Therapy For Acute Heart Failure Research Articles

Clinical profiles in acute heart failure: an urgent need for a new approach.

Acute heart failure (HF) is a major public health concern, responsible for >26 million hospitalizations per year worldwide. Many trials have investigated new therapeutic options for acute HF, with most revealing equivocal results. Successful innovations in therapy for acute HF have remained limited, and standard of care has remained largely unchanged over the past decade, suggesting the need for a new approach for therapeutic decision making and clinical trial design in acute HF. This manuscript focuses on one approach that could prove useful in the development and application of novel therapies: classification of patients based on clinical profiles. While previous attempts at developing clinical profiles were successful in stratifying patients based on clinical and laboratory variables, they have not been utilized for personalized treatment strategies that improve patient outcomes. We suggest a new approach to the creation of clinical profiles that could stratify patients based on their underlying aetiology and their response to novel interventions. We also investigate novel analytic approaches to the creation of new clinical profiles that both investigators and clinicians alike could utilize to inform clinical trial design and the application of new therapies. Despite a large number of clinical trials for new therapeutic options, the treatment of acute HF has seen few advances over the past decades. Innovative approaches to patient selection through the use of clinical profiles could help to identify patients most likely to benefit from novel interventions and lead to the discovery of new therapeutic options.

Early short-term ivabradine treatment in new-onset acute systolic heart failure and sinus tachycardia patients with inflammatory rheumatic disease.

Acute heart failure (AHF) is a common complication of inflammatory rheumatic disease (IRD) and usually coexists with tachycardia. Ivabradine, a direct sinus node inhibitor, which was proven to have favorable effects in patients with chronic HF (CHF), has not been sufficiently evaluated in AHF patients regarding its efficacy and safety. The present study sought to explore the effectiveness of early short-term ivabradine treatment in new-onset AHF and concurrent sinus tachycardia in patients with IRD. A total of 12 consecutive patients with IRD, who had new-onset AHF and concurrent sinus tachycardia, were prescribed ivabradine and were retrospectively recruited. Standard medication therapy for AHF was also administered. The heart rate (HR), left ventricular ejection fraction (LVEF), biomarkers of HF and New York Heart Association (NYHA) classification score were compared prior to and after ivabradine treatment. After 48 h of treatment with ivabradine, the mean resting HR decreased from 118.0±13.8 to 83.3±7.3 bpm (P<0.001). Transthoracic echocardiography indicated a significant improvement in the LVEF on an average of 2 weeks after ivabradine prescription when compared with the baseline evaluation (51.2±8.4 vs. 38.0±9.0%; P<0.001). In addition, ivabradine treatment resulted in significantly decreased N-terminal proB-type natriuretic peptide (4,900±3,672 vs. 16,806±16,130 pg/ml; P=0.045) and improvement of the NYHA classification score (2.3±0.6 vs. 3.5±0.5; P<0.001) at 2 weeks when compared with the baseline. Overall, the results of the present study suggested that early use of ivabradine is safe in IRD patients with new-onset AHF and enhances the sinus rate reduction, which may improve heart function.

Therapeutic Advances in the Management of Acute Decompensated Heart Failure.

Acute decompensated heart failure (ADHF) is the most common presenting phenotype of acute heart failure (AHF). The main goal of this article was to review the contemporary management strategies in these patients and to describe how future clinical trials may address unmet clinical needs. The current pathophysiologic understanding of AHF is incomplete. The guideline recommendations for the management of ADHF are based only on algorithms provided by expert consensus guided by blood pressure and/or clinical signs of congestion or hypoperfusion. The lack of adequately conducted trials to address the unmet need for evidence therapy in AHF has not yet been surpassed, and at this time, there is no evidence-based strategy for targeted decongestive therapy to improve outcomes. The precise time point for initiation of guideline-directed medical therapies (GDMTs), as respect to moment of decompensation, is also unknown. The available data informing current management of patients with ADHF are based on randomized controlled trials, observational studies, and administrative databases. A major step-forward in the management of ADHF patients is recognizing congestion, either clinical or hemodynamic, as a major trigger for heart failure (HF) hospitalization and most important target for therapy. However, a strategy based exclusively on congestion is not sufficient, and at present, comprehensive assessment during hospitalization of cardiac and noncardiovascular substrate with identification of potential therapeutic targets represents "the corner-stone" of ADHF management. In the last years, substantial data have emerged to support the continuation of GDMTs during hospitalization for HF decompensation. Recently, several clinical trials raised hypothesis of "moving to the left" concept that argues for very early implementation of GDMTs as potential strategy to improve outcomes. The management of ADHF is still based on expert consensus documents. Further research is required to identify novel therapeutic targets, to establish the precise time point to initiate GDMTs, and to identify patients at risk of recurrent hospitalization.

Levosimendan as Rescue Therapy for Acute Heart Failure in a Patient with Duchenne Muscular Dystrophy

The longer survival of patients with Duchenne muscular dystrophy due to advances in clinical care has increased the incidence of Duchenne muscular dystrophy-associated cardiomyopathy, a nearly consistent feature in the third decade of life. A 26-year-old patient with Duchenne muscular dystrophy experienced severe acute heart failure triggered by pneumonia. Levosimendan was effective in improving heart function.

Are there sex-based differences in myocardial injury in Acute Heart Failure?

Background and Hypothesis: &#x0D; Myocardial injury in acute heart failure (AHF) contributes to worse outcomes. Whether there are sex-based differences in organ injury in AHF is not well known. This study was designed to assess potential sex-based differences in myocardial injury, as defined by high-sensitivity troponin T (hsTnT) levels, in patients presenting in ED with AHF. We hypothesized that men with AHF have higher hsTnT levels. &#x0D; Project Methods: &#x0D; This is a preliminary analysis from the TACIT study, a large, prospective, multi-center, observational, biomarker cohort study. Adult patients diagnosed and treated for AHF, with a systolic blood pressure &gt;100mmHg, and enrolled within 3 hours of first AHF therapy were eligible. Febrile patients, short life-expectancy, ACS, AF with RVR &gt;130bpm, transplant, VAD, or ESRD were excluded. hsTnT were drawn at baseline and 3 hours later. Hemolyzed samples were disregarded as hemolysis falsely lowers hsTnT. A multivariable linear regression model was used to adjust for potential differences in baseline hsTnT using clinically meaningful covariates. &#x0D; Results: &#x0D; Of 527 enrolled, 499 comprised the final analysis set. Of these patients, 413 had a non-hemolyzed baseline hsTnT. Notably, more men than women were enrolled; men had higher mean baseline hsTnT values (48.3ng/mL, SD(74.5)) than women (28.3ng/mL SD(39.9)). After multivariable adjustment, baseline hsTnT differences by sex remained significant (p &lt;0.0001). &#x0D; Conclusion and Potential Impact: &#x0D; Men with AHF have higher baseline levels of myocardial injury than women. These differences may need to be taken into account for risk-stratification as well as management.

Potentially modifiable factors of dofetilide-associated risk of torsades de pointes among hospitalized patients with atrial fibrillation.

There is a significant variation in the clinical approach of initiation and dose adjustment of dofetilide in atrial fibrillation (AF). Excessive QT prolongation could predispose patients to torsades de pointes (TdP), which can be fatal. We performed a retrospective case-control study at Mayo Clinic Rochester (January 1, 2003 to December 31, 2016). "TdP risk" cases were defined as patients on dofetilide therapy for AF with subsequent TdP or excessive QTc prolongation requiring dose reduction or discontinuation (N = 31). A control group was matched 1:1 with cases by age, gender, year of admission, and dofetilide dose (N = 31). Using multivariate regression analysis, independent predictors of TdP risk included baseline QTc exceeding recommendations (adjusted odd ratio [AOR] 4.57; P = 0.023); underlying AF with rapid ventricular rate (AOR 16.95; P = 0.004); and diuretic therapy for acute heart failure (AOR 8.42; P = 0.007). Poor inter-observer agreement was identified among QT interval measurement in patients with AF and rapid ventricular rate compared to those in rate controlled AF or sinus rhythm. TdP risk cases receiving diuretics for acute heart failure had a significant decline in creatinine clearance than controls, although serum electrolytes and replacement did not differ among the two groups. Excessive QTc prolongation and AF with rapid ventricular rate at time of dofetilide initiation (likely due to difficulty in measuring QT intervals), and diuretic therapy for acute heart failure were independent factors for dofetilide-related TdP risk. Based on these data, possible preventive strategies could be adapted for safety protocols among hospitalized patients.

Failure to Develop New Therapies in Acute Heart Failure—Is It Time to De-focus From Congestion?

Failure to Develop New Therapies in Acute Heart Failure—Is It Time to De-focus From Congestion?

Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial.

Decisive evidence on the optimal diuretic agent, dosing schedule, and administration route is lacking in acute heart failure (AHF) with congestion. The Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial is designed to test the hypothesis that the carbonic anhydrase inhibitor acetazolamide, a potent inhibitor of proximal tubular sodium reabsorption, improves decongestion when combined with loop diuretic therapy in AHF, potentially leading to better clinical outcomes. The ADVOR trial is set up as a multicentre, randomized, double-blind, placebo-controlled study, aiming to recruit 519 patients with AHF and clinically evident volume overload. All study participants receive high-dose intravenous loop diuretics as background therapy and are randomized towards intravenous acetazolamide at a dose of 500 mg once daily vs. placebo, stratified according to including study centre and ejection fraction (< 40% vs. ≥ 40%). The primary endpoint is successful decongestion with no more than trace oedema assessed on the third morning after hospital admission, with good diuretic efficacy defined as a urine output > 3.5 L during the first 30-48 h of decongestive treatment. Secondary endpoints include all-cause mortality or heart failure readmission after 3 months, length of hospital stay for the index admission, and longitudinal changes in the EuroQol-5 dimensions questionnaire. ADVOR will investigate if acetazolamide combined with loop diuretic therapy improves decongestion in AHF with volume overload.

Design and rationale of a randomized trial: Using short stay units instead of routine admission to improve patient centered health outcomes for acute heart failure patients (SSU-AHF)

Nearly 85% of acute heart failure (AHF) patients who present to the emergency department (ED) with acute heart failure are hospitalized. Once hospitalized, within 30 days post-discharge, 27% of patients are re-hospitalized or die. Attempts to improve outcomes with novel therapies have all failed. The evidence for existing AHF therapies are poor: No currently used AHF treatment is known to improve long-term outcomes. ED treatment is largely the same today as 40 years ago. Admitting patients who could have avoided hospitalization may contribute to adverse outcomes. Hospitalization is not benign; patients enter a vulnerable phase post-discharge, at increased risk for morbidity and mortality. When hospitalization is able to be shortened or avoid completely, certain risks can be mitigated, including risk of medication errors, in-hospital falls, delirium, nosocomial infections, and other iatrogenic complications. Additionally, patients would prefer to be home, not hospitalized. Furthermore, hospitalization and re-hospitalization for AHF predominantly affects patients of lower socioeconomic status (SES). Avoiding hospitalization in patients who do not require admission may improve outcomes and quality of life, while reducing costs.Short stay unit (SSU: <24 h, also referred to as an ‘observation unit’) management of AHF may be effective for lower risk patients. However, to date there have only been small studies or retrospective analyses on the SSU management for AHF patients. In addition, SSU management has been considered ‘cheating’ for hospitals trying to avoid 30-day readmission penalties, as SSUs or observation units do not count as an admission. However, more recent analyses demonstrate differential use of observation status has not led to decreases in re-admission, suggesting this concern may be misplaced. Thus, we propose a robust clinical effectiveness trial to demonstrate the effectiveness of this patient-centered strategy.

Optimal Endpoints of Acute Heart Failure Therapy.

Optimal Endpoints of Acute Heart Failure Therapy.

Beneficial effects of adaptive servo-ventilation on natriuretic peptides and diastolic function in acute heart failure patients with preserved ejection fraction and sleep-disordered breathing

Adaptive servo-ventilation (ASV) is a ventilator algorithm able to correct breathing through anticyclic support of breathing in patients with central sleep apnea (CSA). So far, very few data exist regarding the role of ASV on acute heart failure with preserved ejection fraction (HFpEF). We performed a single-center prospective, randomized, case-control study in consecutive acute HFpEF (left ventricle ejection fraction, LVEF ≥ 45%) patients with sleep-disordered breathing (SDB, apnea-hypopnea index, AHI > 15/h) and prevalence of CSA. We included ten consecutive patients randomized for ASV on top of standard therapy for acute heart failure (group 1) versus standard care alone (group 2). ASV therapy significantly reduced AHI and CSA. An improvement in cardiac diastolic function was seen in group 1 compared to group 2 (E/E' 17.5 to 9.6, p < 0.02 vs 18.5 to 14.5, p = 0.4). Brain natriuretic peptide (BNP) markedly decreased in cases, but not in controls (298 to 84pg/ml, p < 0.02 vs 280 to 120pg/ml, p = 0.06). Right ventricle (RV) function significantly improved in group 1, differently from group 2. An acute use of ASV seems effective in reducing BNP and improving diastolic and RV function in acute HFpEF patients with SDB and CSA, compared to standard treatment.

Foreword

Decompensated or acute heart failure (AHF) is characterized by increased ventricular and atrial pressures which may lead to and be caused by circulatory congestion. Unless due to a primary decrease in cardiac function, congestion arises from volume expansion or vasoconstriction. In turn, volume expansion and vasoconstriction are due to neurohormonal imbalance since both result from activation of the sympathetic nervous system, the renin-angiotensin-aldosterone axis and excess secretion of arginine vasopressin. Outcomes in AHF remain dismal. Loop diuretics are the mainstay of therapy for AHF and may themselves aggravate neurohormonal imbalance. No adjunctive pharmacotherapy has yielded improvement in outcomes in AHF despite many attempts with various vasodilators and inotropes. We, therefore, propose that insufficient attention has been paid to neurohormonal imbalance in AHF. As in chronic HF, rectifying the effects of neurohormonal imbalance may lead to better outcomes. The use of alternative decongestive strategies or adjunctive pharmacotherapy directed at neurohormonal activation could yield benefit.

Effects of glycemic control on in-hospital mortality among acute heart failure patients with reduced, mid-range, and preserved ejection fraction.

The relationship between glycemic control and outcome in patients with heart failure (HF) remains contentious. A recent study showed that patients with HF with mid-range ejection fraction (HFmrEF) more frequently had comorbid diabetes relative to other patients. Herein, we examined the association between glycosylated hemoglobin (HbA1c) and in-hospital mortality in acute HF patients with reduced, mid-range, and preserved EF. A multicenter retrospective study was conducted on 5205 consecutive patients with acute HF. Potential risk factors for in-hospital mortality were selected by univariate analyses; then, multivariate Cox regression analysis with backward stepwise selection was performed to identify significant factors. Kaplan-Meier survival curves and log-rank testing were used to compare in-hospital mortality between groups. Across the study cohort, 44% (2288 patients) had reduced EF, 20% had mid-range EF, and 36% had preserved EF. The overall in-hospital mortality rate was 4.6%, with no significant differences among the HF patients with reduced, mid-range, and preserved EF groups. For patients with HFmrEF, higher HbA1c level was a significant risk factor for in-hospital mortality (hazard ratio 1.387; 95% confidence interval 1.014-1.899; P = 0.041). In contrast, HbA1c was not an independent risk factor for in-hospital mortality in HF patients with preserved or reduced EF. In conclusion, HbA1c is an independent risk factor for in-hospital mortality in acute HF patients with mid-range EF, but not in those with preserved or reduced EF. Elucidation of the pathophysiological mechanisms behind these findings could facilitate the development of more effective individualized therapies for acute HF.

Incidence of hospital-acquired hyponatremia by the dose and type of diuretics among patients with acute heart failure and its association with long-term outcomes

BackgroundDiuretics are the cornerstone therapy for acute heart failure (AHF) but can lead to various electrolyte disturbances and inversely affect the patients’ outcome. We aimed to evaluate whether (1) the dose of loop diuretics could predict hospital-acquired hyponatremia (HAH) during AHF treatment, (2) addition of thiazide diuretics could affect development of HAH, and (3) assess their impact on long-term outcomes. MethodsWe analyzed the subjects enrolled in the multicenter AHF registry (WET-HF). Risk of HAH, defined as hyponatremia at discharge with normonatremia upon admission, was evaluated based on oral non-potassium-sparing diuretics via multivariate logistic regression analysis. Additionally, we performed one-to-one matched analysis based on propensity scores for thiazide diuretics use and compared long-term mortality. ResultsOf total 1163 patients (mean age 72.6±13.6 years, male 62.6%), 92 (7.9%) had HAH. Compared with low-dose loop diuretics users (<40mg; without thiazide diuretics), risks for developing HAH were significantly higher in patients with thiazide diuretics, regardless of the dose of loop diuretics (OR 2.67, 95% CI 1.13–6.34 and OR 2.31, 95% CI 1.50–5.13 for low- and high-dose loop diuretics, respectively). The association was less apparent in patients without thiazide diuretics (OR 1.29, 95% CI 0.73–2.27 for high-dose loop diuretics alone). Among 206 matched patients, all-cause and cardiac mortality rate was 27% and 14% in non thiazide diuretics users and 50% and 30% in thiazide diuretics users, respectively (HR 2.46, 95% CI 1.29–4.69, p=0.006 and HR 2.50, 95% CI 1.10–5.67, p=0.028, respectively) during a mean 19.3 months of follow-up. ConclusionsThiazide diuretics use, rather than loop diuretics dose, was independently associated with HAH; and mortality was higher in thiazide diuretics users even after statistical matching.

Update on the management of acute heart failure.

We provide a concise review of recent studies focusing on the management of patients with acute heart failure (AHF). In well designed randomized trials, no mortality benefit has been observed with the use of diuretics, ultrafiltration, inotropes and vasodilators in AHF. Recent trials examining the role of novel inotropes and vasodilators as well as the role of mineralocorticoid receptor antagonists in the AHF population, is reviewed. The focus of therapy in AHF should be directed towards symptom management. No mortality benefit has been observed despite good quality studies.

Effects of the intensity of prehospital treatment on short-term outcomes in patients with acute heart failure: the SEMICA-2 study.

Little is known about treatments provided by advanced life support (ALS) ambulance teams to patients with acute heart failure (AHF) during the prehospital phase, and their influence on short-term outcome. We evaluated the effect of prehospital care in consecutive patients diagnosed with AHF in Spanish emergency departments (EDs). We selected patients from the EAHFE registry arriving at the ED by ALS ambulances with available follow-up data. We recorded specific prehospital ALS treatments (supplemental oxygen, diuretics, nitroglycerin, non-invasive ventilation) and patients were grouped according to whether they received low- (LIPHT; 0/1 treatments) or high-intensity prehospital therapy (HIPHT; >1 treatment) for AHF. We also recorded 46 covariates. The primary endpoint was all-cause 7-day mortality, and secondary endpoints were prolonged hospitalisation (> 10days) and in-hospital and 30-day mortality. Unadjusted and adjusted odds ratios were calculated to compare the groups. We included 1493 patients [mean age 80.7 (10) years; women 54.8%]. Prehospital treatment included supplemental oxygen in 71.2%, diuretics in 27.9%, nitroglycerin in 13.5%, and non-invasive ventilation in 5.3%. The LIPHT group included 1041 patients (70.0%) with an unadjusted OR for 7-day mortality of 1.770 (95% CI 1.115-2.811; p = 0.016), and 1.939 (95% CI 1.114-3.287, p = 0.014) after adjustment for 16 discordant covariables. The adjusted ORs for all secondary endpoints were always > 1 in the LIPHT group, but none reached statistical significance. Patients finally diagnosed with AHF at then ED that have received LIPHT by the ALS ambulance teams have a poorer short-term outcome, especially during the first 7days.

Neurohormonal Imbalance: A Neglected Problem—And Potential Therapeutic Target—In Acute Heart Failure

Decompensated or acute heart failure (AHF) is characterized by increased ventricular and atrial pressures which may lead to and be caused by circulatory congestion. Unless due to a primary decrease in cardiac function, congestion arises from volume expansion or vasoconstriction. In turn, volume expansion and vasoconstriction are due to neurohormonal imbalance since both result from activation of the sympathetic nervous system, the renin-angiotensin-aldosterone axis and excess secretion of arginine vasopressin. Outcomes in AHF remain dismal. Loop diuretics are the mainstay of therapy for AHF and may themselves aggravate neurohormonal imbalance. No adjunctive pharmacotherapy has yielded improvement in outcomes in AHF despite many attempts with various vasodilators and inotropes. We, therefore, propose that insufficient attention has been paid to neurohormonal imbalance in AHF. As in chronic HF, rectifying the effects of neurohormonal imbalance may lead to better outcomes. The use of alternative decongestive strategies or adjunctive pharmacotherapy directed at neurohormonal activation could yield benefit.

A systematic review of in-hospital worsening heart failure as an endpoint in clinical investigations of therapy for acute heart failure.

In-hospital worsening heart failure (WHF) occurs frequently in patients hospitalized for acute heart failure (AHF) and has strongly negative prognostic associations. It may be a useful endpoint in studies of AHF management but important questions remain regarding optimization of its definition and variability in its incidence. Our objective was to survey the full extent of clinical interest in WHF and assess the impact of baseline variables and trial design on outcomes. PubMed, Embase, and BIOSIS were searched systematically for clinical studies that had in-hospital WHF as an endpoint. Differences in definitions of in-hospital WHF were reviewed for their potential impact on observed incidence of WHF and its associations with post-discharge outcomes. The search identified 35 publications representing 13 interventional trials, 3 observational studies, several different classes of therapeutic agent, and 78,752 patients overall. Incidence of in-hospital WHF varied greatly-from 4.2% to 37%. Concerning the impact of differences in the way in which WHF was defined, two important factors were physician determination of worsening and whether intensification of diuretic therapy alone was defined as a WHF event. Patients having in-hospital WHF were at substantially greater risk for death and longer length of stay during index hospitalizations, all-cause and heart-failure rehospitalization, cardiovascular complications, renal failure, all-cause death, cardiovascular death, and higher healthcare costs post-discharge. There is diverse interest in selecting in-hospital WHF as an endpoint in clinical trials. Differences in reported incidence are complexly related to differences in the way in which WHF is defined.

Focused echocardiography and lung ultrasound protocol for guiding treatment in acute heart failure.

AimsThere is little evidence‐based therapy existing for acute heart failure (AHF), hospitalizations are lengthy and expensive, and optimal monitoring of AHF patients during in‐hospital treatment is poorly defined. We evaluated a rapid cardiothoracic ultrasound (CaTUS) protocol, combining focused echocardiographic evaluation of cardiac filling pressures, that is, medial E/e′ and inferior vena cava index, with lung ultrasound (LUS) for guiding treatment in hospitalized AHF patients.Methods and resultsWe enrolled 20 consecutive patients hospitalized for AHF, whose in‐hospital treatment was guided using the CaTUS protocol according to a pre‐specified treatment protocol targeting resolution of pulmonary congestion on LUS and lowering cardiac filling pressures. Treatment results of these 20 patients were compared with those of a standard care sample of 100 patients, enrolled previously for follow‐up purposes. The standard care sample had CaTUS performed daily for follow‐up and received standard in‐hospital treatment without ultrasound guidance. All CaTUS exams were performed by a single experienced sonographer. The CaTUS‐guided therapy resulted in significantly larger decongestion as defined by reduction in symptoms, cardiac filling pressures, natriuretic peptides, cumulative fluid loss, and resolution of pulmonary congestion (P < 0.05 for all) despite a shorter mean length of hospitalization. Congestion parameters were significantly lower also at discharge (P < 0.05 for all), without any significant difference in these parameters on admission. The treatment arm displayed better survival regarding the combined endpoint of 6 month all‐cause death or AHF re‐hospitalization (log rank P = 0.017). No significant difference in adverse events occurred between the groups.ConclusionsThe CaTUS‐guided therapy for AHF resulted in greater decongestion during shorter hospitalization without increased adverse events in this small pilot study and might be associated with a better post‐discharge prognosis.

Past, present, and future of acute heart failure clinical trials-a high-risk population in search of a strategy.

Past, present, and future of acute heart failure clinical trials-a high-risk population in search of a strategy.