Heart failure is a highly debilitating disorder that is widespread in industrialized countries. Two new drugs have demonstrated their superior efficacy compared to current treatments, with their entry into therapy in Europe and the USA, new horizons are opened for the treatment of heart failure
Both the US and European protocols for the treatment of heart failure have been updated with the introduction of two new drug therapies. The first is the one with Entresto®, a drug developed by Novartis, consisting of a combination of two active ingredients: sacubitril is valsartan.
The other treatment is the one with ivabradine a drug derived from the well-known verapamil already in use in Europe since 2012 and approved by the US Food and Drug Administration (FDA) in 2015.
Heart failure, also known as congestive heart failure, is unfortunately a common pathology: the prevalence of heart failure is estimated at around 1-2% of the adult population in developed countries, with peaks of 10% among the over 70s and mortality, at a year from diagnosis, of 17% among hospitalized patients with unstable heart failure and 7% among outpatients with stable disease. It is the leading discharge diagnosis of patients over 65 in the US with an annual cost of $ 18 billion.
Often this is caused by coronary artery disease, heart attack (heart attack), or high blood pressure, and usually gets worse over time. Although currently available treatments have improved the prognosis for people with heart failure, the disease remains dangerous and impairs the patient's ability to enjoy an active life.
Current therapy for heart failure involves the use of drugs such as enalapril (an ACE inhibitor) or digoxin (a drug belonging to the digitalis class).
Recent studies have demonstrated the therapeutic superiority of new drugs over standard therapy, however the most common side effects reported with Entresto® were hypotension, hyperkalaemia (high concentrations of potassium in the blood) and kidney damage. Therefore, EMA's Committee for Medicinal Products for Human Use (CHMP) recommends that treatment should not be initiated in patients with low blood pressure or high blood potassium levels. A follow-up plan has been agreed to monitor the safety of Entresto®.
Certainly the studies carried out so far encourage the use of these new drugs in therapy, but before explaining the functioning of sacubitril / valsartan and ivabradine we will describe the pathogenetic mechanism of heart failure.
Heart failure, or congestive heart failure, occurs when the heart is unable to pump enough blood to meet the metabolic demands of the tissues. The pathology develops when the contractile force of the myocardium, the heart muscle, loses its capacity.
When cardiac function is impaired, various physiological mechanisms maintain blood pressure and vital organ perfusion. The activation of the neurohumoral systems, in particular the release of noradrenaline by the cardiac adrenergic nerves, the activation of the renin-angiotensin-aldosterone system and the release of atrial natriuretic peptide, act by regulating the filling volumes and pressures in the peripheral organs. However, the release of noradrenaline causes increased blood pressure and tachycardia, subjecting the left ventricle to a large number of contractions, with the risk of fatigue following dilation. Since the organism is not able to distinguish between a deficient hemodynamic state due to heart failure from that which arises due to haemorrhage, the feedback control mechanisms that are activated to correct the reduced cardiac function are counter-regulators, i.e. they make the situation worse instead of improving it.
Poor peripheral blood flow causes water retention in the kidney, which can lead to edema (fluid accumulation).
Finally, the molecular and cellular changes in the heart that occur in response to heart damage are called cardiac remodeling. In particular, in the initial stages, these modifications represent adaptive phenomena, but can subsequently evolve into alterations of the structure. Heart failure is usually preceded by hypertrophy (enlarged heart); in some patients suffering from decompensation, the hypertrophic heart can increase its weight up to four times.
Cardiac hypertrophy is associated with increased metabolic demands due to increases in wall tension, heart rate and contractility, which increase cardiac oxygen consumption.
Unlike pathological hypertrophy, physiological hypertrophy produced by regular exercise has different effects on the heart that depend on the type of effort. Aerobic exercise (long-distance running), for example, is associated with volume load hypertrophy, accompanied by the increase in the density of the capillaries that vascularize the myocardium providing more oxygen and by the reduction of the resting heart rate and blood pressure, all positive effects. Static exercise (eg weight lifting) is instead associated with pressure load hypertrophy and is more likely correlated with harmful alterations.
Mechanism of action of sacubitril, valsartan and ivabradine
The efficacy of the sacubitril / valsartan combination, compared with enalapril, was evaluated in a randomized controlled study of over 8,000 adults with heart failure. The study was stopped early when it was found that the drug significantly reduced the number of hospitalizations for heart failure and the risk of death compared to patients treated with the ACE inhibitor enalapril.
The drug valsartan belongs to a class of drugs already available in therapy for several years called sartans, used against arterial hypertension. These compounds act in the body blocking the AT receptor1 of angiotensin II. Angiotensin II is a peptide hormone that causes vasoconstriction and retention of sodium and fluids in the kidney, essential defense mechanisms in case of bleeding, but harmful to the heart when activated in a pathological situation of heart failure. The pharmacological blockade of the AT receptor1 it allows the reduction of work on the decompensated heart by stimulating its recovery capacity.
Sacubitril instead blocks the cleavage and degradation of the atrial natriuretic peptide, a hormone that counteracts the negative effects caused by heart failure on the heart.
The atrial natriuretic peptide is released by specialized cells located in the atria of the heart, sensitive to the distension of the atrial walls following hypervolemia (high blood pressure). The release of the atrial natriuretic peptide counteracts the effects of the renin-angiotensin-aldosterone system, favoring the expulsion with the urine of sodium and liquids that cause hypertension and cardiac overload; at the vascular level it causes vasodilation which contributes to the lowering of blood pressure. The natriuretic peptide is degraded and inactivated by an enzyme called neprilyysin (NEP). Sacubitril is the progenitor of a new generation of drugs called NEP-inhibitors, which, by increasing the survival of the atrial natriuretic peptide, improve the living conditions of people suffering from heart failure.
Ivabradine (Procoralan®) is an active ingredient, derivative of verapamil, used in cardiology in stable angina, and also approved for the treatment of heart failure. Ivabradine works by regulating the heart rate through selective inhibition of pacemaker current If in the sinoatrial node, without affecting myocardial contractility, ventricular repolarization or intracardiac conduction. This mechanism is different from the effect of other drugs such as beta blockers or calcium channel blockers, used for the treatment of arterial hypertension, which cause a negative ionotropic effect and bronchial vasoconstriction (beta blockers) and blockade of cardiac calcium channels and smooth muscle, causing a negative ionotropic effect on the heart, intestinal constipation and hypotension (calcium channel blockers).
Ivabradine-induced reduction in heart rate has been demonstrated in numerous studies, and this effect is beneficial in heart failure.
These new drugs have demonstrated their therapeutic superiority over the old therapies for heart failure with ACE inhibitors and digitalis, reducing hospitalizations and improving the patient's quality of life. The results obtained from clinical trials have encouraged the regulatory bodies to market these new drugs, updating the guidelines for the therapy of heart failure, however, being new drugs, widespread use and constant monitoring are necessary to evaluate and know a background the safety profile of these drugs and the side effects.
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