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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.

Conclusion

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.

References

1. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, Investigators P-H. Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993–1004.

2. Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019; 380: 539–548.

3. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016; 18: 891–975.

4. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O’gara PT. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017; 135: e1159–e1195.

5. Brugts J, Linssen G, Hoes A, Brunner-La Rocca H. Real-world heart failure management in 10,910 patients with chronic heart failure in the Netherlands. Netherlands Heart J 2018; 26: 272–279.

6. Jhund PS, Fu M, Bayram E, Chen C-H, Negrusz-Kawecka M, Rosenthal A, Desai AS, Lefkowitz MP, Rizkala AR, Rouleau JL. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J 2015; 36: 2576–2584.

7. Pellicori P, Urbinati A, Shah P, MacNamara A, Kazmi S, Dierckx R, Zhang J, Cleland JG, Clark AL. What proportion of patients with chronic heart failure are eligible for sacubitril–valsartan? Eur J Heart Fail 2017; 19:768–778.

8. Antol DD, Casebeer AW, DeClue RW, Stemkowski S, Russo PA. An Early View of real-world patient response to sacubitril/valsartan: a retrospective study of patients with heart failure with reduced ejection fraction. Adv Ther 2018; 35: 785–795.

9. Laflamme E, Vachon A, Gilbert S, Boisvert J, Leclerc V, Bernier M, Voisine P, Senechal M, Bergeron S. Usefulness of a titration algorithm for de novo users of sacubitril/valsartan in a tertiary centre heart failure clinic. Cardiovasc J Afr 2018; 29: 1–5.

10. Wachter R, Fonseca AF, Balas B, Kap E, Engelhard J, Schlienger R, Klebs S, Wirta SB, Kostev K. Real-world treatment patterns of sacubitril/valsartan: a longitudinal cohort study in Germany. Eur J Heart Fail 2019; 21: 588–597.

11. Martens P, Lambeets S, Lau C, Dupont M, Mullens W. Impact of sacubitril/valsartan on heart failure admissions: insights from real-world patient prescriptions. Acta Cardiol 2018; 74: 115–122.

12. Martens P, Beliën H, Dupont M, Vandervoort P, Mullens W. The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction. Cardiovasc Ther 2018; 36: e12435.

Find this article online on ESC Heart Fail.

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