A practical approach to sequential nephron blockade in acute decompensated heart failure

Class of medication	Anticipated electrolyte or acid-base disturbances	Add-on diuretic agents to counteract the anticipated primary adverse event
Thiazide diuretics Loop diuretics	Hyponatremia	SGLT2i Vasopressin receptor antagonists
Thiazide diuretics Loop diuretics	Hypokalemia	MRAs
RAASi MRAs ENaC blockers	Hyperkalemia	SGLT2i Loop or thiazide diuretics
Thiazide diuretics Loop diuretics	Metabolic alkalosis	CA inhibitors MRAs
CA inhibitors MRAs	Metabolic acidosis	Thiazide diuretics Loop diuretics
Thiazide diuretics Loop diuretics	Hypomagnesemia	MRAs ENaC blockers
CA inhibitors Loop diuretics	Hypocalcemia	Thiazide diuretics ENaC blockers

1 Abbreviations: RAASi, renin-angiotensin-aldosterone inhibitors; MRAs, mineralocorticoid receptor antagonists; ENaC, epithelial sodium channel; CA, carbonic anhydrase; SGLT2i, sodium-glucose cotransporter 2 inhibitors

Table 2

Trials evaluating sequential nephron blockade.

Site of additional blockade	Trial	Background diuretics	Additional comparator agent versus placebo	Primary endpoint	Results	Additional findings
Proximal nephron blockade	EMPA-RESPONSE-AHF [62]	Loop diuretics	Empagliflozin (10 mg)	- Change in dyspnea - Diuretic response - Change in NT-proBNP - Length of stay	- No difference in any of the primary endpoint events	- Lower incidence of a combined endpoint of inhospital worsening of HF, rehospitalization for HF and mortality at 60 days. - Greater urinary output with empagliflozin
	EMPAG-HF [63]	Loop diuretics	Empagliflozin (25 mg)	- Cumulative urinary output over 5 days	- 25% increase in cumulative urine output over 5 days	- Empagliflozin increased diuretic efficiency compared with placebo, with more pronounced decrease in NT-proBNP
	EMPULSE [64]	Loop diuretics	Empagliflozin (10 mg)	- Weight loss - Weight loss adjusted per mean daily loop diuretic dose - Change in NT-proBNP - Hemoconcentration - Clinical congestion score	- Empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points	- Greater weight loss at Day 15 was associated with significantly higher probability for clinical benefit at Day 90 (composite endpoint of all-cause death, heart failure events, and a 5- point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days)
	DIURESIS-CHF [71]	Loop diuretics	Acetazolamide	- Natriuresis after 24 h	- Natriuresis after 24 h was similar in the combinational treatment vs. loop diuretic only arm	- Loop diuretic efficiency, defined as natriuresis corrected for loop diuretic dose, was higher in the group receiving acetazolamide
	ADVOR [22]	Loop diuretics	Acetazolamide	- Successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy	- Patients with acetazolamide add-on achieved more frequently successful decongestion both within 3 days after randomization (42.2% vs. 30.5%) and at discharge (78.8% vs. 62.5%).	- Acetazolamide led to a greater urinary output and natriuresis - Acetazolamide did not decrease the risk of death or rehospitalization for HF
Distal nephron blockade	CLOROTIC [79]	Loop diuretics	Hydrochlorothiazide	- Change in dyspnea - Change in body weight	- Patients assigned to HCTZ were more likely to lose weight at 72 h than those assigned to placebo, but there were no significant differences in patient-reported dyspnea	- Patients allocated to HCTZ showed greater 24-h diuresis and weight loss for each 40 mg of furosemide - There were no differences in mortality or rehospitalizations
	ATHENA-HF [83]	Standard therapy that may include low-dose spironolactone (12.5 or 25 mg)	Spironolactone 100 mg	- Change in NT-proBNP levels from baseline to 96 hours	- No significant difference in the log NT-proBNP reduction between the 2 groups	- No significant change in clinical congestion score, dyspnea assessment, urinary output, weight change, mortality or rehospitalization for HF.
	EVEREST [84]	Standard therapy	Tolvaptan	- All-cause mortality - Cardiovascular death or hospitalization for HF	- Tolvaptan had no effect on long-term mortality or heart failure–related morbidity	- Tolvaptan improved day 1 patient-assessed dyspnea, day 1 body weight, day 7 edema.
Distal nephron blockade	TACTICS-HF [55]	Loop diuretics	Tolvaptan	- Proportion of patients with at least moderate improvement in dyspnea by 7-point Likert scale at both 8 and 24 h, without death or need for rescue therapy within 24 h (defined as responders)	- The proportion defined as responders at 24 h (primary study endpoint) was 16% for tolvaptan and 20% for placebo (p = 0.32).	- Tolvaptan addition resulted in greater weight loss and net fluid loss compared with placebo
Distal nephron blockade	SECRET of CHF [56]	Loop diuretics	Tolvaptan	- 7-point change in self-assessed dyspnea at 8 and 16 h	- No difference in the primary endpoint of day 1 dyspnea reduction	- Tolvaptan led to a significantly greater weight loss and dyspnea reduction at day 3.

1 Abbreviations: HF, heart failure; HCTZ, hydrochlorothiazide

References

Authors

Metrics

Articles in this issue

DOI: https://doi.org/10.2478/rjc-2023-0021 | Journal eISSN: 2734-6382 | Journal ISSN: 1220-658X

Journal RSS Feed

Language: English, Romanian

Page range: 83 - 92

Published on: Sep 21, 2023

Published by: Romanian Society of Cardiology

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

acute decompensated heart failure,

diuretics,

diuretic resistance,

sequential nephron blockade,

decongestion,

electrolyte abnormalities

Related subjects:

Pediatrics and juvenile medicine,

Paediatric cardiology,

Surgery,

Cardiac surgery

© 2023 Georgiana-Valentina Frățilă, Bogdan Obrişcă, Gener Ismail, published by Romanian Society of Cardiology
This work is licensed under the Creative Commons Attribution 4.0 License.

Volume 33 (2023): Issue 3 (September 2023)