Sacubitril/Valsartan in Patients Post-Left Ventricular Assist Device Implant: A Single-Centre Case Series

Abstract

Guideline-directed medical therapy for heart failure (HF) with reduced ejection fraction (HFrEF) includes the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan.1, 2 Additionally to its effects in HFrEF, clinical studies have revealed its potential for blood pressure (BP) control and tolerability in patients with hypertension.3 Although durable continuous-flow left ventricular assist devices (CF-LVADs) are implanted as therapy for stage D HF worldwide, there is limited knowledge of sacubitril/valsartan use in such patients. Optimal LVAD management requires exquisite BP control; an elevated mean arterial pressure (MAP) has been related to adverse events post-LVAD including stroke, pump thrombosis, aortic insufficiency, and inadequate cardiac support due to increased afterload.4 Thus, management with evidence-based BP targets is important.4, 5 Our primary aim was to analyse our initial experience with sacubitril/valsartan in patients with durable CF-LVAD support for stage D HF with respect to BP control and drug tolerability. Our single-centre case series identified 10 adult patients (mean age 58 ± 9 years, 30% female, and 60% Caucasian) with stage D HF who had CF-LVAD implants from 2016–2018 at our institution, and were subsequently initiated on sacubitril/valsartan. The retrospective chart review was approved by the institutional review board with waiver of informed consent, in compliance with the Declaration of Helsinki. Descriptive statistics are reported, with P-value <0.05 considered statistically significant. The majority of patients had destination therapy (80%) centrifugal (60%) LVADs. Our target population included patients with suboptimal/refractory MAP on conventional therapy. MAP is routinely monitored at our centre by both Doppler ultrasound and BP cuff.6 Table 1 and online supplementary Table S1 summarize our experience. Sacubitril/valsartan use was tolerated over a median duration of 292 (141–422) days in 10 patients with CF-LVADs. Sacubitril/valsartan was started at low (≤24–26 mg, six patients) and moderate (49–51 mg, four patients) doses at median 77 (244–731) days post-CF-LVAD implant, maintained at low and moderate doses in three patients each, and titrated up to the highest dose (97–103 mg) in four patients. Prior to initiation of sacubitril/valsartan, oral vasodilators including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) were discontinued per standard manufacturer's protocol in patients on these medications at baseline. We noted one event (hyperkalaemia >5.5 mmol/L) resulting in drug withdrawal. No patient developed significant acute kidney injury (decline in estimated glomerular filtration rate >25% from baseline), severe hypotension (MAP <60 mmHg), angioedema or death related to sacubitril/valsartan use. One patient had a MAP <65 mmHg requiring drug dose reduction. One patient was bridged to heart transplant; another died from a subdural haemorrhage; and eight patients remain alive on CF-LVAD support. Hospital readmissions (six patients) and emergency department visits (four patients) were unrelated to sacubitril/valsartan use. Moreover, serum potassium (4.14 ± 0.66 to 4.34 ± 0.36 mmol/L; P = 0.46) and creatinine (1.28 ± 0.26 to 1.39 ± 0.26 mg/dL; P = 0.21) remained stable pre/post-sacubitril/valsartan initiation (Table 1). A significant reduction in MAP by 20.0 ± 14.0 mmHg (P = 0.002) was observed with sacubitril/valsartan initiation, from 98.8 ± 12.2 mmHg at baseline to 78.4 ± 12.1 mmHg after a median follow-up of 16 (7–20) days. This was accompanied by an overall decline in the mean total daily doses of non-potassium-sparing diuretics, aldosterone antagonists and other oral vasodilators from baseline after sacubitril/valsartan initiation and optimization (Table 1): (i) furosemide oral equivalents decreased from 220.0 ± 167.9 mg to 120.0 ± 94.3 mg, (ii) spironolactone equivalents decreased from 26.3 ± 9.2 mg to 20.6 ± 15.1 mg, and (iii) all oral vasodilators were tapered as to be expected to 0 mg. Beta-blockers and digoxin doses had a slight but non-statistically significant reduction. Neuro-hormonal blockade with ACEI/ARB use is associated with a lower mortality risk post-CF-LVAD [hazard ratio ((HR) 0.50, P = 0.01],7 and a reduced risk of major gastrointestinal bleeding (GIB) in a dose-dependent manner (HR 0.43, P = 0.04) and from arteriovenous malformation (HR 0.37, P = 0.017).8 In our study cohort, one patient had GIB in the setting of supra-therapeutic international normalized ratio. Future work is required to examine the impact of an improved MAP with sacubitril/valsartan on GIB and other clinical patient outcomes. N-terminal pro-B-type natriuretic peptide (NT-proBNP) was reduced from 2929 pg/mL at baseline to 1530 pg/mL after a median of 19 (5–16) days of follow-up (P = 0.36). The diuretic/natriuretic effect of sacubitril/valsartan, due to the enhanced action of endogenous natriuretic peptides from neutral endopeptidase inhibition by sacubitril,9 may be beneficial in our patients with stage D HF on CF-LVAD given the lower NT-proBNP levels and diuretic doses, and requires further analysis. Future work will need to explore whether this modulation of NT-proBNP by sacubitril/valsartan is accompanied by positive myocardial remodelling in patients on CF-LVAD support and potentially additional benefit impacting right ventricular function and pulmonary vascular resistance.10 This study has limitations. It is a single-centre retrospective analysis. Our preliminary experience with sacubitril/valsartan use in patients with CF-LVADs demonstrates a robust decline in MAP in patients with suboptimal MAP control in the absence of significant drug-related adverse events. Conventional medications failed to achieve BP control and were subsequently weaned (e.g. diuretics or beta-blockers) or discontinued (e.g. oral vasodilators) after initiation of sacubitril/valsartan. In summary, sacubitril/valsartan initiation in patients with CF-LVAD implant effectively reduces MAP. Elevated MAP has been related to adverse events post-CF-LVAD and achieving excellent BP control is essential to reduce adverse events. Future prospective studies are warranted to explore the efficacy and tolerability of sacubitril/valsartan on clinical outcomes in patients on CF-LVADs and the potential for positive myocardial remodelling and/or recovery. Conflict of interest: J.D.E. serves as consultant for Abbott and medical advisor for Medtronic Inc. E.G.S. is a speaker for Abiomed and provides training for Abbott. R.C.S. receives grant support from and is a medical advisor and advisory board member for Novartis; he is also an advisory board member for Medtronic Inc. All other authors have no relevant conflicts of interest to disclose. Table S1. Baseline characteristics of the left ventricular assist device study cohort initiated on sacubitril/valsartan. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.