Contemporary Use and Implications of Beta-Blockers in Patients With HFmrEF or HFpEF: The DELIVER Trial.

BACKGROUND: Although beta-blockers are not recommended for the treatment of heart failure with preserved ejection fraction (HFpEF) according to the latest European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers may adversely influence clinical outcomes by limiting chronotropic response in HFpEF. OBJECTIVES: This study sought to examine the contemporary use and implications of beta-blockers in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF. METHODS: In the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, a total of 6,263 patients with symptomatic heart failure (HF) with a left ventricular ejection fraction (LVEF) >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF. RESULTS: Overall, beta-blockers were used in 5,177 patients (83%), with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR: 0.70; 95% CI: 0.60-0.83). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR: 0.82; 95% CI: 0.72-0.94) and in patients not taking beta-blockers (HR: 0.79; 95% CI: 0.61-1.03; Pinteraction = 0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use. CONCLUSIONS: In patients with HFmrEF or HFpEF who were enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Drive Time and Receipt of Guideline-Recommended Screening, Diagnosis, and Treatment.

Importance: Many patients do not receive recommended services. Drive time to health care services may affect receipt of guideline-recommended care, but this has not been comprehensively studied. Objective: To assess associations between drive time to care and receipt of guideline-recommended screening, diagnosis, and treatment interventions. Design, Setting, and Participants: This cohort study used administrative data from the National Veterans Health Administration (VA) data merged with Medicare data. Eligible participants were patients using VA services between January 2016 and December 2019. Women ages 65 years or older without underlying bone disease were assessed for osteoporosis screening. Patients with new diagnosis of chronic obstructive pulmonary disease (COPD) indicated by at least 2 encounter codes for COPD or at least 1 COPD-related hospitalization were assessed for receipt of diagnostic spirometry. Patients hospitalized for ischemic heart disease were assessed for cardiac rehabilitation treatment. Exposures: Drive time from each patient's residential address to the closest VA facility where the service was available, measured using geocoded addresses. Main Outcomes and Measures: Binary outcome at the patient level for receipt of osteoporosis screening, spirometry, and cardiac rehabilitation. Multivariable logistic regression models were used to assess associations between drive time and receipt of services. Results: Of 110 780 eligible women analyzed, 36 431 (32.9%) had osteoporosis screening (mean [SD] age, 66.7 [5.4] years; 19 422 [17.5%] Black, 63 403 [57.2%] White). Of 281 130 patients with new COPD diagnosis, 145 249 (51.7%) had spirometry (mean [SD] age, 68.2 [11.5] years; 268 999 [95.7%] men; 37 834 [13.5%] Black, 217 608 [77.4%] White). Of 73 146 patients hospitalized for ischemic heart disease, 11 171 (15.3%) had cardiac rehabilitation (mean [SD] age, 70.0 [10.8] years; 71 217 [97.4%] men; 15 213 [20.8%] Black, 52 144 [71.3%] White). The odds of receiving recommended services declined as drive times increased. Compared with patients with a drive time of 30 minutes or less, patients with a drive time of 61 to 90 minutes had lower odds of receiving osteoporosis screening (adjusted odds ratio [aOR], 0.90; 95% CI, 0.86-0.95) and spirometry (aOR, 0.90; 95% CI, 0.88-0.92) while patients with a drive time of 91 to 120 minutes had lower odds of receiving cardiac rehabilitation (aOR, 0.80; 95% CI, 0.74-0.87). Results were similar in analyses restricted to urban patients or patients whose primary care clinic was in a tertiary care center. Conclusions and Relevance: In this retrospective cohort study, longer drive time was associated with less frequent receipt of guideline-recommended services across multiple components of care. To improve quality of care and health outcomes, health systems and clinicians should adopt strategies to mitigate travel burden, even for urban patients.

Interobserver variability among experienced electrocardiogram readers to diagnose acute thrombotic coronary occlusion in patients with out of hospital cardiac arrest: Impact of metabolic milieu and angiographic culprit.

OBJECTIVES: We sought to evaluate interobserver concordance among experienced electrocardiogram (ECG) readers in predicting acute thrombotic coronary occlusion (ATCO) in the context of abnormal metabolic milieu (AMM) following resuscitated out of hospital cardiac arrest (OHCA). METHODS: OHCA patients with initial shockable rhythm who underwent invasive coronary angiography (ICA) were included. AMM was defined as one of: pH < 7.1, lactate > 2 mmol/L, serum potassium < 2.8 or >6.0 mEq/L. The initial ECG following ROSC but prior to ICA was adjudicated by 2 experienced readers using classic ST elevation myocardial infarction [STEMI] and expanded criteria and their combination to predict ATCO on ICA. RESULTS: 152 consecutive patients (mean age 58 years, 76% male) met inclusion criteria. AMM was present in 77%; and 42% had ATCO on ICA. Sensitivity, specificity, PPV, NPV using classic STEMI criteria were 50%, 98%, 94%, 72% (c-statistic 0.74); whereas for combined (STEMI + expanded) criteria they were 69%, 88%, 81%, 79% respectively (c-statistic 0.79). Inter-observer agreement (kappa) was 0.7 for classic STEMI criteria, and 0.66 for combined criteria. Agreement between readers was consistently higher when ATCO was absent and with NMM (kappa 0.78), but lower in AMM (kappa 0.6). CONCLUSIONS: Despite experienced ECG readers, there was only modest overall concordance in predicting ATCO in the context of resuscitated OHCA. Significant interobserver variations were noted dependent on metabolic milieu and angiographic ATCO. These observations fundamentally question the role of the 12-lead ECG as primary triaging tool for early angiography among patients with OHCA.

Implications of peripheral oedema in heart failure with preserved ejection fraction: a heart failure network analysis.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition, and tissue congestion manifested by oedema is not present in all patients. We compared clinical characteristics, exercise capacity, and outcomes in patients with HFpEF with and without oedema. METHODS AND RESULTS: This study was a post hoc analysis of pooled data of patients with left ventricular ejection fraction of ≥50% enrolled in the DOSE, CARRESS-HF, RELAX, ATHENA, ROSE, INDIE, and NEAT trials. Patients were dichotomized by the severity of oedema. Cox proportional hazard regression and generalized linear regression models were used to assess associations between oedema, symptoms, and clinical outcomes. The ambulatory cohort included 393 patients (228 with and 165 without oedema), and the hospitalized cohort included 338 patients (249 with ≥moderate oedema and 89 with mild or none). Among ambulatory patients, patients with oedema had a higher body mass index (35.2 kg/m2 [inter-quartile range, IQR 30.5, 41.6] vs. 31.6 kg/m2 [IQR 27.9, 36.3], P < 0.001), greater burden of co-morbidities, higher intravascular pressures estimated on physical examination (elevated jugular venous pressure: 50% vs. 24.7%, P < 0.001), poorer renal function (creatinine: 1.2 mg/dL [IQR 0.9, 1.5] vs. 1 mg/dL [IQR 0.8, 1.3], P = 0.003), and lower peak VO2 (adjusted mean difference -1.04 mL/kg/min, 95% confidence interval [-1.71, -0.37], P < 0.003). Among hospitalized patients, despite greater in-hospital fluid/weight loss in the ≥moderate oedema group, there was no difference in the improvement in dyspnoea by the visual analogue scale or well-being visual analogue scale from baseline to 3-4 days and no statistically significant difference in the rate of 60 day rehospitalization/death (adjusted hazard ratio 1.44, 95% confidence interval [0.87, 2.39], P = 0.156). CONCLUSIONS: Patients with HFpEF and oedema display higher body mass, greater burden of co-morbidities, and more severe exercise intolerance, but clinical responses to treatment appear similar. Further research is required to better understand the nature of volume distribution in different HFpEF phenotypes.

Ultrafiltration in Acute Heart Failure: Implications of Ejection Fraction and Early Response to Treatment From CARRESS-HF.

Background Ultrafiltration is not commonly used because of higher incidence of worsening renal function without improved decongestion. We examined differential outcomes of high versus low fluid removal and preserved versus reduced ejection fraction (EF) in CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Methods and Results Baseline characteristics in the ultrafiltration arm were compared according to 24-hour ultrafiltration-based fluid removal above versus below the median. Patients were stratified by EF (≤40% or >40%). We compared clinical parameters of clinical decongestion during the hospitalization based on initial (≤24 hours) response to ultrafiltration. Cox-proportional hazards models were used to identify associations between fluid removal <24 hours and composite of death, hospitalization, or unscheduled outpatient/emergency department visit during study follow-up. The intention-to-treat analysis included 93 patients. Within 24 hours, median fluid removal was 1.89 L (Q1, Q3: 1.22, 3.16). The high fluid removal group had a greater urine output (9.08 versus 6.23 L, P=0.027) after 96 hours. Creatinine change from baseline to 96 hours was similar in both groups (0.10 mg/dL increase, P=0.610). The EF >40% group demonstrated larger increases of change in creatinine (P=0.023) and aldosterone (P=0.038) from baseline to 96 hours. Among patients with EF >40%, those with above median fluid removal (n=17) when compared with below median (n=17) had an increased rate of the combined end point (87.5% versus 47.1%, P=0.014). Conclusions In patients with acute heart failure, higher initial fluid removal with ultrafiltration had no association with worsening renal function. In patients with EF >40%, ultrafiltration was associated with worsening renal function irrespective of fluid removal rate and higher initial fluid removal was associated with higher rates of adverse clinical outcomes, highlighting variable responses to decongestive therapy.

Do not disregard the initial 12 lead ECG after out-of-hospital cardiac arrest: It predicts angiographic culprit despite metabolic abnormalities.

OBJECTIVES: The initial 12 lead electrocardiogram (ECG) following return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA), is often disregarded by clinicians in ability to predict acute thrombotic coronary occlusion (ATCO) due to markedly abnormal metabolic milieu (AMM). We sought to evaluate the accuracy of initial vs. follow-up ECG prior to invasive coronary angiography (ICA) to predict ATCO following resuscitated OHCA. METHODS: We included OHCA patients with initial shockable rhythm who underwent invasive coronary angiography (ICA). AMM was defined as one of: pH ​< ​7.1, lactate >2 ​mmol/L, serum potassium <2.8 or >6.0 mEq/L. Two ECGs A (initial) and B (follow-up) following ROSC but prior to ICA were adjudicated by 2 experienced readers using expanded ECG criteria to predict angiographic ATCO on ICA. RESULTS: 152 consecutive patients (mean age 58 years, 75% male) met inclusion criteria, 77% had AMM. Among those with both ECGs (n ​= ​102), overall accuracy, sensitivity, specificity, positive predictive value, negative predictive value for correctly predicting angiographic ATCO for ECG A was 72%, 63%, 81%, 61%, 83% and for ECG B was 71%, 50%, 91%, 73%, 80% respectively. Predictive accuracy for angiographic ATCO was similar between ECG A [odds ratio (OR) 7.31, CI 2.87-18.62, p ​< ​0.0001) and ECG B [OR 10.67; CI 3.6-31.61, p ​< ​0.0001], and consistent in AMM. CONCLUSIONS: In OHCA, despite AMM, the initial post ROSC ECG retains a statistically significant, and similar accuracy as the follow-up ECG to predict angiographic ATCO using expanded criteria.

Renal Effects of Intensive Volume Removal in Heart Failure Patients With Preexisting Worsening Renal Function.

Background The relationship between intensive volume removal in acute decompensated heart failure patients with preexisting worsening renal function (WRF) and renal tubular injury, postdischarge renal function, and clinical outcomes is unknown. Methods and Results We used data from the multicenter CARRESS-HF trial (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) that randomized patients with acute decompensated heart failure and preexisting WRF to intensive volume removal with stepped pharmacological therapy or fixed rate ultrafiltration. Patients in the urinary renal tubular injury biomarker substudy (NAG [N-acetyl-b-D-glucosaminidase], KIM-1 [kidney injury molecule-1], and NGAL [neutrophil gelatinase-associated lipocalin]) were evaluated (N=105). The severity of prerandomization WRF was unrelated to baseline renal tubular injury biomarkers ( r=0.14; P=0.17). During randomized intensive volume removal, creatinine further worsened in 53% of patients. Despite a small to moderate magnitude increase in creatinine in most of these patients, postrandomization WRF was strongly associated with worsening in renal tubular injury biomarkers (odds ratio, 12.6; P=0.004). This observation did not differ by mode of volume removal (stepped pharmacological therapy versus ultrafiltration, Pinteraction=0.46). Increase in renal tubular injury biomarkers was associated with a higher incidence of hemoconcentration (odds ratio, 3.1; P=0.015), and paradoxically, better recovery of creatinine at 60 days ( P=0.01). Conclusions In acute decompensated heart failure patients with preexisting WRF, intensive volume removal resulted in a further worsening of creatinine approximately half of the time, a finding associated with a rise in tubular injury biomarkers. However, decongestion and renal function recovery at 60 days were superior in patients with increased tubular injury markers. These data suggest that the benefits of decongestion may outweigh any modest or transient increases in serum creatinine or tubular injury markers that occur during intensive volume removal. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00608491.

High-Sensitivity Troponin I in Hospitalized and Ambulatory Patients With Heart Failure With Preserved Ejection Fraction: Insights From the Heart Failure Clinical Research Network.

Background We sought to study the prevalence of high-sensitivity troponin and its association with cardiac structure and outcomes in ambulatory and hospitalized patients with heart failure with a preserved ejection fraction ( HF p EF ). Methods and Results A post hoc analysis utilized data from HF p EF patients: DOSE (Diuretic Optimization Strategies Evaluation) and CARRESS - HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) enrolled patients hospitalized with acute HF p EF , and RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) enrolled ambulatory patients with HF p EF . High-sensitivity troponin I (hs-TnI) was measured in hospitalized patients at baseline, at 72 to 96 hours, on day 7, and on day 60. In ambulatory patients hs-TnI was measured at baseline and at week 24. In the ambulatory cohort, correlations between hs-TnI and cardiac structure and function were assessed. The association between hs-TnI and a 60-day composite of emergency room visits, readmissions, and death was assessed for hospitalized patients using multivariable Cox proportional hazard models. The study population included 139 hospitalized and 212 ambulatory patients with HF p EF and hs-TnI measured at baseline. The median (25th, 75th percentiles) baseline troponin was 17.6 (11.1, 41.0) ng/L in hospitalized patients and 9.5 (5.3, 19.7) ng/L in ambulatory patients ( P<0.001). The prevalence of elevated hs-TnI (>99% percentile upper reference limit was 86% in hospitalized patients and 53% among ambulatory patients, with stable elevation in ambulatory patients during follow-up. HF p EF patients with a hs-TnI above the median were older with worse left ventricular hypertrophy and diastolic dysfunction. Continuously valued hs-TnI (per doubling) was associated with increased risk of composite end point (adjusted hazard ratio 1.20, 95% confidence interval 1.00-1.43; P=0.042). Conclusions Hs-TnI is commonly elevated among both hospitalized and ambulatory patients with HF p EF . Increased hs-TnI levels are associated with worse cardiac structure and increased risk of adverse events.

Direct comparison of ultrafiltration to pharmacological decongestion in heart failure: a per-protocol analysis of CARRESS-HF.

AIMS: Mechanical ultrafiltration (UF) involves the removal of an iso-osmotic filtrate from the blood. Its benefit in acute decompensated heart failure, however, remains inconclusive. We sought to better understand the direct effects of UF in comparison to an aggressive, urine output-guided pharmacological protocol for decongestion on fluid loss, renal function, and neurohormonal activation. METHODS AND RESULTS: A per-protocol analysis of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial (n = 188) was performed. Participants were included if randomized to UF and had UF output collected, or if randomized to the pharmacological arm and had urine but not UF output collected. Using these definitions, there were 163 participants at 24 h, 156 at 48 h, 129 at 72 h, and 106 at 96 h. UF was associated with higher cumulative fluid loss (P = 0.003), net fluid loss (P = 0.001), and relative reduction in weight (P = 0.02). UF was also associated with higher serum creatinine and blood urea nitrogen by 72 h (P-interaction <0.05 for both), lower serum sodium by 48 h (P-interaction <0.01) and increased plasma renin activity by 96 h (P = 0.04). The pharmacological arm was associated with higher serum bicarbonate after 24 h (P-interaction <0.002). There were no differences in 60-day outcomes between the UF and pharmacological arms. CONCLUSIONS: Ultrafiltration vs. pharmacological therapy was associated with more fluid removal but also rise in serum creatinine and neurohormonal activation. Additionally, loop diuretic use vs. UF was associated with an increase in serum bicarbonate despite less decongestion, data which question the commonly held conception of a 'contraction alkalosis'.

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.

Methadone and the QTc Interval: Paucity of Clinically Significant Factors in a Retrospective Cohort.

OBJECTIVE: Methadone is associated with prolongation of the electrocardiographic QTc interval. QTc prolongation may be linked to cardiac dysrhythmia and sudden cardiac death. The rate of these events is unknown in methadone-maintained patients. METHODS: This retrospective cohort study of 749 patients with opioid use disorder receiving methadone maintenance therapy through a single safety-net hospital, queried the electronic health record for electrocardiogram results, demographics, methadone dose, and diagnostic codes consistent with cardiac conduction disorder (International Classification of Disease, Ninth Revision [ICD-9] 426) and cardiac dysrhythmia (ICD-9 427). Factors associated with QTc interval were explored; Cox proportional-hazards regression models were used to analyze time to an event that may predispose to sudden cardiac death. RESULTS: One hundred thirty-four patients had an electrocardiogram while on methadone, 404 while off methadone, and 211 both while on and off methadone. Mean QTc interval while on methadone (436 ms, SD 36) was significantly greater than while off methadone (423 ms, SD 33). Age and methadone dose were weakly associated with increased QTc interval (P < 0.01 and P < 0.0005, respectively, adjusted R = 0.05). There were 44 ICD-9 426 and 427 events over 7064 patient-years (6.3 events/1000 patient-yrs). Having a QTc greater than sex-specific cut-off values was significantly associated with time to event (hazard ratio 3.32, 95% confidence interval 1.25-8.81), but being on methadone was not. CONCLUSIONS: Methadone is associated with QTc prolongation in a nonclinically significant dose-related manner. Cardiac events were rare and the sudden cardiac death rate was below that of the general population. Current recommendations for cardiac risk assessment in methadone-maintained patients should be reconsidered.

The effect of targeted temperature management on QT and corrected QT intervals in patients with cardiac arrest.

BACKGROUND: Targeted Temperature Management (TTM) improves outcomes after cardiac arrest but may affect the QT and QTc intervals which could increase the chance of subsequent arrhythmia. We report here the effects of TTM on both computer-derived and manually calculated QT and QTc as well as the relationship of the length of the QTc and serious arrhythmia in a retrospective single-center experience. METHODS: 193 patients undergoing TTM for cardiac arrest were studied. 12-lead electrocardiograms (ECG) were measured before, during and after TTM. We assessed the QT and Bazett-corrected QT intervals (QTc) and examined the relationship between QTc and the occurrence of malignant arrhythmias. RESULTS: Both the QT and QTc increased during TTM whether derived manually or from the computer algorithm, although values were different with the two methods. Neither the QT nor the QTc were significantly longer in those patients with malignant arrhythmias. CONCLUSIONS: QT and QTc prolong during TTM. There was no differential increase in the QTc in patients who experienced malignant arrhythmias. While the mechanism of QTc prolongation is not clear, it would not appear that the degree of QTc prolongation has an adverse effect on cardiac rhythm during TTM.

Differential Response to Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Reduced or Preserved Ejection Fraction: Results From the ROSE AHF Trial (Renal Optimization Strategies Evaluation in Acute Heart Failure).

BACKGROUND: The ROSE AHF trial (Renal Optimization Strategies Evaluation in Acute Heart Failure) found that when compared with placebo, neither low-dose dopamine (2 µg/kg per minute) nor low-dose nesiritide (0.005 µg/kg per minute without bolus) enhanced decongestion or preserved renal function in AHF patients with renal dysfunction. However, there may be differential responses to vasoactive agents in AHF patients with reduced versus preserved ejection fraction (EF). This post hoc analysis examined potential interaction between treatment effect and EF (EF ≤40% versus >40%) on the ROSE AHF end points. METHODS AND RESULTS: ROSE AHF enrolled AHF patients (n=360; any EF) with renal dysfunction. The coprimary end points were cumulative urine volume and the change in serum cystatin-C in 72 hours. The effect of dopamine (interaction P=0.001) and nesiritide (interaction P=0.039) on urine volume varied by EF group. In heart failure with reduced EF, urine volume was higher with active treatment versus placebo, whereas in heart failure with preserved EF, urine volume was lower with active treatment. The effect of dopamine and nesiritide on weight change, sodium excretion, and incidence of AHF treatment failure also varied by EF group (interaction P<0.05 for all). There was no interaction between vasoactive treatment's effect and EF on change in cystatin-C. Compared with placebo, dopamine was associated with improved clinical outcomes in heart failure with reduced EF and worse clinical outcomes in heart failure with preserved EF. With nesiritide, there were no differences in clinical outcomes when compared with placebo in both heart failure with reduced EF and heart failure with preserved EF. CONCLUSIONS: In this post hoc analysis of ROSE AHF, the response to vasoactive therapies differed in patients with heart failure with reduced EF and heart failure with preserved EF. Investigations of AHF therapies should assess the potential for differential responses in AHF with preserved versus reduced EF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01132846.

Serum Bicarbonate in Acute Heart Failure: Relationship to Treatment Strategies and Clinical Outcomes.

BACKGROUND: Though commonly noted in clinical practice, it is unknown if decongestion in acute heart failure (AHF) results in increased serum bicarbonate. METHODS AND RESULTS: For 678 AHF patients in the DOSE-AHF, CARRESS-HF, and ROSE-AHF trials, we assessed change in bicarbonate (baseline to 72-96 hours) according to decongestion strategy, and the relationship between bicarbonate change and protocol-defined decongestion. Median baseline bicarbonate was 28 mEq/L. Patients with baseline bicarbonate ≥28 mEq/L had lower ejection fraction, worse renal function and higher N-terminal pro-B-type natriuretic peptide than those with baseline bicarbonate <28 mEq/L. There were no differences in bicarbonate change between treatment groups in DOSE-AHF or ROSE-AHF (all P > .1). In CARRESS-HF, bicarbonate increased with pharmacologic care but decreased with ultrafiltration (median +3.3 vs -0.9 mEq/L, respectively; P < .001). Bicarbonate change was not associated with successful decongestion (P > .2 for all trials). CONCLUSIONS: In AHF, serum bicarbonate is most commonly elevated in patients with more severe heart failure. Despite being used in clinical practice as an indicator for decongestion, change in serum bicarbonate was not associated with significant decongestion.

Aquapheresis Versus Intravenous Diuretics and Hospitalizations for Heart Failure.

OBJECTIVES: The AVOID-HF (Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure) trial tested the hypothesis that patients hospitalized for HF treated with adjustable ultrafiltration (AUF) would have a longer time to first HF event within 90 days after hospital discharge than those receiving adjustable intravenous loop diuretics (ALD). BACKGROUND: Congestion in hospitalized heart failure (HF) patients portends unfavorable outcomes. METHODS: The AVOID-HF trial, designed as a multicenter, 1-to-1 randomized study of 810 hospitalized HF patients, was terminated unilaterally and prematurely by the sponsor (Baxter Healthcare, Deerfield, Illinois) after enrollment of 224 patients (27.5%). Aquadex FlexFlow System (Baxter Healthcare) was used for AUF. A Clinical Events Committee, blinded to the randomized treatment, adjudicated whether 90-day events were due to HF. RESULTS: A total of 110 patients were randomized to AUF and 114 to ALD. Baseline characteristics were similar. Estimated days to first HF event for the AUF and ALD group were, respectively, 62 and 34 (p = 0.106). At 30 days, compared with the ALD group, the AUF group had fewer HF and cardiovascular events. Renal function changes were similar. More AUF patients experienced an adverse effect of special interest (p = 0.018) and a serious study product-related adverse event (p = 0.026). The 90-day mortality was similar. CONCLUSIONS: Compared with the ALD group, the AUF group trended toward a longer time to first HF event within 90 days and fewer HF and cardiovascular events. More patients in the AUF group experienced special interest or serious product-related adverse event. Due to the trial's untimely termination, additional AUF investigation is warranted.

Intensification of Medication Therapy for Cardiorenal Syndrome in Acute Decompensated Heart Failure.

BACKGROUND: Worsening renal function in heart failure may be related to increased venous congestion, decreased cardiac output, or both. Diuretics are universally used in acute decompensated heart failure, but they may be ineffective and may lead to azotemia. We aimed to compare the decongestive properties of a urine output-guided diuretic adjustment and standard therapy for the management of cardiorenal syndrome in acute decompensated heart failure. METHODS AND RESULTS: Data were pooled from subjects randomized to the stepwise pharmacologic care algorithm (SPCA) in the CARRESS-HF trial and those who developed cardiorenal syndrome (rise in creatinine >0.3 mg/dL) in the DOSE-AHF and ROSE-AHF trials. Patients treated with SPCA (n = 94) were compared with patients treated with standard decongestive therapy (SDT) that included intravenous loop diuretic use (DOSE-AHF and ROSE-AHF; n = 107) at the time of cardiorenal syndrome and followed for net fluid balance, weight loss, and changing renal function. The SPCA group had higher degrees of jugular venous pressure (P < .0001) at the time of cardiorenal syndrome. The group that received SPCA had more weight change (-3.4 ± 5.2 lb) and more net fluid loss (1.705 ± 1.417 L) after 24 hours than the SDT group (-0.8 ± 3.4 lb and 0.892 ± 1.395 L, respectively; P < .001 for both) with a slight improvement in renal function (creatinine change -0.1 ± 0.3 vs 0.0 ± 0.3 mg/dL, respectively; P = .03). CONCLUSIONS: Compared with SDT, patients who received an intensification of medication therapy for treating persisting congestion had greater net fluid and weight loss without being associated with renal compromise.

Rationale and design of the Aquapheresis Versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trial.

BACKGROUND: In patients hospitalized with acutely decompensated heart failure, unresolved signs and symptoms of fluid overload have been consistently associated with poor outcomes. Regardless of dosing and type of administration, intravenous loop diuretics have not reduced heart failure events or mortality in patients with acutely decompensated heart failure. The results of trials comparing intravenous loop diuretics to mechanical fluid removal by isolated venovenous ultrafiltration have yielded conflicting results. Studies evaluating early decongestive strategies have shown that ultrafiltration removed more fluid and was associated with fewer heart failure-related rehospitalization than intravenous loop diuretics. In contrast, when used in the setting of worsening renal function, ultrafiltration was associated with poorer renal outcomes and no reduction in heart failure events. METHODS: The AVOID-HF trial seeks to determine if an early strategy of ultrafiltration in patients with acutely decompensated heart failure is associated with fewer heart failure events at 90 days compared with a strategy based on intravenous loop diuretics. Study subjects from 40 highly experienced institutions are randomized to either early ultrafiltration or intravenous loop diuretics. In both treatment arms, fluid removal therapies are adjusted according to the patients' hemodynamic condition and renal function. The study was unilaterally terminated by the sponsor in the absence of futility and safety concerns after the enrollment of 221 subjects, or 27% of the originally planned sample size of 810 patients. CONCLUSIONS: The AVOID-HF trial's principal aim is to compare the safety and efficacy of ultrafiltration vs that of intravenous loop diuretics in patients hospitalized with acutely decompensated heart failure. Because stepped treatment approaches are applied in both ultrafiltration and intravenous loop diuretics groups and the primary end point is time to first heart failure event within 90 days, it is hoped that the AVOID-HF trial, despite its untimely termination by the sponsor, will provide further insight on how to optimally decongest patients with fluid-overloaded heart failure.