Protocolized Natriuresis-Guided Decongestion Improves Diuretic Response: The Multicenter ENACT-HF Study.

BACKGROUND: The use of urinary sodium to guide diuretics in acute heart failure is recommended by experts and the most recent European Society of Cardiology guidelines. However, there are limited data to support this recommendation. The ENACT-HF study (Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure) investigated the feasibility and efficacy of a standardized natriuresis-guided diuretic protocol in patients with acute heart failure and signs of volume overload. METHODS: ENACT-HF was an international, multicenter, open-label, pragmatic, 2-phase study, comparing the current standard of care of each center with a standardized diuretic protocol, including urinary sodium to guide therapy. The primary end point was natriuresis after 1 day. Secondary end points included cumulative natriuresis and diuresis after 2 days of treatment, length of stay, and in-hospital mortality. All end points were adjusted for baseline differences between both treatment arms. RESULTS: Four hundred one patients from 29 centers in 18 countries worldwide were included in the study. The natriuresis after 1 day was significantly higher in the protocol arm compared with the standard of care arm (282 versus 174 mmol; adjusted mean ratio, 1.64; P<0.001). After 2 days, the natriuresis remained higher in the protocol arm (538 versus 365 mmol; adjusted mean ratio, 1.52; P<0.001), with a significantly higher diuresis (5776 versus 4381 mL; adjusted mean ratio, 1.33; P<0.001). The protocol arm had a shorter length of stay (5.8 versus 7.0 days; adjusted mean ratio, 0.87; P=0.036). In-hospital mortality was low and did not significantly differ between the 2 arms (1.4% versus 2.0%; P=0.852). CONCLUSIONS: A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and diuresis, as well as a shorter length of stay.

Rationale and Design of the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study.

AIMS: Although acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of administration are mainly based upon expert opinion. A recent position paper from the Heart Failure Association (HFA) proposed a step-wise pharmacologic diuretic strategy to increase the diuretic response and to achieve rapid decongestion. However, no study has evaluated this protocol prospectively. METHODS AND RESULTS: The Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT-HF) study is an international, multicentre, non-randomized, open-label, pragmatic study in AHF patients on chronic loop diuretic therapy, admitted to the hospital for intravenous loop diuretic therapy, aiming to enrol 500 patients. Inclusion criteria are as follows: at least one sign of volume overload (oedema, ascites, or pleural effusion), use ≥ 40 mg of furosemide or equivalent for >1 month, and a BNP > 250 ng/L or an N-terminal pro-B-type natriuretic peptide > 1000 pg/L. The study is designed in two sequential phases. During Phase 1, all centres will treat consecutive patients according to the local standard of care. In the Phase 2 of the study, all centres will implement a standardized diuretic protocol in the next cohort of consecutive patients. The protocol is based upon the recently published HFA algorithm on diuretic use and starts with intravenous administration of two times the oral home dose. It includes early assessment of diuretic response with a spot urinary sodium measurement after 2 h and urine output after 6 h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1 day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2 days, change in congestion score, change in weight, in-hospital mortality, and length of hospitalization. CONCLUSIONS: The ENACT-HF study will investigate whether a step-wise diuretic approach, based upon early assessment of urinary sodium and urine output as proposed by the HFA, is feasible and able to improve decongestion in AHF with volume overload.

Diuretic treatment in high-risk acute decompensation of advanced chronic heart failure-bolus intermittent vs. continuous infusion of furosemide: a randomized controlled trial.

BACKGROUND: Diuretic resistance is a common issue in patients with acute decompensation of advanced chronic heart failure (ACHF). The aim of this trial was to compare boluses and continuous infusion of furosemide in a selected population of patients with ACHF and high risk for diuretic resistance. METHODS: In this single-centre, double-blind, double-dummy, randomized trial, we enrolled 80 patients admitted for acute decompensation of ACHF (NYHA IV, EF ≤ 30%) with criteria of high risk for diuretic resistance (SBP ≤ 110 mmHg, wet score ≥ 12/18, and sodium ≤ 135 mMol/L). Patients were assigned in a 1:1 ratio to receive furosemide by bolus every 12 h or by continuous infusion. Diuretic treatment and dummy treatment were prepared by a nurse unassigned to patients' care. The study treatment was continued for up to 72 h. Coprimary endpoints were total urinary output and freedom from congestion at 72 h. RESULTS: 80 patients were enrolled with 40 patients in each treatment arm. Mean daily furosemide was 216 mg in continuous-infusion arm and 195 mg in the bolus intermittent arm. Freedom from congestion (defined as jugular venous pressure of < 8 cm, with no orthopnea and with trace peripheral edema or no edema) occurred more in the continuous infusion than in the bolus arm (48% vs. 25%, p = 0.04), while total urinary output after 72 h was 8612 ± 2984 ml in the bolus arm and 10,020 ± 3032 ml in the continuous arm (p = 0.04). Treatment failure occurred less in the continuous-infusion group (15% vs. 38%, p = 0.02), while there was no significant difference between groups in the incidence of worsening of renal function. CONCLUSION: Among patients with acute decompensation of ACHF and high risk of diuretic resistance, continuous infusion of intravenous furosemide was associated with better decongestion. DRAIN TRIAL: ClinicalTrials.gov number NCT03592836.

Noninvasive Assessment of Hemodynamic Status in HeartWare Left Ventricular Assist Device Patients: Validation of an Echocardiographic Approach.

OBJECTIVES: The aim of this prospective study was to validate an echocardiographic protocol derived from 5 HeartWare left ventricular assist device (HVAD) patients for the noninvasive evaluation of right atrial pressure (RAP) and left atrial pressure (LAP) in HVAD patients. BACKGROUND: Echocardiography is an invaluable tool to optimize medical treatment and pump settings and also for troubleshooting residual heart failure. Little is known about the echocardiographic evaluation of hemodynamic status in HVAD patients. METHODS: Right heart catheterization and Doppler echocardiography were performed in 35 HVAD patients. Echocardiography-estimated RAP (eRAP) was assessed using inferior vena cava diameter, hepatic venous flow analysis, and tricuspid E/e' ratio. Echocardiography-estimated LAP was assessed using E/A ratio, mitral E/e' ratio, and deceleration time. RESULTS: eRAP and estimated LAP significantly correlated with invasive RAP and LAP (respectively, r = 0.839, p < 0.001, and r = 0.889, p < 0.001) and accurately detected high RAP and high LAP (respectively, area under the curve 0.94, p < 0.001, and area under the curve 0.91, p < 0.001). High eRAP was associated with high LAP (area under the curve 0.92, p < 0.001) and correlated with death or hospitalization at 180 days (odds ratio: 8.2; 95% confidence interval: 1.1 to 21.0; p = 0.04). According to estimated LAP and eRAP, patients were categorized into 4 hemodynamic profiles. Fifteen patients (43%) showed the optimal unloading profile (normal eRAP and normal wedge pressure). This profile showed a trend toward a lower risk for adverse cardiac events at follow-up (odds ratio: 0.2; 95% confidence interval: 0.1 to 1.0; p = 0.05) compared with other hemodynamic profiles. CONCLUSIONS: Doppler echocardiography accurately estimated hemodynamic status in HVAD patients. This algorithm reliably detected high RAP and LAP. Notably, high RAP was associated with high wedge pressure and adverse outcome. The benefit of noninvasive estimation of hemodynamic status in the clinical management of patients with left ventricular assist devices needs further evaluation.

Prognostic incremental role of right ventricular function in acute decompensation of advanced chronic heart failure.

AIMS: The purpose of this study was to evaluate the additional prognostic value of echocardiography in acute decompensation of advanced chronic heart failure (CHF), focusing on right ventricular (RV) dysfunction and its interaction with loading conditions. Few data are available on the prognostic role of echocardiography in acute HF and on the significance of pulmonary hypertension in patients with severe RV failure. METHODS AND RESULTS: A total of 265 NYHA IV patients admitted for acute decompensation of advanced CHF (EF 22 ± 7%, systolic blood pressure 107 ± 20 mmHg) were prospectively enrolled. Fifty-nine patients met the primary composite endpoint of cardiac death, urgent heart transplantation, and urgent mechanical circulatory support implantation at 90 days. Pulmonary hypertension failed to predict events, while patients with a low transtricuspid systolic gradient (TR gradient <20 mmHg) showed a worse outcome [hazard ratio (HR) 2.37, 95% confidence interval (CI) 1.12-5.00, P = 0.02]. RV dysfunction [tricuspid annular plane systolic excursion (TAPSE) ≤14 mm] in the presence of a low TR gradient identified patients at higher risk of events (HR 2.97, 95% CI 1.19-7.41, P = 0.02). Multivariate analysis showed as best predictors of outcome low RV contraction pressure index (RVCPI), defined as TAPSE × TR gradient, and high estimated right atrial pressure (eRAP). Adding RVCPI (<400 mm*mmHg) and eRAP (≥20 mmHg) to conventional clinical (ADHERE risk tree and NT-proBNP) and echocardiographic risk evaluation resulted in an increase in net reclassification improvement of +19.1% and +20.1%, respectively (P = 0.01) and in c-statistic from 0.59 to 0.73 (P < 0.01). CONCLUSIONS: In acute decompensation of advanced CHF, pulmonary hypertension failed to predict events. The in-hospital and short-term prognosis can be better predicted by eRAP and RVCPI.

Clinical and prognostic role of ammonia in advanced decompensated heart failure. The cardio-abdominal syndrome?

BACKGROUND: Advanced heart failure is associated with end-organ damage. Recent literature suggested an intriguing crosstalk between failing heart, abdomen and kidneys. Venous ammonia, as a by-product of the gut, could be a marker of abdominal injury in heart failure patients. The aim of the study was to investigate the clinical and prognostic role of ammonia in patients with advanced decompensated heart failure (ADHF). METHODS & RESULTS: 90 patients admitted with ADHF were prospectively studied. The prognostic role of ammonia at admission was evaluated. Primary end-points were: a composite of cardiac death, urgent heart transplantation and mechanical circulatory support at 3 months and need for renal replacement therapies (RRT). In the study cohort (age 59.0 ± 12.0 years, FE 21.6 ± 9.0%, INTERMACS profile 3.7 ± 0.9, creatinine 1.71 ± 0.95 mg/dl) 27 patients (30%) underwent the cardiac composite endpoint, while 9 patients (10%) needed RRT. At ROC curve analysis ammonia ≥ 130 µg/dl (abdominal damage) showed the best diagnostic accuracy. At multivariate analysis abdominal damage predicted the cardiac composite endpoint. Abdominal damage further increased risk among patient with cold profile at admission (HR 2.7, 95% CI 1.1-7.0, p = 0.046). At multivariate analysis abdominal damage also predicted need for RRT (OR 10.8, 95% CI 1.5-75.8, p = 0.017). The combined use of estimated right atrial pressure and ammonia showed the highest diagnostic accuracy and a very high specificity in prediction of need for RRT. CONCLUSION: In a selected population admitted for ADHF ammonia, as a marker of abdominal derangement, predicted adverse cardiac events and need for RRT.

Clinical assessment of hypoperfusion in acute heart failure ­ evergreen or antique?

BACKGROUND: Cold hemodynamic profile assessed on physical examination predicts survival, although it has low specificity and low reproducibility. We herein propose a new cold profile definition (Cold Modified 2014), including renal and hepatic damage. The aim of the study was to evaluate the additional prognostic value of clinical and laboratory identification of hypoperfusion over hypotension in the setting of advanced acute heart failure (AHF). METHODS AND RESULTS: After preliminary analysis on derivation cohort, we studied 223 consecutive NYHA III-IV patients admitted with AHF requiring intensive care. Cold Modified 2014 definition included non-invasive hemodynamic assessment, renal and hepatic injury. Primary endpoint was a composite of cardiac death, urgent heart transplantation and mechanical circulatory support at 6 months. In the validation cohort (age, 60.5 ± 12.8 years; ejection fraction 25.6 ± 8.2%, systolic blood pressure [SBP] 104.3 ± 26.1 mmHg) 77 reached the composite endpoint. Among SBP, ADHERE model, cold profile at admission and INTERMACS profile at 48 h, cold profile had the best diagnostic accuracy. On multivariate analysis only cold profile and INTERMACS predicted events, while SBP <115 mmHg and high risk on ADHERE did not. Cold Modified 2014 was more accurate than the old definition. Net reclassification improvement for Cold Modified 2014 over the old definition was 25.8%. CONCLUSIONS: This prospective study demonstrated the additional prognostic role of hypoperfusion assessment over hypotension in patients with AHF. Cold Modified 2014 improved risk stratification in advanced AHF patients.

Impact of TAVI on mitral regurgitation: a prospective echocardiographic study.

OBJECTIVE: This study aims to assess changes in mitral regurgitation (MR) severity after transcatheter aortic valve implantation (TAVI). BACKGROUND: Existing data on MR after TAVI are contradictory. METHODS: Thirty-five patients with MR graded ≥ 2+ were followed after undergoing TAVI with either the Edwards Sapien or CoreValve device. Echocardiography was performed the week before and 3 months after the procedure. MR was graded on a scale of 0 to 4+, classified as organic or functional, and the effective regurgitant orifice area (EROA) and MR index were calculated. RESULTS: At baseline, MR was graded 4+ in 4 (11.4%) patients, 3+  in 10 (28.6%), and 2+ in 21 (60%). At follow-up, MR was graded at 3+ in 4 (11.4%) patients, 2+ in 8 (22.9%), and 1+ in 19 (54.3%); 4 (11.4%) exhibited no MR. EROA (24.4 ± 11.5 mm(2) pre-TAVI vs. 11.2 ± 10.3 mm(2) post-TAVI, P < 0.001) and MR index (1.9 ± 0.3 pre-TAVI vs. 1.3 ± 0.7 post-TAVI, P < 0.001) were reduced with TAVI, independent of the etiology. MR decreased by at least 1 grade in 28 (80%) patients, with a reduction ≥2 grades in 10 (28.6%) patients; no patient showed a worsened condition. Subgroup analyses showed that the reduction in MR was significant in patients treated with the Edwards Sapien device but not in patients treated with the CoreValve device. CONCLUSIONS: This multiparametric echocardiographic evaluation showed that MR improved significantly after TAVI and that this result may be related to the type of valve implanted.

Echocardiographic evaluation of right ventricular stroke work index in advanced heart failure: a new index?

BACKGROUND: Right ventricular (RV) function plays a pivotal role in advanced heart failure patients, especially for screening those who may benefit from left ventricular assist device (LVAD) implantation. We introduce RV contraction pressure index (RVCPI) as a new echo-Doppler parameter of RV function. The accuracy of RVCPI in detecting RV failure was compared with the criterion standard, the RV stroke work index (RVSWI) obtained through right heart catheterization in advanced heart failure patients referred for heart transplantation or LVAD implantation. METHODS AND RESULTS: Right heart catheterization and echo-Doppler were simultaneously performed in 94 consecutive patients referred to our center for advanced heart failure (ejection fraction (EF) 24 ± 8.8%, 40% NYHA functional class IV). RV stroke volume and invasive pulmonary pressures were used to obtain RVSWI. Simplified RVCPI (sRVCPI) was derived as TAPSE × (RV - right atrial pressure gradient). Close positive correlation between sRVCPI and RVSWI was found (r = 0.68; P < .001). With logistic regression, we found that increased sRVCPI showed an independent reduced risk (odds ratio 0.98, 95% confidence interval [CI] 0.97-0.99; P = .016) for patients to present a depressed RVSWI (<0.25 mm Hg/L·m(2)). Simplified RVCPI showed high diagnostic accuracy (area under the receiver operating characteristic curve 0.94, 95% CI 0.89-0.99) and good sensitivity and specificity (92% and 85%, respectively) to predict depressed RVSWI with the use of a cutoff value of <400 mm·mm Hg. CONCLUSIONS: In patients with advanced heart failure, the new simple bedside sRVCPI closely correlated with RVSWI, providing an independent, noninvasive, and easy tool for the evaluation of RV function.