Effects of Sacubitril/Valsartan (LCZ696) on Natriuresis, Diuresis, Blood Pressures, and NT-proBNP in Salt-Sensitive Hypertension

Abstract

S alt-sensitive hypertension (SSH) is characterized by an increase in blood pressure (BP) in response to sodium load and is associated with an increased risk of cardiovascular events. [1][2][3] Owing to high dietary salt intake and genetic predisposition, salt sensitivity of BP is of particular clinical relevance in Asian populations. [4][5][6][7][8] Considering its pathophysiology, thiazide-type diuretics are the preferred antihypertensive agents for patients with SSH.9-11 However, conditions such as hyponatremia and hypokalemia caused by thiazide-type diuretics often contribute to morbidity and mortality, if left unrecognized. Hence, antihypertensive agents that improve urinary sodium excretion without altering electrolyte concentrations would be a better therapeutic option for patients with SSH. Among multiple pathophysiological mechanisms, a relative deficiency of atrial natriuretic peptide (ANP) is considered to result in sodium retention and a suboptimal vasodilatory response to sodium loading observed in patients with SSH.12-15 The renin-angiotensin-aldosterone system (RAAS) also plays a role in the pathogenesis of SSH by modulating renal sodium reabsorption.16 Therefore, enhancing the activity of natriuretic peptides along with inhibition of the RAAS may be an effective, Abstract-Salt-sensitive hypertension (SSH) is characterized by impaired sodium excretion and subnormal vasodilatory response to salt loading. Sacubitril/valsartan (LCZ696) was hypothesized to increase natriuresis and diuresis and result in superior blood pressure control compared with valsartan in Asian patients with SSH. In this randomized, doubleblind, crossover study, 72 patients with SSH received sacubitril/valsartan 400 mg and valsartan 320 mg once daily for 4 weeks each. SSH was diagnosed if the mean arterial pressure increased by ≥10% when patients switched from low (50 mmol/d) to high (320 mmol/d) sodium diet. The primary outcome was cumulative 6-and 24-hour sodium excretion after first dose administration. Compared with valsartan, sacubitril/valsartan was associated with a significant increase in natriuresis (adjusted treatment difference: 24.5 mmol/6 hours, 50.3 mmol/24 hours, both P<0.001) and diuresis (adjusted treatment difference: 291.2 mL/6 hours, P<0.001; 356.4 mL/24 hours, P=0.002) on day 1, but not on day 28, and greater reductions in office and ambulatory blood pressure on day 28. Despite morning dosing of both drugs, ambulatory blood pressure reductions were more pronounced at nighttime than at daytime or the 24-hour average. Compared with valsartan, sacubitril/valsartan significantly reduced N-terminal pro B-type natriuretic peptide levels on day 28 (adjusted treatment difference: −20%; P=0.001). Sacubitril/valsartan and valsartan were safe and well tolerated with no significant changes in body weight or serum sodium and potassium levels with either treatments. In conclusion, sacubitril/valsartan compared with valsartan was associated with short-term increases in natriuresis and diuresis, superior office and ambulato...

Sacubitril‐Valsartan in a routine community population: attention to volume status critical to achieving target dose

“…Along with the observation that hypotension was the single greatest barrier to tolerance or successful titration of this agent, these two observations indicate that accurate volume assessment is a critical aspect of successful use of this compound. The reasons for diuretic reduction are not certain but are likely multifactorial, including improved diuretic response with preservation of natriuretic peptides, in addition to an overall improvement in ventricular function. A similar, though less impressive, response was observed with cardiac resynchronisation therapy with 19% of patients requiring down‐titration of their diuretic therapy .…”

Activity Sensors to Evaluate the Effect of Sacubitril/Valsartan on Quality‐of‐Life in Heart Failure: rational and design of the AWAKE‐HF study

“…24 Because treatment with sacubitril/valsartan may reduce the requirement for loop diuretic therapy in HFrEF through natriuretic and diuretic effects, 25,26 it is postulated that sacubitril/valsartan may impact fluid volume status, thereby reducing sleep apnoea severity. Although sleep disturbance or disorder is one of the most common complaints among patients with HF, there is a dearth of evidence on the impact of interventions on sleep.…”

Benefits and pitfalls of sacubitril/valsartan treatment in patients with hypertension

“…LCZ696 400 mg/d resulted in significant reduction of BP without changes in serum creatinine, serum urea nitrogen, potassium, or estimated glomerular filtration rate. In a recent study, Wang and colleagues tested the natriuretic, diuretic, and BP‐lowering effects of LCZ696 400 mg/d compared with valsartan 320 mg/d for 4 weeks in 72 Asian patients with salt‐sensitive hypertension. LCZ696 400 mg/d produced greater BP reductions by clinic and ambulatory BP measurements than valsartan 320 mg/d and greater natriuresis at 1 week but not by week 28.…”