Implications of renin-angiotensin-system blocker discontinuation in acute decompensated heart failure with systolic dysfunction

1 INTRODUCTION

Renin-angiotensin-system blockers (RASB) are cornerstones in the treatment of chronic heart failure with reduced left ventricular ejection fraction, leading to a reduction in morbidity and mortality.1-4 However, there remains some ambiguity whether RASB should be continued during the treatment of patients with acute decompensated heart failure (ADHF) who develop hypotension or worsening renal function. These circumstances may explain in part why a portion of patients with ADHF are not discharged on RASB therapy despite that discharge RASB usage is considered a quality of care metric and is associated with reduced readmission rates.5, 6 Herein, in two cohorts of patients with hospitalized ADHF, we have categorized practice patterns of RASB use and determined whether such patterns were associated with renal function and subsequent long-term outcomes.

2 METHODS

3 RESULTS

3.2 Clinical parameter changes during hospitalization

The changes in key clinical parameters, stratified by RASB classification, are shown in Table 3. Patients continued on RASB had a shorter length of stay compared to the other groups (median 6 days compared to 8 days in RASB initiation, 8 days in RASB discontinuation and 19 days in RASB nonuse, P = .02). However, diuretic efficiency measures and changes in serum sodium, hemoglobin, cardiac output or filling pressures were not significantly different among RASB groups.

Table 3. Clinical parameter changes throughout hospitalization in each RASB group for ESCAPE cohort

	Renin-angiotensin system blocker prescription (baseline - discharge)
Characteristicsa	Continuation (n = 305)	Initiation (n = 42)	Discontinuation (n = 21)	Nonuse (n = 23)	P-value
Hospital days	6.0 (4 to 9)	8 (5 to 14)	8 (6 to 16)	19 (10 to 23)	.02
Change in Systolic BP, mm Hg	−4.0 (−14 to 5)	−6 (−25 to 6)	−1.5 (−20.5 to 4)	1 (0 to 15)	.22
Change in total weight, kg	−2.6 (−5.6 to −0.6)	−4.1 (−7.7 to −2.2)	−1.2 (−4 to −0.3)	−0.5 (−9.8 to 0)	.06
Weight change per day, kg	−0.9 (−5.8 to −0.4)	−0.9 (−4.3 to −0.5)	−0.7 (−1.7 to −0.2)	−1.5 (−2.5 to −0.02)	.49
Furosemide dose on admission, mg	200 (120 to 320)	160 (160 to 320)	180 (80 to 300)	280 (160 to 360)	.7
Furosemide equivalent dose on discharge, mg	120 (70 to 200)	120 (60 to 160)	120 (80 to 160)	160 (120-240)	.5
Laboratory Results
Sodium, mmol/l	−1 (−4 to 1)	−2 (−5 to 0)	0 (−4 to 7)	−1.5 (−4 to 0)	.16
Potassium, mmol/l	0.1 (−0.25 to 0.5)	0.2 (−0.3 to 0.7)	0.3 (−0.4 to 0.7)	0.45 (−0.45 to 0.9)	.99
Creatinine, mg/dl	0 (−0.1 to 0.2)	0 (−0.2 to 0.2)	0 (−0.6 to 0.3)	0.1 (0 to 0.4)	.92
Blood urea nitrogen, mg/dl	2 (−4 to 10)	0 (−5 to 10)	−2 (−18 to 22)	0 (−36 to 5.5)	.69
BNP, ng/l	−150.0 (−617 to 13)	−589.9 (−1788 to −277)	57.2 (−3335 to 522)	111.2 (−1830-240)	.22
Hemodynamic Characteristics
RAP, mm Hg	−3 (−7.5 to 0)	−4.5 (−10 to 0)	0 (−2 to 2)	−3 (−6 to 2)	.13
PCWP, mm Hg	−7 (−13 to −2)	−7 (−18 to 0)	−3.5 (−6 to −3)	−2 (−5 to −1)	.16
Cardiac output, l/min	0.7 (−0.1 to 1.4)	0.7 (0.1 to 1.1)	0.5 (0.1 to 2.8)	−0.1 (−0.8 to 1.6)	.31
Cardiac index, l/min/m2	0.7 (−0.1 to 1.4)	0.3 (0.1 to 0.6)	0.7 (0.3 to 1.4)	−0.1 (−0.8 to 1.6)	.07

• Abbreviations: BP, blood pressure; BNP, brain natriuretic peptide; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure.
• ^a Values are presented as median (interquartile range) for continuous and n(%) for categorical variables.

Figure 1 illustrates the results from the mixed effects models testing the association of RASB group on serial measurements of serum creatinine, BUN, systolic blood pressure, and serum potassium through 7 days. In comparison to RASB continuation, RASB discontinuation and nonuse were associated with consistently higher serial serum creatinine and BUN levels (P < .001 for all groups). Furthermore, RASB discontinuation was associated with rising creatinine by days 5 (P-interaction = .02) and 7 (P-interaction = .002). On the other hand, there was no significant difference in serial serum creatinine over time between the RASB continuation or initiation groups (P = .6). In comparison to RASB continuation, RASB initiation, discontinuation, and nonuse were not associated with serial systolic blood pressure measurements or potassium levels.

3.3 Postdischarge RASB prescription

Figure 2 shows RASB use at 2 weeks, 1 month, 3 months, and 6 months according to the index hospitalization discharge RASB status. Those continued or initiated on RASB therapy at the time of discharge had a higher prevalence of RASB use over the next 6 months. Whereas, those with RASB discontinuation and nonuse had less RASB use over the 6 months compared to those with continued or initiated on RASB.

4 DISCUSSION

We demonstrate several findings that advance our understanding of RASB use in ADHF. First, RASB discontinuation and nonuse were associated with higher serial serum creatinine and BUN during hospitalization, but not serial systolic blood pressures or serial serum potassium levels. These data suggest that renal insufficiency, rather than hypotension or potassium disturbance, may be the dominant impetus for RASB discontinuation and nonuse in patients with ADHF. Second, RASB discontinuation was not associated with subsequent diuretic efficiency or hemodynamic parameters during hospitalization. Third, RASB discontinuation and nonuse was associated with longer term RASB nonuse post discharge. Finally, RASB discontinuation and nonuse were associated with a heightened risk for long-term adverse clinical outcomes. Altogether, these findings highlight the implications of renal function on RASB therapies and suggests RASB discontinuation and nonuse identifies a subset of patients with ADHF at higher risk of adverse events.

There remains uncertainty about the role of RASB use in patients with ADHF. The current heart failure practice guidelines caution against RASB use in patients with renal insufficiency, hypotension, or elevated potassium.12 However, there is little guidance regarding specifics, such as if a high baseline creatinine value contraindicates RASB use or if an increase in creatinine value necessitates discontinuation. As randomized trials demonstrating RASB benefit largely enrolled stable patients with chronic heart failure, the generalizability to the acute setting is limited.1-4 Additionally, RASB use can lead to small rises in serum creatinine as reduced glomerular pressure leads to decreased glomerular filtration rate, and although this phenomenon is considered benign in patients with compensated heart failure,13-16 it may create concerns among practitioners in the acute setting.

The present data are consistent with previous studies showing RASB discontinuation during ADHF is associated with worse outcomes.17, 18 In a pooled analysis of three ADHF cohorts, Vader et al similarly showed patients with RASB use at discharge had better renal function and lower risk of readmission and death.6 In a separate heart failure inpatient cohort, Kittleson et al showed that the discontinuation of ACEI for circulatory-renal limitations, specifically symptomatic hypotension or progressive renal dysfunction, was associated with increased mortality.19 In addition to providing further evidence of the adverse RASB discontinuation or nonuse risk-relationship, we expand upon these prior findings by providing insight that RASB discontinuation or nonuse is more likely associated with both higher serum creatinine and BUN rather than evolving hypotension. Importantly, there was a lack of association between RASB discontinuation and changing clinical and hemodynamic characteristics during hospitalization. Furthermore, no changes in renal function were observed in RASB discontinuation. Although this may suggest that RASB discontinuation may not impact the short-term clinical course of patients with ADHF, it is unknown if RASB discontinuation may have prevented adverse hemodynamic events.

Practice patterns underlying RASB discontinuation and nonuse vary without clear supporting evidence currently to justify reasoning, particularly in patients who remain hemodynamically stable. In a cohort of 174 patients admitted with ADHF, Kane et al showed that RASB therapy was reduced or discontinued in 17.2% of patients due to acute kidney injury (56.7%), hypotension (23.3%), and hyperkalemia (10%).20 Admission creatinine and SBP were both associated with RASB discontinuation and nonuse. Although the rationale for RASB discontinuation or nonuse was unknown in our cohorts, the lack of an association between RASB prescription and systolic blood pressure suggests that hypotension may not be the primary impetus for RASB discontinuation. Interestingly, patients off RASB at discharge had a higher rate of hydralazine use at discharge in both cohorts, perhaps due to its substitution for RASB in the setting of increased serum creatinine. To further evaluate the safety of RASB use in those with renal insufficiency or worsening renal failure (WRF) in future studies, it will be important to concomitantly assess clinical congestion. As WRF may be observed in ADHF, adverse outcomes seem to be driven by those who remain congested.21, 22 Thus, elucidating the cause of renal insufficiency in relation to congestion may distinguish the effects of RASB therapy. For instance, in patients with WRF due to over-diuresis, it may be appropriate to hold RASB therapy to prevent hypotension or further reductions in renal function. Conversely, a physiological rationale exists for continued RASB use in ADHF in those who remain congested with elevated creatine. RASB therapy interrupts a vicious maladaptive cycle of excessive neurohormonal activation (meant to preserve cardiac output and renal perfusion) by reducing renal pressures through the dilatation of post-glomerular efferent arterioles and reducing cardiac filling pressures through reducing cardiac afterload, enhancing diuresis, and inhibiting angiotensin II-induced sodium reabsorption.15 Whether continuing or initiating RASB therapy in those who are congested and normotensive with elevated creatinine warrants further investigation.

Although the clinical benefits of RASB use persist across the spectrum of renal function, individuals with renal insufficiency are less likely to be prescribed RASB.23, 24 While this might lead to attempts at re-initiation of RASB in the post-discharge outpatient setting, only a fraction of individuals with RASB discontinuation in our cohort were restarted. Although this might be reflective of the advanced nature of heart failure in our cohort likely at higher risk for more short-term adverse clinical outcomes, it has previously been shown that those discharged without a prescription for ACEI are unlikely to be started as outpatients.5 Whether RASB re-initiation post-discharge has direct impact on clinical events is unclear but given the benefits of ongoing RASB use in both chronic heart failure and chronic renal insufficiency,1-4, 25 the impact of RASB re-initiation post-discharge merits further exploration.

Our study must be interpreted in the context of several limitations inherent to its design. As a post hoc analysis, the direct impact of RASB discontinuation or nonuse in ADHF on outcomes remain uncertain. Yet, these findings highlight a high-risk group that might benefit from further investigation. Secondly, we cannot exclude selection bias for those treated for ADHF in the context of a clinical trial. However, the generalizability of these findings is supported by comparable findings with respect to long-term clinical outcomes in the CC cohort. Thirdly, whether there was active uptitration or downtitration of RASB during the hospitalization was unknown. While RASB uptitration has been associated with favorable clinical outcomes,26 dose changes in RASB were rare in our cohort and the majority (96%) that continued RASB were maintained on the same dose at discharge. As stated previously, the rationale for RASB continuation, discontinuation, initiation, or nonuse was unknown. Next, the composite outcome included all-cause hospitalization, as opposed to heart failure or cardiovascular hospitalization, in order to validate the observations in the Cleveland Clinic cohort, which only included data on all-cause hospitalization. Also, the multivariable models were adjusted for available risk factors to validate these findings in two cohorts. While additional clinical factors may influence the RASB risk relationship, these observations still inform the association between RASB use patterns and risk. Finally, we have equated prescription of RASB with use of RASB. Despite these limitations, detailed daily clinical data from a clinical trial allowed for serial measurements throughout hospitalization, along with validation of long-term outcomes by a separate ADHF cohort, gives practical insight into RASB use in patients with ADHF.

5 CONCLUSION

In comparison to RASB continuation, RASB discontinuation and nonuse was associated with higher baseline and serial serum creatinine and BUN during treatment for ADHF, but not with changes in SBP or other key clinical parameters. Furthermore, RASB discontinuation and nonuse in ADHF were associated with an increased risk of adverse clinical outcomes. These findings further highlight the implications of RASB use at the time of discharge. Prospective study determining the cardiorenal and clinical impacts of continuing RASB therapy in the face of renal insufficiency in individuals ADHF is warranted.

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.