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

Abstract

Aims In the PARADIGM‐heart failure trial, sacubitril‐valsartan demonstrated a reduction in heart failure admissions and reduced all‐cause mortality in patients with heart failure with reduced ejection fraction. Although real world data have shown similar benefits regarding efficacy and safety, there has been difficulty in achieving the target dose (TD). The factors preventing the achievement of TD remains unclear. This study assesses the tolerability, ability to achieve, and factors linked to attaining TD in a routine clinical population. Methods and results This is a retrospective single‐centre review of patients switched from angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers to sacubitril‐valsartan between May 2016 and August 2018. Baseline and follow‐up clinical characteristics and biomarker profiles were collected. Univariate and multivariate analyses were used to analyse predictors of achieving TD. Clinical response to sacubitril‐valsartan was defined as a reduction in N terminal pro BNP of ≥30%, or an increase in left ventricular ejection fraction of ≥5% compared with baseline values. To date, a total of 322 patients (75% male patients) have been switched to sacubitril‐valsartan. Those still in the titration phase were excluded (n = 25). Sacubitril‐valsartan was not tolerated in 40 patients (12.4%). Those intolerant were older (73.4 years [68.3, 80.6] vs. 69.1 years [61.2, 76]; P = 0.003) and had worse renal function with estimated glomerular filtration rate (53.5 mL/min/1.72 m2 [36.8, 60.2] vs 60 mL/min/1.72 m2 [47, 77]; P ≤ 0.001). Of the remaining 257 patients, TD (97/103 mg BD) was achieved in 194 patients (75.5%), while 37 patients (11.4%) were maintained on 49/51 mg BD and 26 patients (8.1%) remained on 24/26 mg BD. Symptomatic hypotension (74.6%) was the main impediment to attaining TD, followed by renal deterioration (12.7%), and to a lesser extent hyperkalaemia and gastrointestinal symptoms (4.8% each). Diuretic dose decrease was achieved in 37.2% of patients, and this was the strongest independent predictor of achieving TD (odds ratio = 2.1; 95% confidence interval [1.16, 3.8]; P = 0.014). Responder status by N terminal pro BNP criterion was observed in 99 of 214 patients (46.3%) while 70 of 142 (49.3%) attained the left ventricular ejection fraction response status. Achieving this response was independently linked to achieving TD. Conclusions Sacubitril‐valsartan was well tolerated. Achievement of TD was possible in the majority of the cohort and was linked to response metrics. Reduction in diuretic was required in a large percentage of the population and was the strongest predictor of attaining TD. Therefore, careful clinical attention to volume status assessment is essential to maximising the benefits of sacubitril‐valsartan.

Canadian Real-World Experience of Using Sacubitril/Valsartan in Patients With Heart Failure With Reduced Ejection Fraction: Insight From the PARASAIL Study

“… 12 Similarly, a more recent retrospective study in patients with HFrEF showed that the target dose of sacubitril/valsartan 97/103 mg was achieved in 65.3% of the total assessed population of 322 patients. 16 …”

<p>Cardiovascular Outcomes with Sacubitril-Valsartan in Heart Failure: Emerging Clinical Data</p>

“…For example: the average age of a patient with heart failure in the UK is 77 years at diagnosis, 87 whereas the average age of a patient in PARADIGM-HF was over 10 years younger. 4 However, data from real-world populations suggest that treatment with sacubitril-valsartan is associated with significant reductions in NTproBNP, 88 increases in LVEF, 88 and reductions in the rate of heart failure hospitalisation compared to pre-initiation. 89,90 The ARIADNE registry, which aims to describe current prescribing trends with regards to sacubitril-valsartan, is recruiting and will highlight any discrepancies.…”

Heart Failure With Mid-range or Recovered Ejection Fraction: Differential Determinants of Transition

“…[ 50 , 51 ] The benefits in terms of prognosis, rehospitalisation and quality of life offered by ARNI suggest that therapy initiated at the maximum tolerated dose, during the HFrEF stage, has to be continued at the same dosage, and should be down-titrated only if acute kidney failure or severe hypotension occur. [ 52 , 53 ] In the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF) trial, ARNI failed to reduce the primary composite endpoint of total hospitalisations for HF and CV death in patients with HF and LVEF ≥45%. [ 54 ] However, when data from Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure (PARADIGM-HF; eligibility criterion LVEF ≤40%; n=8,399) and PARAGON-HF (eligibility criterion LVEF ≥45%; n=4,796) were combined in a prespecified pooled analysis, the therapeutic effects of sacubitril/valsartan (ARNI) compared with a renin–angiotensin system inhibitor alone varied according to LVEF, but treatment benefits, particularly for heart failure hospitalisations, appeared to extend to patients with HFmrEF.…”