1/ ALOFT: a new heart failure medication in chronic heart failure?
Direct renin inhibitors (DRIs) have been recently developed in the treatment of hypertension. The potential benefit of these new compounds is to block the renin angiotensin aldosterone cascade upstream at the level of angiotensinogen production and therefore to inhibit the synthesis of all the downstream components of this key neuro humoral system, such as angiotensin II and aldosterone.
An interesting pilot study, ALOFT, evaluated the effects of a direct renin inhibitor, Aliskiren, in patients with chronic heart failure over 12 weeks. Most of them (80 %) had a low ejection fraction. The primary objective was safety(hypotension/hyperkalemia/renal dysfunction) but efficacy measures included quality of life and Doppler echocardiography parameters in a group of 302 patients randomised either to Aliskiren 150 mg/day or to placebo. The main results were that :
- the drug was safe and, in particular did not induce a significantly greater number of adverse events such as hyperkalemia or renal dysfunction than placebo despite the fact that it was on top of ACE inhibitors and beta blockers.
the neurohormonal changes induced by Aliskiren were favourable and included a fall in plasma natriuretic peptides, plasma renin activity and aldosterone excretion.
There was no significant change in the pre-specified echocardiographic parameters or in symptoms but the study was short term and included a limited number of patients so that it was not powered to detect such changes.
These interesting results should lead to a discussion regarding the development of this new compound in chronic heart failure.
However, several questions need to be addressed: should DRIs be developed on top of ACE inhibitors as in ALOFT, although several heart failure medications are already available(ARBs and Aldosterone antagonists)? Should they rather be developed as an alternative to ACE inhibition? Finally should DRIs be rather used in heart failure with depressed systolic function or in heart failure with preserved ejection fraction?
In any case, the introduction of DRIs in the medical management of heart failure might lead to a revision of existing strategies for the management of chronic heart failure.
2/ 3 CPO: a trial of non invasive ventilation in acute pulmonary oedema.
Non invasive ventilation assistance procedures are commonly used in emergency situations such as pulmonary oedema to improve acidosis, and breathlessness but little is known on the prognostic impact of these procedures.
A British study named 3 CPO assessed the efficacy of two non invasive procedures, continuous positive airway pressure ventilation (CPAP) and non invasive intermittent positive pressure ventilation (NIPPV) compared to standard care in 1156 patients with cardiogenic acute pulmonary oedema. The hypothesis was that these procedures improved outcome of patients as compared to standard therapy.
However, there was no difference in 7 day or 30 day mortality or in hospital stay as compared to standard care and the only benefit observed was a more rapid resolution of metabolic abnormalities and a mild decrease in respiratory distress. These results therefore suggest that the use of non invasive ventilation methods in acute situations is beneficial only on symptoms but does not translate into improved outcome.
3/ New Aquaretic agents: update on the EVEREST trial.
An update on the results of the large outcome trial EVEREST comparing the Arginine Vasopressin Antagonist Tolvaptan to placebo in 4133 patients was presented. This new class of agents blocks the V2 receptor of AVP and therefore might be beneficial on fluid retention and increase serum Na+ without worsening renal function.
In EVEREST, 30mg of Tolvaptan daily were compared to placebo in patients with heart failure and low ejection fraction and with evidence of fluid retention. The short term benefit was an additional but moderate weight loss and dyspnoea improvement in the group under active treatment but there was no benefit on patient global clinical status. Moreover, there was no benefit on long term outcome including all cause mortality and cardiovascular mortality or heart failure hospitalizations. Patients with hyponatremia had a significant increase in serum Sodium. Safety was acceptable overall.
These rather disappointing results raise several issues with respect to the potential indications of this new aquaretic agent: should it be further developed in heart failure at large or should it be abandonned given the limited symptomatic improvement observed in EVEREST? Should it be developed only in patients with heart failure and hyponatremia?
EVEREST is another among many trials which fails to show substantial benefit in patients hospitalised for decompensated heart failure. Obviously, we have not made as much progress in acute heart failure as we did in chronic heart failure in this area and we desperately need new drugs in order to better control these unstable and critically ill patients.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.