, a 15-fold higher risk with a score of 2, a 38-fold higher risk with a score of 3, and an 88-fold higher risk with a score of 4 (P<0.001 for all comparisons; 1-year area under the receiver operating curve, 0.85). The proportion of deaths caused by sudden death versus pump-failure death decreased from a ratio of 7:1 with a SHFM score of 0 to a ratio of 1:2 with a SHFM score of 4 (P trend <0.001). CONCLUSIONS: The SHFM score provides information about the likely mode of death among ambulatory heart failure patients. Investigation is warranted to determine whether such information might predict responses to or cost-effectiveness of specific medications or devices in heart failure patients.

Nine-year trends in achievement of risk factor goals in the US and European outpatients with cardiovascular disease.

BACKGROUND: Although control of major cardiovascular risk factors (hypertension, hyperlipidemia, diabetes) has been the centerpiece of guidelines for the prevention of cardiovascular disease, periodic surveys suggest adherence to recommendations and achievement of goals is poor. Few data are available in outpatients, and no studies describe trends in meeting clinical targets. METHODS: A survey of outpatients with cardiovascular disease or risk factors was conducted annually, with a unique cohort each year, and included medical history, clinical data, and pharmacologic therapies. Data from 1998 to 2006 in the United States, United Kingdom, France, Italy, Spain, and Germany were analyzed for achievement of evidenced-based goals for hypertension, hyperlipidemia, and diabetes. RESULTS: Over 9 years, 102,318 patients were entered, with a mean age of 60 years, half were male, and each had at least one cardiovascular disease risk factor. In 1998, nearly half of patients in the United States were not at their target for blood pressure or low-density lipoprotein cholesterol. In Europe, <1 in 3 was at blood pressure goal, and a minority had low-density lipoprotein recorded. Only modest improvements were observed by 2006. Hemoglobin A(1c) levels improved from 2005 to 2006 in the United States and Europe, indicating improving glycemic control in these cohorts. CONCLUSIONS: Adherence to guidelines in these outpatients was suboptimal and lower in Europe than in the United States. Increased adherence to evidence-based targets for the treatment of hypertension, hyperlipidemia, and diabetes is needed to achieve ideal cardiovascular prevention.

Design of the heart failure endpoint evaluation of AII-antagonist losartan (HEAAL) study in patients intolerant to ACE-inhibitor.

BACKGROUND: In patients with heart failure and reduced left ventricular ejection fraction, angiotensin receptor blockers have been found to reduce mortality and morbidity and to prevent or reverse left ventricular remodelling, compared to optimized background treatment. In light of these data, The Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was developed to determine whether losartan 150 mg is superior to losartan 50 mg (antihypertensive dose) in reducing morbidity and mortality among patients with symptomatic heart failure who are intolerant of angiotensin-converting enzyme (ACE)-inhibitors. AIMS/METHODS: To compare the effect of high and moderate doses of losartan on the primary endpoint of all-cause mortality and hospitalisation due to heart failure in patients (n = 3834) with symptomatic heart failure and an ejection fraction < or = 40% who are intolerant of ACE-inhibitor treatment. RESULTS: This paper presents the rationale, trial design, and baseline characteristics of the study population. The study, which completed recruitment on 31 March 2005, is event-driven and is estimated to accrue the target of 1710 adjudicated primary events during the latter half of 2008. CONCLUSIONS: The results of HEAAL should facilitate selection of an optimal dosing regimen for losartan in patients with symptomatic heart failure who are intolerant of ACE-inhibitors.

Quality management of a large randomized double-blind multi-centre trial: the ACTION experience.

The ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) study was an independent, investigator-initiated, multi-national trial comparing nifedipine GITS to placebo in 7665 patients with stable angina pectoris. The trial was sponsored by the manufacturer of the medication concerned. 291 centers in 19 countries participated. Results have been published. We defined quality management (QM) as all activities directed at ensuring data integrity and consistency; and ensuring appropriate trial conduct, including pro-active prevention of deviations from protocol. We describe the QM framework that was adopted for the ACTION trial and the key tools that were used. In the protocol, particular attention was paid to explicit definition of tasks and responsibilities of all participants, and to unequivocal operational definitions of terms such as 'randomized', 'follow-up', etc. that could be applied by investigators, on-site monitors and during data processing at the coordinating centre. A comprehensive clinical trial and study management system based on simultaneous display of scanned documents and data base content had a central role. We describe in detail how compliance with good clinical practice was ensured, how the intention-to-treat principle was implemented, how compliance with study medication and completeness of follow-up was achieved, how double blinding was maintained throughout the study structure, and how patient safety was protected. The protocol ruled out participation in any other study at the same time by ACTION participants. Our experience showed that the reasons for this are not always understood by investigators. Unequivocal operational definitions of the procedural concepts that characterize randomized clinical trials should not only be the basis of QM, but also of reporting results.

Variation in severity and type of sleep-disordered breathing throughout 4 nights in patients with heart failure.

BACKGROUND: Over 50% of patients with chronic heart failure (CHF) have sleep-disordered breathing (SDB). Any variation in the type of SDB in CHF will have implications for patient management. Currently there is good evidence for treatment of obstructive sleep apnea (OSA) in CHF with continuous positive airway pressure; however, for central sleep apnea (CSA) the treatment is less clear. AIMS: The aim of this study was to investigate the variation in the severity and type of SDB (OSA vs. CSA) throughout 4 consecutive nights in CHF patients with SDB. METHODS: Nineteen male CHF patients (mean+/-sd: age 61+/-9 years; left ventricular ejection fraction: 34+/-10% and percent predicted peak VO2: 67+/-19%) underwent cardiorespiratory monitoring in their own home throughout 4 consecutive nights. RESULTS: There was minimal variation in apnea-hypopnea index (AHI) throughout 4 nights in CHF patients with SDB [intraclass correlation coefficient (95% confidence interval (CI)): 0.97 (95% CI 0.76 and 0.97)]. Eight patients [42% (95% CI 20% and 64%)] demonstrated a shift in the type of their SDB, from CSA to OSA or vice versa; these patients had significantly smaller neck circumference (group mean+/-sd) 42+/-2 vs. 44+/-2 cm; p=0.04), and had significant variation in the central AHI [intraclass correlation coefficient: 0.51 (95% CI 0.16 and 0.85)]. CONCLUSIONS: A single night of cardiorespiratory monitoring is representative of moderate-to-severe SDB in patients with CHF. However, a high proportion of patients shift their type of SDB over 4 nights. These findings may have implications for the management of SDB in CHF.

Long-term cost-effectiveness analysis of nebivolol compared with standard care in elderly patients with heart failure: an individual patient-based simulation model.

BACKGROUND AND OBJECTIVE: The SENIORS trial demonstrated that nebivolol is effective in the treatment of heart failure in elderly patients (e.g. > or = 70 years). This analysis evaluates the cost effectiveness of nebivolol compared with standard treatment. METHODS: An individual patient-simulation model based on a Markov modelling framework was developed to compare costs and outcomes for nebivolol and standard care in patients with heart failure starting treatment at the age of 70 years. Health states were defined by New York Heart Association (NYHA) class and death. At a given NYHA class and a given cycle, patients could die, be hospitalized for cardiovascular disease or remain stable. Risks for these events were derived from individual patient data from the SENIORS trial. The risk of each event in a given cycle was based on the subject's baseline characteristics and time in the current health state. The economic analysis was conducted from the UK NHS perspective with a lifetime horizon. The costs (euro; year 2006 values) considered were drug costs for nebivolol and other cardiac drugs, costs of GP visits, outpatient specialist visits and cardiovascular-related hospitalizations. Univariate and probabilistic sensitivity analysis was conducted. RESULTS: In the baseline analysis, the total cost per patient was euro6740 and euro9288, and QALYs were 5.194 and 5.843 for patients aged 70 years at the start of treatment for the standard treatment and nebivolol groups, respectively. The probabilistic sensitivity analysis provided an incremental cost-effectiveness ratio of euro3926 (95% CI 3731, 4159) per QALY. CONCLUSIONS: This analysis indicates that nebivolol appears to be a cost-effective treatment for elderly patients with heart failure compared with standard care.

Differences in European and North American approaches to the management of heart failure.

In recent years many guidelines on the treatment of specific medical conditions have been published with the goal of advising physicians, promoting good clinical care, and achieving a degree of equity and equality in the delivery of care. Differences exist between European and American guidelines for the management of heart failure not just because of differences in health systems but also because there is little agreement on how to assess clinical trials and convey conclusions in a clear format. Current recommendations can be confusing and often do not reflect the complexities of modern personalized medicine.