Showing papers by "John G.F. Cleland published in 2014"

Developing Therapies for Heart Failure With Preserved Ejection Fraction: Current State and Future Directions

Abstract: The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.

Improving care for patients with acute heart failure: before, during and after hospitalization

Abstract: Acute heart failure (AHF) is a common and serious condition that contributes to about 5% of all emergency hospital admissions in Europe and the USA. Here, we present the recommendations from structured discussions among an author group of AHF experts in 2013. The epidemiology of AHF and current practices in diagnosis, treatment, and long-term care for patients with AHF in Europe and the USA are examined. Available evidence indicates variation in the quality of care across hospitals and regions. Challenges include the need for rapid diagnosis and treatment, the heterogeneity of precipitating factors, and the typical repeated episodes of decompensation requiring admission to hospital for stabilization. In hospital, care should involve input from an expert in AHF and auditing to ensure that guidelines and protocols for treatment are implemented for all patients. A smooth transition to follow-up care is vital. Patient education programmes could have a dramatic effect on improving outcomes. Information technology should allow, where appropriate, patient telemonitoring and sharing of medical records. Where needed, access to end-of-life care and support for all patients, families, and caregivers should form part of a high-quality service. Eight evidence-based consensus policy recommendations are identified by the author group: optimize patient care transitions, improve patient education and support, provide equity of care for all patients, appoint experts to lead AHF care across disciplines, stimulate research into new therapies, develop and implement better measures of care quality, improve end-of-life care, and promote heart failure prevention.

2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy

Abstract: ### Abbreviations 1st AV : First-degree atrioventricular block AF : atrial fibrillation AT : atrial tachyarrhythmia ATP : Anti-tachycardia pacing AV : atrioventricular BBB : bundle branch block CHF : congestive heart failure CI : confidence interval CPG : Committee for Practice Guidelines CRT : cardiac resynchronization therapy CRT-D : cardiac resynchronization therapy and defibrillator CRT-P : cardiac resynchronization therapy and pacemaker ECG : electrocardiogram EDMD : Emery-Dreifuss muscular dystrophy EF : ejection fraction EPS : electrophysiological study ESC : European Society of Cardiology HCM : hypertrophic cardiomyopathy HF : heart failure HR : hazard ratio HV : His-ventricular ICD : implantable cardioverter defibrillator ILR : implantable loop recorder IVCD : intraventricular conduction delay LBBB : left bundle branch block LQTS : long QT syndrome LV : left ventricular LVEF : left ventricular ejection fraction LVSD : left ventricular systolic dysfunction MR : mitral regurgitation MRI : magnetic resonance imaging NYHA : New York Heart Association PM : pacemaker OR : odds ratio QALY : quality-adjusted life year RBBB : right bundle branch block RCT : randomized controlled trial RV : right ventricular SB : sinus bradycardia SNRT : sinus node recovery time SR : sinus rhythm SSS : sick sinus syndrome TAVI : transcatheter aortic valve implantation VF : ventricular fibrillation VT : ventricular tachycardia VV : interventricular (delay) ### Acronyms of the trials referenced in the recommendations or reported in the tables ADEPT : ADvanced Elements of Pacing Randomized Controlled Trial ADOPT : Atrial Dynamic Overdrive Pacing Trial AOPS : Atrial Overdrive Pacing Study APAF : Ablate and Pace in Atrial Fibrillation ASSERT : ASymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial ATTEST : ATrial Therapy Efficacy and Safety Trial AVAIL CLS/CRT : AV Node Ablation with CLS and CRT Pacing Therapies for Treatment of AF trial B4 : Bradycardia detection in Bundle Branch Block BELIEVE : Bi vs. Left Ventricular Pacing: an International Pilot Evaluation on Heart Failure Patients with Ventricular Arrhythmias BIOPACE : Biventricular pacing for atrioventricular block to prevent cardiac desynchronization BLOCK-HF : Biventricular versus right ventricular pacing in patients with AV block B-LEFT : Biventricular versus LEFT Univentricular Pacing with ICD Back-up in Heart Failure Patients CARE-HF : CArdiac REsynchronization in Heart Failure CLEAR : CLinical Evaluation on Advanced Resynchronization COMBAT : COnventional vs. Biventricular Pacing in Heart Failure and Bradyarrhythmia COMPANION : COmparison of Medical Therapy, Pacing and Defibrillation in Heart Failure DANPACE : DANish Multicenter Randomized Trial on Single Lead Atrial PACing vs. Dual Chamber Pacing in Sick Sinus Syndrome DECREASE-HF : The Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2: Assessment of Safety and Effectiveness in Heart Failure FREEDOM : Optimization Study Using the QuickOpt Method GREATER-EARTH : Evaluation of Resynchronization Therapy for Heart Failure in Patients with a QRS Duration GREATER Than 120 ms LESSER-EARTH : Evaluation of Resynchronization Therapy for Heart Failure in Patients with a QRS Duration Lower Than 120 ms HOBIPACE : HOmburg BIventricular PACing Evaluation IN-CHF : Italian Network on Congestive Heart Failure ISSUE : International Study on Syncope of Unexplained Etiology MADIT : Multicenter Automatic Defibrillator Trial MIRACLE : Multicenter InSync RAndomized CLinical Evaluation MOST : MOde Selection Trial in Sinus-Node Dysfunction MUSTIC : MUltisite STimulation In Cardiomyopathies OPSITE : Optimal Pacing SITE PACE : Pacing to Avoid Cardiac Enlargement PAVE : Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation PATH-CHF : PAcing THerapies in Congestive Heart Failure II Study Group PIPAF : Pacing In Prevention of Atrial Fibrillation Study PIRAT : Prevention of Immediate Reinitiation of Atrial Tachyarrhythmias POT : Prevention Or Termination Study PREVENT-HF : PREventing VENTricular Dysfunction in Pacemaker Patients Without Advanced Heart Failure PROSPECT : PRedictors Of Response to Cardiac Resynchronization Therapy RAFT : Resynchronization–Defibrillation for Ambulatory Heart Failure Trial RethinQ : Cardiac REsynchronization THerapy IN Patients with Heart Failure and Narrow QRS REVERSE : REsynchronization reVErses Remodelling in Systolic left vEntricular dysfunction SAFARI : Study of Atrial Fibrillation Reduction SCD HeFT : Sudden Cardiac Death in Heart Failure Trial SMART-AV : The SMARTDelay Determined AV Optimization: a Comparison with Other AV Delay Methods Used in Cardiac Resynchronization Therapy SYDIT : The SYncope DIagnosis and Treatment SYNPACE : Vasovagal SYNcope and PACing TARGET : TARgeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy THEOPACE : Effects of Oral THEOphylline and of Permanent PACEmaker on the Symptoms and Complications of Sick Sinus Syndrome VASIS-PM : VAsovagal Syncope International Study on PaceMaker therapy V-HeFT : Vasodilator in HEart Failure Trial VPSII : Second Vasovagal Pacemaker Study (VPS II) Additional references are mentioned with ‘w’ in the main text and can be found on the online addenda along with 5 figures (1, 6, 7, 9, 11, 12) and 10 tables (3, 4, 5, 9, 11, 12, 19, 21, 22, 23). They are available on the ESC website only at http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/cardiac-pacing-and-cardiac-resynchronisation-therapy.aspx Guidelines summarize and evaluate all available evidence, at the time of the writing process, on a particular issue, with the …

Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure

Abstract: Aim Acute heart failure (AHF) critically deranges haemodynamic and metabolic homoeostasis. Iron is a key micronutrient for homoeostasis maintenance. We hypothesized that iron deficiency (ID) defined as depleted iron stores accompanied by unmet cellular iron requirements would in this setting predict the poor outcome. Methods and results Among 165 AHF patients (age 65 ± 12 years, 81% men, 31% de novo HF), for ID diagnosis we prospectively applied: low serum hepcidin reflecting depleted iron stores (<14.5 ng/mL, the 5th percentile in healthy peers), and high-serum soluble transferrin receptor (sTfR) reflecting unmet cellular iron requirements (≥1.59 mg/L, the 95th percentile in healthy peers). Concomitance of low hepcidin and high sTfR (the most profound ID) was found in 37%, isolated either high sTfR or low hepcidin was found in 29 and 9% of patients, and 25% of subjects demonstrated preserved iron status. Patients with low hepcidin and high sTfR had peripheral oedema, high NT-proBNP, high uric acid, low haemoglobin ( P < 0.05), and 5% in-hospital mortality (0% in remaining patients). During the 12-month follow-up, 33 (20%) patients died. Those with low hepcidin and high sTfR had the highest 12-month mortality [(41% (95% CI: 29–53%)] when compared with those with isolated high sTfR [15% (5–25%)], isolated low hepcidin [7% (0–19%)] and preserved iron status (0%) ( P < 0.001). Analogous mortality patterns were seen separately in anaemics and non-anaemics. Conclusion Iron deficiency defined as depleted body iron stores and unmet cellular iron requirements is common in AHF, and identifies those with the poor outcome. Its correction may be an attractive therapeutic approach.

Decongestion in acute heart failure.

Abstract: Congestion is a major reason for hospitalization in acute heart failure (HF). Therapeutic strategies to manage congestion include diuretics, vasodilators, ultrafiltration, vasopressin antagonists, mineralocorticoid receptor antagonists, and potentially also novel therapies such as gut sequesterants and serelaxin. Uncertainty exists with respect to the appropriate decongestion strategy for an individual patient. In this review, we summarize the benefit and risk profiles for these decongestion strategies and provide guidance on selecting an appropriate approach for different patients. An evidence-based initial approach to congestion management involves high-dose i.v. diuretics with addition of vasodilators for dyspnoea relief if blood pressure allows. To enhance diuresis or overcome diuretic resistance, options include dual nephron blockade with thiazide diuretics or natriuretic doses of mineralocorticoid receptor antagonists. Vasopressin antagonists may improve aquaresis and relieve dyspnoea. If diuretic strategies are unsuccessful, then ultrafiltration may be considered. Ultrafiltration should be used with caution in the setting of worsening renal function. This review is based on discussions among scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from 30 November to 1 December 2012.

Effect of Rosuvastatin on Repeat Heart Failure Hospitalizations: The CORONA Trial (Controlled Rosuvastatin Multinational Trial in Heart Failure)

Abstract: Objectives This study sought to examine the effect of statin therapy hospitalizations for heart failure (HFH) in patients in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) trial. Background HFH is an important, frequently recurrent event. Conventional time-to-first event analyses do not take account repeat events. We used a number of statistical approaches to examine the effect of treatment on first and repeat HFH in the CORONA trial. Methods In the CORONA trial, 5,011 patients ≥60 years of age with chronic New York Heart Association functional classes II to IV systolic heart failure resulting from ischemia were randomized to receive rosuvastatin or placebo. Poisson, Andersen-Gill, and negative binomial methods (NB) were used to analyze the effect of rosuvastatin on HFH, and the NB and a parametric joint frailty model (JF) were used to examine this effect while accounting for the competing risk of cardiovascular (CV) death. Rosuvastatin/placebo rate ratios were calculated, both unadjusted and adjusted. Results A total of 1,291 patients had 1 or more HFH (750 of these had a single HFH only), and there were a total of 2,408 HFHs. The hazard ratio for the conventional time-to-first event analysis for HFH was 0.91 (95% confidence interval [CI]: 0.82 to 1.02, p = 0.105). In contrast, the NB on repeat hospitalizations gave an unadjusted RR (RR) for HFH of 0.86 (95% CI: 0.75 to 0.99, p = 0.030), adjusted 0.82 (95% CI: 0.72 to 0.92, p = 0.001), and after including CV death as the last event, adjusted RR of 0.85 (95% CI: 0.77 to 0.94, p = 0.001). The JF gave an adjusted RR of 0.82 (95% CI: 0.73 to 0.92, p = 0.001). Similar results were found in analyses of all CV hospitalizations and all-cause hospitalizations. Conclusions When repeat events were included, rosuvastatin was shown to reduce the risk of HFH by approximately 15% to 20%, equating to approximately 76 fewer admissions per 1,000 patients treated over a median 33 months of follow-up. Including repeat events could increase the ability to detect treatment effects in heart failure trials.

Is Heart Rate Important for Patients With Heart Failure in Atrial Fibrillation

Abstract: Objectives This study sought to investigate the relationship between resting ventricular rate and mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) who were in sinus rhythm (SR) or atrial fibrillation (AF). Background Slower heart rates are associated with better survival in patients with CHF in SR, but it is not clear whether this is true for those in AF. Methods We assessed 2,039 outpatients with CHF and LVEF ≤50% undergoing baseline assessment, of whom 24% (n = 488) were in AF; and 841 outpatients reassessed after attempted treatment optimization at 1 year, of whom 22% (n = 184) were in AF. Cox proportional hazards models were used to assess the relationships between heart rate and survival in patients with CHF and AF or sinus rhythm. We analyzed heart rate and rhythm data recorded at the baseline review and after 1-year follow-up. Proportional hazards assumptions were checked by Schoenfeld and Martingale residuals. Results The median survival for those in AF was 6.1 years (interquartile range [IQR]: 5.3 to 6.9 years) and 7.3 years (IQR: 6.5 to 8.1 years) for those in SR. In univariable analysis, patients with AF had a worse survival (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.08 to 1.47; p = 0.003) but after covariate adjustment, survival rates were similar. After adjusting Cox regression models, there was no association between heart rate (per 10 beats/min increments) and survival in patients with AF before (HR: 0.94, 95% CI: 0.88 to 1.00, p = 0.07) or after (HR: 1.00, 95% CI: 0.99 to 1.00, p = 0.84) therapy optimization. For patients in SR, higher heart rates were associated with worse survival, both before (HR: 1.10, 95% CI: 1.05 to 1.15, p Conclusions In patients with CHF and a reduced LVEF, slower resting ventricular rate is associated with better survival for patients in SR but not for those with AF.

Predictors of Postdischarge Outcomes From Information Acquired Shortly After Admission for Acute Heart Failure A Report From the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Study

Abstract: Background— Acute heart failure is a common reason for admission, and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for acute heart failure, to determine whether a few selected variables were inferior to an extended data set. Methods and Results— The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing rolofylline and placebo in 2033 patients admitted with acute heart failure. Prespecified outcomes at 30 days were death or rehospitalization for any reason; death or rehospitalization for cardiovascular or renal reasons; and, at both 30 and 180 days, all-cause mortality. No variable had a c-index >0.70, and few had values >0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information, but a reduced model using only 8 items (age, previous heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine, and albumin) performed similarly. For prediction of all-cause mortality at 180 days, the model c-index using all variables was 0.72 and for the simplified model, also 0.72. Conclusions— A few simple clinical variables measured on admission in patients with acute heart failure predict a variety of adverse outcomes with accuracy similar to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included nonfatal events. Better methods of risk stratification are required. Clinical Trial Registration— URL: . Unique identifiers: [NCT00328692][1] and [NCT00354458][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00328692&atom=%2Fcirchf%2F7%2F1%2F76.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2F7%2F1%2F76.atom

Charting a roadmap for heart failure biomarker studies.

Abstract: Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta-analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers.

Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis.

Abstract: MeSH Antioxidants /therapeutic use; Biomarkers /blood; Cardiovascular Agents /therapeutic use; Cardiovascular Diseases /blood /drug therapy /enzymology /physiopathology; Endothelium, Vascular /drug effects /metabolism /physiopathology; Enzyme Inhibitors /therapeutic use; Exercise Tolerance /drug effects; Hemodynamics /drug effects; Humans; Inflammation Mediators /blood; Myocardial Contraction /drug effects; Oxidative Stress /drug effects; Ventricular Function, Left /drug effects; Xanthine Oxidase /antagonists & inhibitors /metabolism

Heart rate: a prognostic factor and therapeutic target in chronic heart failure. The distinct roles of drugs with heart rate-lowering properties

Abstract: Heart rate not only predicts outcome but may also be a therapeutic target in patients with chronic heart failure. Several classes of pharmacological agents can be used to modulate heart rate, including beta-blockers, ivabradine, digoxin, amiodarone, and verapamil. Choice of agent will depend on heart rhythm, co-morbidities, and disease phenotype. Beneficial and harmful interactions may also exist. The aim of this paper is to summarize the current body of knowledge regarding the relevance of heart rate as a prognostic factor (risk marker) and particularly as a therapeutic target (risk factor) in patients with chronic heart failure, with a special focus on ivabradine, a novel agent that is currently the only available purely bradycardic agent.

International differences in clinical characteristics, management, and outcomes in acute heart failure patients: better short-term outcomes in patients enrolled in Eastern Europe and Russia in the PROTECT trial.

Abstract: AimsThe 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. Methods and resultsThe 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. ConclusionsIn 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.

Global longitudinal strain in patients with suspected heart failure and a normal ejection fraction: does it improve diagnosis and risk stratification?

Abstract: Many patients have clinical, structural or bio-marker evidence of heart failure (HF) but a normal left ventricular ejection fraction (LVEF; HeFNEF). Measurement of global longitudinal strain (GLS) may add diagnostic and prognostic information. Patients with symptoms suggesting heart failure and LVEF ≥50 % were studied: 76 had no substantial cardiac dysfunction (left atrial diameter (LAD) <40 mm and amino-terminal pro-brain natriuretic peptide (NTproBNP) <400 ng/l); 99 had “possible HeFNEF” (LAD ≥40 mm or NTproBNP ≥400 ng/l); and 138 had “definite HeFNEF” (LAD ≥40 mm and NTproBNP ≥400 ng/L). Mean LVEF was 58 % in each subgroup. Patients with definite HeFNEF were older, more likely to have atrial fibrillation, had more symptoms and signs of fluid retention, were more likely to have right ventricular dysfunction and had higher pulmonary pressures than other groups. Mean GLS (SD) was less negative in patients with definite HeFNEF (−13.6 (3.0) % vs. possible HeFNEF: −15.2 (3.1) % vs. no substantial cardiac dysfunction: −15.9 (2.4) %; p < 0.001). GLS was −19.1 (2.1) % in 20 controls. During a median follow up of 647 days, cardiovascular death or an unplanned hospitalisation for heart failure occurred in 62 patients. In univariable analysis, GLS but not LVEF predicted events. However, in a multi-variable analysis, only urea, NTproBNP, left atrial volume, inferior vena cava diameter and atrial fibrillation independently predicted adverse outcome. GLS is abnormal in patients who have other evidence of HeFNEF, is associated with a worse prognosis in this population but is not a powerful independent predictor of outcome.

Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions

Abstract: There are over 1 million hospitalizations for heart failure (HF) annually in the United States alone, and a similar number has been reported in Europe. Recent clinical trials investigating novel therapies in patients with hospitalized HF (HHF) have been negative, and the post-discharge event rate remains unacceptably high. The lack of success with HHF trials stem from problems with understanding the study drug, matching the drug to the appropriate HF subgroup, and study execution. Related to the concept of study execution is the importance of including appropriate study sites in HHF trials. Often overlooked issues include consideration of the geographic region and the number of patients enrolled at each study center. Marked differences in baseline patient co-morbidities, serum biomarkers, treatment utilization and outcomes have been demonstrated across geographic regions. Furthermore, patients from sites with low recruitment may have worse outcomes compared to sites with higher enrollment patterns. Consequently, sites with poor trial enrollment may influence key patient end points and likely do not justify the costs of site training and maintenance. Accordingly, there is an unmet need to develop strategies to identify the right study sites that have acceptable patient quantity and quality. Potential approaches include, but are not limited to, establishing a pre-trial registry, developing site performance metrics, identifying a local regionally involved leader and bolstering recruitment incentives. This manuscript summarizes the roundtable discussion hosted by the Food and Drug Administration between members of academia, the National Institutes of Health, industry partners, contract research organizations and academic research organizations on the importance of selecting optimal sites for successful trials in HHF.

Renal Function Trajectories and Clinical Outcomes in Acute Heart Failure

Abstract: Background— Prior studies have demonstrated adverse risk associated with baseline and worsening renal function in acute heart failure, but none has modeled the trajectories of change in renal function and their impact on outcomes. Methods and Results— We used linear mixed models of serial measurements of blood urea nitrogen and creatinine to describe trajectories of renal function in 1962 patients with acute heart failure and renal dysfunction enrolled in the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function study. We assessed risk of 180-day mortality and 60-day cardiovascular or renal readmission and used Cox regression to determine association between renal trajectories and outcomes. Compared with patients alive at 180 days, patients who died were older, had lower blood pressure and ejection fraction, and higher creatinine levels at baseline. On average for the entire cohort, creatinine rose from days 1 to 3 and increased further after discharge, with the trajectory dependent on the day of discharge. Blood urea nitrogen, creatinine, and the rate of change in creatinine from baseline were the strongest independent predictors of 180-day mortality and 60-day readmission, whereas the rate of change of blood urea nitrogen from baseline was not predictive of outcomes. Baseline blood urea nitrogen >35 mg/dL and increase in creatinine >0.1 mg/dL per day increased the risk of mortality, whereas stable or decreasing creatinine was associated with reduced risk. Conclusions— Patients with acute heart failure and renal dysfunction demonstrate variable rise and fall in renal indices during and immediately after hospitalization. Risk of morbidity and mortality can be predicted based on baseline renal function and creatinine trajectory during the first 7 days. Clinical Trial Registration— URL: . Unique identifiers: [NCT00328692][1] and [NCT00354458][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00328692&atom=%2Fcirchf%2F7%2F1%2F59.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2F7%2F1%2F59.atom

Breathlessness at rest is not the dominant presentation of patients admitted with heart failure.

Abstract: Aims Many assume that most patients hospitalized with heart failure (HF) are short of breath at rest (SOBAR). The National HF Audit for England and Wales suggests that this assumption is false, which has profound implications for management Methods and results A retrospective case-note review was carried out of patients hospitalized with HF to determine how many present with shortness of breath at rest or are comfortable at rest but breathless on slight exertion (CARBOSE). Vital signs were tracked for 24 h and mortality for 180 days. Of 311 patients, those who were SOBAR (42%) had higher median heart rate (HR) (100 vs. 85 b.p.m.; P 125 mmHg in 73% of patients who were SOBAR and in 46% who were CARBOSE, dropping to 52% and 37%, respectively, by 4–6 h. Mortality amongst those who were SOBAR and those who were CARBOSE was, respectively, 19% and 34% (odds ratio 2.29; P = 0.005, 95% confidence interval 1.29–4.06). Conclusion Many patients admitted with HF are CARBOSE. Shortness of breath at rest may be more alarming, but those who are CARBOSE have a worse prognosis, perhaps reflecting more severe right heart dysfunction. Clinical trials of hospitalized HF may inappropriately exclude patients if they focus on shortness of breath at rest rather than peripheral congestion.

Exercise Capacity and Mortality in Patients With Ischemic Left Ventricular Dysfunction Randomized to Coronary Artery Bypass Graft Surgery or Medical Therapy: An Analysis From the STICH Trial (Surgical Treatment for Ischemic Heart Failure)

Abstract: Objectives The objective of this study was to assess the prognostic significance of exercise capacity in patients with ischemic left ventricular (LV) dysfunction eligible for coronary artery bypass graft surgery (CABG). Background Poor exercise capacity is associated with mortality, but it is not known how this influences the benefits and risks of CABG compared with medical therapy. Methods In an exploratory analysis, physical activity was assessed by questionnaire and 6-min walk test in 1,212 patients before randomization to CABG (n = 610) or medical management (n = 602) in the STICH (Surgical Treatment for Ischemic Heart Failure) trial. Mortality (n = 462) was compared by treatment allocation during 56 months (interquartile range: 48 to 68 months) of follow-up for subjects able (n = 682) and unable (n = 530) to walk 300 m in 6 min and with less (Physical Ability Score [PAS] >55, n = 749) and more (PAS ≤55, n = 433) limitation by dyspnea or fatigue. Results Compared with medical therapy, mortality was lower for patients randomized to CABG who walked ≥300 m (hazard ratio [HR]: 0.77; 95% confidence interval [CI]: 0.59 to 0.99; p = 0.038) and those with a PAS >55 (HR: 0.79; 95% CI: 0.62 to 1.01; p = 0.061). Patients unable to walk 300 m or with a PAS ≤55 had higher mortality during the first 60 days with CABG (HR: 3.24; 95% CI: 1.64 to 6.83; p = 0.002) and no significant benefit from CABG during total follow-up (HR: 0.95; 95% CI: 0.75 to 1.19; p = 0.626; interaction p = 0.167). Conclusions These observations suggest that patients with ischemic left ventricular dysfunction and poor exercise capacity have increased early risk and similar 5-year mortality with CABG compared with medical therapy, whereas those with better exercise capacity have improved survival with CABG. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595 )

Fatigue as a predictor of outcome in patients with heart failure: analysis of CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure).

Abstract: Objectives The purpose of this study was to examine the relationship between fatigue and clinical outcomes, using dyspnea as a comparator, in patients with left ventricular ejection fraction (LVEF) ≤35% enrolled in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study. Background Although fatigue is a common symptom in heart failure (HF), little is known about its association with prognosis. Methods At baseline in CORONA, fatigue “during the past few days” was measured using a 5-point exertion scale (0 = none, 1 = heavy exertion, 2 = moderate exertion, 3 = slight exertion, 4 = rest); a 4-point scale was used for dyspnea (1 to 4 as for fatigue). Patients were grouped into 3 categories: a fatigue score 0 to 1 (n = 535), fatigue score 2 (n = 1,632), and fatigue score 3 to 4 (n = 1,663); and a dyspnea score of 1 (n = 292), dyspnea score of 2 (n = 1,695), and dyspnea score of 3 to 4 (n = 1,843). The association between fatigue and dyspnea and the composite outcome of cardiovascular (CV) death or HF hospital stay and each component separately was examined using Kaplan-Meier analysis and Cox proportional-hazard models. We also examined all-cause mortality. Results In univariate analyses, symptom severity was associated with a higher risk of CV death or HF hospital stay (fatigue: group 3, 49% [n = 810], vs. group 1, 30% [n = 160]; dyspnea: group 3, 50% [n = 918], vs. group 1, 28% [n = 82]) and all-cause mortality (fatigue: group 3, 38% [n = 623], vs. group 1, 24% [n = 130]; dyspnea: group 3, 38% [n = 697], vs. group 1, 23% [n = 66], log-rank p Conclusions In HF, greater fatigue is associated with worse clinical outcomes. Closer attention should be paid to this symptom in clinical practice, with more done to standardize its measurement and understand its origins, with a view to improving treatment.

The Long-Term Prognostic Significance of 6-Minute Walk Test Distance in Patients with Chronic Heart Failure

Abstract: Background. The 6-minute walk test (6-MWT) is used to assess patients with chronic heart failure (CHF). The prognostic significance of the 6-MWT distance during long-term followup (>5 years) is unclear. Methods. 1,667 patients (median [inter-quartile range, IQR]) (age 72 [65–77]; 75% males) with heart failure due to left ventricular systolic impairment undertook a 6-MWT as part of their baseline assessment and were followed up for 5 years. Results. At 5 years’ followup, those patients who died (n = 959) were older at baseline and had a higher log NT pro-BNP than those who survived to 5 years (n = 708). 6-MWT distance was lower in those who died [163 (153) m versus 269 (160) m; P 360 m. 6-MWT distance was a predictor of all-cause mortality (HR 0.97; 95% CI 0.96-0.97; Chi-square = 184.1; P < 0.0001). Independent predictors of all-cause mortality were decreasing 6-MWT distance, increasing age, increasing NYHA classification, increasing log NT pro-BNP, decreasing diastolic blood pressure, decreasing sodium, and increasing urea. Conclusion. The 6-MWT is an important independent predictor of all-cause mortality following long-term followup in patients with CHF.

Worsening heart failure, a critical event during hospital admission for acute heart failure: results from the VERITAS study.

Abstract: AimsWorsening heart failure (WHF) in the first 7 days after an admission for acute HF (AHF) has been proposed as a therapeutic target in several recent AHF studies and was a co-primary endpoint of the VERITAS studies. Methods and resultsPatients were randomized within 24h of admission for AHF. WHF was defined as worsening or persistent signs and symptoms of HF requiring additional intravenous or mechanical therapy for HF or death within 7 days of randomization. Multivariable models were developed to predict the time to WHF through day 7. Unadjusted and multivariable-adjusted associations of WHF with the length of stay (LOS) of the index hospitalization, and 30- and 90-day outcomes were estimated. WHF occurred by day 7 in 27% of the 1347 patients enrolled. Age, co-morbidities, and markers of HF severity were moderately predictive of WHF; the C-index for a multivariable model for WHF was 0.66. After multivariable adjustment for baseline characteristics, WHF was associated with an increase in LOS of 4.33days [95% confidence interval (CI) 3.54-5.13days], a hazard ratio (HR) for 30-day HF readmission or death of 2.43 (95% CI 1.75-3.40), and a HR for 90-day mortality of 2.57 (95% CI 1.81-3.65), all with P <0.0001.The associations of WHF with these outcomes remained largely unchanged after adjustment for both baseline characteristics and changes in markers of renal and hepatic dysfunction during the first day of admission. ConclusionsIn patients admitted for AHF, WHF is a significant clinical event that is associated with delays in discharge and higher rates for readmission and death.

Development and course of heart failure after a myocardial infarction in younger and older people.

Abstract: Background Acute myocardial infarction (AMI) is a common cause of heart failure (HF), which can develop soon after AMI and may persist or resolve or develop late. HF after an MI is a major source of mortality. The cumulative incidence, prevalence and resolution of HF after MI in different age groups are poorly described. This study describes the natural history of HF after AMI according to age. Methods Patients with AMI during 1998 were identified from hospital records. HF was defined as treatment of symptoms and signs of HF with loop diuretics and was considered to have resolved if loop diuretic therapy could be stopped without recurrence of symptoms. Patients were categorised into those aged 75 years. Results Of 896 patients, 311, 297 and 288 were aged 75 years and of whom 24%, 57% and 82% had died respectively by December 2005. Of these deaths, 24 (8%), 68 (23%) and 107 (37%) occurred during the index admission, many associated with acute HF. A further 37 (12%), 63 (21%) and 82 (29%) developed HF that persisted until discharge, of whom 15, 44 and 62 subsequently died. After discharge, 53 (24%), 55 (40%) and 37 (47%) patients developed HF for the first time, of whom 26%, 62% and 76% subsequently died. Death was preceded by the development of HF in 35 (70%), 93 (91%) and 107 (85%) in aged 75 years, respectively. Conclusions The risk of developing HF and of dying after an MI increases progressively with age. Regardless of age, most deaths after a MI are preceded by the development of HF.

Thyroid-stimulating hormone and clinical outcomes: the CORONA trial (controlled rosuvastatin multinational study in heart failure).

Abstract: Objectives This study sought to examine the association between thyroid status and clinical outcomes in patients in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study. Background Hypo- and hyperthyroidism were associated with worse clinical outcomes in the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial). Methods In CORONA, 4,987 patients underwent baseline thyroid-stimulating hormone (TSH) measurement, 237 of which (4.8%) were receiving thyroid replacement therapy (TRT). Patients were classified as euthyroid (TSH: 0.3 to 5.0 μU/ml, and no TRT), hyperthyroid (l0.3 μU/ml and no TRT), or hypothyroid (>5.0 μU/ml and no TRT). The outcome composites of cardiovascular (CV) death or hospitalization for heart failure (HF), the components of this composite, and all-cause death were compared among hyperthyroid, hypothyroid, and euthyroid states, using multivariable models adjusting for previously reported prognostic variables. Results A total of 91.3% of patients were euthyroid, 5.0% were hypothyroid, and 3.7% were hyperthyroid. Compared with euthyroid patients, hypothyroid patients were more likely to have a history of stroke, had worse renal function and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, were more likely to be treated with an antiarrhythmic drug (or have an implantable cardioverter defibrillator), and were less likely to smoke or be treated with a beta-blocker or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. In univariate analyses, hypothyroidism was associated with an increased risk of the composite outcome of CV death or HF hospitalization (hazard ratio: 1.29; 95% confidence interval: 1.07 to 1.57; p = 0.008), as well as all-cause death (HR: 1.36; 95% confidence interval: 1.03 to 1.76; p = 0.004). However, after adjustment for other known predictors of outcome, the associations were weakened, and when NT-proBNP was added to the models, the association between hypothyroidism and all outcomes was eliminated. Conclusions Thyroid status is not an independent predictor of outcome in heart failure with reduced ejection fraction. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310 )

Development of a composite model derived from cardiopulmonary exercise tests to predict mortality risk in patients with mild-to-moderate heart failure

Abstract: Objective Cardiopulmonary exercise testing (CPET) is used to predict outcome in patients with mild-to-moderate heart failure (HF). Single CPET-derived variables are often used, but we wanted to see if a composite score achieved better predictive power. Methods Retrospective analysis of patient records at the department of cardiology, Castle Hill Hospital, Kingston-upon-Hull. 387 patients (median (25th–75th percentile)) (age 65 (56–72) years; 79% men; LVEF 34 (31–37) %) were included. Patients underwent a symptom-limited, maximal CPET on a treadmill. During a median follow-up of 8.6±2.1 years in survivors, 107 patients died. Survival models were built and validated using a hybrid approach between the bootstrap and Cox regression. Nine CPET-derived variables were included. Z-score defined each variable’s predictive strength. Model coefficients were converted to a risk score. Results Four CPET-related variables were independent predictors of all-cause mortality in the survival model: the presence of exertional oscillatory ventilation (EOV), increasing slope of the relation between ventilation and carbon dioxide production (VE/VCO 2 slope), decreasing oxygen uptake efficiency slope (OUES), and an increase in the lowest ventilatory equivalent for carbon dioxide (VEqCO 2 nadir). Individual predictors of mortality ranged from 0.60 to 0.71 using Harrell9s C-statistic, but the optimal combination of EOV+VE/VCO 2 slope+OUES+VEqCO 2 nadir reached 0.75. The Hull CPET risk score had a significantly higher area under the curve (0.78) when compared to the HF Survival Score (AUC=0.70; p Conclusions A composite risk score using variables from CPET out-performs the traditional single variable approach in predicting outcome in patients with mild-to-moderate HF.

Issues in the Mining of Heart Failure Datasets

Abstract: This paper investigates the characteristics of a clinical dataset using a combination of feature selection and classification methods to handle missing values and understand the underlying statistical characteristics of a typical clinical dataset. Typically, when a large clinical dataset is presented, it consists of challenges such as missing values, high dimensionality, and unbalanced classes. These pose an inherent problem when implementing feature selection and classification algorithms. With most clinical datasets, an initial exploration of the dataset is carried out, and those attributes with more than a certain percentage of missing values are eliminated from the dataset. Later, with the help of missing value imputation, feature selection and classification algorithms, prognostic and diagnostic models are developed. This paper has two main conclusions: 1) Despite the nature of clinical datasets, and their large size, methods for missing value imputation do not affect the final performance. What is crucial is that the dataset is an accurate representation of the clinical problem and those methods of imputing missing values are not critical for developing classifiers and prognostic/diagnostic models. 2) Supervised learning has proven to be more suitable for mining clinical data than unsupervised methods. It is also shown that non-parametric classifiers such as decision trees give better results when compared to parametric classifiers such as radial basis function networks (RBFNs).

Relationship between angina pectoris and outcomes in patients with heart failure and reduced ejection fraction: an analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).

Abstract: Aim Angina pectoris is common in patients with heart failure and reduced ejection fraction (HF-REF) but its relationship with outcomes has not been well defined. This relationship was investigated further in a retrospective analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Methods and results Four thousand, eight hundred and seventy-eight patients were divided into three categories: no history of angina and no chest pain at baseline (Group A; n = 1240), past history of angina but no chest pain at baseline (Group B; n = 1353) and both a history of angina and chest pain at baseline (Group C; n = 2285). Outcomes were examined using Kaplan–Meier and Cox regression survival analysis. Compared with Group A, Group C had a higher risk of non-fatal myocardial infarction or unstable angina (HR: 2.36, 1.54–3.61; P < 0.001), this composite plus coronary revascularization (HR: 2.54, 1.76–3.68; P < 0.001), as well as HF hospitalization (HR: 1.35, 1.13–1.63; P = 0.001), over a median follow-up period of 33 months. There was no difference in cardiovascular or all-cause mortality. Group B had a smaller increase in risk of coronary events but not of heart failure hospitalization. Conclusion Patients with HF-REF and ongoing angina are at an increased risk of acute coronary syndrome and HF hospitalization. Whether these patients would benefit from more aggressive medical therapy or percutaneous revascularization is not known and merits further investigation.