Diuretic Therapy in Acute Decompensated Heart Failure
Fluid overload is a major pathophysiological mechanism underlying both acute decompensation episodes of HF and the progress of the syndrome. Loop diuretics remain a cornerstone in the pharmacological treatment of ADHF and are administered in about 90 % of patients hospitalised for HF.1 These drugs are routinely used as initial therapy in ADHF due to their ability to greatly improve the symptoms. Conversely, because of their lower natriuretic effect, thiazide diuretics are used infrequently and are limited to cases where there is diuretic resistance. The same is true for potassium-sparing diuretics, which are only used in cases of refractory oedema or concomitant hypokalaemia.
One of the major concerns of clinicians is the effect of excessive diuretic therapy on the intra-arterial volume and, consequently, on the possible deleterious effects on renal function. Several studies have, indeed, demonstrated that there is a correlation between doses of diuretics and the worsening of the prognosis in patients with acute decompensated HF.35 However, no definite causal relationship has been established between diuretic therapy, its dosage, and cardiovascular mortality. It is, indeed, virtually impossible to distinguish between the multiple confounding factors, because sicker patients present often with greater congestion and therefore receive higher doses of diuretics. The pathophysiological basis of many of these concerns is that these drugs, which cause intravascular volume depletion, could increase the hyperactivation of the neuroendocrine system with resulting detrimental consequences.36,37
Nowadays, despite many studies in ADHF on diuretic therapy, the only certainty is that such therapies can relieve the patient’s symptoms and reduce vascular congestion. It remains unclear what the preferred loop diuretic should be, what should be the appropriate combination, what is the optimal dosage and what should be the clinical goal. Current guidelines from the American College of Cardiology and the American Heart Association suggest that ‘Diuretics should be administered at doses sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume.’38
Although in the majority of patients congestion symptoms are controlled by loop diuretic therapy, in a minority of cases other adjunctive therapies are needed. This is because of the progression of the disease or the worsening of the renal function.
Other solutions have been tested in addition to the aforementioned combination therapy (sequential nephron blockade). Some trials demonstrated the positive effects of incorporating hypertonic saline solution (HSS) with standard loop diuretic therapy.39 In a large study of 1,771 patients, the SMAC-HF study, in-hospital HSS administration, combined with moderate sodium restriction, reduces hospitalisation time and increased diuresis. However, a long-term follow-up found that moderate salt restriction was associated with a better prognosis than a low sodium diet.40 The potential benefits of this therapy are the faster recovery of intra-arterial volume. This reduces the neuro-endocrine stimulation and improves glomerular perfusion, thus counteracting the common mechanisms that underlie fluid overload in various clinical scenarios.36 Regardless, this was an unblinded study and use of HSS is not recommended in current guidelines. Larger prospective and blinded studies need to be undertaken before this approach can be recommended for clinical use.
HF with concomitant severe hyponatraemia is of particular clinical relevance, due to its particular prognostic and therapeutic implications.41 Such patients may benefit from treatment with arginin vasopressin antagonist (vaptans). This class of drugs can be useful in several cases of resistance to diuretics because of their specific action mechanisms.42 Despite this and other anecdotal reports, after the results of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial (Everest), tolvaptan is today approved by the US Food and Drug Administration only for the treatment of clinically significant hypervolaemic and euvolaemic hyponatraemia (serum sodium less than 125 meq/lL). This includes patients with HF and the syndrome of inappropriate antidiuretic hormone secretion.
Indeed in the EVEREST trial, an international, multicentre, randomised, double-blind, placebo-controlled trial in a population of hospitalised chronic HF patients, there was no difference in the global clinical status of the two groups, although the tolvaptan group had significantly decreased dyspnoea on day 1, and decreased weight and oedema after 7 days. It is noteworthy that patients in the tolvaptan group had significantly decreased loop diuretic use compared with the placebo group. Despite these initial results, the long-term primary outcome trial showed no significant difference in overall mortality.43 In the future It would be interesting to design a specific clinical trial on use of vaptans in patients who developed diuretic resistance.
Another option to be used in most complex patients is the use of diuretics in association with ultrafiltration (UF) therapy. UF moves water and small to medium weight solutes across a semi-permeable membrane to reduce volume overload.
The first interesting, but controversial, data comes from the Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated HF (UNLOAD) trial. In this study treatment with UF resulted in significantly fewer hospital readmissions due to HF during a 90-day follow-up.44 Unfortunately, the study was harshly criticised because of the low doses of diuretics used and the consequent reduced clinical reproducibility. In the recent Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), a study designed to compare the effect of UF with that of stepped pharmacological therapy on renal function and weight loss in patients with HF who have worsening renal function and persistent congestion, UF patients in the UF group had a significantly greater increase in serum creatinine and more adverse events, including bleeding and vascular complications, as well as progressive renal dysfunction. Moreover, there was no significant difference in the outcome, including mortality and rehospitalisation, at 60 days.45 However the latest American guidelines suggest that UF may be considered for use after all diuretic strategies have failed.38 Further studies will be needed to assess what should be the exact role of UF in the management of patients with ADHF.