[Show abstract][Hide abstract] ABSTRACT: Aims:
In the EVEREST trial, tolvaptan improved symptoms and body weight during hospitalization for heart failure (HF), but did not improve post-discharge cardiovascular outcomes. We hypothesized that this disconnect between the short- and long-term effects may be related to changes in serum osmolality. We describe the longitudinal profile of osmolality and its response to tolvaptan during and after hospitalization for HF.
Methods and results:
EVEREST enrolled 4133 patients hospitalized for HF and reduced EF. Serum osmolality data were available in 3744 (91%). We assessed the effects of tolvaptan on serum osmolality and related these effects to in-hospital changes in body weight and physician-assessed symptoms. Calculated values of osmolality, determined from serum sodium, blood urea nitrogen, and glucose, were 3-4 mOsm/kg higher than concurrently measured serum osmolality at enrolment and discharge in both treatment arms. During hospitalization in the placebo group, serum osmolality slightly increased throughout hospitalization, whereas serum sodium decreased and blood urea nitrogen increased until discharge. Tolvaptan increased osmolality by hospital day 1, but this effect diminished by post-discharge week 4-8 and disappeared by post-discharge week 56. In-hospital changes in osmolality were poorly correlated with in-hospital changes in body weight and physician-assessed dyspnoea.
Tolvaptan increased serum osmolality during hospitalization for HF, a time frame when the drug also improved signs and symptoms of HF. However, this effect on osmolality declined in the early post-discharge period, when tolvaptan failed to influence clinical outcomes. Serum osmolality, which can be estimated based on readily available laboratory parameters, may be a marker or a target of response to tolvaptan.
European Journal of Heart Failure 10/2015; DOI:10.1002/ejhf.415 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myocardial recovery in heart failure (HF) is possible, but its determinants are not fully defined. At least partial functional improvement is possible with current evidence-based therapies. However, once significant HF symptoms develop, patients have varied trajectories, including: 1) structural and functional recovery; 2) stabilization (remission); and 3) acceleration to end-stage HF/death. All 3 trajectories may be interrupted by sudden death. These trajectories may represent the interplay of heterogeneous causality, genetic predeterminants, and disease phenotypes. Enhanced phenotypic description with cardiac magnetic resonance imaging, molecular imaging, or circulating biomarkers of the heterogeneous HF population may provide insights regarding specific biological targets amenable to existing and novel therapeutic strategies. The identification of patients in "remission," before progression to the end stage of predominantly nonviable tissue (e.g., fibrosis), has implications for clinical practice and future trials because such patients may be more likely to experience myocardial recovery (cardiac reserve). The identification of dysfunctional but viable myocardium and its diverse pathophysiological causes may provide opportunities to investigate existing and novel therapeutics aimed at enhancing myocardial recovery.
[Show abstract][Hide abstract] ABSTRACT: Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality.
Expert Review of Cardiovascular Therapy 07/2015; 13(7):799-809. DOI:10.1586/14779072.2015.1053872
[Show abstract][Hide abstract] ABSTRACT: With one possible exception, the last decade of clinical trials in hospitalized heart failure (HHF) patients has failed to demonstrate improvement in long-term clinical outcomes. This trend necessitates a need to evaluate optimal drug development strategies and standards of trial conduct. It has become increasingly important to recognize the heterogeneity among HHF patients and the differential characterization of novel drug candidates. Targeting these agents to specific subpopulations may afford optimal net response related to the particular mode of action of the drug. Analyses of previous trials demonstrate profound differences in the baseline characteristics of patients enrolled across global regions and participating sites. Such differences may influence risks for events and interpretation of results. Therefore, the actual execution of trials and the epidemiology of HHF populations at the investigative sites must be taken into consideration. Collaboration among participating sites including the provision of registry data tailored to the planned development program will optimize trial conduct. Observational data prior to study initiation may enable sites to feedback and engage in protocol development to allow for feasible and valid clinical trial conduct. This site-centered, epidemiology-based network environment may facilitate studies in specific patient populations and promote optimal data collection and clear interpretation of drug safety and efficacy. This review summarizes the roundtable discussion held by a multidisciplinary team of representatives from academia, National Institutes of Health, industry, regulatory agencies, payers, and contract and academic research organizations to answer the question: Who should be targeted for novel therapies in HHF?