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Myocardial fibrosis, identified by late gadolinium enhancement cardiovascular magnetic resonance, predicts outcomes in chronic heart failure (HF). Its prognostic significance in new-onset HF and reduced left ventricular ejection fraction (LVEF) is unclear. We investigated whether the pattern and extent of fibrosis predict survival in new-onset HF and reduced LVEF of initially uncertain pathogenesis.Of 120 consecutive patients with new-onset (6 months) HF and reduced LVEF, 31 (26%) had infarct fibrosis, 25 (21%) had midwall fibrosis, and 64 (53%) had no fibrosis. During median follow-up of 8.9 years, 33 (28%) patients died. Patients with infarct fibrosis (hazard ratios [HR], 3.32; 95% CI, 1.46-7.58; P=0.004) or midwall fibrosis (HR, 2.99; 95% CI, 1.24-7.19; P=0.014) were more likely to die compared with those without fibrosis. On multivariable analysis, the pattern and extent of fibrosis were both associated with all-cause mortality (by fibrosis pattern: infarct: HR, 2.60; 95% CI, 1.08-6.27; P=0.033; midwall: HR, 2.64; 95% CI, 1.08-6.47; P=0.034; by fibrosis extent per 1%: HR, 1.07; 95% CI, 1.03-1.12; P0.001). Fibrosis pattern also predicted composites of cardiovascular mortality or aborted sudden cardiac death (infarct: HR, 3.45; 95% CI, 1.20-9.90; P=0.022; midwall: HR, 6.59; 95% CI, 2.26-19.22; P0.001), and all-cause mortality, HF hospitalization, or aborted sudden cardiac death (infarct: HR, 2.69; 95% CI, 1.26-5.76; P=0.011; midwall fibrosis: HR, 2.97; 95% CI, 1.37-6.45; P=0.006). Addition of fibrosis pattern to LVEF improved risk prediction for all-cause mortality (LVEF versus LVEF+fibrosis C statistic: 0.66 versus 0.71; P=0.033). Importantly, the absence of fibrosis heralded a favorable prognosis with an 85% survival rate over the duration of follow-up.The pattern and extent of myocardial fibrosis predict adverse outcomes in new-onset HF and reduced LVEF. In contrast, the absence of fibrosis portends a durable warranty period with a low incidence of adverse events. These findings support a role for late gadolinium enhancement cardiovascular magnetic resonance in the early risk stratification of patients with HF of uncertain pathogenesis.

This study sought to investigate the association between the extent, location, and pattern of late gadolinium enhancement (LGE) and outcome in a large dilated cardiomyopathy (DCM) cohort.The relationship between LGE and prognosis in DCM is incompletely understood.The authors examined the association between LGE and all-cause mortality and a sudden cardiac death (SCD) composite based on the extent, location, and pattern of LGE in DCM.Of 874 patients (588 men, median age 52 years) followed for a median of 4.9 years, 300 (34.3%) had nonischemic LGE. Estimated adjusted hazard ratios for patients with an LGE extent of 0 to 2.55%, 2.55% to 5.10%, and5.10%, respectively, were 1.59 (95% confidence interval [CI]: 0.99 to 2.55), 1.56 (95% CI: 0.96 to 2.54), and 2.31 (95% CI: 1.50 to 3.55) for all-cause mortality, and 2.79 (95% CI: 1.42 to 5.49), 3.86 (95% CI: 2.09 to 7.13), and 4.87 (95% CI: 2.78 to 8.53) for the SCD endpoint. There was a marked nonlinear relationship between LGE extent and outcome such that even small amounts of LGE predicted a substantial increase in risk. The presence of septal LGE was associated with increased mortality, but SCD was most associated with the combined presence of septal and free-wall LGE. Predictive models using LGE presence and location were superior to models based on LGE extent or pattern.In DCM, the presence of septal LGE is associated with a large increase in the risk of death and SCD events, even when the extent is small. SCD risk is greatest with concomitant septal and free-wall LGE. The incremental value of LGE extent beyond small amounts and LGE pattern is limited.

To evaluate the relationship between sex, age and outcome in dilated cardiomyopathy (DCM).We used proportional hazard modelling to examine the association between sex, age and all-cause mortality in consecutive patients with DCM. Overall, 881 patients (290 women, median age 52 years) were followed for a median of 4.9 years. Women were more likely to present with heart failure (64.0% vs. 54.5%; P = 0.007) and had more severe symptoms (P 0.0001) compared to men. Women had smaller left ventricular end-diastolic volume (125 mL/mWomen with DCM have better survival compared to men, which may partly be due to less severe left ventricular dysfunction and a smaller scar burden. There is increased mortality driven by non-sudden death in patients60 years of age that is less marked in women. Outcomes with contemporary treatment were favourable, with a low incidence of sudden death.

The authors sought to report the prevalence, clinical associations, and prognostic consequences of malnutrition in outpatients with heart failure (HF).Malnutrition may be common in HF and associated with adverse outcomes, but few data exist.We applied the geriatric nutritional risk index (GNRI), controlling nutritional status (CONUT) score, and prognostic nutritional index (PNI) to consecutive patients referred with suspected HF to a clinic serving a local population (n = 550,000).Of 4,021 patients enrolled, HF was confirmed in 3,386 (61% men; median age: 75 years; interquartile range [IQR]: 67 to 81 years, median N-terminal pro-B-type natriuretic peptide [NT-proBNP]: 1,103 ng/l [IQR: 415 to 2,631 ng/l]). Left ventricular ejection fraction was 40% in 35% of patients. Using scores for GNRI ≤91, CONUT4, and PNI ≤38, 6.7%, 10.0%, and 7.5% patients were moderately or severely malnourished, respectively; 57% were at least mildly malnourished by at least 1 score. Worse scores were most strongly related to older age, lower body mass index, worse symptoms and renal function, atrial fibrillation, anemia, and reduced mobility. During a median follow-up of 1,573 days (IQR: 702 to 2,799 days), 1,723 (51%) patients died. For patients who were moderately or severely malnourished, 1-year mortality was 28% for CONUT, 41% for GNRI, and 36% for PNI, compared with 9% for those with mild malnutrition or normal nutritional status. A model including only age, urea, and logNT-proBNP, predicted 1-year survival (C-statistic: 0.719) and was slightly improved by adding nutritional indices (up to 0.724; p 0.001) but not body mass index.Malnutrition is common among outpatients with HF and is strongly related to increased mortality.

Prognostic models for hospitalized heart failure (HHF) were developed predominantly for patients of European origin in the United States of America; it is unclear whether they perform similarly in other health care systems or for different ethnicities. We sought to validate published prediction models for HHF in the United Kingdom (UK) and Japan.Patients in the UK (n =894) and Japan (n =3158) were prospectively enrolled and were similar in terms of sex (∼60% men) and median age (∼77 years). Models predicted that British patients would have a higher mortality than Japanese, which was indeed true both for in-hospital (4.8% vs. 2.5%) and 180-day (20.7% vs. 9.5%) mortality. The model c-statistics for the published/derivation (range 0.70-0.76) and Japanese (range 0.75-0.77) cohorts were similar and higher than for the UK (0.62-0.75) but models consistently overestimated mortality in Japan. For in-hospital mortality, the OPTIMIZE-HF model performed best, providing similar discrimination in published/derivation, UK and Japanese cohorts [c-indices: 0.75 (0.74-0.77); 0.75 (0.68-0.81); and 0.77 (0.70-0.83), respectively], and least overestimated mortality in Japan. For 180-day mortality, the c-statistics for the ASCEND-HF model were similar in published/derivation (0.70) and UK [0.69 (0.64-0.74)] cohorts but higher in Japan [0.75 (0.71-0.79)]; calibration was good in the UK but again overestimated mortality in Japan.Calibration of published prediction models appears moderately accurate and unbiased when applied to British patients but consistently overestimates mortality in Japan. Identifying the reason why patients in Japan have a better than predicted prognosis is of great interest.

Background To address the need for personalized prevention, we conducted a subject‐level meta‐analysis within the framework of the Heart “OMics” in AGEing (HOMAGE) study to develop a risk prediction model for heart failure (HF) based on routinely available clinical measurements. Methods and Results Three studies with elderly persons (Health Aging and Body Composition [Health ABC], Valutazione della PREvalenza di DIsfunzione Cardiaca asinTOmatica e di scompenso cardiaco [PREDICTOR], and Prospective Study of Pravastatin in the Elderly at Risk [PROSPER]) were included to develop the HF risk function, while a fourth study (Anglo‐Scandinavian Cardiac Outcomes Trial [ASCOT]) was used as a validation cohort. Time‐to‐event analysis was conducted using the Cox proportional hazard model. Incident HF was defined as HF hospitalization. The Cox regression model was evaluated for its discriminatory performance (area under the receiver operating characteristic curve) and calibration (Grønnesby‐Borgan χ 2 statistic). During a follow‐up of 3.5 years, 470 of 10 236 elderly persons (mean age, 74.5 years; 51.3% women) developed HF . Higher age, BMI, systolic blood pressure, heart rate, serum creatinine, smoking, diabetes mellitus, history of coronary artery disease, and use of antihypertensive medication were associated with increased HF risk. The area under the receiver operating characteristic curve of the model was 0.71, with a good calibration (χ 2 7.9, P =0.54). A web‐based calculator was developed to allow easy calculations of the HF risk. Conclusions Simple measurements allow reliable estimation of the short‐term HF risk in populations and patients. The risk model may aid in risk stratification and future HF prevention strategies.

The PARADIGM-HF trial showed that sacubitril-valsartan, an ARB-neprilysin inhibitor, is more effective than enalapril for some patients with heart failure (HF). It is uncertain what proportion of patients with HF would be eligible for sacubitril-valsartan in clinical practice.Between 2001 and 2014, 6131 patients consecutively referred to a community HF clinic with suspected HF were assessed. The criteria required to enter the randomized phase of PARADIGM-HF, including symptoms, NT-proBNP, and current treatment with or without target doses of ACE inhibitors or ARBs, were applied to identify the proportion of patients eligible for sacubitril-valsartan. Recognizing the diversity of clinical opinion and guideline recommendations concerning this issue, entry criteria were applied singly and in combination. Of 1396 patients with reduced left ventricular ejection fraction (≤40%, HFrEF) and contemporary measurement of NT-proBNP, 379 were on target doses of an ACE inhibitor or ARB at their initial visit and, of these, 172 (45%) fulfilled the key entry criteria for the PARADIGM-HF trial. Lack of symptoms (32%) and NT-proBNP600 ng/L (49%) were common reasons for failure to fulfil criteria. A further 122 patients became eligible during follow-up (n = 294, 21%). However, if background medication and doses were ignored, then 701 (50%) were eligible initially and a further 137 became eligible during follow-up.Of patients with HFrEF referred to a clinic such as ours, only 21% fulfilled the PARADIGM-HF randomization criteria, on which the ESC Guidelines are based; this proportion rises to 60% if background medication is ignored.

Summary Background Heart failure with preserved ejection fraction (HFPEF) is a common, globally recognised, form of heart failure for which no treatment has yet been shown to improve symptoms or prognosis. The pathophysiology of HFPEF is complex but characterised by increased left atrial pressure, especially during exertion, which might be a key therapeutic target. The rationale for the present study was that a mechanical approach to reducing left atrial pressure might be effective in HFPEF. Methods The REDUCe Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF) study was an open-label, single-arm, phase 1 study designed to assess the performance and safety of a transcatheter interatrial shunt device (IASD, Corvia Medical, Tewkesbury, MA, USA) in patients older than 40 years of age with symptoms of HFPEF despite pharmacological therapy, left ventricular ejection fraction higher than 40%, and a raised pulmonary capillary wedge pressure at rest (>15 mm Hg) or during exercise (>25 mm Hg). The study was done at 21 centres (all departments of cardiology in the UK, Netherlands, Belgium, France, Germany, Austria, Denmark, Australia, and New Zealand). The co-primary endpoints were the safety and performance of the IASD at 6 months, together with measures of clinical efficacy, including functional capacity and clinical status, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01913613. Findings Between Feb 8, 2014, and June 10, 2015, 68 eligible patients were entered into the study. IASD placement was successful in 64 patients and seemed to be safe and well tolerated; no patient had a peri-procedural or major adverse cardiac or cerebrovascular event or need for cardiac surgical intervention for device-related complications during 6 months of follow-up. At 6 months, 31 (52%) of 60 patients had a reduction in pulmonary capillary wedge pressure at rest, 34 (58%) of 59 had a lower pulmonary capillary wedge pressure during exertion, and 23 (39%) of 59 fulfilled both these criteria. Mean exercise pulmonary capillary wedge pressure was lower at 6 months than at baseline, both at 20 watts workload (mean 32 mm Hg [SD 8] at baseline vs 29 mm Hg [9] at 6 months, p=0·0124) and at peak exercise (34 mm Hg [8] vs 32 [8], p=0·0255), despite increased mean exercise duration (baseline vs 6 months: 7·3 min [SD 3·1] vs 8·2 min [3·4], p=0·03). Sustained device patency at 6 months was confirmed by left-to-right shunting (pulmonary/systemic flow ratio: 1·06 [SD 0·32] at baseline vs 1·27 [0·20] at 6 months, p=0·0004). Interpretation Implantation of an interatrial shunt device is feasible, seems to be safe, reduces left atrial pressure during exercise, and could be a new strategy for the management of HFPEF. The effectiveness of IASD compared with existing treatment for patients with HFPEF requires validation in a randomised controlled trial. Funding Corvia Medical Inc.

Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure.This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF).Patients admitted for AHF with left ventricular ejection fraction ≤40%, dyspnea, and elevated plasma concentrations of natriuretic peptides were randomized to receive a double-blind, 48-h intravenous infusion of placebo or OM in 3 sequential, escalating-dose cohorts.In 606 patients, OM did not improve the primary endpoint of dyspnea relief (3 OM dose groups and pooled placebo: placebo, 41%; OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; p = 0.33) or any of the secondary outcomes studied. In supplemental, pre-specified analyses, OM resulted in greater dyspnea relief at 48 h (placebo, 37% vs. OM, 51%; p = 0.034) and through 5 days (p = 0.038) in the high-dose cohort. OM exerted plasma concentration-related increases in left ventricular systolic ejection time (p0.0001) and decreases in end-systolic dimension (p0.05). The adverse event profile and tolerability of OM were similar to those of placebo, without increases in ventricular or supraventricular tachyarrhythmias. Plasma troponin concentrations were higher in OM-treated patients compared with placebo (median difference at 48 h, 0.004 ng/ml), but with no obvious relationship with OM concentration (p = 0.95).In patients with AHF, intravenous OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group. (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure [ATOMIC-AHF]; NCT01300013).

Patients with left ventricular (LV) systolic dysfunction, coronary artery disease (CAD), and angina are often thought to have a worse prognosis and a greater prognostic benefit from coronary artery bypass graft (CABG) surgery than those without angina.This study investigated: 1) whether angina was associated with a worse prognosis; 2) whether angina identified patients who had a greater survival benefit from CABG; and 3) whether CABG improved angina in patients with LV systolic dysfunction and CAD.We performed an analysis of the STICH (Surgical Treatment for Ischemic Heart Failure) trial, in which 1,212 patients with an ejection fraction ≤35% and CAD were randomized to CABG or medical therapy. Multivariable Cox and logistic models were used to assess long-term clinical outcomes.At baseline, 770 patients (64%) reported angina. Among patients assigned to medical therapy, all-cause mortality was similar in patients with and without angina (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 0.79 to 1.38). The effect of CABG was similar whether the patient had angina (HR: 0.89; 95% CI: 0.71 to 1.13) or not (HR: 0.68; 95% CI: 0.50 to 0.94; p interaction = 0.14). Patients assigned to CABG were more likely to report improvement in angina than those assigned to medical therapy alone (odds ratio: 0.70; 95% CI: 0.55 to 0.90; p 0.01).Angina does not predict all-cause mortality in medically treated patients with LV systolic dysfunction and CAD, nor does it identify patients who have a greater survival benefit from CABG. However, CABG does improve angina to a greater extent than medical therapy alone. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595).

Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure.We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes.Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists.Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).

Most studies on acute heart failure (HF) exploring the relationship between admissions to hospital for HF and subsequent outcomes have focused only on HF coded as the primary diagnosis, but many other patients have admissions complicated by HF requiring attention. Failure to quantify the total hospital burden of HF underestimates its health economic impact, leading to underprovision of resources for its care.The First Euro Heart Failure Survey (EHFS-1) screened consecutive deaths and discharges, regardless of cause, from medical wards in 115 hospitals from 24 European countries during 2000-2001, to identify patients with known or suspected HF. Information on presenting symptoms and signs were gathered. Of 10 701 patients enrolled, HF was reported as the primary reason for admission in 4234 (40%), a secondary reason for admission if it complicated or prolonged stay in 1772 (17%), and in 4695 (43%) patients it was uncertain whether HF was actively contributing to the admission. Mortality on the index admission was 301 (7%), 290 (16%), and 189 (4%), respectively, with hazard ratios of 1.73 (P0.001) and 3.26 (P0.001) compared with the 'uncertain' group. In the 12 weeks following discharge, 287 (7%) patients with a primary, 117 (8%) with a secondary, and 238 (5%) with an incidental or uncertain diagnosis of HF died.Patients admitted to hospital with HF as a secondary rather than a primary diagnosis have a high mortality. More attention should be focused on patients with a secondary diagnosis of HF in terms of both care and research.

We aimed to study the relationships of loop diuretic dose with renal function and clinical outcomes in patients with chronic heart failure (HF).Loop diuretic dose at baseline was recorded in patients included in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). The relationship to change in estimated glomerular filtration rate (eGFR) over time and to the first occurrence of the composite outcome of cardiovascular (CV) death or hospitalization owing to HF was examined in propensity score matched cohorts. Of the 5011 patients, 2550, 745, and 449 were receiving80 mg (high), 41-80 mg (medium) and ≤40 mg (low) of loop diuretics in furosemide equivalent daily dosages, respectively, which were used to assemble 229, 385, and 1045 pairs of propensity-matched high, medium, and low dose cohorts. Compared with matched no loop diuretic groups, eGFR declined 0.3 ± 0.2, 0.3 ± 0.3 and 1.2 ± 0.5 mL/min/1.73 m(2) /year in the low-, medium-, and high-dose groups, respectively. Compared with matched no loop diuretic groups, hazard ratios (HR) (95% confidence intervals) for outcome associated with low-, medium- and high-dose groups were 1.71 (1.41-2.06), 1.99 (1.50-2.64), and 2.94 (1.95-4.41), respectively. Higher loop diuretic dose was particularly associated with increased risk for hospitalization owing to HF: HR 4.80 (2.75-8.37), P 0.001.The use of loop diuretics was associated with a slightly greater rate of decline in eGFR, which did not vary significantly by diuretic dose.Loop diuretic dose was associated with higher risks of (CV) mortality and predominantly hospitalization owing to HF, which appeared to be higher among those receiving higher daily doses.

This study sought to characterize patients attending a community heart failure (HF) clinic and identified those who were eligible for optimization of beta-blockers (BB) or ivabradine.Among patients with HF due to left ventricular systolic dysfunction in sinus rhythm, those with higher resting heart rate have a worse prognosis. Reducing sinus rate to 50 to 60 beats/min might improve outcomes.A total of 1,000 consecutively scheduled HF clinic follow-up appointments over a 6-month period were reviewed. Demographic, clinical, and echocardiographic data were collected for patients who attended (824 unique patients; 555 men). Mean age was 74 ± 11 years, median N-terminal pro-B-type natriuretic peptide levels were 1,002 ng/l (interquartile range: 367 to 2,151 ng/l), and the mean left ventricular ejection fraction (LVEF) was 44 ± 11%. A total of 202 (25%), 252 (31%), and 370 (45%) patients had LVEFs of ≤35%, 36% to 49%, and ≥50%, respectively. Of patients with LVEF ≤35%, 142 (70%) were in sinus rhythm.At 70 clinic visits, 58 patients with LVEFs of ≤35% were in sinus rhythm and had heart rates ≥70 beats/min. Of these, 13 patients had their BB dose increased, 20 were potentially eligible for, but did not have, BB uptitration, 15 were already taking target doses of BBs, and 10 patients were reported to be intolerant of higher doses. Thus, 25 patients were potentially eligible for ivabradine according to European Society of Cardiology guidelines; this number dropped to 14 when the United Kingdom National Institute for Health and Care Excellence guidelines were applied.Among patients with LVEFs of ≤35%, most are treated with BBs and have a heart rate at rest of 70 beats/min; 12% of these patients might be eligible for ivabradine.

To investigate the prognostic significance of hospitalization for worsening heart failure (WHF), myocardial infarction (MI), and stroke in patients with chronic heart failure (HF).We studied 5011 patients with HF and reduced EF (HF-REF) in the CORONA trial and 4128 patients with HF and preserved EF (HF-PEF) in the I-Preserve trial. Adjusted hazard ratios (HRs) for death were estimated for 0-30 days and ≥31 days after first post-randomization WHF, MI, or stroke used as a time-dependent variable, compared with patients with none of these events. In CORONA, 1616 patients (32%) had post-randomization first events (1223 WHF, 216 MI, 177 stroke), and the adjusted HR for mortality ≤30 days after an event was: WHF 7.21 [95% confidence interval (CI) 2.05-25.40], MI 23.08 (95% CI 6.44-82.71), and stroke 32.15 (95% CI 8.93-115.83). The HR for mortality at30 days was: WHF 3.62 (95% CI 3.11-4.21), MI 4.41 (95% CI 3.23-6.02), and stroke 3.19 (95% CI 2.21-4.61). In I-Preserve, 896 patients (22%) experienced a post-randomization event (638 WHF, 111 MI, 147 stroke). The HR for mortality ≤30 days was WHF 31.77 (95% CI 7.60-132.81), MI 154.77 (95% CI 34.21-700.17), and stroke 223.30 (95% CI 51.42-969.78); for30 days it was WHF 3.36 (95% CI 2.79-4.05), MI 3.29 (95% CI 2.14-5.06), and stroke 5.13 (95% CI 3.61-7.29).In patients with both HF-REF and HF-PEF, hospitalization for WHF was associated with high early and late mortality. The early relative risk of death was not as great as following MI or stroke, but the longer term relative risk of death was similar following all three types of event. Numerically, more deaths occurred following WHF because it was a much more common event.

The implications of geographical variation are unknown following adjustment for hospital length of stay (LOS) in heart failure (HF) trials that included patients whether or not they had systolic dysfunction. We investigated regional differences in an international acute HF trial.The PROTECT trial investigated 2033 patients with acute HF and renal dysfunction hospitalized at 173 sites in 17 countries with randomization to rolofylline or placebo. We grouped enrolling countries into six regions. Baseline characteristics, in-hospital management, and outcomes were explored by region. The primary study outcome was 60-day mortality or cardiovascular/renal hospitalization. Secondary outcomes included 180-day mortality. Of 2033 patients, 33% were from Eastern Europe, 19% from Western Europe, 16% from Israel, 15% from North America, 14% from Russia, and 3% from Argentina. Marked differences in baseline characteristics, HF phenotype, in-hospital diuretic and vasodilator strategies, and LOS were observed by region. LOS was shortest in North America and Israel (median 5 days) and longest in Russia (median 15 days). Regional event rates varied significantly. Following multivariable adjustment, region was an independent predictor of the risk of mortality/hospitalization at 60 days, with the lowest risk in Russia (hazard ratio 0.39, 95% confidence interval 0.23-0.64 vs. Western Europe) due to lower rehospitalization; mortality differences were attenuated by 180 days.In an international HF trial, there were differences in baseline characteristics, treatments, LOS, and rehospitalization amongst regions, but little difference in longer term mortality. Rehospitalization differences exist independent of LOS. This analysis may help inform future trial design and should be externally validated.

Aspirin and statins are established therapies for acute myocardial infarction (MI), but their benefits in patients with chronic heart failure (HF) remain elusive. We investigated the impact of aspirin and statins on long-term survival in patients hospitalized with acute MI complicated by HF.Of 4251 patients in the Evaluation of Methods and Management of Acute Coronary Events (EMMACE)-1 and -2 observational studies, 1706 patients had HF. A propensity score-matching method estimated the average treatment effects (ATEs) of aspirin and statins on survival over 90 months. ATEs were calculated as relative risk differences in all-cause mortality comparing patients receiving aspirin and statins with controls, respectively. Moreover, combined aspirin and statins vs. none (ATE I), aspirin or statins vs. none (ATE II), and aspirin and statins vs. aspirin or statins (ATE III) were assessed. The median survival times of the ATE I, ATE II and ATE III were 25, 50, and 85 months, respectively. Regarding aspirin, the ATE was significantly improved at 6, 12, and 90 months [ATE 6 months: 10%, 95% confidence interval (CI) 3-18%], where the ATE of statins favoured survival at 1-24 months (ATE 1 month: 5%, 95% CI 0.3-10%). Mortality was lower at 1, 6, and 24 months in those who received aspirin and statins (ATE I). When the combination was compared with either treatment alone, an effect persisted between 6 and 90 months (ATE III).In patients with acute MI complicated by HF, prescription of aspirin and statins either alone or together was associated with better long-term survival.

The aim of this study was to assess the relation between inferior vena cava (IVC) diameter, clinical variables, and outcome in patients with chronic heart failure (HF).The IVC distends as right atrial pressure rises. Therefore it might represent an index of HF severity independent of left ventricular ejection fraction (LVEF). The relation between IVC diameter and other clinical variables and its prognostic significance in patients with HF has not been explored.Outpatients attending a community HF service between 2008 and 2010 were enrolled. Heart failure was defined as the presence of relevant symptoms and signs and objective evidence of cardiac dysfunction: either LVEF45% or the combination of both left atrial dilation (≥4 cm) and raised amino-terminal pro-brain natriuretic peptide (NT-proBNP) ≥400 pg/ml. Patients were followed for a median of 567 (interquartile range: 413 to 736) days. The primary composite endpoint was cardiovascular death and HF hospitalization.Among the 693 patients enrolled, median age was 73 years, 33% were women, and 568 had HF. Patients with HF in the highest tertile of IVC diameter were older; had lower body mass index; were more likely to have atrial fibrillation and to be treated with diuretics; and had larger left atrial volumes, higher pulmonary pressures, and less negative values for global longitudinal strain. The LVEF and systolic blood pressure were similar across tertiles of IVC diameter. The IVC diameter and log [NT-proBNP] were correlated (r = 0.55, p0.001). During follow-up, 158 patients reached a primary endpoint. In a multivariable Cox regression model, including NT-proBNP, only increasing IVC diameter, urea, and the trans-tricuspid systolic gradient independently predicted a poor outcome. Neither global longitudinal strain nor LVEF were adverse predictors.In patients with chronic HF with or without a reduced LVEF, increasing IVC diameter identifies patients with an adverse outcome.

The purpose of this study was to determine whether coenzyme Q₁₀ is an independent predictor of prognosis in heart failure.Blood and tissue concentrations of the essential cofactor coenzyme Q₁₀ are decreased by statins, and this could be harmful in patients with heart failure.We measured serum coenzyme Q₁₀ in 1,191 patients with ischemic systolic heart failure enrolled in CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) and related this to clinical outcomes.Patients with lower coenzyme Q₁₀ concentrations were older and had more advanced heart failure. Mortality was significantly higher among patients in the lowest compared to the highest coenzyme Q₁₀ tertile in a univariate analysis (hazard ratio: 1.50, 95% confidence interval: 1.04 to 2.6, p = 0.03) but not in a multivariable analysis. Coenzyme Q₁₀ was not an independent predictor of any other clinical outcome. Rosuvastatin reduced coenzyme Q₁₀ but there was no interaction between coenzyme Q₁₀ and the effect of rosuvastatin.Coenzyme Q₁₀ is not an independent prognostic variable in heart failure. Rosuvastatin reduced coenzyme Q₁₀, but even in patients with a low baseline coenzyme Q₁₀, rosuvastatin treatment was not associated with a significantly worse outcome. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310).

We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective.Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile.In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke.Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin.Patients with heart failure due to ischemic heart disease who have NT-proBNP values103 pmol/l (868 pg/ml) may benefit from rosuvastatin.

This study was designed to investigate the loss of well-being, in terms of life-years, overall and in patients randomized to metoprolol versus carvedilol in the Carvedilol Or Metoprolol European Trial (COMET).The ultimate objectives of treating patients with heart failure are to relieve suffering and prolong life. Although the effect of treatment on mortality is usually described in trials, the effects on patient well-being throughout the trials' courses are rarely reported.A total of 3,029 patients randomized in the COMET study were included in the analysis. "Patient journey" was calculated by adjusting days alive and out of hospital over four years using a five-point score completed by the patient every four months, adjusted according to the need for intensification of diuretic therapy. Scores ranged from 0% (dead or hospitalized) to 100% (feeling very well).Over 48 months, 17% of all days were lost through death, 1% through hospitalization, 23% through impaired well-being, and 2% through the need for intensified therapy. Compared with metoprolol, carvedilol was associated with fewer days lost to death, with no increase in days lost due to impaired well-being or days in hospital. The "patient journey" score improved from a mean of 54.8% (SD 26.0) to 57.4% (SD 26.3%) (p0.0068).Despite treatment with beta-blockers, heart failure remains associated with a marked reduction in well-being and survival. Loss of quality-adjusted life-years through death and poor well-being seemed of similar magnitude over four years, and both were much larger than the loss that could be attributed to hospitalization.

We sought to identify whether home telemonitoring (HTM) improves outcomes compared with nurse telephone support (NTS) and usual care (UC) for patients with heart failure who are at high risk of hospitalization or death.Heart failure is associated with a high rate of hospitalization and poor prognosis. Telemonitoring could help implement and maintain effective therapy and detect worsening heart failure and its cause promptly to prevent medical crises.Patients with a recent admission for heart failure and left ventricular ejection fraction (LVEF)40% were assigned randomly to HTM, NTS, or UC in a 2:2:1 ratio. HTM consisted of twice-daily patient self-measurement of weight, blood pressure, heart rate, and rhythm with automated devices linked to a cardiology center. The NTS consisted of specialist nurses who were available to patients by telephone. Primary care physicians delivered UC. The primary end point was days dead or hospitalized with NTS versus HTM at 240 days.Of 426 patients randomly assigned, 48% were aged70 years, mean LVEF was 25% (SD, 8) and median plasma N-terminal pro-brain natriuretic peptide was 3,070 pg/ml (interquartile range 1,285 to 6,749 pg/ml). During 240 days of follow-up, 19.5%, 15.9%, and 12.7% of days were lost as the result of death or hospitalization for UC, NTS, and HTM, respectively (no significant difference). The number of admissions and mortality were similar among patients randomly assigned to NTS or HTM, but the mean duration of admissions was reduced by 6 days (95% confidence interval 1 to 11) with HTM. Patients randomly assigned to receive UC had higher one-year mortality (45%) than patients assigned to receive NTS (27%) or HTM (29%) (p = 0.032).Further investigation and refinement of the application of HTM are warranted because it may be a valuable role for the management of selected patients with heart failure.

Angiotensin-converting enzyme (ACE) inhibitors reduce heart failure death and hospitalization. Prescribed doses often are lower than randomized clinical trial (RCT) targets and practice guideline recommendations.To assess the cost-effectiveness of high- versus low-dose ACE inhibitor therapy in the ATLAS trial.A 19-nation RCT of high-dose (32.5-35.0 mg/day) versus low-dose (2.5-5.0 mg/day) lisinopril in 3164 patients with class II-IV heart failure and left ventricular ejection fractionor = 30%.Data on clinical outcomes and major cost events (hospitalizations and drug utilization) were collected prospectively. Hospital costs were estimated using Medicare and representative managed care diagnosis-related group reimbursement rates. ACE inhibitor drug costs were estimated using US average wholesale prices. Costs were discounted at 3% annually.Patients in the high-dose lisinopril group had fewer hospitalizations (1.98 vs 2.22, P = .014) and hospital days (18.28 vs 22.22, P = .002), especially heart failure hospitalizations (0.64 vs 0.80, P = .006) and heart failure hospital days (6.02 vs 7.45, P = .028) compared with the low-dose group. The high-dose lisinopril group also had lower heart failure hospital costs (dollars 5114 vs dollars 6361, P = .006) but higher ACE inhibitor drug costs (dollars 1368 vs dollars 855, P = .0001). Total hospital and drug costs were similar between high- and low-dose lisinopril groups (mean difference dollars -875, 95% CI dollars -2613 to dollars 884). Sensitivity analyses confirmed these findings.Cost savings from fewer heart failure hospitalizations offset higher ACE inhibitor costs in the high-dose group. The improved clinical outcomes were achieved without increased treatment costs.

Patients with heart failure are prone to a variety of arrhythmias, symptomatic and asymptomatic, that are prognostically significant and have an important bearing on the management of these patients. However there are some inherent problems in assessing the frequency of these arrhythmias within a large patient population, due to a lack of uniformity in defining heart failure and the transient nature of these rhythms. Patients with heart failure commonly die suddenly. The causes of these deaths are difficult to ascertain accurately and are often presumed arrhythmic. With the advent of effective interventions to prevent sudden death, accurately defining the causal relationship between the arrhythmias and sudden death has assumed great importance to appropriately target therapy. Several attempts have been made to predict such deaths on the basis of non-invasive and invasive diagnostic investigations with variable success. In this article we review the incidence and prevalence of atrial and ventricular arrhythmias and sudden deaths in epidemiological studies, surveys and randomised control trials of patients with heart failure. We discuss the prognostic significance of these arrhythmias, the inherent problems in their diagnosis and whether their presence predicts the risk of sudden deaths and the mode of such deaths in the heart failure population. The role of various investigations in risk stratification of sudden death has also been discussed.

ContextPlasma concentrations of the vasoconstrictor peptide endothelin-1 are increased in patients with heart failure, and higher concentrations are associated with worse outcomes. Tezosentan is an intravenous short-acting endothelin receptor antagonist that has favorable hemodynamic actions in heart failure.ObjectiveTo determine if tezosentan improves outcomes in patients with acute heart failure.Design, Setting, and ParticipantsThe Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure Studies, 2 independent, identical, and concurrent randomized, double-blind, placebo-controlled, parallel-group trials conducted from April 2003 through January 2005 at sites in Australia, Europe, Israel, and North America. Patients admitted within the previous 24 hours with persisting dyspnea and a respiratory rate of 24/min or greater were eligible provided they fulfilled 2 of 4 criteria: (1) elevated plasma concentrations of B-type or N-terminal pro–B-type natriuretic peptide, (2) clinical pulmonary edema, (3) radiologic pulmonary congestion or edema, or (4) left ventricular systolic dysfunction.InterventionInfusion of tezosentan (5 mg/h for 30 minutes, followed by 1 mg/h for 24 to 72 hours [n = 730]) or placebo (n = 718).Main Outcome MeasuresThe coprimary end points were change in dyspnea (measured at 3, 6, and 24 hours using a visual analog scale from 0-100) over 24 hours (as area under the curve) in the individual trials and incidence of death or worsening heart failure at 7 days in both trials combined.ResultsOf the 1435 patients who received treatment as assigned, 855 (60%) were men; mean age was 70 years. Mean left ventricular ejection fraction (measured in 779 patients [54%]) was 29% (SD, 11%). Baseline dyspnea scores were similar in the 2 treatment groups. Tezosentan did not improve dyspnea more than placebo in either trial, with a mean treatment difference of −12 (95% confidence interval [CI], −105 to 81) mm · h (P = .80) in the first trial and −25 (95% CI, −119 to 69) mm · h (P = .60) in the second. The incidence of death or worsening heart failure at 7 days in the combined trials was 26% in each treatment group (odds ratio, 0.99; 95% confidence interval, 0.82-1.21; P = .95).ConclusionThe endothelin receptor antagonist tezosentan did not improve symptoms or clinical outcomes in patients with acute heart failure.Trial Registrationclinicaltrials.gov Identifiers: NCT00525707 (VERITAS-1) and NCT00524433 (VERITAS-2).