Article Information

Samiullah Arshad^1*, Tayyaba Haq², Dan Stephens³, Gaurang N Vaidya⁴

¹Internal Medicine, University of Kentucky, Lexington, KY, USA

²Internal Medicine, Nishtar Medical University, Pakistan

³Medical Student, University of Washington School of Medicine, Seattle, WA, USA

⁴Advanced Heart Failure and Transplant, Gill Heart and Vascular Institute, University of Kentucky, Lexington, Kentucky, USA

*Corresponding author: Samiullah Arshad, Internal Medicine, University of Kentucky, Lexington, KY, USA.

Received: 18 July 2022; Accepted: 28 July 2022; Published: 5 August 2022

Citation: Samiullah Arshad, Tayyaba Haq, Dan Stephens, Gaurang N Vaidya. Sacubitril-Valsartan in LVAD patients: Potentials for the Future?. Cardiology and Cardiovascular Medicine 6 (2022): 390-393.

Abstract

Keywords

ARNI; Efficacy; LVAD; Safety; Sacubitril-Valsartan

Article Details

Manuscript

Sacubitril-Valsartan is the most commonly used Angiotensin Receptor Neprilysin Inhibitor (ARNI) which is now a front-line pharmacological therapy for heart failure with reduced ejection fraction. Sacubitril inhibits neprilysin, an endopeptidase that breaks down several vasoactive peptides- including natriuretic peptides, bradykinin, and adrenomedullin. Increased levels of these vasoactive peptides counteract the neurohormonal activation that contribute to cardiac remodeling in heart failure. Valsartan is an Angiotensin Receptor Blocker (ARB) that antagonizes angiotensin- 1 (AT-1) which inhibits the Renin-Angiotensin Activation System (RAAS), also known for its detrimental cardiac remodeling effects in the heart. The Paradigm HF trial showed Sacubitril-Valsartan was superior to Valsartan in reducing hospitalization and death from cardiovascular causes [1]. In the Pioneer HF trial, initiation of Sacubitril-Valsartan during hospitalization with decompensated heart failure resulted in a greater reduction of NT-proBNP concentration than Enalapril alone, without a significant increase in rates of adverse events [2]. In a study by Martens et al., there was a reduction in Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) burden, Non-Sustained Ventricular Tachycardia (nsVT) burden, and Premature Ventricular Contractions (PVCs) after initiation of Sacubitril-Valsartan compared to ACE-i/ARBs alone in heart failure patients, which was attributed to improvement in cardiac function due to reverse cardiac remodeling. LVEF improved in 44% of patients after initiation of Sacubitril-Valsartan by at least 5%. The authors suggested that the reduction in sudden cardiac deaths seen in the Paradigm HF trial (particularly in patients with non-ischemic cardiomyopathy) could partially be linked to the reduction in the ventricular tachyarrhythmias after initiation of the drug [3,4]. An important effect of Sacubitril-valsartan compared to Enalapril was a reduction in the profibrotic biomarkers studied by Zile et al [5]. Initiation of Sacubitril-Valsartan during hospitalization in patients with heart failure with reduced ejection fraction is predicated to be cost-effective than starting as an outpatient or continued use of enalapril [7]. In patients with LVADs, continuous flow without pulsatility triggers RAAS with aggressive pharmacological therapy targeting RAAS inhibition is known to result in myocardial recovery and successful explantation of LVADs [7]. Vaidya et al. have shown that the use of ACE-i/ARBs in LVAD patients significantly reduced ProBNP levels at six months and twelve months and improved survival [8]. In addition to promoting myocardial recovery, ACE-i/ARBs have reduced the risk of gastrointestinal bleeding and AV-malformations among LVAD patients [9]. The question then arises, does sacubitril-valsartan impart the above benefits among patients with LVADs? A literature search conducted on PubMed, Google Scholar, and SCOPUS for terms related to ‘sacubitril-valsartan’ and ‘LVAD’ revealed ten retrospective cohort studies and one prospective cohort study with a combined total of 628 patients. The literature search was conducted from July 10th 2022. The primary outcome consistently assessed throughout all but one study (Schnettler et. al.) was reduction in mean arterial pressure (MAP). Nine of the ten studies that reported this outcome found a significant reduction of MAP with initiation of sacubitril-valsartan, ranging from 5 mmHg to 20 mmHg. In addition to MAP reduction, Dobarro et. al reported a significant reduction in NT-proBNP levels following ANRI initiation of 1,466 pg/ml [13]. Study by Alishetti et. al also found a reduction in NT-proBNP of 501 pg/ml [17]. Six of the eleven studies reported the types of LVADs in the patients. Follow up time throughout these studies ranged from 3 months to 27.5 months. Adverse effects related to sacubitril-valsartan initiation in LVAD patients were rare and included hyperkalemia, symptomatic hypotension, allergic reaction/angioedema, and acute kidney injury. Among the 628 total patients, the most common adverse effect was symptomatic hypotension as reported in 61 patients (10%). In addition, there were 6 reports (1%) of hyperkalemia, 1 (0.01%) report of acute kidney injury, 9 (2%) reports of allergic reactions. Details of each study have been provided in table 1.

Table 1: Literature Review of Studies With Use of ARNI’s among LVAD Patients.

With the approval of Sacubitril-Valsartan in 2015 by FDA for systolic heart failure patients, and with its increasing identified benefits, it will find its way in LVAD patients. Sacubitril-Valsartan has a role in remodeling of cardiac tissue, reduction in NT-proBNP levels, prevention of ventricular arrythmias, and improvement in the pump flow with blood pressure control when compared to standard therapies in heart failure patients, with a potential of reducing the number of hospital readmissions as well as stroke among LVAD patients. Further, reduction of arrhythmias in general heart failure patients may be of significant importance among LVAD patients. Its role in conserving the kidney function in patients of systolic heart failure makes it superior to ACE-I alone. In our opinion, it would be safe to extrapolate the beneficial effects of ARNIs to LVAD patients, and it is possible that their use in the early post-implantation phase may significantly impact outcomes. Although the long-term implications of ARNIs among LVAD patients are unknown, it is an avenue worth exploring. Notable barriers to generalized utility would include known side effects - acute kidney injury, hypotension, hyperkalemia and risk of angioedema. Two prospective clinical trials (NCT04103554 and NCT04191681) are currently underway to assess the safety and tolerability of Sacubitril-Valsartan among LVAD.

Conflicts of Interest

The authors report no conflicts of interest.

References

1. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 371 (2014): 993-1004.
2. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med 380 (2019): 539-548.
3. Martens P, Nuyens D, Rivero-Ayerza M, et al. Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction. Clin Res Cardiol 108 (2019): 1074-1082.
4. Rohde LE, Chatterjee NA, Vaduganathan M, et al. Sacubitril/Valsartan and Sudden Cardiac Death According to Implantable Cardioverter-Defibrillator Use and Heart Failure Cause. JACC: Heart Failure 8 (2020): 844-855.
5. Zile MR, O’Meara E, Claggett B, et al. Effects of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFrEF. Journal of the American College of Cardiology 73 (2019): 795-806.
6. Gaziano TA, Fonarow GC, Velazquez EJ, et al. Cost-effectiveness of Sacubitril-Valsartan in Hospitalized Patients Who Have Heart Failure With Reduced Ejection Fraction. JAMA Cardiol 5 (2020): 1236.
7. Briasoulis A, Ruiz Duque E, Mouselimis D, et al. The role of renin-angiotensin system in patients with left ventricular assist devices. J Renin Angiotensin Aldosterone Syst 21 (2020): 147032032096644.
8. Vaidya G, Birks E, Pillarella J, et al. Effects of Beta Blockers and ACE Inhibitors after Left Ventricular Assist Device Implantation (2018).
9. Converse MP, Sobhanian M, Taber DJ, et al. Effect of Angiotensin II Inhibitors on Gastrointestinal Bleeding in Patients With Left Ventricular Assist Devices. Journal of the American College of Cardiology 73 (2019): 1769-1778.
10. Freed K, Goldberg RL, Marino B, et al. Sacubitril-valsartan Improves Blood Pressure And Heart Failure In Left Ventricular Assist Device (lvad) Patients. Journal of Cardiac Failure 26 (2020): S40.
11. Straw LB, McCann P, Napier R, et al. Successful Use of Sacubitril/Valsartan in Patients with a Left Ventricular Assist Device. The Journal of Heart and Lung Transplantation 39 (2020): S505-S506.
12. Randhawa VK, West L, Luthman J, et al. Sacubitril-Valsartan Initiation Post-Left Ventricular Assist Device is Safe and Effective. Journal of Cardiac Failure 25 (2019): S62.
13. Dobarro D, Diez-López C, Couto-Mallón D, et al. Use of sacubitril-valsartan in blood pressure control with left ventricular assist devices. The Journal of Heart and Lung Transplantation 39 (2020): 1499-1501.
14. Sharma A, Moayedi Y, Duclos S, et al. Tolerability of Sacubitril/Valsartan in Patients With Durable Left Ventricular Assist Devices. ASAIO Journal 66 (2020): e44-e45.
15. Nicolsen E, Curran L, Dixon S, et al. Sacubitril-Valsartan versus Standard Anti-Hypertensives in Left Ventricular Assist Device Patients. Journal of Cardiac Failure 24 (2018): S30.
16. Njue F, Collins K, Hayes H, et al. Neurohormonal Blockade with Sacubitril/Valsartan in Left Ventricular Assist Device (LVAD) Patients. The Journal of Heart and Lung Transplantation 37 (2018): S484.
17. Alishetti S, Braghieri L, Jennings DL, et al. Angiotensin receptor neprilysin inhibitor use in patients with left ventricular assist devices: A single-center experience. Int J Artif Organs 45 (2022): 118-120.
18. Straw LB, Bowe S, Sloan B, et al. Safety and Effectiveness of Sacubitril/Valsartan in Patients with a Left Ventricular Assist Device. The Journal of Heart and Lung Transplantation 40 (2021): S445-446.
19. Roberts S, Stoller DA, Lyden E, et al. Sacubitril/Valsartan Improves Outcomes in Left Ventricular Assist Device Recipients. The Journal of Heart and Lung Transplantation 41 (2022): S352-353.
20. Schnettler, Jessica Kristin, Luise Roehrich, et al. Safety of Contemporary Heart Failure Therapy in Patients with Continuous-Flow Left Ventricular Assist Devices. Journal of Cardiac Failure 27 (2020): 1328-1336.