Abstract
Background
Heart failure (HF) is one of the most common medical conditions in the United States, with about 8 million Americans expected to have HF by 2030. 1 The American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of American (HFSA) guidelines currently recommend initiating sacubitril/valsartan over an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) to further reduce mortality or HF rehospitalization in symptomatic patients with HF with reduced ejection fraction. 2 This treatment recommendation was developed because a landmark trial showed that sacubitril/valsartan was superior to the ACE-I, enalapril. 2 It also showed that approximately 80% of patients with HF who were receiving sacubitril/valsartan were also receiving loop diuretics. 3 The co-administration of sacubitril/valsartan and loop diuretics may cause over-diuresis because both sacubitril and loop diuretics have diuretic effects, which can lead to hypotension or acute kidney injury (AKI). However, there are no official recommendations/suggestions from HF guidelines for managing loop diuretic therapies or doses after the initiation of sacubitril/valsartan because there is little data available on the concomitant use of both treatments. Two published retrospective studies have evaluated long-term (>6 month) changes in loop diuretic doses following the initiation of sacubitril/valsartan.4,5 One single-center, small-scale study has investigated the effect of sacubitril/valsartan on the required dose of loop diuretic over the short term (i.e., during the 3 months after the initiation of sacubitril/valsartan) but it only had 2 time points, before and after sacubitril/valsartan initiation and did not evaluate longitudinal changes in loop diuretic use and dose. 6 The objective of this study was to investigate longitudinal trends in loop diuretic use and doses during the 6 months following the initiation of sacubitril/valsartan in academic tertiary center-affiliated cardiology clinics.
Methods
This was a retrospective multicenter cohort study that included all patients who were initiated on sacubitril/valsartan in West Virginia University (WVU)-affiliated clinics between January 1, 2015 and February 28, 2020. Inclusion criteria were patients who were greater than 18 years old; diagnosed with heart failure with reduced ejection fraction (ejection fraction ≤40%); and initiated on sacubitril/valsartan in an outpatient setting at any WVU system institution. We excluded clinically hypervolemic patients who required an increased dose of loop diuretic at enrollment; patients with heart failure with ejection fraction >40%, those who were admitted to the hospital during the initiation of sacubitril/valsartan; and patients who were already receiving sacubitril/valsartan.
A list of patients who had a record of receiving sacubitril/valsartan was initially obtained from the WVU medicine database. For each patient, information on patient demographics, comorbidities, laboratory test results, medication history, and clinical outcomes were retrospectively collected. Patients who died or were lost to follow-up within 6 months were also included. Information for patients who died or were lost within 6 months were collected until the time point following death or loss to follow-up.
Primary outcomes were longitudinal trends in the prevalence of loop diuretic use and furosemide equivalent dose at baseline, 2 weeks, 1 month, 3 month and 6 months after the initiation of sacubitril/valsartan. The furosemide equivalent dose was based on the standard oral equivalent dose conversion among bumetanide, torsemide, and furosemide (1:20:40).
Independent samples t-tests for continuous variables and χ2 tests for categorical variables were used for baseline characteristic comparisons. Cochran’s Q test for multiple comparisons of paired categorical variables and Friedman’s two-way ANOVA for multiple comparisons of continuous variables were used to compare data across five time points. If any of the multiple comparisons were significantly different, McNemar’s χ2 test for paired categorical variables and a paired t-test for continuous variable were performed for each comparison. Bonferroni adjustments for multiple comparisons were performed. The significance level was set at .05. Statistical analyses were performed using IBM SPSS Statistics version 26. In order to detect an overall difference of 65% reduction in the prevalence of loop diuretic use and an overall difference of 30 mg in furosemide equivalent dose between baseline and 6 months with 80% power at the 5% significance level, 450 subjects would be sufficient to detect the statistically significant difference in the prevalence and furosemide equivalent dose. The parameters used in the power analysis were from previous literature. 5 This study was approved by the WVU institutional review board.
Results
Baseline Characteristics of the Study Cohort.
Abbreviations: ACC, American College of Cardiology; BNP, B-type natriuretic peptide; CRT, cardiac resynchronization therapy; DM, diabetes; EF, ejection fraction; HTN, hypertension; ICD, implantable cardioverter defibrillator; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; SGLT-2, sodium-glucose cotransporter-2 inhibitor.
Prevalence of Loop Diuretic Use/Diuretic Dose in Each Time Point.
Median [IQR].
Discussion
There were no significant changes in the loop diuretic use and dose during the 6 months following the initiation of sacubitril/valsartan treatment. These results support that the initiation of sacubitril/valsartan may minimally impact the prevalence of loop diuretic therapy and loop diuretic dose during the short term.
Neprilysin is an enzyme that degrades vasoactive peptides, including natriuretic peptides, angiotensin II, and bradykinins. Sacubitril is a neprilysin inhibitor which allows for increased expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). 6 Wang et al compared the effects of sacubitril/valsartan to the effects of valsartan alone, on natriuresis, diuresis, and serum potassium levels in Asian patients with salt-sensitive hypertension. 7 They found that the first dose of sacubitril/valsartan significantly increased 6- and 24-hour natriuresis and diuresis compared to the first dose of valsartan only. However, these diuretic effects were not maintained after 4-weeks of sacubitril/valsartan treatment due to the ANPs’ diminishing diuretic effects caused by compensatory sodium and water reabsorption in the renal collecting duct. 7 This compensatory mechanism might explain why we similarly found no significant changes in the use or dose of loop diuretics following the initiation of sacubitril/valsartan treatment in our study.
Post hoc analysis of the PARADIGM-HF trial revealed that treatment with sacubitril/valsartan was significantly associated with loop diuretic dose reduction compared to treatment with enalapril. 4 However, the PARADIGM-HF study had a longer follow-up period that spanned from at least 6 months to 2 years, and the sacubitril/valsartan treatment was compared with the active control treatment with enalapril. Another retrospective cohort study by Orvin et al investigated the effects of sacubitril/valsartan on the total daily dose of loop diuretics during the 3 ± 1 months following the initiation of sacubitril/valsartan. 6 They found that only 20% of adults experiencing HF with reduced ejection fraction (n = 24) required a reduction in their total daily dose (TDD) of loop diuretics, 70% (n = 84) had no changes in their TDD, and 10% required an increased TDD of loop diuretics (n = 12). 6 The median TDD of loop diuretics at baseline and follow-up was not statistically different (40 mg [interquartile range (IQR) 20-80] vs 40 mg [IQR 20-80]; P = .13). However, Orvin et al 6 did not evaluate longitudinal changes in loop diuretic use and dose and instead collected diuretic use and dose information at only 2 time points, before and after sacubitril/valsartan initiation. 6 The study was therefore unable to evaluate the timing or magnitude of loop diuretic dose changes following treatment with sacubitril/valsartan. The study was also limited by a small sample size of 120 patients. 6 Our study included more than 400 patients and showed that there were no significant differences in the dose of loop diuretic during 6-month follow-up period following the initiation of sacubitril/valsartan therapy. The diuretic effects of sacubitril/valsartan may not be clinically significant during 6-month follow-up period. Further evaluation is needed to assess changes in the use or dose of the loop diuretics more than 6-months after the initiation of sacubitril/valsartan.
Our study has several limitations. First, patient data were obtained retrospectively from electronic medical records and adherence to diuretic therapy and sacubitril/valsartan were not assessed. Second, almost 75% of subjects were excluded during our screening process. The main reasons for exclusion were incomplete patient data and/or the initiation of sacubitril/valsartan treatment during hospital admissions. Despite this reduction in our study size, the exclusion of subjects who started sacubitril/valsartan in an inpatient setting allows for a more specific investigation of the effects of outpatient diuretic treatment. Third, our study subjects were predominantly Caucasian, which may limit the generalizability of our results to other minority groups. Fourth, only small number of patients were receiving SGLT-2 inhibitors and further investigation of the concomitant use with the SGLT 2 inhibitor and sacubitril/valsartan need to be evaluated in the future studies. Finally, this is a retrospective cohort study and therefore can only identify association. Further investigation with prospective studies will be needed.
Conclusion
The use of sacubitril/valsartan was not associated with reductions in the use or dose of loop diuretics over 6-month follow-up period. Initiation of sacubitril/valsartan may not need a pre-emptive loop diuretic dose reduction.
Footnotes
Acknowledgments
Authors would like to acknowledge Wei Fang for sample size estimation and Mary Kowal and Kathleen Herrick for data collection.
Declaration of Conflicting Interests
George Sokos was a speaker for Novartis Pharmaceutical sponsored presentation. Other authors declare no conflicts of interest.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number 5U54GM104942-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
