Sacubitril/valsartan in heart failure with reduced ejection fraction patients: Real world experience on advanced chronic kidney disease, hypotension, and dose escalation

Abstract

Background: Angiotensin receptor and neprilysin inhibition (ARNI) has been shown to reduce cardiovascular mortality by 20% as compared with enalapril in a randomized controlled trial. However, there is a paucity of real-world data on the effects of ARNI in heart failure patients with reduced ejection fraction (HFrEF), especially those with concurrent renal impairment or hypotension. Methods: Between 2016 and 2017, we recruited 466 HFrEF patients treated with sacubitril/valsartan (Group A) and 466 patients managed with standard HF treatment without ARNI (Group B) in a HF referral center. Baseline characteristics and clinical outcomes were collected between both groups. Results: Baseline characteristics were comparable between the two groups. During a follow-up period of 15 months, death from cardiovascular causes or first unplanned hospitalization for HF occurred in 100 patients in Group A (21.5%) and 144 in Group B (30.9%, hazard ratio 0.66; 95% CI 0.51-0.85; p = 0.001). The incidences of deaths from any causes, cardiovascular death, sudden death, and HF re-hospitalization were all significantly lower in Group A than Group B patients. Among patients with different chronic kidney disease stages and normotensive patients, treatment with sacubitril/valsartan showed more favorable outcomes than treatment with standard HF care without ARNI. However, in patients with baseline systolic blood pressure lower than 100 mmHg, there were no significant differences of outcomes in both groups. Among Group A patients, escalation of sacubitril/valsartan was associated with better outcomes. Conclusions: Our study demonstrated the effectiveness of sacubitril/valsartan on HFrEF patients in real world practice, including those with advanced renal impairment.

Efficacy and safety of sacubitril‐valsartan in heart failure: a meta‐analysis of randomized controlled trials

“…28,24 In clinical practice, patients with all stages of kidney disease who receive treatment with sacubitril-valsartan have fewer cardiovascular deaths or hospitalizations for HF than those treated with standard therapy. 23 According to the pooled analysis of serum potassium concentrations greater than 5.5 mmol/L, there was no significant difference between the groups (OR 0.93, P = 0.10), although these concentrations were found in 13.2% of the sacubitril-valsartan group and 15.3% of the valsartan group (P = 0.048) in the PARAGON-HF study. 13 However, regarding the rate of serious hyperkalaemia (≥6.0 mmol/L), sacubitril-valsartan was associated with a lower rate than enalapril or valsartan (OR 0.75, P = 0.0007) in the PARAGON-HF, 13 PARAMOUNT, 9 and PARADIGM-HF studies.…”

“…The TRANSITION study 22 showed that the early initiation of sacubitril‐valsartan was selected for patients with acute decompensated heart failure with a reduced ejection fraction either in the hospital or shortly after discharge. A real‐world study involving 932 HFrEF patients verified the effectiveness of sacubitril‐valsartan 23 …”

“…However, because sacubitril‐valsartan blocks the renin‐angiotensin system and enhances the activity of vasoactive substances, such as bradykinin and natriuretic peptides, 32–34 treatment with sacubitril‐valsartan was associated with a higher rate of symptomatic hypotension, but there was no increase in the discontinuation rate due to adverse effects associated with hypotension 11 . The greater hypotension caused by sacubitril‐valsartan might impair renal perfusion, but several trials involving HF populations, including PARADIGM‐HF, 11 suggested that sacubitril‐valsartan slowed the decline in renal function compared with ACE inhibitors or ARBs alone and discontinuations of the study drug due to renal impairment were less frequent in the sacubitril‐valsartan group 23,31,35,36 . The UK HARP‐III study 28 included 414 participants with moderate‐to‐severe chronic kidney disease and showed that sacubitril‐valsartan was well tolerated and had similar effects on kidney function and albuminuria as irbesartan over 12 months of follow‐up.…”

“…The UK HARP‐III study on moderate‐to‐severe chronic kidney disease showed that treatment with sacubitril‐valsartan did not significantly affect kidney function 28,24 . In clinical practice, patients with all stages of kidney disease who receive treatment with sacubitril‐valsartan have fewer cardiovascular deaths or hospitalizations for HF than those treated with standard therapy 23 . According to the pooled analysis of serum potassium concentrations greater than 5.5 mmol/L, there was no significant difference between the groups (OR 0.93, P = 0.10), although these concentrations were found in 13.2% of the sacubitril‐valsartan group and 15.3% of the valsartan group ( P = 0.048) in the PARAGON‐HF study 13 .…”

Altered serum levels of neprilysin in heart failure patients with reduced ejection fraction

“…Importantly, impressive benefi ts of combining NEP inhibition and angiotensin II type 1 receptor (AT1R) blockade have been demonstrated in the heart failure with a reduced ejection fraction (HFrEF) (7), what markedly turned the clinical attention to NEP. Though a slower clinical acceptation (8), real-world data also confi rmed the effectiveness and safety of NEP inhibitor containing pharmacotherapy (9,10), supporting that NEP plays an important role in the pathophysiology of HFrEF and accentuating NEP as an attractive biotarget in clinical research of HF. It is assumed that NEP levels and/or activity are elevated in settings of HF and, consequently, its inhibition slows the degradation of NPs, enhancing diuresis, natriuresis, myocardial relaxation and anti-remodelling, thus providing clinical benefi t (3,11).…”