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Down-titration of diuretics predicts achievement of target dose of ARNI in real-world HFrEF patients

Literature - Pharithi RB, Ferre-Vallverdu M, Maisel AS et al., - ESC Heart Fail. 2020. doi: 10.1002/ehf2.12547.

Introduction and methods

The PARADIGM-HF trial demonstrated that sacubitril-valsartan reduced mortality and HF hospitalization in patients with HFrEF [1]. In addition, sacubitril-valsartan was found to be safe and effective when started during acute decompensated HF admission [2]. Sacubitril-valsartan is licensed for use in well-defined circumstances [3,4]. Real-world HFrEF patients are likely to be older, frailer and have an increased burden of comorbidities compared to clinical trial populations [5-7]. Furthermore, the majority of real-world studies on sacubitril-valsartan reported that the target dose was achieved in less than 50% of patients [8-10]. Achievement of the maximum dose influences outcomes [11,12]. There is therefore a need to better understand how real-world patients respond to sacubitril-valsartan with special focus on the tolerability, achieved dose and response patterns.

This single-center, retrospective, observational study examined the effect of sacubitril-valsartan in HFrEF (LVEF ≤35%) patients treated in outpatient clinics. 297 Stable HFrEF patients who were on maximally tolerated doses of ACEi/ARB therapy switched to sacubitril-valsartan. The median age was 70.0 years (61.9,76.2), 75% were male patients, and the median LVEF was 28% (23.7%,33.0%). Median follow-up in patients who tolerated sacubitril-valsartan was 519 days (281-738 days).

The primary endpoints were tolerability of sacubitril-valsartan and achievement of the target dose. Secondary endpoints were I) a reduction in NT-proBNP ≥ 30%, II) an increase in LVEF of ≥ 5% and III) an alteration of diuretic need.

Main results

  • 40 Patients (13.4%) did not tolerate sacubitril-valsartan. Main reasons for intolerability were: Symptomatic hypotension (20 patients, 50%), decline in eGFR of ≥30% (9 patients, 22.5%), gastrointestinal symptoms (5 patients, 12.5%) and hyperkalemia (4 patients, 10.0%).
  • Patients intolerant for sacubitril-valsartan were older (73.4 years [68.3,80.6] vs. 69.1 years [61.2,76], P=0.003), had worse renal function (median eGFR 53.5 mL/min.1.73 m² [36.8, 60.2] vs. 60 mL/min.1.73 m² [47,77], P≤0.001) and had higher but not statistically significant ST2 levels (43.6 ng/mL [25.3, 60.8] vs. 35.5 ng/mL [27.3, 51.8], P=0.30) compared those who tolerated sacubitril-valsartan.
  • The target dose of sacubitril-valsartan (97/103 mg BD) was achieved in 194 patients (75.5% of patients tolerating sacubitril-valsartan). 37 Patients (11.4%) received the intermediate dose (49/51 mg BD) and 26 patients (8.1%) received a low dose (24/26 mg BD). Main reasons for not achieving the target dose were: symptomatic hypotension (47 patients, 74.6%), renal deterioration (8 patients, 12.7%), hyperkalemia (3 patients, 48%) and gastrointestinal symptoms (3 patients, 4.8%). The strongest independent predictor of achieving the target dose was lowering of diuretic therapy dose (OR: 2.1, 95%CI: 1.16-3.8, P=0.014).
  • A reduction of ≥ 30% in NT-proBNP was observed in 46.3% of the cohort. An increase in LVEF of ≥ 5% was seen in 49.3% of the patients. Diuretic dose was reduced in 37.2% of the population with a mean reduction of 10 ± 38 mg furosemide equivalent in the entire population.


This single-center, retrospective, observational analysis of stable HFrEF patients who switched from ACEi/ARB therapy to sacubitril-valsartan, showed that sacubitril-valsartan was well tolerated in a routine community population. Target dose was achieved in the majority of the population. Reduction in diuretic dose was the strongest independent predictor of achieving the target dose of sacubitril-valsartan. These findings underline the importance of careful clinical assessment of volume status during the titration period.


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Find this article online on ESC Heart Fail.

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Schedule27 May 2024