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Novel Therapies in Acute Heart Failure

List of key references prepared and regularly updated by the Heart Failure association (HFA)



Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study.

Teerlink JR, Metra M, Felker GM, Ponikowski P, Voors AA, Weatherley BD, Marmor A, Katz A, Grzybowski J, Unemori E, Teichman SL, Cotter G.
Lancet

2009;373(9673):1429-39.

Synopsis:

The study was carried out in 234 patients with acute heart failure, dyspnoea, congestion on chest radiograph, and increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure >125 mm Hg who were randomized to 48-hour intravenous infusion of relaxin (at dose of 0, 10, 30 and 100 g/kg).  Therapy with relaxin resulted in an alleviation of dyspnoea, a reduction of hospital stay and a reduced rate of cardiovascular death or readmission due to heart or renal failure at further follow-up.  The relaxin dose of 30 g/kg was the most effective regarding the aforementioned favourable effects.

Commentary:

Relaxin is a human peptide hormone that through specific receptors affects multiple vascular control pathways and has also anti-remodeling properties, demonstrated so far in experimental models.  The study Pre-RELAX-AHF, a randomised phase II trial, targeted patients with acute heart failure with normal or increased blood pressure that were treated with a new vasodilator, relaxin.  Taking into consideration the fact that most previously published trials with novel therapies applied in acute heart failure have failed to prove efficacy, the present study is of a particular importance.  The applied acute therapy with relaxin could improve congestive symptoms and relief dyspnoea as well as had positive effect on postdischarge outcomes and 180-day cardiovascular mortality.

Low-dose nitroglycerin improves microcirculation in hospitalized patients with acute heart failure.

den Uil CA, Lagrand WK, Spronk PE, van der Ent M, Jewbali LS, Brugts JJ, Ince C, Simoons ML.
Eur J Heart Fail 2009;11(4):386-90

Synopsis:
Impaired tissue perfusion is a common pathophysiological feature of patients with acute heart failure.  Perfused capillary density can be assessed within sublingual microvascular perfusion as Using Sidestream Dark Field (SDF).  In 20 patients admitted due to acute heart failure, low-dose intravenous nitroglycerin (33 g/min) decreased central venous pressure and pulmonary capillary wedge pressure, but additionally improved perfused capillary density.  This effect was not observed in 30% of examined patients.

Commentary:
Vasodilators play a crucial role in the treatment of patients with acute heart failure.  The mechanisms of their beneficial effects on haemodynamics and circulation are not completely understood.  This study provides evidence that low-dose nitroglycerin can also improve the perfusion within microcirculation, an element that is severely deranged during decompensation.

Low-dose nitroglycerin improves microcirculation in hospitalized patients with acute heart failure.

den Uil CA, Lagrand WK, Spronk PE, van der Ent M, Jewbali LS, Brugts JJ, Ince C, Simoons ML.
Eur J Heart Fail 2009 Apr;11(4):386-90

Synopsis:
The authors investigated the effect of low-dose nitroglycerine infusion in patients with acute heart failure (AHF) on capillary perfusion.  They used a novel technique, i.e. Sidestream Dark Field imaging device to obtain two dimensional video images of sublingual microcirculatory blood flow.  Emitted green light is absorbed by red blood cells within microvessels, and red blood cells are used as the contrast agent to visualize sublingual blood flow in patent microvessels.  Low-dose intravenous nitroglycerine infusion was shown to significantly improve microcirculatory perfusion beyond the reduction in cardiac filling pressure in patients admitted due to AHF.

Commentary:
The treatment of acute heart failure (AHF) remains a clinical challenge, but vasodilators (such as nitroglycerine) are recommended in patients with AHF without symptomatic hypotension, due to its haemodynamic effects related to venodilatation, lowering cardiac filling pressures, increasing the pressure gradient for myocardial perfusion, and decreasing myocardial oxygen demand.  This is the first, however preliminary, study demonstrating that an impaired microcirculation can be improved by low-dose intravenous nitroglycerine infusion.  One of the unanswered issue is resistance to nitroglycerine observed in a subset of patients with AHF.

Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study.

Teerlink JR, FESC, Metra M, FESC, Felker GM, Ponikowski P, FESC, Voors AA, Weatherley BD, Marmor A, Katz A, FESC, Grzybowski J, FESC, Unemori E, Teichman SL, FESC, Cotter G.
Lancet. 2009 Apr 25;373(9673):1429-39.

Synopsis:
This initial pilot study (a randomized placebo-controlled parallel-group trial) demonstrates that a 48-hour intravenous infusion of relaxin added in an early phase to standard treatment in patients hospitalized for acute heart failure with dyspnoea at rest or with minimal exertion, pulmonary congestion, mild-to-moderate renal insufficiency, and normal-to-increased blood pressure is safe, significantly diminishes dyspnoea and some clinical outcomes.  The trend towards a reduction in risk of cardiovascular death or readmission due to heart failure or renal failure over a 60-day follow-up period has also been noted.

Commentary:
Relaxin is a natural human peptide hormone that is responsible for haemodynamic and renovascular adaptive changes that occur during pregnancy.  Its effects, including the enhanced nitric oxide production and the inhibition of entothelin-1 and angiotensin II effects, that result in systemic and renal vasodilatation together with increased arterial compliance, may be particularly beneficial in patients hospitalized for acute decompensated heart failure with high arterial blood pressure and increase vascular systemic resistance.  Relaxin, a novel promising therapeutic approach for acute heart failure, is being tested in RELAX-AHF study.  The preliminary results regarding its safety and efficacy are very promising.