Home Blog CHF Mortality Reduction: Ivabradine and Sacubitril-Valsartan

    CHF Mortality Reduction: Ivabradine and Sacubitril-Valsartan


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    Diastolic dysfunction therapy is based on managing symptoms and treating comorbid conditions. There aren’t any medications that have proven to reduce mortality in this patient population.

    Systolic dysfunction: ACE/ARBs and beta blockers are your main drugs in terms of lowering mortality. Specific beta blockers you should know are carvedilol, bisoprolol, and metoprolol succinate – these have the most proven benefit in reducing mortality. Small caveat: never give beta blockers during an acute exacerbation.

    Diuretics are given to reduce symptoms: fluid overload. Digoxin is also used for symptom control such as SOB. Digoxin decreases the time spent hospitalized, but does not reduce mortality in patients. Spironolactone or eplerenone (less endocrine side effects than spironolactone) are only beneficial to those who are classified as having class 3 or class 4 CHF.

    Be careful with the use of calcium channel blockers, as they may increase mortality in CHF patients. For those patients who continue to be symptomatic, the addition of nitrates and hydralazine has proven benefit (more so with African Americans).

    That’s what is known and that is what is in the current guidelines. But, there are a couple new medications that have been approved for the treatment of CHF which have shown to reduce mortality: Ivabradine and Sacubitril.

    Ivabradine inhibits the SA node by prolonging the depolarization phase. Ultimately, the heart rate is reduced which provides benefit for the patient (similar to how beta blockers provide benefit).

    Those who have an ejection fraction less than 35 percent, are in sinus rhythm, and whos heart rate is at less than 70 beats per minute (cannot be due to pacemaker) are candidates. The patient should be on the maximum tolerated dose of a beta blocker (this is not a substitute for beta blockers) if there is no contraindication to using a beta blocker.

    Contraindications for Ivabradine:
    Acute CHF exacerbation, hypotension (90/50), SA dysfunction, severe hepatic impairment, and/ or taking a strong cytochrome CYP34A inhibitor.

    The SHIFT trial had 6558 patients with the above criteria and were given either Ivabradine or placebo and then watched for 2 years. There were less deaths and hospital admissions for patients taking Ivabradine.

    Before initiating therapy, patients need to be on maximum beta blocker and Ace inhibitor doses. If the patient has a contraindication to a beta blocker make sure to start the ACE inhibitor first.

    Guidelines state to start dosing at 5mg twice daily with food. Those at risk for conduction disturbances should be started on 2.5 mg twice daily. Increase the dose every two weeks until a maximum dose of 7.5 mg BID is reached. Stop/reduce the medication if the heart rate is lowered below 50 bpm or if the patient is having symptoms of bradycardia.

    Adverse reactions include: bradycardia, hypertension, atrial fibrillation, and heart block. Moving on to sacubitril.

    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 them with an ARB – because we need to block the RAAS system.

    Originally was a combination ACE-neprilysin inhibitor – but this caused angioedema and was taken off the market. It was believed that 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 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 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.