Valente MA, Voors AA, Damman K, et al.
Eur Heart J. 2014 Feb 28. [Epub ahead of print]

Background

Loop diuretics are central to therapy of acute heart failure (AHF), although conflicting data have been published about possible worse outcomes being associated with higher doses [1-4]. It remains unclear whether diuretics cause poor outcomes, or whether this reflects disease severity [5,6].
A frequently mentioned complication of diuretic therapy in AHF is diuretic resistance, which is associated with worsening renal function and cardiorenal syndromes [7]. Few studies have explicitly examined the importance of effective decongestion upon diuretic administration in the context of AHF.
HF guidelines recommend monitoring volume status on the basis of weight loss [8], although some limitations of examining body weight alone are evident, including that diuretic dose did not predict weight loss [1,9]. Considering the non-linear dose-response relationship and the diuretic resistance commonly seen in HF, this may be expected [10].
This study aimed to define a simple, continuous, quantitative and therefore clinically applicable measure for diuretic response, by combining decongestive effect and diuretic dose, and to characterise the unresponsive patient and to determine the prognostic significance of diuretic response. Data of 1745 patients enrolled in the PROTECT trial were used to this end [11,12].

Main results

• Mean weight change on day 4 was -2.8 + 3.0 kg. The median diuretic dose through day 3 was 240 mg (95%CI: 140-400), and 97% of patients received furosemide. The median diuretic response was -0.38 (95%CI: -0.80 to -0.13) kg/40 mg furosemide.
• Low systolic blood pressure, low serum potassium, high blood urea nitrogen (BUN), diabetes, and atherosclerotic disease were associated with poor diuretic response, while rolofylline treatment independently predicted good diuretic response (-0.39 (95%CI: -0.82 to 0.14), vs. -0.38 (95%CI: -0.75 to 0.133) kg/40mg furosemide in patients on placebo, P=0.018), an effect driven by greater weight loss for rolofylline vs. placebo.
• When analysing quintiles, patients with a poor diuretic response had worse outcomes on all endpoints. In Cox proportional hazards models, worse diuretic response remained independently associated with a poor outcomes (including 180-day mortality and 60-day rehospitalisation) after multivariable adjustment.
• When the effect of change in diuretic response between day 2 and day 4 was considered, no difference was seen with regard to 180-day mortality or the 60-day endpoints, between patients with stable vs. improving diuretic response. Patients who were reclassified to a worse diuretic response quintile were more likely to meet all endpoints. In multivariable correction, this only remained statistically significant for the 60-day death or rehospitalisation outcomes.
• In univariable models, diuretic response showed a greater effect size per SD than its individual components weight change and diuretic dose alone.
  In multivariable 180-day mortality models, inclusion of diuretic response showed similar performance as compared to its components, with a trend favouring diuretic response. A similar favourable trend was seen for diuretic response vs the components with respect to 60-day death or renal or CV rehospitalisation.
  With regard to 60-day HF rehospitalisation, diuretic response performed better than its components, both in the full population and in patients with manifest congestion.

Conclusion

A novel measure for diuretic response in acute HF was presented, combining weight loss with diuretic use, with at least equivalent prognostic information as compared with its components separately. Poor diuretic response was associated with more advanced HF, renal impairment, diabetes, atherosclerotic disease and in-hospital worsening HF, and it independently predicts HF rehospitalisation and mortality.
The authors feel that the simple measure of weight change per unit of diuretic provides better insight into patient response to therapy than examining weight loss or diuretic dose independently. After further investigation and validation, diuretic response could be used in clinical research settings to help identify patients who might benefit from alternative or adjuvant decongestive therapies.

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