Clinical Question: Twice daily administration of lisinopril vs once daily for heart failure?

Clinical Question: What is the evidence to choose twice daily administration of lisinopril over once daily among individuals with heart failure and left ventricular dysfunction?

Author: Alicyn Magruder, PharmD Candidate 2016

Clinical Review: Kelly Cochran, PharmD, BCPS

Background information: An individual with left ventricular heart failure was on a twice-daily regimen of lisinopril. To aid in adherence a once daily dosing regimen would be preferred to simplify their medication use, but before making this recommendation it would be important to know if twice daily dosing has a superior benefit over once daily dosing.  The half-life of lisinopril in patients with normal renal function is 12 hours.[1]

When Heart failure (HF) occurs so does activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS). There is an increase in concentration of catecholamines and brain natriuretic peptide (BNP). These concentrations correlate with the degree of left ventricular dysfunction and mortality in patients with HF.[2]  The benefits of angiotensin converting enzyme inhibitors (ACE-I) have been well established in the treatment of HF patients with left ventricular dysfunction with reduced ejection fraction (HFrEF) as ACE-Is reduce the deleterious effects of the RAAS and the sympathetic nervous system in HF.  The effect to reduce morbidity and mortality in heart failure has been show throughout the class of ace-inhibitors. [3]The Assessment of Treatment with Lisinopril and Survival (ATLAS) study was one of the first studies to establish that higher doses of lisinopril were more beneficial than lower doses of the drug in the treatment of HF and that lisinopril improves survival in these patients. [4] The most recent guidelines for the treatment of HF recommend that all patients with HFrEF should receive an ACE-I unless they are not tolerated or are contraindicated.[5]  The target dose for lisinopril in this population is 20 to 40mg a day because studies have determined these doses as non-inferior to other ACE-Is used in clinical trials that demonstrated a reduction in morbidity and mortality.[6]

Evidence Based Findings: The University of Missouri-Kansas City’s library database and PubMed, were used to complete a search including the terms lisinopril, twice daily dosing, multiple daily dosing, long acting ace-inhibitors, dosing strategy, heart failure, and left ventricular diastolic dysfunction.

A majority of the studies used to show the benefit of lisinopril in heart failure have only used once daily dosing. Only one study has compared and evaluated the effects of the administration lisinopril using once-daily or twice-daily regimens on RAAS and autonomic nervous activity in patients with HFrEF. This study by Hirooka et al. was a small prospective study with 32 patients who had either been on a once daily dose or twice daily dose of lisinopril for greater then 3 months. The patients were then crossed over to the other dosing schedule for 3 more months. Blood levels were drawn for plasma concentrations of creatinine, blood urea nitrogen, BNP norepinephrine (NE), plasma renin activity (PRA), and aldosterone were measured.

Overall the hemodynamic parameters were similar during once-daily and twice-daily use of lisinopril. There was also no differences in the plasma concentrations of BNP and aldosterone, but power was not set in the study. However, the plasma concentration of norepinephrine was significantly lower, and the plasma renin activity was also lower with the twice-daily administration regimen. The authors hypothesized that twice daily administration may lower the activation of the sympathetic nervous system as compared to the once daily dosing, which is important in the prevention of heart failure worsening. While we know these concentrations correlate with the degree of left ventricular dysfunction and mortality in patients with HFrEF, we still need to show clinical outcomes when these concentrations change.  The strengths of this study include using appropriate medication dose and randomization was similar among groups before the treatment crossover.  Another strength was the total daily doses remained the same among the groups, so the beneficial effect seen was not due to a higher dose. [7] However, the type of study (non-blinded, non-randomized) and its size makes this weak evidence.  The study also did not differentiate between the types of heart failure patients had in the study.  While ACE-Is can be used in both HFrEF and heart failure with preserved ejection fraction, the benefit has been more established in HFrEF. A meta-analysis evaluated studies from 1966–June 2005 that researched the use of twice-daily ACE-Is compared to one daily dosing in HF and found supporting evidence for twice daily dosing but deemed it insufficient to recommend the use of twice daily dosing of long acting ACE-Is in HF over once daily dosing.[8]  This meta-analysis included captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril, and trandolapril and did not differentiate between different types of heart failure.  Their meta-analysis included drugs whose FDA approval includes twice daily dosing.  The studies included large randomized clinical trials.  Many of these articles researched clinical outcomes such effects on functional class, ejection fraction and exercise duration, but others also assessed lab results that may not correlate to clinical outcomes such as BNP, NE, and PRA. This study did not include any trials that compare mortality among dosing regimens of lisinopril.

Recommendation: Due to a 12-hour half-life, twice daily dosing of lisinopril is acceptable as long as the total daily dose is the same.  There is a small amount of evidence to suggest that twice daily dosing of lisinopril may be more beneficial than once a day dosing in HFrEF but the evidence is weak and no one has researched outcome differences such as morbidity and mortality between the two dosing choices. There is no harm in twice daily dosing if the patient can be adherent to this regimen, but there may be an increased cost when choosing a twice-daily frequency. This regimen may be useful in getting those patients who cannot tolerate a higher once daily dose to the target daily dose of 20mg to 40mg that has shown the most benefit in HFrEF. However, in patients who may have issues with adherence that can tolerate the target daily dose at one time a once daily dosing would be recommended over a twice daily dosing. Ultimately when choosing a medication regimen we want to improve clinical outcomes and decrease mortality, but we do not have good data to determine if one dosing regiment provides more benefit. We do have data from large clinical trials such as the ATLAS study and Zannad et al. that daily doses between 20-40mg a day provides these benefit. Ultimately, reaching a target daily dose safely should be our focus until further research is conducted.

 

[1] Lisinopril. Micromedex 2.0.  Truven Health Analytics, Inc.  Greenwood Village, CO.  Available at: http://www.micromedexsolutions.com.
[2] Swedberg K, Eneroth P, Kjekshus J, et al. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group.Circulation. 1990; 82:1730–1736.

[3] Garg, R., Yusuf, S.,  Bussmann, D., et al. Overview of randomized trials of angiotensin converting enzyme inhibitors on mortality and morbidity in patients with heart failure.  JAMA. 1995;273(18):1450-1456

[4]  Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999; 100:2312–2318.

[5]  Jessup M., Abraham W. T., Casey D. E., et al. ACCF/AHA guidelines for the management of heart failure in adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013.62;16:147-239

[6] Zannad F, van den Broek SA, Bory M. Comparison of treatment with lisinopril versus enalapril for congestive heart failure. Am J Cardiol.1992;70:78C–83C.

[7] Hirooka K, Koretsune Y, Yoshimoto S, Irino H, Abe H, Yasuoka Y, et al. Twice-daily administration of a long-acting angiotensin-converting enzyme inhibitor has greater effects on neurohumoral factors than a once-daily regimen in patients with chronic congestive heart failure. J Cardiovasc Pharmacol. 2004;43:56-60.

[8] Belgeri, M. Long-Acting Angiotensin-Converting Enzyme Inhibitors in Congestive Heart Failure: Does Multiple-Daily Dosing Provide Additional Benefit over Once-Daily Dosing? J Pharm Tech. 2005;21:203-206