A couple days back we discussed ivabradine for the treatment of CHF. If you didn’t get a chance to read about it – you can do so here.
Today, we’re going to discuss sacubitril – which has also been shown to decrease mortality in systolic dysfunction. Sacubitril is a neprilysin inhibitor which has been combined with valsartan (ARB).
First, some very brief physiology.
Ace inhibitors work by blocking the renin-angiotensin-aldosterone system. Natriuretic peptides are hormones responsible for maintaining sodium and fluid homoeostasis; their release is triggered by increased myocardial filling pressures. They cause vasodilation, increase GFR, and reduce the release of renin from the kidneys.
Neprilysin reduces natriuretic peptides, breaks down angiotensin II, and reduces bradykinin. When we block neprilysin we raise natriuretic peptides and bradykinin. This is why we have to combine sacubitril with an ARB – because we need to block the RAAS system.
Originally, there was a combination ACE-neprilysin inhibitor – but this caused severe angioedema and was taken off the market. It was believed that the severe angioedema was caused by inhibiting three enzymes responsible for bradykinin degradation.
The new combination only blocks one of these enzymes.
Sacubitril-valsartan is an ARB-neprilysin inhibitor. The combination increases natriuretic peptide, blocks the RAAS system, and reduces the risk of angioedema.
Sacubitril-valsartan is indicated in New York Heart Association (NYHA) functional Class II to IV HF with a reduced ejection fraction. It’s not clear if patients should be treated with an ACE, monotherapy ARB, or with the combination Sacubitril-valsartan as first line therapy.
What is clear is that if an ACE isn’t tolerated, then the combination drug is better than ARB monotherapy when there are elevated BNP levels, patients have a systolic blood pressure over 100, and a GFR over 30. Starting doses are 49/51 mg twice daily. After 2-4 weeks the dose is doubled to the target dose of 97/103 twice daily. Those with severe renal impairment are started at half the recommended dose.
Remember, this is and ARB and should not be combined with another ACE inhibitor or ARB.
This recommendation comes from the PARADIGM-HF trial. This trial had 8442 patients with an LVEF ≤40 percent and NYHA functional class II-IV. Patients either received the combination drug or enalapril 10mg and then followed for 2 years. The trial showed that all cause mortality and hospital admission was reduced more so with the combination therapy vs enalapril.
Contraindications include any contraindications to any ARB (angioedema, pregnancy, etc), breast feeding, and in those with severe hepatic impairment.
Adverse reactions include: hypotension, hyperkalemia, cough, dizziness, and renal failure. Angioedema may rarely occur.
There you have it. Two new drugs that have proven mortality reduction in CHF. It doesn’t matter how long you’ve been practicing medicine – you need to make sure you are staying current!