Down the road from challenges in acute heart failure trials
Authors: Jozine M. ter Maaten, Kevin Damman
Journal: European Journal of Heart Failure (2019)

‘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.