Tolerability of Sacubitril/Valsartan in Patients With Durable Left Ventricular Assist Devices

Current guidelines from the International Society of Heart and Lung (ISHLT1) indicate that treatment with evidence-based heart failure (HF) medical therapies for HF and reduced ejection fraction (HFrEF) may also be beneficial in patients with durable left ventricular assist devices (LVADs). However, these recommendations were published before the “Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure” (PARADIGM-HF) trial which demonstrated that among stable patients with symptomatic HFrEF, treatment with the neprilysin–angiotensin receptor inhibitor sacubitril/valsartan, versus placebo, was associated with a 20% relative risk reduction in cardiovascular mortality or HF hospitalization.2 HF medical therapy may improve the likelihood of myocardial recovery3,4 and optimize hemodynamic parameters in patients with LVADs. Neprilysin inhibition with sacubitril/valsartan increases the levels of vasoactive peptides, thereby counteracting the neurohormonal activation in patients with HF.2 Sacubatril/valsartan results in increases in brain natriuretic peptide levels, but not N-terminal pro b-type natriuretic peptide (NT-proBNP) levels. Clinicians should use NT-proBNP in clinical settings where patients are using sacubitril/valsartan. Given these potential benefits, the clinical practice at Stanford University has been to consider sacubitril/valsartan as a potential antihypertensive therapy among patients with LVADs. However, to date, there is no prospective evidence supporting the use of sacubitril/valsartan for patients with durable LVADs. Furthermore, there is limited evidence of the tolerability of sacubitril/valsartan among these patients. To address this knowledge gap, we conducted a retrospective chart review of patients at Stanford University Hospital with LVADs who had been prescribed sacubitril/valsartan. We aimed to evaluate the safety of administration of sacubitril/valsartan among patients with LVADs. Our primary outcomes were short-term (1 month) and long-term (to end of follow-up) tolerability of sacubitril/valsartan. Tolerability was defined as absence of drug discontinuation because of symptomatic postural dizziness or postural hypotension (defined as a drop in mean arterial pressure [MAP] going from supine/sitting to standing of ≥ 20 mm Hg), acute kidney injury (AKI; defined as a rise in serum creatinine ≥ 0.3 mg/dl from baseline), or hyperkalemia (K ≥ 5.5 mmol/L at any time). Patients selected for this analysis received at least two doses of sacubitril/valsartan. From July 2015 to December 2017, we identified five patients who met our study criteria (Table 1). No patient was taking sacubitril/valsartan before LVAD implantation. The cohort consisted predominantly of men (%), with a mean age of 67 years (standard deviation [SD], 6.9) and the mean time from LVAD implantation to sacubitril/valsartan initiation was 849 days (SD, 740). The median time on therapy was 166 days (interquartile range, 76–386 days). The median MAP at baseline was 94 mm Hg (interquartile range, 86–100). All patients had ischemic cardiomyopathy. As per discretion of the treating physician, the primary clinical indication to initiate sacubitril/valsartan was for resistant hypertension (MAP ≥ 90 mm Hg) unresponsive (uncontrolled with) three or more antihypertensive medications. In our institution, Doppler pressure is the preferred method of obtaining MAP. All patients were receiving angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) before sacubitril/valsartan initiation. ACEi/ARBs were discontinued as per Food and Drug Administration guidelines before initiation of sacubitril/valsartan. No other therapies were discontinued to facilitate the initiation of sacubitril/valsartanTable 1.: Baseline CharacteristicsWithin 1 month, the median dose of sacubitril/valsartan achieved was 49 of 51 mg orally twice daily. In this time frame, one patient discontinued the medication at day 6, because of symptomatic postural hypotension. The LVAD speed at discontinuation was 2,620 rpm among patients remaining on sacubitril/valsartan, there was a significant decline in median MAP from baseline to one month (94 vs. 74 mm Hg; paired t-test p = 0.003; Figure 1). There was no evidence of AKI, hyperkalemia, or other adverse events associated with sacubitril/valsartan in the short-term period. At 1 month among patients remaining on sacubitril/valsartan, renal function, and serum potassium levels were not significantly different (Figure 1). By the end of follow-up, an additional two patients discontinued sacubitril/valsartan: one because of postural symptomatic hypotension at day 68 (LVAD speed at discontinuation 8,800 rpm); one because of AKI in the context of a LVAD thrombosis. Both patients who experience postural hypotension were also concomitantly prescribed beta-blockersFigure 1.: A comparison of baseline and 1 month mean arterial pressure, creatinine, and potassium. Values are presented as median with interquartile ranges. Sample size n = 5. p values are calculated using paired t-tests.In this small sample of patients with LVADs, sacubitril/valsartan successfully lowered MAP without resulting in AKI hyperkalemia. However, two of the five patients developed postural hypotension requiring discontinuation of therapy. To our knowledge, this is the first report evaluating the efficacy and tolerability of sacubitril/valsartan among patients with a LVAD. In the PARADIGM-HF trial, hypotension was the most common adverse event noted in patients randomized to sacubitril/valsartan.2 In our population two patients had the therapy discontinued due to postural hypotension. The PARADIGM-HF trial also demonstrated a mean difference of –2.7 mm Hg between sacubitril/valsartan and placebo. Although our study showed a more dramatic effect (a difference of 18 mm Hg in median MAP between baseline and 1 month of follow-up), which likely a consequence of our smaller sample size. Overall, the rates of myocardial recovery post LVAD implantation have been low, roughly 3% at 3 years.3 Aggressive optimization of HF pharmacologic therapy may play a role in weaning strategies and stabilization of right ventricular function.1,4 Control of MAP is critical to minimize the risk of adverse cardiovascular events, such as stroke, among LVAD patients.1 The use of concomitant antihypertensive agents must also be carefully evaluated as both patients who experience postural hypotension when prescribed sacubitril/valsartan were also prescribed a beta-blocker. The perioperative management of patients with LVADs going undergoing heart transplant should also be considered when evaluating the use of sacubitril/valsartan in this patient population as vasoplegia post heart transplant has been described.5 Given these considerations, although our analysis is limited by a small sample size, sacubitril/valsartan may play a role in the medical management of refractory hypertension among carefully selected patients with LVADs. However, currently, there is insufficient evidence regarding safety and efficacy of sacubitril/valsartan to recommend the use of this therapy in LVAD patients. Adequately powered prospective studies with longer-term results are needed to determine the tolerability and potential improvement of other cardiovascular clinical outcomes associated with the use of sacubitril/valsartan among patients with LVADs.

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