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Novel Combination Drug Takes on Heart Failure

Monday, April 18, 2016   (0 Comments)
Posted by: Elizabeth Maynard
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Novel Combination Drug Takes On Heart Failure 

Joyce Gambrah, PharmD Candidate 2017

Stacy Pasciolla, PharmD Candidate 2018

Jennifer Andres, PharmD, BCPS

Temple University School of Pharmacy

 

Heart failure is a life-threatening condition that affects approximately 5.7 million people over the age of 20 in the United States.1 Heart Failure can be broken down into systolic or diastolic, which differentiates trouble contracting or relaxing. As heart failure progresses, the heart’s pumping action grows weaker. Currently there is no cure for heart failure, but management is made up of drug combinations and lifestyle modifications. Current drug therapies of choice include a combination of beta-blockers, angiotensin converting enzyme inhibitors (ACE-I)/angiotensin II receptor blockers (ARB), and mineralocorticoid receptor antagonists.

 

In July 2015, the FDA approved a new oral combination medication, Entresto™ (sacubitril and valsartan), for the treatment of heart failure, after being granted fast-track designation. It is the first neprilysin inhibitor/angiotensin receptor blocker drug to receive FDA approval for this indication. Sacubitril is a prodrug of LBQ657 that inhibits neprilysin,2 an enzyme that degrades vasoactive peptides such as bradykinin, and natriuretic peptides. The inhibition of neprilysin, leads to increased levels of these peptides which decreases vasoconstriction and sodium retention.2 Valsartan inhibits the effects of angiotensin II, by blocking the angiotensin II type-1 receptor leading to a decrease in both vasoconstriction and aldosterone release.

 

Sacubitril/valsartan was approved based on the double-blind, randomized controlled PARADIGM-HF trial. In this trial, 8442 patients with New York Heart Association (NYHA) class II-IV heart failure, reduced ejection fraction of < 40%, and increased levels of BNP or NT-proBNP, were randomized to receive enalapril 10 mg twice daily or sacubitril/valsartan 200 mg twice daily.3 This is equivalent to a total of 320 mg of valsartan daily. The dose of enalapril was chosen based on SOLVD clinical trial, that showed that 10 mg twice daily can reduce mortality when compared to placebo.4 Patients were allowed to continue on background medications including beta-blockers and mineralocorticoid receptor antagonists. The average age was 63.8 years. Most patients had NYHA class II heart failure. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure. The study was projected to continue for at least 34 months, but was stopped at 27 months due to the overwhelming benefit from sacubitril/valsartan. In comparison to enalapril, sacubitril/valsartan reduced the risk of death by 16%, the risk of hospitalizations due from HF by 21%, and the overall mortality was lower in the sacubitril/valsartan group (17% vs. 19.8%). The most common adverse effects due to sacubitril/valsartan were symptomatic hypotension and angioedema, while the most common adverse effects due to enalapril were renal deterioration, cough, and hyperkalemia. Fewer patients needed to stop their medication due to adverse effects in the sacubitril/valsartan group.4  

 

The recommended starting dose of sacubitril/valsartan is 49/51 mg twice daily. After 2 to 4 weeks of treatment, the dose should be increased to a target maintenance dose of 97/103 mg twice daily, if tolerated by the patient. A reduced starting dose of 24/26 mg is recommended for patients who have not been taking an ACE or an ARB previously, patients with severe renal impairment (defined as eGFR <30mL/min/1.73 m2), and patients with hepatic impairment (defined by Child-Pugh class B).5 Refer to table 1 for dosing information. Drug interactions may occur with simultaneous use of an ACE-I/ARB due to the dual blockade of the renin-angiotensin system which can increase the risk of hyperkalemia, hypotension and renal impairment. Sacubitril/valsartan should also be avoided in use with aliskiren especially in patients with diabetes. Other potential drug interactions that may occur are with potassium-sparing diuretics which can potentiate hyperkalemia, NSAIDs for the risk of renal impairment, and lithium due to increased risk of lithium toxicity.5  

 

Being the first combination neprilysin inhibitor and ARB, sacubitril/valsartan offers a new treatment option for patients with heart failure with reduced ejection fraction. Favorable results from PARADIGM-HF have shown sacubitril/valsartan to be safe and effective in the studied population, but only time will tell when and how clinicians will integrate it into patient care. PARADIGM-HF focused on patients with mild to moderate HF so there is limited experience in those with acutely decompensated HF.5 Additional use of the drug will inform us of the tolerability in more severe HF, as well as in the elderly.

 

Table 1: Dosing of sacubitril/valsartan5

ACEi

Patients receiving a total daily dose of >10mg of enalapril or therapeutically equivalent doses of another ACEi

Stop ACEi 36 hours before starting sacubitril/
valsartan

Start sacubitril/valsartan 49/51 mg twice daily

Double the dose of sacubitril/
valsartan after 2 to 4 weeks, as tolerated by the patient to reach the target maintenance dose of 97/103 mg twice daily

Patients receiving a total daily dose of <10mg of enalapril or therapeutically equivalent doses of another ACEi

Stop ACEi 36 hours before starting sacubitril/
valsartan

Start sacubitril/
valsartan 24/26 mg twice daily

Double the dose after 2 to 4 weeks to 49/51 mg twice daily as tolerated by the patient

ARB

Patients receiving a total daily dose of >160mg of valsartan or therapeutically equivalent doses of another ARB

Start sacubitril/valsartan 49/51 mg twice daily

Patients receiving a total daily dose of<160mg of valsartan or therapeutically equivalent dose of another ARB

Start sacubitril/valsartan 24/26 mg twice daily

Double the dose after 2 to 4 weeks to 49/51 mg twice daily as tolerated by the patient

Not on ACEi or ARB

Not currently taking ACEi or ARB

Start sacubitril/valsartan 24/26 mg twice daily

Double the dose after 2 to 4 weeks to 49/51 mg twice daily as tolerated by the patient

Note: 103 mg of valsartan in Entresto is equivalent to 160 mg of valsartan in other formulations.

 

References: 

  1. Mozaffarian D., Benjamin EJ., Go AS, et al.; for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015; 131:e29–e322.
  2. Sacubitril/Valsartan (Entresto) for Heart Failure. JAMA. 2015;314(7):722-723.
  3. McMurray JJ, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014. 371(11):993-1004.

4.     The SOLVD Investigators. Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure. N Engl J Med. 1991. 325:293-302.

5.     Entresto [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

 

 


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