Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.

BACKGROUND: Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed. RESULTS: A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups. CONCLUSIONS: The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).

Bromocriptine treatment and outcomes in peripartum cardiomyopathy: the EORP PPCM registry.

BACKGROUND AND AIMS: Peripartum cardiomyopathy (PPCM) remains a serious threat to maternal health around the world. While bromocriptine, in addition to standard treatment for heart failure, presents a promising pathophysiology-based disease-specific treatment option in PPCM, the evidence regarding its efficacy remains limited. This study aimed to determine whether bromocriptine treatment is associated with improved maternal outcomes in PPCM. METHODS: PPCM patients from the EORP PPCM registry with available follow-up were included. The main exposure of this exploratory non-randomized analysis was bromocriptine treatment, and the main outcome was a composite endpoint of maternal outcome (death or hospital readmission within the first 6 months after diagnosis, or persistent severe left ventricular dysfunction [left ventricular ejection fraction <35%] at 6-month follow-up). Inverse probability weighting was used to minimize the effects of confounding by indication. Multiple imputation was used to account for missing data. RESULTS: Among 552 patients with PPCM, 85 were treated with bromocriptine (15%). The primary endpoint was available in 491 patients (89%) and occurred in 18 out of 82 patients treated with bromocriptine in addition to standard of care (22%) and in 136 out of 409 patients treated with standard of care (33%) (p=0.044). In complete case analysis, bromocriptine treatment was associated with reduced adverse maternal outcome (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.10-0.83, p=0.021). This association remained after applying multiple imputation and methods to correct for confounding by indication (inverse probability weighted model on imputed data OR 0.39, 95% CI 0.19-0.81, p=0.011). Thrombo-embolic events were observed in 5.9% of the patients in the bromocriptine group versus 5.6% in the standard of care group (p=0.900). CONCLUSIONS: Among women with PPCM, bromocriptine treatment in addition to standard of care was associated with better maternal outcomes after 6 months.

Proenkephalin Improves Cardio-Renal Risk Prediction in Acute Coronary Syndromes: The KID-ACS Score.

BACKGROUND AND AIMS: Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndromes (ACS). METHODS: Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n=4787) and in validation cohorts from the UK (n=1141), Czechia (n=927), and Germany (n=220). A biomarker-enhanced risk score (KID-ACS score) for simultaneous prediction of in-hospital acute kidney injury (AKI) and 30-day mortality was derived and externally validated. RESULTS: On multivariable adjustment for established risk factors, circulating PENK remained associated with in-hospital AKI (per log2 increase: adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.13-2.09, P=0.007) and 30-day mortality (adjusted hazard ratio [HR] 2.73, 95% CI 1.85-4.02, P<0.001). The KID-ACS score integrates PENK and showed an area under the receiver operating characteristic curve (AUC) of 0.72 (95% CI 0.68-0.76) for in-hospital AKI, and of 0.91 (95% CI 0.87-0.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS achieved similarly high performance for in-hospital AKI (Zurich: AUC 0.73, 95% CI 0.70-0.77; Czechia: AUC 0.75, 95% CI 0.68-0.81; Germany: AUC 0.71, 95% CI 0.55-0.87) and 30-day mortality (UK: AUC 0.87, 95% CI 0.83-0.91; Czechia: AUC 0.91, 95% CI 0.87-0.94; Germany: AUC 0.96, 95% CI 0.92-1.00) outperforming the CA-AKI score and the GRACE 2.0 score, respectively. CONCLUSIONS: Circulating PENK offers incremental value for predicting in-hospital AKI and mortality in ACS. The simple 6-item KID-ACS risk score integrates PENK and provides a novel tool for simultaneous assessment of renal and mortality risk in patients with ACS.

Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial.

BACKGROUND: Acetazolamide inhibits proximal tubular sodium reabsorption and improved decongestion in the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. It remains unclear whether the decongestive effects of acetazolamide differ across the spectrum of left ventricular ejection fraction (LVEF). METHODS: This is a prespecified analysis of the randomized, double-blind, placebo-controlled ADVOR trial that enrolled 519 patients with acute heart failure (HF), clinical signs of volume overload (eg, edema, pleural effusion, or ascites), NTproBNP (N-terminal pro-B-type natriuretic peptide) >1000 ng/L, or BNP (B-type natriuretic peptide) >250 ng/mL to receive intravenous acetazolamide (500 mg once daily) or placebo in addition to standardized intravenous loop diuretics (twice that of the oral home maintenance dose). Randomization was stratified according to LVEF (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload within 3 days from randomization without the need for mandatory escalation of decongestive therapy because of poor urine output. RESULTS: Median LVEF was 45% (25th to 75th percentile; 30% to 55%), and 43% had an LVEF ≤40%. Patients with lower LVEF were younger and more likely to be male with a higher prevalence of ischemic heart disease, higher NTproBNP, less atrial fibrillation, and lower estimated glomerular filtration rate. No interaction on the overall beneficial treatment effect of acetazolamide to the primary end point of successful decongestion (OR, 1.77 [95% CI, 1.18-2.63]; P=0.005; all P values for interaction >0.401) was found when LVEF was assessed per randomization stratum (≤40% or >40%), or as HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction, or on a continuous scale. Acetazolamide resulted in improved diuretic response measured by higher cumulative diuresis and natriuresis and shortened length of stay without treatment effect modification by baseline LVEF (all P values for interaction >0.160). CONCLUSIONS: When added to treatment with loop diuretics in patients with acute decompensated HF, acetazolamide improves the incidence of successful decongestion and diuretic response, and shortens length of stay without treatment effect modification by baseline LVEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03505788.

Standardized Definitions for Cardiogenic Shock Research and Mechanical Circulatory Support Devices: Scientific Expert Panel From the Shock Academic Research Consortium (SHARC).

The Shock Academic Research Consortium is a multi-stakeholder group, including representatives from the US Food and Drug Administration and other government agencies, industry, and payers, convened to develop pragmatic consensus definitions useful for the evaluation of clinical trials enrolling patients with cardiogenic shock, including trials evaluating mechanical circulatory support devices. Several in-person and virtual meetings were convened between 2020 and 2022 to discuss the need for developing the standardized definitions required for evaluation of mechanical circulatory support devices in clinical trials for cardiogenic shock patients. The expert panel identified key concepts and topics by performing literature reviews, including previous clinical trials, while recognizing current challenges and the need to advance evidence-based practice and statistical analysis to support future clinical trials. For each category, a lead (primary) author was assigned to perform a literature search and draft a proposed definition, which was presented to the subgroup. These definitions were further modified after feedback from the expert panel meetings until a consensus was reached. This manuscript summarizes the expert panel recommendations focused on outcome definitions, including efficacy and safety.

Risk Factors and Outcome Associated With Fungal Infections in Patients With Severe Burn Injury: 10-year Retrospective IFI-BURN Study.

BACKGROUND: In burn patients, skin barrier disruption and immune dysfunctions increase susceptibility to invasive fungal diseases (IFDs) like invasive candidiasis (IC) and invasive mold infections (IMI). We provide an in-depth analysis of IFD-related factors and outcomes in a 10-year cohort of severe burn patients. METHODS: This retrospective cohort study includes adult patients admitted to the burn intensive care unit (BICU) between April 2014 and May 2023 with total burn surface area (TBSA) ≥15%. Patients were classified as proven IFD according to EORTC/MSGERC criteria applicable for IC. Putative IMIs were defined with: ≥2 positive cultures from a skin biopsy/bronchoalveolar lavage or ≥2 positive blood specific-quantitative polymerase chain reactions (qPCRs) or a combination of both. RESULTS: Among 1381 patients admitted, 276 consecutive patients with TBSA ≥15% were included. Eighty-seven (31.5%; IC n = 30; IMI n = 43; both n = 14) patients fulfilled the criteria for probable/putative IFD. At Day 30 after the burn injury, the estimated cumulative incidence proven/putative (pr/pu) IFD was 26.4% (95% confidence interval [CI], 21.4%-31.8%). Factors independently associated with IFDs were TBSA, severity scores and indoor burn injury (ie, from confined space fire). Overall mortality was 15.3% and 36.8% in the no IFD, pr/pu IFD groups respectively (P < .0001). IFD was independently associated with a risk of death (hazard ratio [HR]: 1.94 for pr/pu IFD; 95% CI, 1.12-3.36; P = .019). CONCLUSIONS: This study describes twenty-first-century characteristics of IFDs in severe burn patients confirming known risk factors with thresholds and identifying the indoor injury as an independent factor associated to IFDs. This suggests a link to contamination caused by fire damage, which is highly susceptible to aerosolizing spores.

Left ventricular ejection fraction digit bias and reclassification of heart failure with mildly reduced vs reduced ejection fraction based on the 2021 definition and classification of heart failure.

AIMS: Aims were to evaluate (1) reclassification of patients from heart failure with mildly reduced (HFmrEF) to reduced (HFrEF) ejection fraction when an EF = 40% was considered as HFrEF, (2) role of EF digit bias, ie, EF reporting favouring 5% increments; (3) outcomes in relation to missing and biased EF reports, in a large multinational HF registry. METHODS AND RESULTS: Of 25,154 patients in the European Society of Cardiology (ESC) HF Long-Term registry, 17% had missing EF and of those with available EF, 24% had HFpEF (EF≥50%), 21% HFmrEF (40%-49%) and 55% HFrEF (<40%) according to the 2016 ESC guidelines´ classification. EF was "exactly" 40% in 7%, leading to reclassifying 34% of the HFmrEF population defined as EF = 40% to 49% to HFrEF when applying the 2021 ESC Guidelines classification (14% had HFmrEF as EF = 41% to 49% and 62% had HFrEF as EF≤40%). EF was reported as a value ending with 0 or 5 in ∼37% of the population. Such potential digit bias was associated with more missing values for other characteristics and higher risk of all-cause death and HF hospitalization. Patients with missing EF had higher risk of all-cause and CV mortality, and HF hospitalization compared to those with recorded EF. CONCLUSIONS: Many patients had reported EF = 40%. This led to substantial reclassification of EF from old HFmrEF (40%-49%) to new HFrEF (≤40%). There was considerable digit bias in EF reporting and missing EF reporting, which appeared to occur not at random and may reflect less rigorous overall care and worse outcomes.

Characteristics, treatment, and outcomes of early vs. late enrollees of the STRONG-HF trial.

BACKGROUND: The STRONG-HF trial showed that high-intensity care (HIC) consisting of rapid up-titration of guideline-directed medical therapy (GDMT) and close follow-up reduced all-cause death or heart failure (HF) readmission at 180 days compared to usual care (UC). We hypothesized that significant differences in patient characteristics, management, and outcomes over the enrolment period may exist. METHODS: Two groups of the 1,078 patients enrolled in STRONG-HF were created according to the order of enrolment within center. The early group consisted of the first 10 patients enrolled at each center (N = 342) and the late group consisted of the following patients (N = 736). RESULTS: Late enrollees were younger, had more frequently reduced ejection fraction, slightly lower NT-proBNP and creatinine levels compared with early enrollees. The primary outcome occurred less frequently in early compared to late enrollees (15% vs. 21%, aHR 0.65, 95% CI 0.42-0.99, P = .044). No treatment-by-enrolment interaction was seen in respect to the average percentage of optimal dose of GDMT after randomization, which was consistently higher in early and late patients randomized to HIC compared to UC. The higher use of renin-angiotensin-inhibitors in the HIC arm was more pronounced in the late enrollees both after randomization (interaction-P = .013) and at 90 days (interaction-P < .001). No interaction was observed for safety events. Patients randomized late to UC displayed a trend toward more severe outcomes (26% vs. 16%, P = .10), but the efficacy of HIC showed no interaction with the enrolment group (aHR 0.77, 95% CI 0.35-1.67 in early and 0.58, 95% CI 0.40-0.83 in late enrollees, adjusted interaction-P = .51) with similar outcomes in the HIC arm in late and early enrollees (16% vs. 13%, P = .73). CONCLUSIONS: Late enrollees have different clinical characteristics and higher event rates compared to early enrollees. GDMT implementation in the HIC arm robustly achieved similar doses with consistent efficacy in early and late enrollees, mitigating the higher risk of adverse outcome in late enrollees. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03412201.

High Circulating Dipeptidyl Peptidase 3 Predicts Mortality and Need for Organ Support in Cardiogenic Shock: An Ancillary Analysis of the ACCOST-HH Trial.

BACKGROUND: Cardiogenic shock (CS) is burdened with high mortality. Efforts to improve outcome are hampered by the difficulty of individual risk stratification and the lack of targetable pathways. Previous studies demonstrated that elevated circulating dipeptidyl peptidase 3 (cDPP3) is an early predictor of short-term outcome in CS, mostly of ischemic origin. Our objective was to investigate the association between cDPP3 and short-term outcomes in a diverse population of patients with CS. METHODS AND RESULTS: cDPP3 was measured at baseline and after 72 hours in the AdreCizumab against plaCebO in SubjecTs witH cardiogenic sHock (ACCOST-HH) trial. The association of cDPP3 with 30-day mortality and need for organ support was assessed. Median cDPP3 concentration at baseline was 43.2 ng/mL (95% confidence interval [CI], 21.2-74.0 ng/mL) and 77 of the 150 patients (52%) had high cDPP3 over the predefined cutoff of 40 ng/mL. Elevated cDPP3 was associated with higher 30-day mortality (adjusted hazard ratio [aHR] = 1.7; 95% CI, 1.0-2.9), fewer days alive without cardiovascular support (aHR, 3 days [95% CI, 0-24 days] vs aHR, 21 days [95% CI, 5-26 days]; P < .0001) and a greater need for renal replacement therapy (56% vs 22%; P < .0001) and mechanical ventilation (90 vs 74%; P = .04). Patients with a sustained high cDPP3 had a poor prognosis (reference group). In contrast, patients with an initially high but decreasing cDPP3 at 72 hours had markedly lower 30-day mortality (aHR, 0.17; 95% CI, 0.084-0.34), comparable with patients with a sustained low cDPP3 (aHR, 0.23; 95% CI, 0.12-0.41). The need for organ support was markedly decreased in subpopulations with sustained low or decreasing cDPP3. CONCLUSIONS: The present study confirms the prognostic value of cDPP3 in a contemporary population of patients with CS.

The Effects of Burst Steroid Therapy on Short-term Decongestion in Acute Heart Failure Patients With Pro-inflammatory Activation: A Post Hoc Analysis of the CORTAHF Randomized, Open-label, Pilot Trial.

BACKGROUND: The effect of steroids on congestion in patients with acute heart failure (AHF) is not known. METHODS AND RESULTS: Patients with AHF, NT-proBNP levels > 1500 pg/mL and high-sensitivity C-reactive protein (hsCRP) levels > 20 mg/L were randomized to once-daily oral 40 mg prednisone for 7 days or usual care. In this post hoc analysis, congestion score was calculated on the basis of orthopnea, edema and rales (0 reflecting lack of congestion, and 9 maximal congestion) at each time point. Among 100 eligible patients randomized, those assigned to prednisone had a greater improvement in congestion score at day 31 (win odds for the prednisone group compared to usual care at day 31 was 1.77 (95% CI 1.17-2.84; P = 0.0066) in all patients and 2.41 (95% CI 1.37-5.05; P = 0.0016) in patients with IL-6 > 13 pg/mL at baseline. In patients with congestion scores ≥ 7 at baseline, the effects of prednisone therapy on the EQ-5D visual analog scale score were 4.30 (95% CI 0.77-7.83) points at day 7 and 5.40 (0.51-10.29) points at day 31, accompanied by lower heart rate and respiratory rate and higher oxygen saturation compared to usual care. CONCLUSIONS: In patients with AHF and inflammatory activation, 7-day steroid therapy was associated with reduction in signs of congestion up to day 31. These results need confirmation in larger studies examining potential effects of steroids on congestion, diuresis, fluid redistribution and vascular permeability as well as clinical effects in AHF.

Safety Indicators in Patients Receiving High-intensity Care After Hospital Admission for Acute Heart Failure: The STRONG-HF Trial.

BACKGROUND: Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies (STRONG-HF) demonstrated the safety and efficacy of rapid up-titration of guideline-directed medical therapy (GDMT) with high-intensity care (HIC) compared with usual care in patients hospitalized for acute heart failure (HF). In the HIC group, the following safety indicators were used to guide up-titration: estimated glomerular filtration rate of <30 mL/min/1.73 m2, serum potassium of >5.0 mmol/L, systolic blood pressure (SBP) of <95 mmHg, heart rate of <55 bpm, and N-terminal pro-B-type natriuretic peptide concentration of >10% higher than predischarge values. METHODS AND RESULTS: We examined the impact of protocol-specified safety indicators on achieved dose of GDMT and clinical outcomes. Three hundred thirteen of the 542 patients in the HIC arm (57.7%) met ≥1 safety indicator at any follow-up visit 1-6 weeks after discharge. As compared with those without, patients meeting ≥1 safety indicator had more severe HF symptoms, lower SBP, and higher heart rate at baseline and achieved a lower average percentage of GDMT optimal doses (mean difference vs the HIC arm patients not reaching any safety indicator, -11.0% [95% confidence interval [CI] -13.6 to -8.4%], P < .001). The primary end point of 180-day all-cause death or HF readmission occurred in 15.0% of patients with any safety indicator vs 14.2% of those without (adjusted hazard ratio 0.84, 95% CI 0.48-1.46, P = .540). None of each of the safety indicators, considered alone, was significantly associated with the primary end point, but an SBP of <95 mm Hg was associated with a trend toward increased 180-day all-cause mortality (adjusted hazard ratio 2.68, 95% CI 0.94-7.64, P = .065) and estimated glomerular filtration rate decreased to <30 mL/min/1.73 m2 with more HF readmissions (adjusted hazard ratio 3.60, 95% CI 1.22-10.60, P = .0203). The occurrence of a safety indicator was associated with a smaller 90-day improvement in the EURO-QoL 5-Dimension visual analog scale (adjusted mean difference -3.32 points, 95% CI -5.97 to -0.66, P = .015). CONCLUSIONS: Among patients with acute HF enrolled in STRONG-HF in the HIC arm, the occurrence of any safety indicator was associated with the administration of slightly lower GDMT doses and less improvement in quality of life, but with no significant increase in the primary outcome of 180-day HF readmission or death when appropriately addressed according to the study protocol.

Evolution, control and success of combination therapy with Ampicilin-sulbactam/Ceftazidime-Avibactam during a Carbapenem-Resistant Acinetobacter baumannii outbreak in burn Intensive Care Unit.

We present our findings on interpatient transmission, epidemic control measures, and the outcomes of a series of ten critically ill burn patients who were either colonized or infected with carbapenem-resistant Acinetobacter baumannii (CRAB). None of the five infected patients achieved clinical cure, and all experienced relapses. Microbiological failure was observed in 40% of the infected patients. The isolated CRAB strains were found to carry blaOXA-23 and armA resistance genes. Despite the lack of clinical cure, all five infected patients survived and were discharged from the Burn Intensive Care Unit.

Trending Ability of End-Tidal Capnography Monitoring During Mechanical Ventilation to Track Changes in Arterial Partial Pressure of Carbon Dioxide in Critically Ill Patients With Acute Brain Injury: A Monocenter Retrospective Study.

BACKGROUND: Changes in arterial partial pressure of carbon dioxide (Pa co2 ) may alter cerebral perfusion in critically ill patients with acute brain injury. Consequently, international guidelines recommend normocapnia in mechanically ventilated patients with acute brain injury. The measurement of end-tidal capnography (Et co2 ) allows its approximation. Our objective was to report the agreement between trends in Et co2 and Pa co2 during mechanical ventilation in patients with acute brain injury. METHODS: Retrospective monocenter study was conducted for 2 years. Critically ill patients with acute brain injury who required mechanical ventilation with continuous Et co2 monitoring and with 2 or more arterial gas were included. The agreement was evaluated according to the Bland and Altman analysis for repeated measurements with calculation of bias, and upper and lower limits of agreement. The directional concordance rate of changes between Et co2 and Pa co2 was evaluated with a 4-quadrant plot. A polar plot analysis was performed using the Critchley methods. RESULTS: We analyzed the data of 255 patients with a total of 3923 paired ΔEt co2 and ΔPa co2 (9 values per patient in median). Mean bias by Bland and Altman analysis was -8.1 (95 CI, -7.9 to -8.3) mm Hg. The directional concordance rate between Et co2 and Pa co2 was 55.8%. The mean radial bias by polar plot analysis was -4.4° (95% CI, -5.5 to -3.3) with radial limit of agreement (LOA) of ±62.8° with radial LOA 95% CI of ±1.9°. CONCLUSIONS: Our results question the performance of trending ability of Et co2 to track changes in Pa co2 in a population of critically ill patients with acute brain injury. Changes in Et co2 largely failed to follow changes in Pa co2 in both direction (ie, low concordance rate) and magnitude (ie, large radial LOA). These results need to be confirmed in prospective studies to minimize the risk of bias.

Acute heart failure: current pharmacological treatment and perspectives.

Acute heart failure (AHF) represents the most frequent cause of unplanned hospital admission in patients older than 65 years. Symptoms and clinical signs of AHF (e.g. dyspnoea, orthopnoea, oedema, jugular vein distension, and variation of body weight) are mostly related to systemic venous congestion secondary to various mechanisms including extracellular fluids, increased ventricular filling pressures, and/or auto-transfusion of blood from the splanchnic into the pulmonary circulation. Thus, the initial management of AHF patients should be mostly based on decongestive therapies on admission followed, before discharge, by rapid implementation of guideline-directed oral medical therapies for heart failure. The therapeutic management of AHF requires the identification and rapid diagnosis of the disease, the diagnosis of the cause (or triggering factor), the evaluation of severity, the presence of comorbidities, and, finally, the initiation of a rapid treatment. The most recent guidelines from ESC and ACC/AHA/HFSA have provided updated recommendations on AHF management. Recommended pharmacological treatment for AHF includes diuretic therapy aiming to relieve congestion and achieve optimal fluid status, early and rapid initiation of oral therapies before discharge combined with a close follow-up. Non-pharmacological AHF management requires risk stratification in the emergency department and non-invasive ventilation in case of respiratory failure. Vasodilators should be considered as initial therapy in AHF precipitated by hypertension. On the background of recent large randomized clinical trials and international guidelines, this state-of-the-art review describes current pharmacological treatments and potential directions for future research in AHF.

Renal function and decongestion with acetazolamide in acute decompensated heart failure: the ADVOR trial.

BACKGROUND AND AIMS: In the ADVOR trial, acetazolamide improved decongestion in acute decompensated heart failure (ADHF). Whether the beneficial effects of acetazolamide are consistent across the entire range of renal function remains unclear. METHODS: This is a pre-specified analysis of the ADVOR trial that randomized 519 patients with ADHF to intravenous acetazolamide or matching placebo on top of intravenous loop diuretics. The main endpoints of decongestion, diuresis, natriuresis, and clinical outcomes are assessed according to baseline renal function. Changes in renal function are evaluated between treatment arms. RESULTS: On admission, median estimated glomerular filtration rate (eGFR) was 40 (30-52) mL/min/1.73 m². Acetazolamide consistently increased the likelihood of decongestion across the entire spectrum of eGFR (P-interaction = .977). Overall, natriuresis and diuresis were higher with acetazolamide, with a higher treatment effect for patients with low eGFR (both P-interaction < .007). Acetazolamide was associated with a higher incidence of worsening renal function (WRF; rise in creatinine ≥ 0.3 mg/dL) during the treatment period (40.5% vs. 18.9%; P < .001), but there was no difference in creatinine after 3 months (P = .565). This was not associated with a higher incidence of heart failure hospitalizations and mortality (P-interaction = .467). However, decongestion at discharge was associated with a lower incidence of adverse clinical outcomes irrespective of the onset of WRF (P-interaction = .805). CONCLUSIONS: Acetazolamide is associated with a higher rate of successful decongestion across the entire range of renal function with more pronounced effects regarding natriuresis and diuresis in patients with a lower eGFR. While WRF occurred more frequently with acetazolamide, this was not associated with adverse clinical outcomes. CLINICALTRIALS.GOV IDENTIFIER: NCT03505788.

Pre-treatment bicarbonate levels and decongestion by acetazolamide: the ADVOR trial.

AIMS: Acetazolamide inhibits proximal tubular sodium and bicarbonate re-absorption and improved decongestive response in acute heart failure in the ADVOR trial. It is unknown whether bicarbonate levels alter the decongestive response to acetazolamide. METHODS AND RESULTS: This is a sub-analysis of the randomized, double-blind, placebo-controlled ADVOR trial that randomized 519 patients with acute heart failure and volume overload in a 1:1 ratio to intravenous acetazolamide (500 mg/day) or matching placebo on top of standardized intravenous loop diuretics (dose equivalent of twice oral maintenance dose). The primary endpoint was complete decongestion after 3 days of treatment (morning of day 4). Impact of baseline HCO3 levels on the treatment effect of acetazolamide was assessed. : Of the 519 enrolled patients, 516 (99.4%) had a baseline HCO3 measurement. Continuous HCO3 modelling illustrated a higher proportional treatment effect for acetazolamide if baseline HCO3 ≥ 27 mmol/l. A total of 234 (45%) had a baseline HCO3 ≥ 27 mmol/l. Randomization towards acetazolamide improved decongestive response over the entire range of baseline HCO3- levels (P = 0.004); however, patients with elevated baseline HCO3 exhibited a significant higher response to acetazolamide [primary endpoint: no vs. elevated HCO3; OR 1.37 (0.79-2.37) vs. OR 2.39 (1.35-4.22), P-interaction = 0.065), with higher proportional diuretic and natriuretic response (both P-interaction < 0.001), greater reduction in congestion score on consecutive days (treatment × time by HCO3-interaction <0.001) and length of stay (P-interaction = 0.019). The larger proportional treatment effect was mainly explained by the development of diminished decongestive response in the placebo arm (loop diuretics only), both with regard to reaching the primary endpoint of decongestion as well as reduction in congestion score. Development of elevated HCO3 further worsened decongestive response in the placebo arm (P-interaction = 0.041). A loop diuretic only strategy was associated with an increase in the HCO3 during the treatment phase which was prevented by acetazolamide (day 3: placebo 74.8% vs. acetazolamide 41.3%, P < 0.001). CONCLUSION: Acetazolamide improves decongestive response over the entire range of HCO3- levels; however, the treatment response is magnified in patients with baseline or loop diuretic-induced elevated HCO3 (marker of proximal nephron NaHCO3 retention) by specifically counteracting this component of diuretic resistance.

NT-proBNP and high intensity care for acute heart failure: the STRONG-HF trial.

AIMS: STRONG-HF showed that rapid up-titration of guideline-recommended medical therapy (GRMT), in a high intensity care (HIC) strategy, was associated with better outcomes compared with usual care. The aim of this study was to assess the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and its changes early during up-titration. METHODS AND RESULTS: A total of 1077 patients hospitalized for acute heart failure (HF) and with a >10% NT-proBNP decrease from screening (i.e. admission) to randomization (i.e. pre-discharge), were included. Patients in HIC were stratified by further NT-proBNP changes, from randomization to 1 week later, as decreased (≥30%), stable (<30% decrease to ≤10% increase), or increased (>10%). The primary endpoint was 180-day HF readmission or death. The effect of HIC vs. usual care was independent of baseline NT-proBNP. Patients in the HIC group with stable or increased NT-proBNP were older, with more severe acute HF and worse renal and liver function. Per protocol, patients with increased NT-proBNP received more diuretics and were up-titrated more slowly during the first weeks after discharge. However, by 6 months, they reached 70.4% optimal GRMT doses, compared with 80.3% for those with NT-proBNP decrease. As a result, the primary endpoint at 60 and 90 days occurred in 8.3% and 11.1% of patients with increased NT-proBNP vs. 2.2% and 4.0% in those with decreased NT-proBNP (P = 0.039 and P = 0.045, respectively). However, no difference in outcome was found at 180 days (13.5% vs. 13.2%; P = 0.93). CONCLUSION: Among patients with acute HF enrolled in STRONG-HF, HIC reduced 180-day HF readmission or death regardless of baseline NT-proBNP. GRMT up-titration early post-discharge, utilizing increased NT-proBNP as guidance to increase diuretic therapy and reduce the GRMT up-titration rate, resulted in the same 180-day outcomes regardless of early post-discharge NT-proBNP change.

Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial.

BACKGROUND: There is a paucity of evidence for dose and pace of up-titration of guideline-directed medical therapies after admission to hospital for acute heart failure. METHODS: In this multinational, open-label, randomised, parallel-group trial (STRONG-HF), patients aged 18-85 years admitted to hospital with acute heart failure, not treated with full doses of guideline-directed drug treatment, were recruited from 87 hospitals in 14 countries. Before discharge, eligible patients were randomly assigned (1:1), stratified by left ventricular ejection fraction (≤40% vs >40%) and country, with blocks of size 30 within strata and randomly ordered sub-blocks of 2, 4, and 6, to either usual care or high-intensity care. Usual care followed usual local practice, and high-intensity care involved the up-titration of treatments to 100% of recommended doses within 2 weeks of discharge and four scheduled outpatient visits over the 2 months after discharge that closely monitored clinical status, laboratory values, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations. The primary endpoint was 180-day readmission to hospital due to heart failure or all-cause death. Efficacy and safety were assessed in the intention-to-treat (ITT) population (ie, all patients validly randomly assigned to treatment). The primary endpoint was assessed in all patients enrolled at hospitals that followed up patients to day 180. Because of a protocol amendment to the primary endpoint, the results of patients enrolled on or before this amendment were down-weighted. This study is registered with ClinicalTrials.gov, NCT03412201, and is now complete. FINDINGS: Between May 10, 2018, and Sept 23, 2022, 1641 patients were screened and 1078 were successfully randomly assigned to high-intensity care (n=542) or usual care (n=536; ITT population). Mean age was 63·0 years (SD 13·6), 416 (39%) of 1078 patients were female, 662 (61%) were male, 832 (77%) were White or Caucasian, 230 (21%) were Black, 12 (1%) were other races, one (<1%) was Native American, and one (<1%) was Pacific Islander (two [<1%] had missing data on race). The study was stopped early per the data and safety monitoring board's recommendation because of greater than expected between-group differences. As of data cutoff (Oct 13, 2022), by day 90, a higher proportion of patients in the high-intensity care group had been up-titrated to full doses of prescribed drugs (renin-angiotensin blockers 278 [55%] of 505 vs 11 [2%] of 497; ß blockers 249 [49%] vs 20 [4%]; and mineralocorticoid receptor antagonists 423 [84%] vs 231 [46%]). By day 90, blood pressure, pulse, New York Heart Association class, bodyweight, and NT-proBNP concentration had decreased more in the high-intensity care group than in the usual care group. Heart failure readmission or all-cause death up to day 180 occurred in 74 (15·2% down-weighted adjusted Kaplan-Meier estimate) of 506 patients in the high-intensity care group and 109 (23·3%) of 502 patients in the usual care group (adjusted risk difference 8·1% [95% CI 2·9-13·2]; p=0·0021; risk ratio 0·66 [95% CI 0·50-0·86]). More adverse events by 90 days occurred in the high-intensity care group (223 [41%] of 542) than in the usual care group (158 [29%] of 536) but similar incidences of serious adverse events (88 [16%] vs 92 [17%]) and fatal adverse events (25 [5%] vs 32 [6%]) were reported in each group. INTERPRETATION: An intensive treatment strategy of rapid up-titration of guideline-directed medication and close follow-up after an acute heart failure admission was readily accepted by patients because it reduced symptoms, improved quality of life, and reduced the risk of 180-day all-cause death or heart failure readmission compared with usual care. FUNDING: Roche Diagnostics.

Advances in the Management of Cardiogenic Shock.

OBJECTIVES: To review a contemporary approach to the management of patients with cardiogenic shock (CS). DATA SOURCES: We reviewed salient medical literature regarding CS. STUDY SELECTION: We included professional society scientific statements and clinical studies examining outcomes in patients with CS, with a focus on randomized clinical trials. DATA EXTRACTION: We extracted salient study results and scientific statement recommendations regarding the management of CS. DATA SYNTHESIS: Professional society recommendations were integrated with evaluated studies. CONCLUSIONS: CS results in short-term mortality exceeding 30% despite standard therapy. While acute myocardial infarction (AMI) has been the focus of most CS research, heart failure-related CS now predominates at many centers. CS can present with a wide spectrum of shock severity, including patients who are normotensive despite ongoing hypoperfusion. The Society for Cardiovascular Angiography and Intervention Shock Classification categorizes patients with or at risk of CS according to shock severity, which predicts mortality. The CS population includes a heterogeneous mix of phenotypes defined by ventricular function, hemodynamic profile, biomarkers, and other clinical variables. Integrating the shock severity and CS phenotype with nonmodifiable risk factors for mortality can guide clinical decision-making and prognostication. Identifying and treating the cause of CS is crucial for success, including early culprit vessel revascularization for AMI. Vasopressors and inotropes titrated to restore arterial pressure and perfusion are the cornerstone of initial medical therapy for CS. Temporary mechanical circulatory support (MCS) is indicated for appropriately selected patients as a bridge to recovery, decision, durable MCS, or heart transplant. Randomized controlled trials have not demonstrated better survival with the routine use of temporary MCS in patients with CS. Accordingly, a multidisciplinary team-based approach should be used to tailor the type of hemodynamic support to each individual CS patient's needs based on shock severity, phenotype, and exit strategy.

Urinary peptides provide information about the risk of mortality across a spectrum of diseases and scenarios.

BACKGROUND: There is evidence of pre-established vulnerability in individuals that increases the risk of their progression to severe disease or death, although the mechanisms causing this are still not fully understood. Previous research has demonstrated that a urinary peptide classifier (COV50) predicts disease progression and death from SARS-CoV-2 at an early stage, indicating that the outcome prediction may be partly due to vulnerabilities that are already present. The aim of this study is to examine the ability of COV50 to predict future non-COVID-19-related mortality, and evaluate whether the pre-established vulnerability can be generic and explained on a molecular level by urinary peptides. METHODS: Urinary proteomic data from 9193 patients (1719 patients sampled at intensive care unit (ICU) admission and 7474 patients with other diseases (non-ICU)) were extracted from the Human Urinary Proteome Database. The previously developed COV50 classifier, a urinary proteomics biomarker panel consisting of 50 peptides, was applied to all datasets. The association of COV50 scoring with mortality was evaluated. RESULTS: In the ICU group, an increase in the COV50 score of one unit resulted in a 20% higher relative risk of death [adjusted HR 1.2 (95% CI 1.17-1.24)]. The same increase in COV50 in non-ICU patients resulted in a higher relative risk of 61% [adjusted HR 1.61 (95% CI 1.47-1.76)], consistent with adjusted meta-analytic HR estimate of 1.55 [95% CI 1.39-1.73]. The most notable and significant changes associated with future fatal events were reductions of specific collagen fragments, most of collagen alpha I (I). CONCLUSION: The COV50 classifier is predictive of death in the absence of SARS-CoV-2 infection, suggesting that it detects pre-existing vulnerability. This prediction is mainly based on collagen fragments, possibly reflecting disturbances in the integrity of the extracellular matrix. These data may serve as a basis for proteomics-guided intervention aiming towards manipulating/ improving collagen turnover, thereby reducing the risk of death.