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Reviews in Cardiovascular Medicine  2019, Vol. 20 Issue (3): 111-120     DOI: 10.31083/j.rcm.2019.03.562
Special Issue: Cardiovascular disorders in chronic kidney disease
Review | Next articles
Continuation of Chronic Heart Failure Therapies During Heart Failure Hospitalization - a Review
Girish Singhania1, *(), Abutaleb A. Ejaz2, Peter A. McCullough3, 4, 5, 6, Aaron Y. Kluger3, 7, Saravanan Balamuthusamy8, 9, Bhagwan Dass10, Namrata Singhania11, Adhish Agarwal12
1 Department of Hospital Medicine, CHI St. Vincent Infirmary, Little Rock, AR, 72205, USA
2 Division of Nephrology, University of Florida, Gainesville, FL, 32610, USA
3 Baylor Heart and Vascular Institute, Dallas, TX, 75226, USA
4 Texas A&M College of Medicine Health Science Center, Dallas, TX, 75246, USA
5 Baylor University Medical Center, Dallas, TX,75246, USA
6 Baylor Heart and Vascular Hospital, Dallas, TX,75226, USA
7 Baylor Scott and White Research Institute, Dallas, TX,75204, USA
8 Texas Christian University/University of North Texas School of Medicine, Fort Worth, TX, 76129, USA
9 Tarrant Nephrology, Fort Worth, Texas, 76132, USA
10 Department of Hospital Medicine, University of Florida, Gainesville, FL, 32610, USA
11 Department of Hospital Medicine, Mount Carmel East Hospital, Columbus, OH, 43213, USA
12 Division of Nephrology, University of Utah, Salt Lake City, UT, 84112, USA
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Randomized controlled trials have demonstrated the benefits of guideline-directed medical therapy in the outpatient setting for treatment of chronic heart failure. However, the benefits of continuation (or discontinuation) of major chronic heart failure therapies when treating acute heart failure during hospitalization are less clear. Real and anticipated worsening renal function, hyperkalemia and hypotension are the three major reasons for discontinuation of renin-angiotensin-aldosterone system inhibitors during hospitalization, and a failure to resume renin-angiotensin-aldosterone system inhibitors before discharge could worsen cardiovascular outcomes. Available data, mostly observational, shows that continuation or initiation of renin-angiotensin-aldosterone system inhibitors appears efficacious, safe, and well tolerated in majority of acute heart failure patients during hospitalization. Worsening renal function portends poor prognosis only if associated with congestion in acute heart failure, and clinicians should not de-escalate diuretic therapy routinely for worsening renal function.

Key words:  Acute heart failure      cardiorenal syndrome      cardiovascular outcomes      medication continuation      medication discontinuation     
Submitted:  01 September 2019      Accepted:  23 September 2019      Published:  30 September 2019     
*Corresponding Author(s):  Girish Singhania     E-mail:

Cite this article: 

Girish Singhania, Abutaleb A. Ejaz, Peter A. McCullough, Aaron Y. Kluger, Saravanan Balamuthusamy, Bhagwan Dass, Namrata Singhania, Adhish Agarwal. Continuation of Chronic Heart Failure Therapies During Heart Failure Hospitalization - a Review. Reviews in Cardiovascular Medicine, 2019, 20(3): 111-120.

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Figure 1.  Physiological benefits of renin-angiotensin-aldosterone system inhibitors and neprilysin inhibitors in acute heart failure. RAASi, renin-angiotensin-aldosterone system inhibitors; AT1, angiotensin II receptor type 1; ADH, antidiuretic hormone; NEPi, neprilysin inhibitors, ANP, atrial natriuretic peptide; BNP, b-type natriuretic peptide or brain natriuretic peptide; CNP, c-type natriuretic peptide; PCWP, pulmonary capillary wedge pressure.

Table 1  Studies showing the effects of angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers and/or diuretics in patients with acute heart failure.
First Author/ Year/ Reference Study Design N Intervention Outcomes
Major findings/comments
Renal outcomes Hypotension Hyperkalemia (HK) Mortality/CV outcomes
Iglesias et al., 2019 Retrospective Age ≥ 65 years patients 2,361 Role of ACEi/ARB on mortality in CRS1 CRS1 occurred in 637 patients NA NA In-hospital mortality decreased significantly in patients receiving ACEi/ARB (6.8% vs 32.8%, OR 0.34, 95% CI 0.25-0.49). Development of CRS1 was significantly associated with increased in-hospital mortality (6.0% vs 3.9%, OR 1.54, 95% CI 1.03-2.3) Two strongest independent predictors of in-hospital mortality were CRS1 development (OR 7.8, 95% CI 3.9-15.5) and lack of ACEI/ARB usage (OR 0.49, 95% CI 0.25-0.93)
Kane et al., 2017 Retrospective chart review 174 30 patients reduced/Discontinued (r/d) ACEi/ARB 13 patients had WRF 4 patients had SBP less than 100 3 patients had HK ACEi/ARB dose r/d group had a significantly greater median LOS (5.5 vs 3.0 days) versus those without dose r/d Most common reasons for r/d of ACEi/ARB were WRF, Hypotension and HK
Gilstrap et al., 2017 Analysis of (GWTG-HF) registry 16,052 90.5% patients continued and started ACEi/ARB Incidence of WRF in each group: Continued ACEi/ARB: 11.84%
Started: 11.38% Discontinued: 15.58%,
Not started 13.23%
Incidence of SBP < 90: Continued: 2.80%, Started: 2.42%, Discontinued: 3.90%, Not started 1.82% Incidence of HK Continued:2.37%, Started: 1.59%, Discontinued: 3.90%, Not started 2.40% 30-day mortality higher on discontinued group HR: 1.92; (1.32-2.81) versus continued group
30-day mortality higher on not started group HR 1.50;(1.12-2.00) vs started.
1-year mortality on discontinued group HR 1.35 (1.13-1.61), and not started group HR of 1.28 (1.14-1.43) was higher compared to continued and started group respectively.
1-year composite endpoint (mortality or readmission) was higher in those discontinued
Sanam et al., 2016 Retrospective chart review 1,384 734 patients were initiated on ACEi/ARB NA NA NA 30-day all-cause mortality was lower in patients received ACEi/ARB compared to those who did not HR 0.56 (0.33-0.98). Patients on ACEi/ARB had lower risk of 30-day all-cause readmission HR 0.74 (0.56-0.97)
Yoshioka et al., 2019 Post hoc analysis of the REALITY-AHF trial 900 ACEi/ARB initiation within 48 hour of admission vs no ACEi/ARB 148 patients had WRF within 5 days. NA NA No significant difference was found for in-hospital mortality or incidence of WRF between two groups. The ACEi/ARB group had significantly higher event-free survival HR 0.51 (0.32-0.82)
Siddiqui et al., 2015 Retrospective 8,049 Studied medicare beneficiaries hospitalized for HF 2,180 patients had WRF NA NA 30-day all-cause mortality occurred in 5% and 9% of patients receiving and not receiving ACEi or ARB, respectively HR 0.89 (0.79-1.00). Benefit persisted at 1-year 30-day all-cause readmission occurred in 21% and 27% of patients receiving and not receiving ACEi or ARB, respectively HR 0.77 (0.62-0.95)
Fudim et al., 2018 Post hoc analysis of ESCAPE trial 433 AHF (EF ≤ 30%) therapy guided by measures of decongestion 68 patients had temporary WRF, 67 had persistent WRF NA NA Persistent congestion + WRF at discharge was associated with increased mortality HR 3.46 (1.89-6.31) compared to no WRF + no congestion. WRF was not significantly associated with 180-day all-cause death among decongested HR: 0.52 (0.20-1.35) Persistent congestion with concomitant WRF at discharge was associated with worse outcomes compared to patients without congestion and WRF
Aronson and Burger, 2010 Post hoc analysis VMAC trial 467 Comparing the hemodynamic and clinical effects of Nesiritide to nitroglycerin WRF occurred in 115 patients (24.2%) Persistent in 76 patients, Transient WRF in 39 patients NA NA Increased mortality in patients with persistent WRF HR 3.2 (2.1-5.0). Mortality of patients with transient WRF was similar to that of patients without WRF HR 0.8 (0.4-1.7) Transient WRF appears to be associated with a better outcome as compared with persistent WRF
Metra et al., 2018 A Post Hoc Analysis of the PROTECT Data 1,684 Rolofylline for AHF to Assess effect on Congestion and Renal Function Only studied patients with WRF NA NA WRF + congestion has higher 30-day mortality or HF hospitalization HR 1.49 (1.06-2.09) in congested patients. Congestion score ≤ 2 with WRF was not associated with worse outcomes HR 0.98 (0.76-1.27) LOS because of WRF was 3.51 (1.29-5.73) more days
Metra et al., 2012 Prospective 599 Patients were subdivided into 4 groups according to development or not of WRF and the persistence of congestion at discharge WRF + congestion: 45 patients. WRF + no congestion: 253 patients NA NA WRF + congestion HR 2.44 (1.24, 4.81). WRF + no congestion HR 1.04 (0.62, 1.73) WRF alone is not an independent determinant of outcomes in patients with AHF
Ahmad et al., 2018 Post hoc analysis of ROSE-AHF trial 283 High dose diuretics therapy and study of renal biomarkers 60 patients had WRF NA NA WRF in aggressively diuresed patients was not associated with worsened 180-day survival (adjusted P = 0.84) WRF in the setting of aggressive diuresis was not associated with renal tubular injury
Table 2  Studies showing the effects of mineralocorticoid receptor blockers and angiotensin II receptor blockers - neprilysin inhibitors in patients with acute heart failure.
First Author/ Year/ Reference Study Design N Intervention Outcomes
Major findings/comments
Renal outcomes Hypotension Hyperkalemia (HK) Mortality/CV outcomes
Ferreira et al., 2014 Prospective single center single blind 100 Standard therapy + spironolactone (treatment group) vs standard (control group) WRF was more frequent in control group 20% (10 patients) vs. 4% (2 patients); P = 0.038). NA Serum potassium did not differ significantly between groups Greater proportion of patients in the treatment group were free of congestion at day 3 NA
Maisel et al., 2014 Secondary analysis of COACH study 534 30-day outcome between patients treated with spironolactone vs not Spironolactone treatment was significantly beneficial in groups with elevated SCr (P = 0.009) NA NA Patients discharged on spironolactone had significantly less 30-day event (death or rehospitalization) HR 0.538 (0.299-0.968) 55% patients got spironolactone at discharge
Hamaguchi et al., 2010 Prospective 946 Prescription of Spironolactone at discharge NA NA NA All cause and cardiac death in spironolactone group was significantly reduced vs other HR 0.619 (0.413-0.928) and HR 0.524 (0.315-0.873) respectively 46% patients got spironolactone at discharge
Hernandez et al. , 2012 Retrospective. Medicare registry data 5,887 Studied patients who got MRA therapy (treated group) at discharge NA NA 30-day Incidence of HK was 2.9% vs 1.2% (P < .001) between treated vs not.
1-year (8.9% vs 6.3%)
No significant differences in mortality at 3-year between two groups HR 1.05 (0.97-1.15). 3-year HF readmission rate was lower among patients on MRA therapy at discharge HR 0.87 (0.77-0.98) Significant increase
in the risk of readmission with hyperkalemia at 30-day HR 2.54 (1.51-4.29) and 1-year HR 1.50 (1.23-1.84)
Tromp et al., 2017 Post hoc analysis of PROTECT trial 1,867 Studied association between HK at admission and mortality NA NA 176 patients (9%) had HK Potassium levels at admission or its change during hospitalization are not associated with mortality after multivariate adjustment. NA
Rossignol et al. , 2012 Post hoc analysis of EPHESUS trial 5,792 Post-acute MI patients were given Eplerenone vs placebo 914 patients had WRF (16.9% in eplerenoneand 14.7% in placebo). More frequent early decline in eGFR with Eplerenone NA Potassium level > 6 in 1 patient Early WRF was independently associated with all-cause mortality, cardiovascular death. Eplerenone continued to show clinical benefit on CV outcomes on patients with early WRF. Eplerenone is safe and beneficial in patients
with HF after myocardial infarction with a SCr
< 2.5 mg/dL and a serum potassium < 5.0 mmol/L
Greene et al., 2019 Post hoc analysis of ATHENA-HF 360 High dose Spironolactone (100mg) vs standard care (25 mg or placebo) WRF from baseline to 96 hours/discharge were similar in 2 groups NA HK from baseline to 96 hours and 30-day were similar in 2 groups eGFR ≤ 50 is associated with higher risk for mortality HR 12.11 (1.37-107.22) High-dose spironolactone did not improve congestion more than usual care, irrespective of renal function
Oh et al., 2015 Retrospective 1,035 Studied MRA use in CKD Patient with severe CKD 4-5 may not benefit from spironolactone NA Incidence of HK was 11.9% at admission, 3.6% at discharge, and 10.3% at 1 month after discharge Spironolactone use was not an independent predictor of all-cause mortality after adjusting other HF risk factors HR 0.974 (0.681-1.392) Spironolactone may not benefit AHF patients with severe renal dysfunction (eGFR < 45 mL/min per 1.73 m2)
Velazquez et al. , 2018 Randomized 881 ARNI vs enalapril group No change in renal function between two groups RR 0.93 (0.67 -1.28) No change in BP between two groups
RR 1.18 (0.85-1.64)
No change in potassium between two groups RR 1.23 (0.84-1.84) No change in mortality between two groups. 0.66 (0.3-1.48) Greater reduction in NT-proBNP level in ANI group
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[10] Leonardo De Luca, William T. Abraham, Gregg C. Fonarow<, Mihai Gheorghiade. Congestion in Acute Heart Failure Syndromes: Importance of Early Recognition and Treatment[J]. Reviews in Cardiovascular Medicine, 2006, 7(2): 69-74.
[11] Gregg C. Fonarow. Pharmacologic Therapies for Acutely Decompensated Heart Failure[J]. Reviews in Cardiovascular Medicine, 2002, 3(S4): 18-27.
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