In-hospital worsening heart failure Butler, Javed; Gheorghiade, Mihai; Kelkar, Anita ...
European journal of heart failure,
November 2015, Letnik:
17, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Acute worsening heart failure (WHF) is seen in a sizable portion of patients hospitalized for heart failure, and is increasingly being recognized as an entity that is associated with an adverse ...in‐hospital course. WHF is generally defined as worsening heart failure symptoms and signs requiring an intensification of therapy, and is reported to be seen in anywhere from 5% to 42% of heart failure admissions. It is difficult to ascertain the exact epidemiology of WHF due to varying definitions used in the literature. Studies indicate that WHF cannot be precisely predicted on the basis of baseline variables assessed at the time of admission. Recent data suggest that some experimental therapies may reduce the risk of development of WHF among hospitalized heart failure patients, and this is associated with a reduction in risk of subsequent post‐discharge cardiovascular mortality. In this respect, WHF holds promise as a endpoint for acute heart failure clinical trials to better elucidate the benefit of targeted novel therapies. Better understanding of the pathophysiology and a consensus on the definition of WHF will further improve our epidemiological and clinical understanding of this entity.
Aims
We aimed to determine the relation between baseline systolic blood pressure (SBP), change in SBP, and worsening renal function (WRF) in acute heart failure (AHF) patients enrolled in the ...Pre‐RELAX‐AHF trial.
Methods and results
The Pre‐RELAX‐AHF study enrolled 234 patients within 16 h of admission (median 7 h) for AHF and randomized them to relaxin given intravenous (i.v.) for 48 h or placebo. Blood pressure was measured at baseline, at 3, 6, 9, 12, 24, 36, and 48 h and at 3, 4, and 5 days after enrolment. Worsening renal function was defined as a serum creatinine increase of ≥0.3 mg/dL by Day 5. Worsening renal function was found in 68 of the 225 evaluable patients (30%). Patients with WRF were older (73.5 ± 9.4 vs. 69.1 ± 10.6 years; P= 0.003), had a higher baseline SBP (147.3 ± 19.9 vs. 140.8 ± 16.7 mmHg; P= 0.01), and had a greater early drop in SBP (37.9 ± 16.0 vs. 31.4 ± 12.2 mmHg; P= 0.004). In a multivariable model, higher age, higher baseline creatinine, and a greater early drop in SBP, but not baseline SBP, remained independent predictors of WRF. Furthermore, WRF was associated with a higher Day 60 (P= 0.01), and Day 180 (P= 0.003) mortality.
Conclusions
Worsening renal function in hospitalized AHF patients is related to a poor clinical outcome and is predicted by a greater early drop in SBP.
Trial registration clinicaltrials.gov identifier NCT00520806.
Intravenous diuretics are the cornerstone of management for patients hospitalized for heart failure. Physiologic data suggest that intermittent high-dose furosemide promotes neurohormonal activation, ...which a slow continuous infusion might remediate. However, the limited clinical data comparing dosing schemes are confounded. This study was a randomized, open-label, single-center trial of twice-daily bolus injection versus continuous infusion furosemide in patients hospitalized with heart failure and volume overload. The primary outcome was change in creatinine from admission to hospital day 3 or discharge. Twenty-one patients were randomized to bolus injection and 20 patients to continuous infusion. Baseline characteristics were balanced between study arms except for gender, with a mean age of 60 ± 15 years, a mean ejection fraction of 35 ± 19%, and a mean creatinine level of 1.9 ± 1.2 mg/dl. The mean doses of furosemide were similar between arms over the first 48 hours (162 ± 48 and 162 ± 52 mg/24 hours). None of the outcomes differed significantly between bolus and continuous dosing from admission to hospital day 3 or discharge (mean change in creatinine −0.02 vs 0.13 mg/dl, p = 0.18; urine output 5,113 vs 4,894 ml, p = 0.78; length of stay 8.8 vs 9.9 days, p = 0.69). All patients survived to discharge. In conclusion, there were no substantial differences between bolus injection and continuous infusion of equal doses of furosemide for the treatment of patients hospitalized with heart failure. Given the high prevalence of heart failure hospitalization and the disparate results of small studies regarding optimal dosing of loop diuretics to treat these patients, larger multicenter blinded studies are needed.
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?
Heart failure (HF) is a systemic disease associated with a high risk of morbidity, mortality, increased risk of hospitalizations, and low quality of life. Therefore, effective, systemic treatment ...strategies are necessary to mitigate these risks. In this manuscript, we emphasize the concept of high-intensity care to optimize guideline-directed medical therapy (GDMT) in HF patients. The document highlights the importance of achieving optimal recommended doses of GDMT medications, including beta-blockers, renin–angiotensin–aldosterone inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter inhibitors to improve patient outcomes, achieve effective, sustainable decongestion, and improve patient quality of life. The document also discusses potential obstacles to GDMT optimization, such as clinical inertia, physiological limitations, comorbidities, non-adherence, and frailty. Lastly, it also attempts to provide possible future scenarios of high-intensive care that could improve patient outcomes.
Abstract Background The natural evolution of signs and symptoms during acute heart failure (AHF) is poorly characterized. Methods and Results We followed a prospective international cohort of 182 ...patients hospitalized with AHF. Patient-reported dyspnea and general well-being (GWB) were measured daily using 7-tier Likert (–3 to +3) and visual analog scales (VAS, 0–100). Physician assessments were also recorded daily. Mean age was 69 years and 68% had ejection fraction <40%. Likert measures of dyspnea initially improved rapidly (day 1, 0.22; day 2, 1.31; P <.001) with no significant improvement thereafter (day 7, 1.51; day 2 versus 7 P = .16). In contrast, VAS measure of dyspnea improved throughout hospitalization (day 1, 50.1; day 2, 64.7; day 7, 83.2; day 1 versus 2 P < .001, day 2 versus 7 P < .001). Symptoms of dyspnea and GWB tracked closely (correlation r = .813, P < .001). Physical signs resolved more completely than did symptoms (eg, from day 1 to discharge/day 7, absence of edema increased from 33% to 72% of patients, whereas significant improvements in dyspnea increased from 27% to 52% of patients; P < .001). Conclusions Changes in patient-reported symptoms and physician-assessed signs followed different patterns during an AHF episode and are influenced by the measurement scales used. Multiple clinical measures should be considered in discharge decisions and evaluation of AHF therapies.
Biomarkers play an important role in heart failure. They provide us information about the mechanisms involved in specific types of heart failure and can identify patients at higher risk. Although the ...majority of biomarker studies in heart failure focus on their prognostic value, the clinical applicability of prognostication in heart failure needs to be established. However, biomarkers can be used for many other purposes. For example, they can help us with the diagnosis of heart failure, and they can be used to select our therapy, leading to personalized tailored therapy. Finally, when biomarkers are causally involved in the disease process, they can even become targets for therapy. The present paper reviews the established and potential value of the novel heart failure biomarkers, mid-regional atrial natriuretic peptide, soluble ST2, growth differentiation factor 15, galectin-3, renal tubular damage markers, and microRNAs. Their potential clinical value will be discussed and compared with the reference markers, the natriuretic peptides.
Aims
Our aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF).
Methods and results
Plasma miRNA profiling included 137 patients with AHF from 3 different ...cohorts, 20 with chronic heart failure (CHF), 8 with acute exacerbation of COPD, and 41 healthy controls. Levels of circulating miRNAs were measured using quantitative reverse transcription–polymerase chain reaction (qRT–PCR). Plasma levels of miRNAs in patients with AHF were decreased compared with CHF patients or healthy subjects, whereas no significant changes were observed between acute COPD patients and controls. Fifteen miRNAs found in the discovery phase to differ most significantly between healthy controls and patients with AHF were further investigated in an extended cohort of 100 AHF patients at admission and a separate cohort of 18 AHF patients at different time points. Out of these 15 miRNAs, 12 could be confirmed in an additional AHF validation cohort and 7 passed the Bonferroni correction threshold (miR‐18a‐5p, miR‐26b‐5p, miR‐27a‐3p, miR‐30e‐5p, miR‐106a‐5p, miR‐199a‐3p, and miR‐652‐3p, all P < 0.00005). A further drop in miRNA levels within 48 h after AHF admission was associated with an increased risk of 180‐day mortality in a subset of the identified miRNAs.
Conclusions
Declining levels of circulating miRNAs were associated with increasing acuity of heart failure. Early in‐hospital decreasing miRNA levels were predictive for mortality in a subset of miRNAs in patients with AHF. The discovered miRNA panel may serve as a launch‐pad for molecular pathway studies to identify new pharmacological targets and miRNA‐based therapies.
Background:
Renal function is a powerful prognostic variable in patients with heart failure (HF). Hospitalisations for acute HF (AHF) may be associated with further worsening of renal function (WRF).
...Methods and results:
We analysed the clinical significance of WRF in 318 consecutive patients admitted at our institute for AHF. WRF was defined as the occurrence, at any time during the hospitalisation, of both a ≥25% and a ≥0.3 mg/dL increase in serum creatinine (s-Cr) from admission (WRF-Abs-%).
Results:
Patients were followed for 480±363 days. Fifty-three patients (17%) died and 132 (41%) were rehospitalised for HF. WRF-Abs-% occurred in 107 (34%) patients. At multivariable survival analysis, WRF-Abs-% was an independent predictor of death or HF rehospitalisation (adjusted HR, 1.47; 95%CI, 1.13-1.81; p=0.024). The independent predictors of WRF-Abs-%, evaluated using multivariable logistic regression, were history of chronic kidney disease (p=0.002), LV ejection fraction (p=0.012), furosemide daily dose (p=0.03) and NYHA class (p=0.05) on admission.
Conclusion:
WRF is a frequent finding in patients hospitalised for AHF and is associated with a poor prognosis. Severity of HF and daily furosemide dose are the most important predictors of the occurrence of WRF.
Plasma 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.
To determine if tezosentan improves outcomes in patients with acute heart failure.
The 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.
Infusion of tezosentan (5 mg/h for 30 minutes, followed by 1 mg/h for 24 to 72 hours n = 730) or placebo (n = 718).
The 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.
Of 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 x 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).
The endothelin receptor antagonist tezosentan did not improve symptoms or clinical outcomes in patients with acute heart failure.
clinicaltrials.gov Identifiers: NCT00525707 (VERITAS-1) and NCT00524433 (VERITAS-2).
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