Abstract
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.
Discussion
In this multicenter, randomized, placebo-controlled trial involving patients with acute decompensated heart failure and volume overload, the addition of acetazolamide to standardized intravenous loop-diuretic therapy was associated with a higher incidence of successful decongestion within 3 days after randomization. Patients who had been treated with acetazolamide had more diuresis and natriuresis, had a shorter hospital stay, and were more likely to be discharged without residual signs of volume overload than those who had received placebo. There did not appear to be a higher incidence of adverse events with acetazolamide treatment.
Our trial involving patients with acute decompensated heart failure showed that acetazolamide, a diuretic agent blocking proximal tubular sodium reabsorption, added to loop-diuretic therapy led to more and faster decongestion and was associated with a shorter duration of hospital stay. The benefit with acetazolamide treatment with regard to decongestion was maintained at discharge, with a higher percentage of patients being discharged from the hospital without residual congestion (difference vs. placebo, 16.3 percentage points). The attainment of successful decongestion (euvolemia) has a class I recommendation from the European and American guidelines for the diagnosis and treatment of heart failure.1,14 According to clinical trial and registry data, only a minority of patients with acute decompensated heart failure have decongestion at the end of the study period or are discharged without residual congestion.4,5,12,13,15-19 Given that residual congestion is linked to adverse outcomes, the beneficial effects of acetazolamide therapy are important. The higher incidences of decongestion with acetazolamide treatment than with placebo were most probably related to the early and sustained increase in diuresis and natriuresis that were associated with the addition of acetazolamide. These findings highlight the importance of targeting congestion both early and aggressively and support the use of natriuresis as an indicator of diuretic response.1,6,20
The improvement with regard to successful decongestion with acetazolamide was generally consistent across all the prespecified subgroups, except for one comparison suggesting possible heterogeneity, which showed less treatment benefit among patients receiving a higher oral maintenance dose of loop-diuretic therapy. Other subgroups that were defined to reflect more congestion or more diuretic resistance (e.g., a higher congestion score, lower estimated GFR, or higher NT-proBNP level) did not show any heterogeneity in treatment effect.
The addition of acetazolamide to loop-diuretic therapy was not associated with an increased incidence of adverse events, and the higher incidence of successful decongestion was associated with a shorter duration of hospital stay. However, the risk of death from any cause or rehospitalization for heart failure (secondary composite end point) did not differ significantly between the two trial groups. In our trial, the risk of death or rehospitalization was considerably lower than that in the DOSE trial (50% at 60 days) and in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF; 40% at 60 days).4,12 The higher incidence of decongestion at discharge and the increase in the dose of neurohumoral blockers during the remainder of the hospital stay in our trial may account for the better outcomes, despite the fact that our trial patients had many coexisting conditions and advanced age. It was reassuring that acetazolamide treatment was not associated with higher incidences of hypokalemia, hypotension, or renal end points. To elucidate the complex relations among degree of decongestion, quality of life, and outcomes in patients with acute decompensated heart failure, more trials of diuretic agents with larger sample sizes are needed.
Our trial has certain limitations. Nearly all the patients who participated in the trial were White, given that the trial recruited exclusively in Belgium, which may limit the generalizability of our results to other racial or ethnic groups. Second, patients also had a history of chronic heart failure and had been receiving long-term outpatient treatment with at least 40 mg of furosemide equivalent. Therefore, results of the strategy we tested may not be applicable to patients with newly diagnosed heart failure. Third, patients in the two trial groups received similar standardized loop diuretics. It is unknown whether similar results may have been obtained with other dose regimens of loop diuretics or other diuretic agents. Fourth, the congestion score that was used for the assessment of the primary end point focused on the presence of edema in the lower limb, pleural effusion, and ascites — findings that are reflective of an assessment of mainly extracellular volume overload. Finally, during most of the trial period, SGLT2 inhibitors were not indicated and had not been approved as drugs to treat heart failure. To avoid confounding by any imbalance in their use between the trial groups, the trial design excluded their use. Although SGLT2 inhibitors and acetazolamide both exert natriuretic and diuretic effects on the proximal tubules, their mode of action and potency differ substantially.6 Only 5% of proximal sodium uptake is mediated by SGLT2, whereas 60% is mediated by the apical sodium–hydrogen exchange that is inhibited by acetazolamide.21-24
In this placebo-controlled trial, we found that the addition of acetazolamide to standardized intravenous loop-diuretic therapy in patients with acute decompensated heart failure led to a higher incidence of successful decongestion.
SOURCE: NEJM
ARYAN'S BLOG 