This randomized, placebo-controlled clinical trial evaluated the effect of adding HCTZ to usual treatment in patients with ADHF. We have demonstrated that the mean daily weight loss, for the first three days of admission, were 0,6 Kg/day higher than in placebo group. For each 40 mg of intravenous furosemide used in the treatment of ADHF, HCTZ provided a statistically significant additional effect of 0.4 kg/day. Diuretic response at the beginning of ADHF therapy has been associated, with less symptoms, better quality of life (15), less signs of congestion (16), less admissions (8), and with reduced mortality (18). Our study has found a better diuretic response on the first days of therapy by adding HCTZ 50 mg per day to the usual care of patients with ADHF. When our data, based on the effect of adding HCTZ on weight change for each 40 mg of furosemide, is compared to data of a larger study investigating prognosis of diuretic response, regardless of HCTZ use or not, we have found that our data perfectly match with Valente’s data (18). We, therefore, could possibly raise the hypothesis that having a better diuretic response at the early phase of therapy, by adding HCTZ, could possibly positively impact on patients’ prognosis (Fig. 6).
Figure 6: Effect of adding Hydrochlorothiazide (in our trial) plotted over Valente et al. data estimation of mortality based on diuretic response.
Adapted from Valente MAE et al. (18), which suggested lower mortality with greater diuretic response.
Other diuretics have been investigated in the setting of ADHF. Initial data were encouraging for the use of spironolactone in a diuretic dose, suggesting that it could translate into less signs of congestion and lower levels of natriuretic peptides (19). Moreover, spironolactone was found to be a predictor of diuretic response (18). The ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) trial was then conducted to assess spironolactone 100 mg added to usual treatment of ADHF, and previous findings were not confirmed. There was no reduction in natriuretic peptides nor was there any additional weight loss when compared to placebo (20).
The use of loop diuretics for the management of ADHF is well established. In the DOSE study, a comparison between high and low diuretic doses showed no differences in the primary outcomes of renal function and symptoms nor in weight loss, which was a secondary outcome in the study. However, a post hoc analysis demonstrated a greater use of thiazide diuretics in patients in the low-dose furosemide group, with a trend towards statistical significance (15). Such finding might be an explanation for neutrality in that study and adds another element to confirm the findings of our study.
Our study has some limitations. It was a single-center study with a relatively small number of patients. Significance was not reached because the standard deviation was larger than predicted in sample size calculation, based on a previous study (17). Although the primary outcome reached borderline significance, a post hoc analysis adjusted to the dose of intravenous furosemide showed a statistically significant result, which is consistent with the hypothesis of synergy when adding HCTZ to furosemide, with a clinically relevant effect on daily weight loss.
Regarding safety outcomes, there was a greater change in creatinine levels in patients using HCTZ. However, there was no difference between the groups when analyzing onset of acute renal failure, defined as an increase in creatinine > 0.3 mg/dL. According to previous studies, increased creatinine is not related to poor prognosis when patients have reduced congestion (18, 21), which occurred more consistently in patients using HCTZ. In terms of quality of life during the process of compensation in ADHF, there was no difference in thirst between the groups. In a previous study of patients with ADHF, thirst was exacerbated during a non-pharmacologic intervention targeting decongestion (22).
Other congestion-related data did not differ between the groups; however, congestion is difficult to assess. The development of new technologies for assessing congestion will contribute to the definition of outcomes in future studies. Moreover, there was neither quantification of diuresis nor assessment of fractional excretion of sodium, which are difficult to measure in an emergency room setting, where the study was conducted. Our HCTZ study was designed to assess weight reduction, with no power for hard outcomes. However, the result could be interpreted as a promising one for ADHF patients.