Novel doses of sacubitril/valsartan in patients unable to tolerate traditional therapy: Effects on N‐terminal pro B‐type natriuretic peptide levels

Abstract Background Widespread use of angiotensin receptor blocker and neprilysin inhibitor (ARNI) remains low, and many patients are unable to tolerate the medication due to hypotension at the currently recommended starting dose. Hypothesis The aim of this study is to assess if lower than standard doses of ARNI, sacubitril/valsartan (S/V), significantly reduces NT‐proBNP and leads to any change in diuretic dose, serum potassium, or creatinine. Methods In a retrospective study of 278 patients who were started on a low dose S/V at a single medical center, 45 patients were selected for the study cohort. Patients were subcategorized to Group 1 (n = 10): very low dose S/V (half a tab of 24/26 mg BID), Group 2 (n = 10): very low dose titrated to low dose S/V, and Group 3 (n = 25): low dose S/V (24/26 mg BID). NT‐proBNP, diuretic dose, serum potassium, and creatinine were compared before and after initiation of S/V. Results Among all groups, there was a significant reduction in NT‐proBNP level (Group 1: p < .01, Group 2: p < .01, and Group 3: p < .001). In addition, there was a significant reduction in diuretic dose across all groups combined (furosemide 53 mg/day vs. 73 mg/day; p = .03), with 17.8% (8/45) patients being able to discontinue their diuretic completely. There was no significant change in potassium or creatinine. Conclusions Lower than standard dose of S/V significantly reduces NT‐proBNP and diuretic requirement without change in potassium or creatinine, which provides hope that patients who cannot tolerate standard doses of S/V due to hypotension may be able to receive the benefits of S/V therapy.


| INTRODUCTION
Heart failure (HF) is one of the most detrimental and costly disease processes in medicine. Its influence is far reaching, affecting patient morbidity and mortality as well as overall healthcare costs. It is estimated that over 6.5 million adults suffer from HF in the United States and nearly 40 million adults affected worldwide. 1,2 Recently, the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial demonstrated significant promise for the future of pharmaceutical therapy in treatment of HF patients. 3 Sacubitril/valsartan (S/V) has been shown to be efficacious in many trials that have been completed or are ongoing. [3][4][5][6][7] The ability to act not only on RAAS system and reduce afterload as well as capitalize on the volume titration properties of NPs seems, in hindsight, to be an ideal combination. Furthermore, it is well established that NPs play a pivotal role in the process of natriuresis-and in turn diuresis-ultimately becoming a pivotal regulator of cardiovascular homeostasis through their paracrine and endocrine actions. 4,8,9 In the PARADIGM-HF trial, a 20% reduction in cardiovascular death or hospitalization for HF in the PARADIGM-HF led to the approval of S/V from the US Food and Drug Administration (FDA) as well as the European Commission in July 2015 and November 2015, respectively. 3 Furthermore, S/V earned designation as the first line therapy in a focused update of the ACC/AHA guidelines for the treatment of HF as well as the European HF clinical practice guidelines. [10][11][12][13] After a run-in phase that ensured all patients were able to tolerate enalapril 10 mg twice daily, patients were switched to S/V 49/51 mg twice daily and finally S/V to a goal dose of 97/103 mg twice daily. 6 Ultimately, the FDA approved three doses: a 23/24 mg (low dose), 49/51, and 97/103 mg (high dose). Subsequent to PARADIGM-HF, many post-hoc analysis were conducted to investigate hypotension with S/V. While patients were more likely to experience hypotension in the run-in phase of PARADIGM-HF with S/V therapy as compared to ACEI, these patients still derived benefits from S/V therapy. 14,15 Although the dose of S/V used was still among the standard dosing. 15 Subsequent "real world" studies also show a significant increase in hypotensive episodes with S/V as compared with ACEI. 16 Thus, despite estimates of profound benefit to HF patients, in current clinical practice, many patients cannot tolerate high doses of S/V, or even the smallest approved dose of 24/26 mg twice daily due to several factors including hypotension. 10,17,18 This remains even more so in older patients. 14 It remains unclear if lower doses of S/V are associated with reduction in NT-proBNP levels. In the current study, we aimed to investigate if S/V doses below the lowest approved 24/26 mg tablet correlate with reduction in NT-proBNP and associated beneficial effects in patients with HFrEF.

| Statistical analysis
All statistical analyses were performed using the Wilcoxon Rank-Sum test using GraphPad Prism software, Version (La Jolla, CA). Analysis for NT-proBNP level was performed between the baseline and final assessment after therapy. Difference in diuretic dosing was assessed for statistical significance as well with the Wilcoxon Rank-Sum test.
Significance was assessed by p ≤ .05. All analyses were conducted at the two-tailed level, and the significance was set at α ≤ .05.     (Table 1). Furthermore, 18% (8/45) were able to discontinue their diuretic therapy completely (none in Group 1, 3 in Group 2, and 5 in Group 3).

| Changes in serum potassium and creatinine
Overall, creatinine did not change across all groups. There was a trend for improvement in serum creatinine levels although Group 1 had non-significant increase in creatinine (1.14-1.18 mg/dl) ( Table 1).
There was a non-significant trend towards increase in potassium. Interestingly, when comparing the VLDS/V and LDS/V, about 30% of the patients were able to meet this reduction threshold.
In addition, patients were able to achieve reduction in diuretic dosing on S/V therapy, with some being able to discontinue all diuretic therapy. Reduction in diuretic therapy may be tied to the natriuresis resulting from increased circulating NP levels. 22 Given that no patient in Group 1 on VLDS/V therapy was able to discontinue diuretic therapy, it seems that while there is significant reduction in NT-proBNP levels with VLDS/V, concurrent diuretic therapy is still needed to achieve euvolemic state. However, there were patients both in Group 2 who were bridged from VLDS/V to LDS/V and in Group 3 on LDS/V, who were able to discontinue all diuretics while on S/V therapy.
As yet there is minimal data on the efficacy of S/V at doses below the target dose of PARADIGM-HF. One study reported that patients in PRADIGM-HF who were down-titrated to reduced doses of S/V did better than those on reduced doses of enalapril, although the reduction was from high dose to moderate dose S/V therapy. 15

| CONCLUSION
S/V is a hallmark therapy that reduces mortality and morbidity in HFrEF patients as evidenced in PARADIGM-HF trial. Usage of S/V in clinical practice remains low, in part limited by hypotension. This study supports the concept that patients who may not have received S/V due to low blood pressure can tolerate VLDS/V and LDS/V, which results in a significant reduction of NT-proBNP without any significant change in serum potassium or creatinine. Moreover, in patients who were able to tolerate LDS/V, there was a significant decrease in their diuretic dose and some were able to stop their diuretic completely.
While our study demonstrates a significant biomarker response to lower than standard dose of S/V, further investigation is needed to confirm clinical benefit with non-target doses of S/V.

ACKNOWLEDGMENTS
We would like to thank Ed Yoon, PharmD for his valuable technical assistance in querying for patients to be included in the study.
Amitabh C. Pandey is supported from the NIH NCATS CTSA Award to Scripps Research (KL2TR002552).

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.