Can saline repletion be the true TARGET for achieving fluid balance in acute heart failure?

DOPPLER ULTRASOUND ASSESSMENT OF INTRA-RENAL VENOUS FLOW IN PATIENTS WITH ACUTE DECOMPENSATE HEART FAILURE: A POTENTIAL ACUTE CARDIORENAL SYNDROME BIOMARKER

Despite advances in heart failure management, treatment for acute decompensated heart failure (ADHF) remains largely unchanged. Loop diuretics are the mainstay for fluid overload due to their rapid onset and efficacy. However, insufficient decongestion, poor diuretic response, and resistance lead to suboptimal symptom relief, prolonged hospital stays, and increased mortality. Evidence suggests that adding acetazolamide to loop diuretics improves decongestion without escalating diuretic doses. However, limited data regarding its efficacy and safety preclude its incorporation in clinical guidelines. Objective: To determine the efficacy and safety of acetazolamide combined with loop diuretics in patients with ADHF. Methods: A systematic review was conducted to assess studies comparing loop diuretics alone versus with acetazolamide in ADHF patients. Eligible studies included prospective and retrospective observational studies, and randomized controlled trials. The primary outcomes evaluated were natriuresis, fluid balance, and weight loss. Secondary outcomes included rate of rehospitalization, all-cause mortality, and presence of adverse events. This review followed PRISMA-P guidelines. Data were analyzed using Review Manager Version 5.4.1. Statistical methods adhered to the Cochrane Handbook for Systematic Reviews of Interventions. Results: Six studies were selected from the initial 681 studies identified through the literature search. Analyses revealed acetazolamide supplementation significantly increased natriuresis by day 3 [SMD 0.68, 95% CI (0.32, 1.04), P=0.0002] and resulted in a more negative fluid balance [SMD -0.77, 95% CI (-1.23, -0.32) P=0.0008]. Weight loss [SMD 0.17, 95% CI, (-0.19, 0.53) P=0.36] was also higher in the acetazolamide group, but the effect was not statistically significant. In terms of safety, the all-cause mortality, rate of rehospitalization, and presence of adverse events were similar between the two groups. Conclusion: This study provides significant evidence regarding the clinical benefit of adding acetazolamide to standard loop diuretic therapy in decongesting patients with ADHF.

This editorial refers to 'Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes', by M. Gheorghiade et al., published in this issue on pages 1056–1066. Over the last decades, pharmacological treatment of patients hospitalized for acute decompensated heart failure have remained unchanged. Virtually all patients are treated with a loop diuretic, and the use of additional drugs depends on the type of heart failure and mainly on blood pressure. Only in patients with a blood pressure >110 mmHg is the addition of intravenous nitrates recommended.1 In rare patients with cardiogenic shock, inotropes are administered. Nevertheless, evidence for this approach is generally lacking. Also, the majority of patients remain symptomatic, and in-hospital mortality remains ∼4%.2 More importantly, outcome after discharge is very poor. Most deaths and re-hospitalizations occur early after discharge, and 1 year mortality or re-hospitalization occurs in ∼40% of the patients.1 Therefore, there is a great need for improvement. In the current issue of this journal, clinical results of the COMPOSE programme are presented. The COMPOSE programme studied the effects of cinaciguat, a novel vasodilator, in three randomized, double-blind, placebo-controlled studies in acute decompensated heart failure patients with (COMPOSE 1 and 2) or without (COMPOSE EARLY) a requirement for invasive haemodynamic monitoring.3 Cinaciguat activates soluble guanylate cyclase, leading to increased cyclic guanosine monophosphate (cGMP). cGMP causes relaxation of smooth muscle cells, and has antiproliferative, anti-inflammatory, and antiremodelling effects.4 Cinaciguat is therefore a potent vasodilator, with specific antiplatelet activity, a long-lasting antihypertensive effect, and a haemodynamic profile similar to that of nitrates. In an uncontrolled clinical study in patients (n = 60) with acute decompensated heart failure, cinaciguat produced strong reductions in preload and afterload, with increased cardiac output and preservation of renal function.5 The drug was well tolerated, with hypotension reported only in 10% of patients. In the present paper in this journal, the authors also referred to another unpublished placebo-controlled study, in which cinaciguat produced rapid, sustained improvement in pulmonary capillary wedge pressure (PCWP) at 8 h compared with placebo. However, the majority (73%) of patients receiving cinaciguat developed hypotension, especially those who received cinaciguat doses ≥200 µg/h. The COMPOSE programme was therefore aimed to study the safety and efficacy of lower doses of intravenous cinaciguat (<200 µg/h) as add-on to standard therapy in patients hospitalized with acute decompensated heart failure and a left ventricular ejection fraction of <40%. COMPOSE was terminated early due to an excess of non-fatal hypotension and recruitment difficulties. COMPOSE was composed of three parts. In COMPOSE 1, a reduction in wedge pressure was confirmed but, considering the low number of patients (n = 12), no meaningful conclusion could be drawn. In COMPOSE 2, only four patients were included, and no results were reported. Both studies had problems with their inclusion, since there had to be a clinical indication requiring invasive haemodynamic monitoring, and recent data indicated that haemodynamic monitoring is no longer routinely recommended in acute decompensated heart failure patients.6 In the third part of this programme, COMPOSE EARLY (n = 62), no meaningful difference in dyspnoea was shown between cinaciguat and placebo. The authors conclude that 'Given the lack of effect on dyspnoea and cardiac index and the hypotensive effect seen even with low doses, it is doubtful that further studies with intravenous cinaciguat would prove beneficial in this patient population.' So, why did cinaciguat fail? A consistent strong reduction in PWCP was found with cinaciguat, which is considered as the main mechanism to improve symptoms and clinical outcome in acute heart failure.7 However, with the same dose that reduced wedge pressure by 6 mm in COMPOSE 1, no effect was found on improvement of dyspnoea in COMPOSE EARLY. This is remarkable, given the general consensus that reducing wedge pressure in acute heart failure is a major treatment goal. However, such a strong and fast reduction of the wedge pressure might also have deleterious effects, and a sudden drop in blood pressure can cause other organs, such as the kidney, to fail as well.8,9 Unfortunately, cinaciguat is not the first acute heart failure drug that fails to demonstrate meaningful beneficial effects in patients with acute heart failure. Other failures include phosphodiesterase inhibitors (e.g. milrinone), endothelin antagonists (e.g. tezosentan), calcium sensitizers (e.g. levosimendan), arginine vasopressin antagonists (e.g. tolvaptan), adenosine A1-receptor antagonists (e.g. rolofylline), and human recombinant natriuretic peptides (e.g. nesiritide). Why do these drugs fail, while many drugs in chronic heart failure have been proven to reduce mortality and morbidity?10 First, the wrong drugs might have been studied. This is unlikely, however, since all of the studied drugs showed promising effects in pre-clinical and mechanistic studies, and in early phase II trials. Secondly, maybe the wrong population has been studied. For example, vasodilators might be harmful in patients with low blood pressure, and several large randomized clinical trials in patients with acute decompensated heart failure have allowed inclusion of patients with a blood pressure of <100 mmHg, which might have negatively influenced the results. However, in COMPOSE, only patients with a systolic blood pressure >120 mmHg were included. Thirdly, maybe the wrong endpoints were chosen for these trials. The PCWP might not be the ideal surrogate marker, as explained before. Also, in phase III trials, is it reasonable to believe that a drug that was given for only 48 h would reduce mortality? However, on the other hand, dyspnoea is a soft endpoint, and difficult to assess in an unbiased way. Recently, there have been attempts proposed to standardize and unify measurements of dyspnoea.11,12 In addition, improvement of renal function was shown to be a bad choice when studying rolofylline.13 Therefore, choosing the correct endpoint might strongly influence the outcome of the trial. Finally, the design of acute heart failure studies might have caused the neutral/negative results. For example, most studies allowed the study drug to be started 24–48 h after hospital admission. It is well known that dyspnoea has already improved in many patients by that time. An early start of treatment (within 6 h) might improve early and sustained relief of dyspnoea. However, in COMPOSE EARLY, treatment was started within 12 h of admission. So, haemodynamically active doses of cinaciguat were used only in patients with elevated blood pressures, and treatment was started early. Therefore, the assumptions above cannot fully explain the failure of cinaciguat. So, maybe it is the drug itself. Ideally, a drug that is used in patients hospitalized for heart failure lowers preload of the heart, leads to decongestion, but maintains cardiac output and organ perfusion, and preferably does not lower arterial blood pressure. For cinaciguat, the arterial effects (i.e. lowering of blood pressure) seem to have outweighed the effects of venous dilatation and decongestion. Of note, the most frequently used drugs in acute decompensated heart failure (i.e. loop diuretics and nitrates) have preferential effects on venous dilatation, with only modest effects on blood pressure. Again, a large and sudden drop in both venous and arterial pressures might be unfavourable in patients with acute decompensated heart failure. Unfortunately, the findings of the present study and similar findings from another unpublished placebo-controlled study seem to be the end of the development of the intravenous form of cinaciguat. Potentially, the oral form might show a different clinical profile, and might deserve further study, either in acute or in chronic heart failure. Conflict of interest: none declared.

Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Most hospitalizations for ADHF are related to symptoms of congestion, and the vast majority of ADHF patients are treated with intravenous loop diuretics. Despite this nearly ubiquitous use, data supporting the safety and efficacy of loop diuretics in ADHF are limited, and controversy exists about the best way to use loop diuretics with regard to both dosing and means of administration (continuous infusion vs. intermittent boluses). We reviewed the data supporting the safety and efficacy of loop diuretics in patients with ADHF. A large body of observational literature suggests that loop diuretics, especially at higher doses, may be associated with increased mortality in patients with heart failure even after detailed adjustment for other measures of disease severity. Additionally, multiple small underpowered trials suggest that continuous infusion may be equivalent or superior to intermittent bolus dosing. In summary, there is a critical need to develop more robust data on the use of loop diuretics in ADHF. In that context, the NIH Heart Failure Clinical Research Network has begun the Diuretics Optimization Strategies Evaluation (DOSE) study, a multi-center, double-blind, randomized controlled trial that will enroll 300 patients with ADHF. The DOSE study will randomize patients using a 2 × 2 factorial design to low dose vs. high dose furosemide, and intermittent bolus vs. continuous infusion. Successful completion of the DOSE study will provide important data on the optimal clinical use of loop diuretics in ADHF.

Anp Production Is Impaired in Acute Decompensated Heart Failure

Aim. To assess the risk factors and diagnostic significance of the N-terminal probrain natriuretic peptide (NT-proBNP) in patients with acute decompensated heart failure (ADHF) and diabetic kidney disease (DKD).Material and methods. A total of 125 patients with ADHF and type 2 diabetes (T2D) were examined. They were divided into 2 groups depending on the presence/ absence of chronic kidney disease (CKD). The first group consisted of 43 (34,4%) patients with DKD, the second — 82 (65,6%) without CKD. The inclusion criterion was the presence of ADHF and T2D. There were following exclusion criteria: cardiogenic shock, pulmonary edema, acute thromboembolic events, type 1 diabetes, prediabetes, acute coronary syndrome, stroke, prior transient ischemic attack (&lt;1 month old), dissecting aneurysm or aortic dissection, acute valvular disorders, major surgery (&lt;1 month old), cardiac trauma, infective endocarditis, acute hepatitis and cirrhosis, terminal CKD, alcohol abuse, non-cardiac edema, cancer, dementia and mental disorders.Results. With the development of a hypertensive crisis and an increase in diastolic blood pressure &gt;100 mm Hg, the odds ratio (OR) and the relative risk (RR) of ADHF in patients with DKD increases by 5,1 and 4,5 times, 2,5 and 1,8 times, respectively. In the presence of grade III-V premature ventricular contractions, OR and RR of ADHF in patients with DKD were 2,6 and 1,9, respectively. OR and RR of ADHD in patients with DKD and prior stroke or transient ischemic attack were 3,8 and 3,2, respectively. Verification of anemia at a hemoglobin level of 5 mmol/l, the OR of ADHF in patients with DKD increases by 3,7 times, the OR — by 2,3 times. The NT-proBNP &gt;1289 pg/ml is diagnostic for verifying ADHF in DKD patients with the sensitivity of 64,3% and specificity of 93,3%.Conclusion. Every third patient with ADHF and T2D is diagnosed with DKD. A certain range of risk factors for the development of ADHF in patients with DKD has been identified. As the glomerular filtration rate (GFR) decreases, the NT-proBNP level increases. With a decrease in GFR of 60 ml/min/1,73 m2 in patients with T2D, the diagnostic value of NT-proBNP &gt;1289 pg/ml should be considered to verify ADF.

Treatment of volume overload in the setting of acute decompensated heart failure (ADHF) is typically achieved through the use of loop diuretics. While they are highly effective, some patients may develop loop diuretic resistance. One strategy to overcome this scenario includes sequential nephron blockade with a thiazide-type diuretic; however, it is unknown which thiazide-type diuretic used in this setting is most effective. A systematic review and meta-analysis were performed to compare the efficacy and safety of chlorothiazide with metolazone as add-on therapy in the setting of loop diuretic resistance for the treatment of ADHF. Literature searches were conducted through PubMed, Google Scholar, and Science Direct from inception through February 2020 using the following search terms alone or in combination: metolazone, chlorothiazide, acute decompensated heart failure, loop diuretic, and urine output. All English-language prospective and retrospective trials and abstracts comparing metolazone to chlorothiazide for the treatment of ADHF were evaluated. Studies were included if they analyzed urine output for at least 24hours in patients with ADHF. Meta-analysis was conducted to evaluate pooled effect size by using a random-effect model. Primary outcomes included net and total urine output. Secondary outcomes included commonly reported safety outcomes. Four studies comparing the use of metolazone to chlorothiazide as an adjunct to loop diuretics to treat ADHF were included in the evaluation. Metolazone was as effective as chlorothiazide to augment loop diuretic therapy in ADHF in most studies with no pooled difference in net or total urine output. However, there were notable differences in baseline loop diuretic dosing, ejection fraction, renal function, race, and endpoint timing across studies. Adverse effects were commonly observed and included electrolyte abnormalities, change in renal function, and hypotension but were comparable between groups. Metolazone is as effective as chlorothiazide as add-on to loop diuretics in treating ADHF without an increase in safety concerns.

For acute decompensated heart failure (ADHF) therapy, combination of carperitide, a human atrial natriuretic peptide, and tolvaptan, a novel vasopressin type 2 receptor antagonists, has not been used. Tolvaptan is a drug newly developed to treat volume overload in ADHF patients. Of 102 consecutive cases treated upon admission for ADHF between April and October 2012, we analyzed 51 patients treated with carperitide plus tolvaptan (tolvaptan+carperitide group) and 51 patients treated with carperitide plus conventional diuretics (carperitide group). On comparison between both groups, total dose of carperitide and loop diuretic doses during 48 h in tolvaptan +carperitide group were lower than those in the carperitide group (both p<0.001). Urine output at 24 h and 48 h after admission in the tolvaptan+carperitide group were significantly higher than those in carperitide group (p=0.02 and p<0.001, respectively). Changes in NT-pro brain-type natriuretic peptide levels in tolvaptan+carperitide group were significantly higher than those in carperitide group (p=0.01). No significant differences were detected in worsening renal function. On conclusion, in ADHF therapy, coadministration of tolvaptan and carperitide was more effective and safe compared with conventional therapy.

Renal dysfunction is a common and progressive complication of chronic heart failure, with a clinical course that typically fluctuates with the patient’s clinical status and treatment. Despite growing recognition of the frequent presentation of combined cardiac and renal dysfunction, or “cardiorenal syndrome,” its underlying pathophysiology is not well understood, and no consensus as to its appropriate management has been achieved. Because patients with heart failure are surviving longer and dying less frequently from primary arrhythmia, we expect that the cardiorenal syndrome will become more common. Against this background, the article by Wang and colleagues1 in the present issue of Circulation is particularly significant because it is the first prospective, controlled therapeutic trial in patients with this condition. To place the findings and implications of this study in context, we first briefly review what is currently known about the cardiorenal syndrome and its treatment options. See p 1620 In ambulatory heart failure patients, the presence of concomitant renal dysfunction consistently has been one of the strongest risk factors for mortality.2–4 This risk becomes evident even at serum creatinine clearance levels >1.3 mg/dL and estimated creatinine clearance values ≤60 to 70 mL/min. Furthermore, renal function is at least as powerful an adverse prognostic factor as most clinical variables, including ejection fraction and New York Heart Association function class. Although renal dysfunction predicts all-cause mortality, it is most predictive of death from progressive heart failure, which suggests that it is a manifestation of and/or exacerbating factor for left ventricular dysfunction.2 In the setting of hospitalization for decompensated heart failure, worsening renal function is even more important than baseline renal function for predicting adverse outcomes.5–8 Although any increase in creatinine is associated with poorer survival rates, longer hospitalization, and more frequent readmission, several studies have used a threshold of a …

Background: Thiazide diuretics are often utilized to overcome loop diuretic resistance when treating acute decompensated heart failure (ADHF). In addition to a large cost advantage, several pharmacokinetic advantages exist when administering oral metolazone (MTZ) compared with intravenous (IV) chlorothiazide (CTZ), yet many providers are reluctant to utilize an oral formulation to treat ADHF. The purpose of this study was to compare the increase in 24-hour total urine output (UOP) after adding MTZ or CTZ to IV loop diuretics (LD) in patients with heart failure with reduced ejection fraction (HFrEF). Methods and Results: From September 2013 to August 2016, 1002 patients admitted for ADHF received either MTZ or CTZ in addition to LD. Patients were excluded for heart failure with preserved ejection fraction (HFpEF) (n = 469), <24-hour LD or UOP data prior to drug initiation (n = 129), or low dose MTZ/CTZ (n = 91). A total of 168 patients were included with 64% receiving CTZ. No significant difference was observed between the increase in 24-hour total UOP after MTZ or CTZ initiation (1458 [514, 2401] mL vs 1820 [890, 2750] mL, P = .251). Conclusions: Both MTZ and CTZ similarly increased UOP when utilized as an adjunct to IV LD. These results suggest that while thiazide agents can substantially increase UOP in ADHF patients with HFrEF, MTZ and CTZ have comparable effects.

The Renal Effects of Aggressive Volume Removal in Heart Failure Patients with Preexisting Worsening Renal Function

Cardiac Natriuretic Peptide And Cgmp Impairment In Human Decompensated Heart Failure: Employing A Novel Ex Vivo Natriuretic Peptide/GC-A/cGMP Potency Assay To Evaluate Natriuretic Peptide Therapeutic Capacity

BackgroundIn Indonesia, heart failure has become a major community problem because of the high cost of care, low quality of life, and premature death. Until now, loop diuretics are still the main therapy in patients with acute decompensated heart failure with clinical congestion. Diuretic responsiveness can be assessed objectively by measuring sodium urine. This study aimed to determine the response of natriuresis 2 h after loop diuretic administration and its relationship to length of stay and readmission within 30 days in daily clinical practice.MethodsThis is a prospective cohort study conducted at the National Cardiovascular Center Harapan Kita Hospital in acute decompensated heart failure patients. Patient characteristics were collected from medical records. Response to intravenous (IV) loop diuretics was assessed using urinary sodium laboratory panels. The primary outcomes of interest in this study were length of stay and rehospitalization. Analyses were conducted between the outcome of interests and patient characteristics.ResultsThere were 51 acute decompensated heart failure patients in this study with 78.4% males. The mean age was 52.47 ± 13.62. The mean ejection fraction was 37.53±17.95%, with the majority of patients having a left ventricular ejection fraction less than 40% (62.7% of study subjects). The average glomerular filtration rate of subjects in this study was 57.29 ± 27.25 mL/min. Pearson correlation test between pre- and post-loop diuretic urinary sodium showed trends of significant correlation (r = -0.238, P = 0.093) and (r = -0.308, P = 0.028), respectively. Patients with lower pre-loop diuretic urinary sodium were shown to have a shorter length of stay (8.57 ± 6.161 vs. 5.30 ± 4.01, P = 0.04), while patients with lower post-loop diuretic urinary sodium showed trends of longer length of stay (8.67 ± 4.14 vs. 6.03 ± 5.39, P = 0.126).ConclusionsIn this study, we observe lower rehospitalization in patients with higher pre-loop diuretic urinary sodium levels. Post-loop diuretic urinary sodium level was shown to be inversely related to length of stay in acute decompensated heart failure patients.

Arthur Kornberg, who shared with Severo Ochoa the 1959 Nobel Prize for Physiology or Medicine, stated in his autobiography that he had never met a dull enzyme.1 We strongly believe that soluble guanylate cyclase (sGC; E.C.4.6.1.2) is no exception to this. Article see p 2781 Nitric oxide (NO) plays an important physiological role as a signaling molecule as well as a cytotoxic agent. It is produced by 3 distinct NO synthases, specifically endothelial, neuronal, and inducible NO synthase. In the vasculature, endothelial NO synthase plays an important role in vascular homeostasis because NO generated in endothelial cells promotes vascular smooth muscle cell relaxation and inhibits platelet aggregation. Importantly, bioavailability of NO can be reduced in cardiovascular diseases, a condition which has been termed “endothelial dysfunction.” This phenomenon provides a rationale for therapeutic intervention. The primary target of NO is sGC, which is a heterodimeric enzyme consisting of an α- and β-subunit and a prosthetic heme group, which is located in the β-subunit. The heme group contains a ferrous iron atom (Fe2+). Binding of NO to this iron changes the conformation of the enzyme and leads to a >100-fold increase in catalytic rate (ie, the conversion of guanosine triphosphate to the second messenger cyclic guanosine monophosphate [cGMP]). The NO-induced cGMP signal modulates intracellularly the activity of several effector molecules: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cGMP-gated ion channels. Of note, both heme iron oxidation (Fe3+) and heme removal render sGC unresponsive to NO (Figure). These 2 conditions could therefore provide a mechanism for “vascular smooth muscle cell dysfunction” in cardiovascular disease states, which are often characterized by marked vasoconstriction either systemically or in specific organs. Figure. Schematic illustrating 3 different forms of soluble guanylate cyclase and their respective responsiveness to nitrovasodilators, sGC stimulators (eg, BAY 41–2272), and sGC …

‘The road goes ever on and on, Down from the door where it began’. J.R.R. Tolkien The treatment of chronic heart failure has significantly improved over the last decades, with the introduction of beta-blockers, angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists and the most recent addition of angiotensin receptor–neprilysin inhibition.1 This however cannot be said for the treatment of acute heart failure (AHF). Since the introduction of loop diuretics in the 1960s, they are the first-choice drug for the treatment of volume overload in AHF.2 Multiple studies have investigated different treatment strategies or modalities since, but they all failed to show decongestive or prognostic benefit. Several reasons for this have been suggested (Figure 1). First, the drugs studied might not have exhibited the desired pharmacological effects, despite positive signals in phase II trials. Second, the enrolled population, which were mostly AHF all-comers, could have contributed to neutral findings as (i) patients with other diagnoses causing dyspnoea may have also been enrolled, resulting in a mixed population in which part of the population was unlikely to benefit from the studied drug, and/or; (ii) add-on therapies to loop diuretics may not be necessary in diuretic naïve patients, or patients with a good diuretic response during the first 24 h, as these are most likely to respond well to therapy and will already exhibit a lower event rate. As such the additional effect of a novel therapy could be hampered by the law of diminishing returns. Third, the endpoints used in these trials might have contributed to neutral findings. In most trials hard clinical endpoints, such as reduction in 180-day mortality, were used. However, the expectation of a beneficial effect on such endpoint could be considered a stretch, as these drugs are often only administered during the first hours/days of an AHF hospitalization to improve decongestion. Therefore, a long-term effect beyond this time period might be unlikely. Other AHF studies have used softer, intermediate endpoints (such as improvement in dyspnoea scores, or clinical congestion), or combined endpoints of improved clinical outcome and no worsening of renal function. These endpoints have the limitations that they are notoriously difficult to assess objectively, and are hindered by several factors, such as high inter-observer variability. Finally, worsening renal function in the context of a good diuretic response has recently been suggested to be associated with improved outcomes, and could therefore also be an ambiguous endpoint to use in this setting.3 Therefore, a different approach to the study of ‘novel’ drugs in AHF is warranted. In this issue of the Journal, Verbrugge et al.4 have studied the effect of acetazolamide on natriuresis in AHF patients at high risk for diuretic resistance. In this study, 34 AHF patients admitted for decongestive treatment were enrolled. All patients had to be on an outpatient maintenance dose of loop diuretic, and had to have at least one high-risk criteria for poor diuretic response, e.g. hyponatraemia, elevated blood urea nitrogen to creatinine ratio, or worsening renal function at admission. After enrolment patients were randomized to acetazolamide on top of low-dose diuretics vs. high-dose diuretic stand-alone therapy. Even though patients randomized to acetazolamide received lower doses of loop diuretics, natriuresis after 24 h in this group was similar compared with the high-dose diuretic group, and loop diuretic efficiency (natriuresis adjusted for loop diuretic dose) was significantly better in the acetazolamide group (P = 0.048). There was however a significant increase in the incidence of worsening renal function (increase in serum creatinine > 26.5 μmol/L (0.3 mg/dL)) in the acetazolamide group. Based on these findings, the authors conclude that combination diuretic therapy of acetazolamide and loop diuretics increases the natriuretic response to loop diuretics in AHF patients at high risk for a poor diuretic response. The concept, design and results of this small study are interesting. Despite the fact that several comments can be made, e.g. the small sample size, the fact that the authors were unable to randomize the intended number of patients, only two centres enrolled patients, and that the study was not blinded, several lessons can be taken from this study (Figure 1). First, the drug under investigation in this trial is acetazolamide, a carbonic anhydrase inhibitor. Looking at the physiology of sodium reabsorption in the kidney, this occurs across all segments of the tubule, yet in AHF we only target the reabsorption in the loop of Henle.5 Acetazolamide stimulates alkaline diuresis through bicarbonate excretion with sodium and potassium by inhibiting carbonic anhydrase in the proximal tubule.2, 6 In heart failure, up to 80% of sodium is reabsorbed in the proximal tubule, and this occurs before loop diuretics even have a chance to exert their action.6 Based on this, a drug inhibiting sodium reabsorption in the proximal tubule is likely to improve natriuresis by a direct effect proximally and by improving the efficacy of loop diuretics in the loop of Henle. Prior to the findings of the study by Verbrugge et al., several small studies already found an effect of add-on acetazolamide therapy to loop diuretics on natriuresis. The current study confirms that add-on therapy with acetazolamide significantly improves loop diuretic efficiency. Interestingly, sodium–glucose co-transporter 2 (SGLT2) inhibitors have also been suggested to improve natriuresis by inhibiting proximal sodium absorption.6 Studies investigating the effect of add-on SGLT2 inhibitors to loop diuretics in AHF patients are currently ongoing. Second, the authors intentionally enrolled patients at high risk of diuretic resistance. An impaired response to diuretics is common in patients with AHF, and strongly associated with poor outcomes.2 Predictors of a poor response to diuretics are for instance poorer renal function, higher blood urea nitrogen, and lower plasma sodium levels.7 Exactly these characteristics have been selected by the authors to identify patients at an increased risk of a poor diuretic response in which addition of acetazolamide is more likely to have an additional effect. Furthermore, the primary endpoint in this study was natriuresis. From a pathophysiological perspective assessing natriuresis to determine the effectiveness of diuretics in the setting of AHF seems very logical, however until recently studies using natriuresis in AHF were scarce. Hodson et al.8 showed that poor natriuresis, even in the setting of a negative fluid balance, was associated with poor outcomes, suggesting that natriuresis is a more sensitive marker of decongestion than fluid loss. Additionally, even though urine collections are considered cumbersome, assessment of natriuresis might be more reliable and objective than net fluid loss or weight change. Possibly in the future assessment of natriuresis could be performed using spot urine samples, as one study has already shown fairly accurate prediction of 6 h natriuretic response to diuretics using spot urine samples collected 1 and 2 h after administration of diuretics.9 In the recent position statement on diuretics of the Heart Failure Association of the European Society of Cardiology, assessment of natriuresis in spot urine samples is recommended 2 h after the first administration of loop diuretics, based on which adjustment of diuretic doses should be considered.6 Finally, in the study by Verbrugge et al.,4 assessment of clinical congestion was performed by the same investigator and increases in diuretic doses in both groups were standardized based on the persistent presence of congestion and poor urine output. Despite this, only 30% of patients were considered euvolaemic after 72 h. These rates are slightly better than the number observed in the DOSE trial (11–18%), however still remain poor.10 This once again underscores the importance of additional studies assessing novel treatment strategies in AHF patients to improve decongestion. At the moment a large, multicentre, randomized controlled trial assessing the effect of acetazolamide in acute decompensated heart failure with volume overload on decongestion (ADVOR) is ongoing.11 In contrast to the paper published in this issue of the Journal, the ADVOR trial enrols all-comer AHF patients, and the primary endpoint is euvolaemia at day 4 as assessed by a clinical congestion score by local investigators. Despite these possible shortcomings, the results of this trial are eagerly awaited. An updated approach to the design of AHF trials concerning the points raised, i.e. the drugs studied, patients enrolled, study design, and endpoints, will hopefully lead to alternative roads down the door from loop diuretics (Figure 1). Acetazolamide could very well become an important additional player in the treatment of (diuretic resistant) AHF patients in the coming years. Until we are better able to adequately treat these patients and improve outcomes, the search for novel therapies in AHF goes ever on and on. Conflict of interest: none declared.