Correction to: Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

The values given for copeptin levels in men in quartiles 1 and 2 (Table 1) were incorrect, and should have read.

Novel endotypes in heart failure: effects on guideline-directed medical therapy.

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

A comparison of the prognostic value of BNP versus NT-proBNP after hospitalisation for heart failure.

AIMS: Concentrations of circulating B­type natriuretic peptides provide important prognostic information in heart failure (HF) patients. We directly compared the prognostic performance of brain natriuretic peptide (BNP) versus N­terminal-proBNP (NT-proBNP) measurements in a large population of HF patients at hospital discharge after an admission for decompensated HF. METHODS AND RESULTS: BNP and NT-proBNP were measured in 563 stable HF patients before discharge. All patients were followed for a fixed period of 18 months. The primary endpoint was time to first major event (HF hospitalisation or death). Patients were in NYHA class II (47%) or III/IV (53%) at discharge and the mean age of the patients was 71 ± 11 years, 217 (39%) females, mean left ventricular ejection fraction was 0.32 ± 0.14 and 234 (42%) had an ischaemic aetiology of HF. During the study, 236 patients (42%) reached the primary endpoint. Multivariate odds ratios of the primary endpoint for doubling of baseline levels of BNP and NT-proBNP were 1.46 (95% CI 1.19-1.80, p < 0.001) and 1.45 (95% CI 1.18-1.78, p < 0.001), respectively. The multivariable adjusted areas under the receiver-operating characteristic curve for prediction of the primary endpoint for doubling of BNP and NT-proBNP were 0.69 and 0.68, respectively. Direct comparison of the prognostic value of BNP and NT-proBNP did not reveal significant differences. CONCLUSIONS: BNP and NT-proBNP at discharge for hospitalisation for HF are powerful, and equally strong and independent predictors of all-cause death and HF rehospitalisation.

"Not getting worse" a qualitative study of patients perceptions of treatment goals in patients with heart failure.

BACKGROUND: Knowledge of patient reported outcomes helps to provide personalized care on a patient level, optimize care on a population level, and identify the most appropriate patient reported outcomes for clinical trials. To be able to provide personalized care to patients with HF, it is important to know which treatment goals patients with HF consider the most important. This is particularly useful for interventions aimed at improving symptoms, functional status, or health-related quality of life. AIM: The aim of this study was (1) to explore which treatment goals patients with heart failure (HF) perceive as important for their treatment and (2) to identify which treatment goals take priority over other treatment goals. METHODS: The study had a qualitative design and included one focus group interview with 6 patients with HF. Data were analyzed using qualitative content analysis. RESULTS: The overall theme of this study was found to be 'Not getting worse'. This theme was composed of 4 categories that described how the patients perceived the goals of treatment: to decrease symptoms, to improve physical function, to prevent readmission, and to live a normal life. None of the participants mentioned improved survival or being cured of their HF as a treatment goal. CONCLUSION: 'Not getting worse' was perceived as the treatment goal that matters to patients with HF and is in line with currently used endpoints for the evaluation of a treatment in a clinical trial. More research is necessary to develop endpoints that are consistent with the perception of patients, useful for clinical practice, and measurable.

Optimism and quality of life in patients with heart failure.

OBJECTIVES: Health-related quality of life (HR-QoL) of patients with heart failure (HF) is low despite the aim of HF treatment to improve HR-QoL. To date, most studies have focused on medical and physical factors in relation to HR-QoL, few data are available on the role of emotional factors such as dispositional optimism. This study examines the prevalence of optimism and pessimism in HF patients and investigates how optimism and pessimism are associated with different patient characteristics and HR-QoL. METHODS: Dispositional optimism was assessed in 86 HF patients (mean age 70 ± 9 years, 28% female, mean left ventricular ejection fraction 33%) with the Revised Life Orientation Test (LOT-R). HR-QoL was assessed with the Minnesota Living with Heart Failure Questionnaire and the EuroQol. RESULTS: The (mean ± SD) total score on the LOT-R was 14.6 ± 2.9 (theoretical range 0-24) and the scores on the subscales optimism and pessimism were 8.1 ± 1.9 and 5.5 ± 2.5, respectively. Higher age was related to more optimism (r = 0.22, p < 0.05), and optimism was associated with higher generic HR-QoL (B = 0.04, p < 0.05).Significance of resultsThe association found between optimism and generic HR-QoL of HF patients can lead to promising strategies to improve HF patients' HR-QoL, particularly because the literature has indicated that optimism is a modifiable condition.

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

INTRODUCTION: Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. METHODS AND RESULTS: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). CONCLUSION: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

Incorporating patient preferences into drug development and regulatory decision making: Results from a quantitative pilot study with cancer patients, carers, and regulators.

Currently, patient preference studies are not required to be included in marketing authorization applications to regulatory authorities, and the role and methodology for such studies have not been agreed upon. The European Medicines Agency (EMA) conducted a pilot study to gain experience on how the collection of individual preferences can inform the regulatory review. Using a short online questionnaire, ordinal statements regarding the desirability of different outcomes in the treatment of advanced cancer were elicited from 139 participants (98 regulators, 29 patient or carers, and 12 healthcare professionals). This was followed by face-to-face meetings to gather feedback and validate the individual responses. In this article we summarize the EMA pilot study and discuss the role of patient preference studies within the regulatory review. Based on the results, we conclude that our preference elicitation instrument was easy to implement and sufficiently precise to learn about the distribution of the participants' individual preferences.

Perception of impairments by patients with heart failure.

BACKGROUND: One of the major aims in the treatment of patients with heart failure (HF) is symptom relief and an improvement in the health-related quality of life (HR-QoL). The perception of impairments due to HF may differ between patients. A knowledge of the prevalence and perceived harshness of impairments due to HF is essential in providing personalized care on a patient level, in optimizing care on a population level and in finding the most appropriate patient-reported outcome for clinical trials. AIM: The aim of this study was to explore the prevalence and perceived harshness of impairments due to HF and the relation between perceived harshness and HR-QoL in patients with HF. METHODS AND RESULTS: The prevalence of impairments due to HF was assessed using items of the Minnesota Living with Heart Failure Questionnaire and the degree of perceived harshness was assessed using a structured self-assessment. A total of 100 outpatients (mean±SD age 70±9 years, 71% men) from an HF outpatient clinic were included. The prevalence of impairments was between 18 and 77%. The most prevalent impairments included tiredness and impairments in physical activity. Impairments that were frequently perceived as severely harsh included tiredness (67%), dyspnoea (57%) and impairments in physical activity (55%). Corrected item-total correlation (range 0.10-0.59) showed that tiredness (r=0.54) and impairments related to resting (r=0.59) and to participation in physical (r=0.52) and social (r=0.55) activities contributed highly to the sum-score of the Minnesota Living with Heart Failure Questionnaire. CONCLUSION: Highly prevalent impairments are not by definition perceived as severely harsh by patients with HF and do not contribute to the overall HR-QoL except for the impairments tiredness and working around the house/yard. These insights are important in providing personalized and optimized care for patients with HF.

Structured Frameworks to Increase the Transparency of the Assessment of Benefits and Risks of Medicines: Current Status and Possible Future Directions.

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions.

Risk attitudes and personality traits predict perceptions of benefits and risks for medicinal products: a field study of European medical assessors.

BACKGROUND: Risk attitudes and personality traits are known predictors of decision making among laypersons, but very little is known of their influence among experts participating in organizational decision making. METHODS: Seventy-five European medical assessors were assessed in a field study using the Domain Specific Risk Taking scale and the Big Five Inventory scale. Assessors rated the risks and benefits for a mock "clinical dossier" specific to their area of expertise, and ordinal regression models were used to assess the odds of risk attitude or personality traits in predicting either the benefit or the risk ratings. RESULTS: An increase in the "conscientiousness" score predicted an increase in the perception of the drug's benefit, and male assessors gave higher scores for the drug's benefit ratings than did female assessors. Extraverted assessors saw fewer risks, and assessors with a perceived neutral-averse or averse risk profile saw greater risks. CONCLUSIONS: Medical assessors perceive the benefits and risks of medicines via a complex interplay of the medical situation, their personality traits and even their gender. Further research in this area is needed to determine how these potential biases are managed within the regulatory setting.

Telomere length loss due to smoking and metabolic traits.

OBJECTIVES: Human age-dependent telomere attrition and telomere shortening are associated with several age-associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length. DESIGN AND METHODS: Leucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. Follow-up data were available at two time-points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16 783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics. RESULTS: We observed an average attrition rate of 0.47 ± 0.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39-60) years at baseline. Annual telomere attrition rate increased with age (P < 0.001) and was faster on average in men than in women (P for interaction 0.043). The major independent factors determining telomere attrition rate were active smoking (approximately tripled the loss of RTLU per year, P < 0.0001) and multiple traits of the metabolic syndrome (waist-hip ratio, P = 0.007; blood glucose level, P = 0.045, and HDL cholesterol level, P < 0.001). CONCLUSIONS: Smoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age-associated diseases.

Routine versus aggressive upstream rhythm control for prevention of early atrial fibrillation in heart failure: background, aims and design of the RACE 3 study.

BACKGROUND: Rhythm control for atrial fibrillation (AF) is cumbersome because of its progressive nature caused by structural remodelling. Upstream therapy refers to therapeutic interventions aiming to modify the atrial substrate, leading to prevention of AF. OBJECTIVE: The Routine versus Aggressive upstream rhythm Control for prevention of Early AF in heart failure (RACE 3) study hypothesises that aggressive upstream rhythm control increases persistence of sinus rhythm compared with conventional rhythm control in patients with early AF and mild-to-moderate early systolic or diastolic heart failure undergoing electrical cardioversion. DESIGN: RACE 3 is a prospective, randomised, open, multinational, multicenter trial. Upstream rhythm control consists of angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers, mineralocorticoid receptor antagonists, statins, cardiac rehabilitation therapy, and intensive counselling on dietary restrictions, exercise maintenance, and drug adherence. Conventional rhythm control consists of routine rhythm control therapy without cardiac rehabilitation therapy and intensive counselling. In both arms, every effort is made to keep patients in the rhythm control strategy, and ion channel antiarrhythmic drugs or pulmonary vein ablation may be instituted if AF relapses. Total inclusion will be 250 patients. If upstream therapy proves to be effective in improving maintenance of sinus rhythm, it could become a new approach to rhythm control supporting conventional pharmacological and non-pharmacological rhythm control.

Prosthetic valves in adult patients with congenital heart disease: Rationale and design of the Dutch PROSTAVA study.

BACKGROUND: Data on long-term complications in adult patients with congenital heart disease (ACHD) and a prosthetic valve are scarce. Moreover, the influence of prosthetic valves on quality of life (QoL) and functional outcome in ACHD patients with prosthetic valves has not been studied. OBJECTIVES: The primary objective of the PROSTAVA study is to investigate the relation between prosthetic valve characteristics (type, size and location) and functional outcome as well as QoL in ACHD patients. The secondary objectives are to investigate the prevalence and predictors of prosthesis-related complications including prosthesis-patient mismatch. METHODS: The PROSTAVA study, a multicentre cross-sectional observational study, will include approximately 550 ACHD patients with prosthetic valves. Primary outcome measures are maximum oxygen uptake during cardiopulmonary exercise testing and QoL. Secondary outcomes are the prevalence and incidence of valve-related complications including prosthesis-patient mismatch. Other evaluations are medical history, physical examination, echocardiography, MRI, rhythm monitoring and laboratory evaluation (including NT-proBNP). IMPLICATIONS: Identification of the relation between prosthetic valve characteristics in ACHD patients on one hand and functional outcome, QoL, the prevalence and predictors of prosthesis-related complications on the other hand may influence the choice of valve prosthesis, the indication for more extensive surgery and the indication for re-operation.

Health-related quality of life and anemia in hospitalized patients with heart failure.

BACKGROUND: Anemia is a serious and highly prevalent co-morbidity in chronic heart failure (HF) patients. Its influence on health-related quality of life (HR-QoL) has rarely been studied, and no data is available regarding the role it plays in hospitalized HF patients. METHODS: Baseline data from the COACH study (Coordinating study evaluating Outcomes of Advising and Counselling in Heart Failure) were used. HR-QoL was assessed by means of generic and disease-specific questionnaires. Analyses were performed using ANOVA and ANCOVA, with covariates of age, gender, eGFR, diabetes, and NYHA class. RESULTS: In total, 1013 hospitalized patients with a mean age of 71 (SD 11) years were included; 70% of these patients had no anemia (n=712), 14% had mild anemia (n=141), and 16% had moderate-to-severe anemia (n=160). Independent associations were found between anemia and physical functioning (p=0.019), anemia and role limitations due to physical functioning (p=0.002), anemia and general health (p=0.024), and anemia and global well-being (p=0.003). CONCLUSION: In addition to the burden of HF itself, anemia is an important factor which influences HR-QoL in hospitalized HF patients, and one that is most pronounced in the domain related to physical functioning and general health.

Design and methodology of the COACH-2 (Comparative study on guideline adherence and patient compliance in heart failure patients) study: HF clinics versus primary care in stable patients on optimal therapy.

BACKGROUND: Since the number of heart failure (HF) patients is still growing and long-term treatment of HF patients is necessary, it is important to initiate effective ways for structural involvement of primary care services in HF management programs. However, evidence on whether and when patients can be referred back to be managed in primary care is lacking. AIM: To determine whether long-term patient management in primary care, after initial optimisation of pharmacological and non-pharmacological treatment in a specialised HF clinic, is equally effective as long-term management in a specialised HF clinic in terms of guideline adherence and patient compliance. METHOD: The study is designed as a randomised, controlled, non-inferiority trial. Two-hundred patients will be randomly assigned to be managed and followed in primary care or in a HFclinic. Patients are eligible to participate if they are (1) clinically stable, (2) optimally up-titrated on medication (according to ESC guidelines) and, (3) have received optimal education and counselling on pre-specified issues regarding HF and its treatment. Furthermore, close cooperation between secondary and primary care in terms of back referral to or consultation of the HF clinic will be provided.The primary outcome will be prescriber adherence and patient compliance with medication after 12 months. Secondary outcomes measures will be readmission rate, mortality, quality of life and patient compliance with other lifestyle changes. EXPECTED RESULTS: The results of the study will add to the understanding of the role of primary care and HF clinics in the long-term follow-up of HF patients.

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women.

The fibrosis marker galectin-3 and outcome in the general population.

OBJECTIVE: Galectin-3 is involved in fibrosis and inflammation and plays a role in heart failure, renal disease, obesity and cancer. We aimed to establish the relationship between galectin-3 and cardiovascular (CV) risk factors and mortality in the general population. DESIGN AND SUBJECTS: This study included 7968 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, with a median follow-up of approximately 10 years. Plasma galectin-3 was measured in baseline samples. MAIN OUTCOME MEASURES: We investigated the relationships between galectin-3 levels, demographic characteristics and risk factors of CV disease. We determined the prognostic value for all-cause, CV and cancer mortality. RESULTS: The mean age of the population was 50 ± 13 years. Mean blood pressure was 129/74 mmHg, mean cholesterol was 5.7 ± 1.1 mmol L(-1) and median galectin-3 was 10.9 ng mL(-1) [interquartile range (IQR) 9.0-13.1]. Galectin-3 levels correlated with a wide range of risk factors of CV disease, including blood pressure, serum lipids, body mass index, renal function and N-terminal pro-B-type natriuretic peptide (P < 0.0001). We observed a strong association between galectin-3 and age. Furthermore, we found a gender interaction, with female subjects (n = 4001) having higher median galectin-3 levels (11.0 ng mL(-1) , IQR 9.1-13.4 vs. men (n = 3967) 10.7 ng mL(-1) , IQR 8.9-12.8; P < 0.0001), and galectin-3 levels in women more strongly correlated with risk factors of CV disease. After correction for the classical CV risk factors (smoking, blood pressure, cholesterol and diabetes), galectin-3 levels independently predicted all-cause mortality (hazard ratio per SD galectin-3 1.09, 95% CI 1.01-1.19; P = 0.036), but not CV and cancer mortality separately. CONCLUSIONS: Galectin-3 is associated with age and risk factors of CV disease, with a strong gender interaction for these correlations. Galectin-3 predicts all-cause mortality in the general population.

Heart failure patients monitored with telemedicine: patient satisfaction, a review of the literature.

BACKGROUND: Remote monitoring of the clinical status of heart failure patients has developed rapidly and is the subject of several trials. Patient satisfaction is an important outcome, as recommended by the U.S. Food and Drug Administration to use in clinical research, and should be included in studies concerning remote monitoring. The objective of this review is to describe the current state of the literature on patient satisfaction with noninvasive telemedicine, regarding definition, measurement, and overall level of patient satisfaction with telemedicine. METHODS AND RESULTS: The Pubmed, Embase, Cochrane, and Cinahl databases were searched using heart failure-, satisfaction-, and telemedicine-related search terms. The literature search identified 193 publications, which were reviewed by 2 independent reviewers. Fourteen articles were included. None of the articles described a clear definition or concept of patient satisfaction with telemedicine. Patient satisfaction with telemedicine was measured with self-developed questionnaires or face-to-face or telephonic interviews. None of the articles used the same questionnaire or telephonic survey to measure patient satisfaction. Only one questionnaire was assessed for validity and reliability. In general, patients seemed to be satisfied or very satisfied with the use of telemedicine. CONCLUSIONS: Measurement of patient satisfaction is still underexposed in telemedicine research and the measurement of patient satisfaction with telemedicine underappreciated with poorly constructed questionnaires.