Compare Sacubitril in the treatment of heart failureHeart

Compare and contrast the efficacy of Omapatrilat and Sacubitril in the treatment of heart failureHeart failure occurs when there is a decrease in cardiac output. Due to this, the body releases more noradrenaline and adrenaline as a response to compact this change. Thereby, the heart beats more rapidly and gets bigger. These changes can cause and lead to other complications associated with heart failure such as hypertension , arrhythmias, aneurysms and so forth. Stages of heart failure is popularity identified using the New York Association Heart Failure Scale which defines the symptoms of heat failure in classes as shown in the table below:Looking at the renin-angiotensin-aldosterone-system(RAAS) is used as an indicator of conceding heart failure. The RAAS helps in regulation of cardiac function and blood pressure.

Angiotensinogen is broken down by the enzyme renin to produce angiotensin I. The release of renin is due to a response to decrease in blood pressure. Angiotensin I is converted into angiotensin II by an angiotensin-converting-enzyme(ACE). Angiotensin II is a known to be a potent vasoconstrictor. 2High levels of angiotensin II leads to increased levels of aldosterone and a higher affinity for water retention and uptake of sodium.This also affects the sympathetic nervous system.

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In heart failure when blood pressure decreases, there is an increase in the volume of blood produced. This causes more strain on the heart leading to enlargement of the heart and for the heart muscles to be misshapen 2and bagging, giving it a lower ability to pump blood.Omapatrilat an inhibitor of neutral endopeptidase (NEP) and ACE. ACE inhibitors work by stopping the conversion of angiotensin I to angiotensin II. There will be less angiotensin II to bind to AT1 receptors on the smooth muscle, which are coupled to a Gq protein and the IP3 signal transduction pathway.3due to this blood vessels dilate more and blood pressure also decreases. The sympathetic nervous system is affected as norepinephrine release 3is decreased.

More blood can then be pumped to the heart. Bradykinin, a vasodilator, which is usually broken down by ACE is no longer inhibited so further vasodilation of blood vessels occur. The NEP inhibitor increases the availability of natriuretic peptides-consisting of atrial, brain and C-type. ANP and BNP bind to NPR-A receptors to lead to higher concentrations of cyclic guanosine monophosphate.4 This causes vasodilation and induces natriuresis.Two main clinical trials are looked at for the effectiveness of Omapatrilat. The OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) study in contrast received a subdued reception, very little publicity and is yet to be published. 5770 NYHA class II-IV heart failure patients (LVEF

The primary end-point of all cause mortality or heart failure related hospitalisation did not differ significantly: 914/2884 for Enalapril and 914/2886 for Omapatrilat (hazard ratio 0.94, CI’s 0.86-1.03, P=0.187). Mortality was also similar: 509 for Enalapril and 477 for Omapatrilat (hazard ratio 0.

94, CI’s 0.83-1.07, P=0.339). 5The OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) study was also presented at this time. 25,267 hypertensives were randomised to Omapatrilat or enalapril and a difference of approximately 3 mmHg in favour of Omapatrilat was seen.

5 The main side effects that were found using Omapatrilat was angioodeoma. The worrying trend was however, that angioedema was more common with Omapatrilat; 24 (0.8%) versus 14 cases (0.

5%). 5 Also, it is thought that the increased levels of bradykinin due to ACE inhibition leads to dry cough in patients.Sacubitril has the active metabolite LBQ657 which inhibits Neprilysin. Neprilysin is an endopeptidase which causes the breakdown of peptides that vasodilate and vasoconstrictors e.

g. angiotensin I and II. Thereby, inhibiting the Neprilysin leads to increased levels of angiotensin II. The mechanism and effects are mentioned earlier in terms of increased concentration and effect of natriuretic peptides.

The main clinical trial for Sacubitril was a ‘8442 patient PARADIGM-HF study showed in patients with New York Heart Association (NYHA) class II–IV and reduced ejection fraction treated with LCZ696 (versus enalapril), the following benefits: reduction of the risk of death from cardiovascular causes by 20%; reduction of HF hospitalizations by 21%; reduction of the risk of all-cause mortality by 16%. Overall there was a 20% risk reduction on the primary endpoint, composite measure of cardiovascular (CV) death or time to first HF hospitalization.’ 6The main side effect seen with Sacubitril Sacubitril is a more favoured drug over Omapatrilat. The trials showed that when both compared to enalapril, Sacubitril as a NEP inhibitor reduced risk of death and reduced symptomsReferenceReference (Vancouver)