Abstract
Background
Reduction in systolic blood pressure (SBP reduction) during the treatment of acute decompensated heart failure (ADHF) is strongly and independently associated with worsening renal function (WRF). Our objective was to determine if SBP reduction or titration of oral neurohormonal antagonists during ADHF treatment negatively influences diuresis and decongestion.
Methods and Results
SBP reduction was evaluated from admission to discharge in consecutive ADHF admissions (n=656). Diuresis and decongestion was examined across a range of parameters such as diuretic efficiency, fluid output, hemoconcentration, and diuretic dose. The average reduction in SBP was 14.4 ± 19.4 mmHg and 77.6% of the population had discharge SBP lower than admission. SBP reduction was strongly associated with WRF (OR=1.9, 95% CI: 1.2-2.9, p=0.004), a finding that persisted after adjusting for parameters of diuresis and decongestion (OR=2.0, 95% CI: 1.3-3.2, p=0.002). However, SBP reduction did not negatively impact diuresis or decongestion (p≥0.25 for all parameters). Uptitration of neurohormonal antagonists occurred in over 50% of admissions and was associated with a modest additional reduction in blood pressure (≤ 5.6 mmHg). Notably, WRF was not increased and diuretic efficiency was significantly improved with the uptitration of neurohormonal antagonists.
Conclusions
Despite a higher rate of WRF, blood pressure reduction was not associated with worsening of diuresis or decongestion. Furthermore, titration of oral neurohormonal antagonists was actually associated with improved diuresis in this cohort. These results provide reassurance that the guideline recommended titration of chronic oral medication during ADHF hospitalization may not be antagonistic to the short-term goal of decongestion.
Keywords: renal function, acute heart failure, diuretics, blood pressure
Acute decompensated heart failure (ADHF) is predominantly a syndrome characterized by congestion and volume overload.1, 2 As such, the primary treatment objective in most ADHF hospitalizations is decongestion. Loop diuretics remain the mainstay of therapy to achieve this goal, meaning that the kidney serves as the primary conduit for volume removal in the majority of patients.3 Recently it has been reported in several studies that a reduction in blood pressure during the treatment of ADHF is strongly linked to worsening renal function (WRF).4-7 Importantly, major cardiovascular society guidelines recommend using hospitalization for ADHF as an opportunity to optimize or initiate chronic oral medications such as beta blockers and angiotensin converting enzyme (ACE) inhibitors.8-10 Given that these guideline directed medical therapies can reduce blood pressure, it is unclear whether the goal of initiating/titrating long term oral medications is antagonistic to the short term goal of decongesting the hospitalized patient. Although blood pressure reduction is strongly linked to worsening renal function, given the positive neurohormonal and hemodynamic effects of drugs such as angiotensin converting enzyme inhibitors, it is unclear if blood pressure reduction or the titration of these medications will actually negatively impact renal function or diuresis.11, 12 Therefore, the primary goal of this study was to investigate if either reduction in blood pressure or the initiation/uptitration of neurohormonal antagonists would negatively influence metrics of decongestion, either directly or indirectly as a precipitant of a reduction in blood pressure.
Methods
We reviewed consecutive admissions to the Hospital of the University of Pennsylvania with a primary discharge diagnosis of congestive HF admitted to the non-interventional cardiology and internal medicine services between 2004 and 2009 (n=656). The details of assembly of this cohort including a consort diagram have been previously published.13 Inclusion required a B-type natriuretic peptide (BNP) level of > 100pg/mL within 24 hours of admission, receipt of intravenous loop diuretics, and availability of data on fluid intake and output during the hospitalization. One additional patient was excluded as day of discharge systolic blood pressure was not recorded. Patients were selected who had a length of stay ≥ 3 and <14 days. Patients requiring renal replacement therapy were excluded. In the event of multiple hospitalizations for a single patient, only the first admission that satisfied the inclusion and exclusion criteria was used. The Social Security Death Index was used to determine all-cause mortality status.14 All-cause mortality was ascertained 2.5 years after discharge of the last patient in the cohort.
Focus of this analysis was on relative change in systolic blood pressure (SBP) as our prior work identified systolic blood pressure to be the most important determinant of change in renal function.4 Admission SBP was calculated as the mean of the first three values recorded in the chart and discharge SBP from the last three. SBP reduction was dichotomized about the median to define presence or absence of significant SBP reduction.4 Estimated glomerular filtration rate (eGFR) was calculated using the four variable Modification in Diet for Renal Disease (MDRD) formula.15 Worsening renal function (WRF) was defined as ≥ 20% decrease and improvement in renal function (IRF) as a ≥ 20% improvement in eGFR to account for the non-linear relationship between renal function and serum creatinine.16 Comparisons in eGFR were from admission to discharge. Hemoconcentration was defined as an increase in both hemoglobin and hematocrit at discharge as compared to admission values.17 Proportional pulse pressure was calculated as the ratio of the difference between systolic and diastolic blood pressure to systolic blood pressure at admission and discharge.
Loop diuretic doses were converted to furosemide equivalents with 1 mg bumetanide = 20 mg torsemide = 80 mg furosemide for oral doses, and 1 mg bumetanide = 20 mg torsemide = 40 mg furosemide for intravenous doses.18, 19 Diuretic efficiency was calculated by dividing the cumulative net fluid output during hospitalization by the cumulative IV loop diuretic dose (expressed as per 40 mg intravenous furosemide equivalents) over the hospitalization.13 Uptitration of neurohormonal antagonists was considered to have occurred if the dose of either ACE/ARB or beta blocker was greater at any time during the hospitalization than the dose prior to admission.
This study was approved or determined to qualify as exempt by the Institutional Review Boards of the Hospital of the University of Pennsylvania and Yale University.
Statistical analysis
Values are reported as Mean ± standard deviation, median (quartile 1 to quartile 3), or percentage. Student t test, Wilcoxon rank-sum test, or Kruskal-Wallis Test was used to compare continuous variables between groups. Categorical variables were compared using the chi squared test. The independent relationships between blood-pressure reduction, worsening renal function, diuretic efficiency, and medication initiation/titration was determined using logistic regression. Baseline variables with a univariate association with any of the above variables p<0.2 and with <10% missing values were entered into the model. These included age, sex, race, hypertension, diabetes, ischemic heart failure etiology, ejection fraction, heart rate, systolic blood pressure, edema, blood urea nitrogen, hemoglobin, b-type natriuretic peptide, serum sodium, eGFR, and baseline medication use. Models were built using backward elimination such that covariates with an association with mortality at p<0.2 were retained.20 Cox proportional hazards models were used to evaluate time-to event associations with all-cause mortality. Logistic regression using fractional polynomials of discharge SBP on the outcomes of low diuretic efficiency and worsening renal function were performed. Plots of the odds of outcome over discharge SBP were then created to visually assess non-linear relationships. A two sided p-value <0.05 was considered significant for all study analysis. Statistical analysis was performed with IBM SPSS Statistics version 21.0 (IBM Corp, Armonk, NY) and Stata 13.1 (StataCorp, College Station, TX).
Results
Baseline characteristics of the cohort are presented in Table 1. Overall, 77.6% of patients had a discharge SBP lower than the admission value, which translated into a mean absolute SBP reduction of 14.4 ± 19.4 mmHg. The median relative reduction in SBP was 9.9% (1.4% to 18.2%), and patients with an SBP reduction larger than this value were classified as having had significant SBP reduction. Patients with significant SBP reduction were more commonly African American, female, had a lower prevalence of diabetes, and less ischemic heart failure (Table 1). Systolic blood pressure and heart rate were higher and edema was less prevalent at the time of admission in patients with SBP reduction (Table 1). Baseline parameters of renal function tended to be better in patients that experienced SBP reduction (Table 1). Medications were similar with the exception of the loop diuretic dose, which tended to be lower in patients that experienced SBP reduction (Table 1). SBP reduction was associated with improved survival on univariate analysis (HR=0.79, 95% CI 0.64-0.97, p=0.03), however this relationship was no longer present after adjustment for baseline systolic blood pressure (p=0.40).
Table 1.
Baseline characteristics of the population
| Significant systolic blood pressure reduction | |||
|---|---|---|---|
| Yes (n=328) | No (n=328) | p-value | |
| Demographics | |||
| Age (years) | 62.4 ± 15.0 | 63.2 ± 15.9 | 0.54 |
| Male | 52% | 61% | 0.03 |
| African American | 71% | 58% | <0.001 |
| Medical History | |||
| Hypertension | 75% | 71% | 0.33 |
| Diabetes mellitus | 38% | 46% | 0.04 |
| Ischemic heart failure | 22% | 29% | 0.04 |
| Ejection fraction ≥40% | 30% | 35% | 0.11 |
| Heart rate (bpm) | 91.0 ± 19.4 | 87.8 ± 20.5 | 0.04 |
| Systolic blood pressure (mmHg) | 142.3 ± 29.7 | 120.8 ± 23.8 | <0.001 |
| Diastolic blood pressure (mmHg) | 83.9 ± 18.4 | 70.3 ± 15.6 | <0.001 |
| Jugular venous distension | 64% | 58% | 0.13 |
| Hepatojugular reflux | 23% | 22% | 0.82 |
| Moderate to severe Edema | 42% | 51% | 0.03 |
| Cardiac function | |||
| Ejection fraction (%) | 30.4 ± 19.6 | 33.8 ± 20.7 | 0.03 |
| Laboratory values | |||
| Creatinine (mg/dl) | 1.5 ± 0.9 | 1.7 ± 0.9 | 0.002 |
| Blood urea nitrogen (mg/dL) | 26.3 ± 18.4 | 34.3 ± 25.7 | <0.001 |
| Hematocrit (%) | 37.1 ± 6.0 | 35.7 ± 6.6 | 0.01 |
| Hemoglobin (g/dL) | 12.3 ± 2.0 | 11.9 ± 2.2 | 0.02 |
| BNP (pg/mL) | 1700 ± 1149 | 1687 ± 1238 | 0.89 |
| Sodium (mmol/L) | 139 ± 4.4 | 138 ± 4.9 | 0.002 |
| eGFR (mL/min per 1.73 m2) | 62 ± 28 | 55 ± 28 | 0.001 |
| Medications | |||
| ACE or ARB | 66% | 62% | 0.40 |
| Beta blocker | 71% | 75% | 0.37 |
| Thiazide | 14% | 11% | 0.20 |
| Aldosterone antagonist | 18% | 16% | 0.53 |
| Digoxin | 25% | 26% | 0.66 |
| Furosemide equivalents (mg) | 40 (0 to 80) | 40 (20 to 160) | 0.04 |
Systolic blood pressure reduction defined as relative decline in blood pressure from admission to discharge greater than the median value (>9.9% reduction). ACE: Angiotensin converting enzyme inhibitor. ARB: Angiotensin receptor blocker. BNP: B-type natriuretic peptide. eGFR: Estimated glomerular filtration rate.
SBP reduction and renal function
Similar to previous reports, SBP reduction was associated with WRF (OR=1.9, 95% CI: 1.2-2.9, p=0.004; Figure 1) and this association remained after adjusting for baseline characteristics including systolic blood pressure (OR=1.8, 95% CI 1.1-3.0, p=0.01). Furthermore, this relationship did not appear to be driven by aggressive diuresis since after controlling for in-hospital diuretic/treatment related parameters such as net fluid loss, total intravenous loop diuretic received, peak loop diuretic given in 24 hours, length of stay, hemoconcentration, diuretic efficiency, and inotrope use, SBP reduction remained strongly linked to WRF (OR=2.0, 95% CI: 1.3-3.2, p=0.002). Furthermore, the relationship appeared to be primarily driven by the change rather than the absolute level of discharge blood pressure since the risk of WRF was unchanged after adjustment for discharge blood pressure (OR=1.9, 95% CI: 1.2-2.9, p=0.004). SBP reduction was associated with a lower incidence of improvement in renal function (OR=0.4, 95% CI: 0.3-0.7, p<0.001) and the odds for WRF compared to IRF were substantially greater in patients that experienced SBP reduction (OR=3.4, 95% CI: 2.0-6.0, p<0.001). In sensitivity analysis examining the changes in proportional pulse pressure rather than SBP, we were unable to identify an association with risk of either WRF (p=0.96) or low DE (p=0.84).
Figure 1. Association between renal or diuresis related parameters with systolic blood pressure reduction.
Continuous variables on the Y axis were dichotomized about the median value. Odds ratio represents association between systolic blood pressure reduction above the median and the Y axis parameter. Bars represent 95% confidence intervals.
SBP reduction and diuresis
Diuretic efficiency was similar between patients with and without SBP reduction [523 mL/ 40 mg (194-1086) vs. 429 mL/ 40 mg (192-977), p=0.30]. Patients with SBP reduction had similar rates of low diuretic efficiency (defined as value < median; OR=0.8, 95% CI: 0.6-1.1, p=0.27; Figure 1) and this lack of association remained after adjusting for baseline characteristics (OR=0.9, 95% CI: 0.3-1.3, p=0.47). SBP reduction did not affect other metrics of diuresis and decongestion such as total and daily net-urine output, loop diuretic dose, use of adjuvant thiazides, hemoconcentration, percent of loop diuretic given intravenously, and length of stay (Figure 1 and Table 2).
Table 2.
Metrics of diuresis and decongestion in patients with and without reduction in systolic blood pressure
| Parameter | Significant systolic blood pressure reduction | ||
|---|---|---|---|
| No | Yes | p-value | |
| Diuretic Efficiency (net fluid output/40mg furosemide) | 429 (192-977) | 523 (194-1086) | 0.30 |
| Net fluid output (mL) | 4933 ± 5913 | 5440 ± 6741 | 0.31 |
| Net fluid output per day (mL/day) | 781 ± 903 | 854 ± 875 | 0.29 |
| Total intravenous loop diuretic (mg furosemide) | 300 (120-635) | 240 (120-600) | 0.88 |
| Intravenous loop diuretic received per day (mg furosemide/day) | 77 ± 78 | 72 ± 80 | 0.35 |
| Maximum IV loop diuretic dose received in 24 hours (mg furosemide) | 162 ± 140 | 149 ±148 | 0.23 |
| Proportion of loop diuretic given intravenously (%) | 65 ± 25 | 66 ± 28 | 0.90 |
| Hospital day transitioned to oral loop diuretic (days) | 4.5 ± 2.5 | 4.2 ± 2.4 | 0.24 |
| Adjuvant thiazide diuretic used | 16% | 15% | 0.73 |
| Hemoconcentration at discharge | 34% | 31% | 0.43 |
| Worsening renal function | 12% | 21% | 0.003 |
| Length of stay (days) | 6.7 ± 3.3 | 6.4 ± 3.2 | 0.25 |
Significant systolic blood pressure reduction defined as relative decline in blood pressure from admission to discharge greater than the median value (>9.9% reduction).
Importance and interactions with discharge systolic blood pressure
The average systolic blood pressure at the time of discharge was 117 ± 22 mmHg. Overall there was no linear interaction between the risk of WRF (p interaction=0.78) and low diuretic efficiency (p interaction=0.26) with discharge systolic blood pressure. However, this lack of interaction was likely driven by the fact that there were few patients with severe hypotension as only 67 (10%) patients had an SBP ≤ 90 mmHg, 39 (6%) ≤ 85 mmHg and 20 (3.0%) ≤ 80 mmHg. Across the majority of the spectrum of discharge blood pressure, the risk of WRF and low diuretic efficiency was flat (Figure 2A). However, below a systolic blood pressure of 85 mmHg a trend toward increased WRF (OR=1.6, p=0.26) and low diuretic efficiency (OR=1.6, p=0.14) emerged. A statistically significant increase in WRF and low diuretic efficiency emerged with a discharge systolic blood pressure <80 mmHg (WRF OR=3.6, 95% CI 1.4 to 8.9, p=0.004; low diuretic efficiency OR=3.1, 95% CI 1.1 to 8.6, p=0.02; Figure 2B).
Figure 2. Relationship between discharge blood pressure and worsening renal function (Panel A) and low diuretic efficiency (Panel B).
Red line represents the odds for either WRF or low DE as a function of discharge systolic blood pressure with a reference blood pressure of 117 mmHg (the mean value in the population). The cutpoint of a discharge systolic blood pressure of 80 mmHg, below which odds of both WRF and low DE were significantly increased, is marked in gray. WRF: Worsening renal function. DE: Diuretic efficiency.
Titration of neurohormonal antagonists
Titration or initiation of neurohormonal antagonists was common with 48.7% of the population starting or uptitrating ACE/ARB, 39.0% beta blockade, 22.9% both medications, and 65.1% one of the two classes of medication during hospitalization. Among patients who initiated ACEI therapy during hospitalization, the median starting dose was 5 mg (5 to 10 mg) of lisinopril equivalents, while the median uptitration was by 10 mg (5 to 20 mg). Among patients who initiated ARB therapy during hospitalization, the median starting dose was 37.5 mg (25 to 50 mg) of losartan equivalents, while the median uptitration was by 50 mg (25 to 50 mg). Newly starting or increasing the dosage of ACE/ARB and/or beta blocker was associated with a greater incidence of SBP reduction on univariable analysis (Table 3). However, the magnitude of additional blood pressure reduction was modest (ACE/ARB=4.7 mmHg, beta blocker=5.6 mmHg, both=5.4 mmHg, p<0.003 for all) and after adjustment for baseline characteristics there was no longer a significant relationship between initiation or uptitration of these medications and SBP reduction (Table 3). There was no relationship between initiation or uptitration of ACE/ARB and/or beta blockers with WRF both on univariable and multivariable analysis (Table 3). Similarly, the incidence of IRF vs. WRF was similar between patients that did or did not start/uptitrate ACE/ARB (OR=1.0, 95% CI 0.6 to 1.7, p=0.92). Interestingly, there was a strong relationship between initiation or uptitration of ACE/ARB and improved diuretic efficiency (Table 3). Median diuretic efficiency was significantly higher in patients with initiation/uptitration of ACE/ARB compared to those on stable doses [605 ml/40mg furosemide (251-1245) vs. 399 ml/40mg furosemide (176-853); p=0.001]. This relationship persisted after extensive adjustment for baseline characteristics including medication use (Table 3) in addition to in-hospital parameters such as length of stay, inotrope use, hemoconcentration, SBP reduction, and WRF (OR=1.5, 95% CI 1.0-2.1, p=0.04). Initiation or uptitration of beta blockers did not significantly influence diuretic efficiency (Table 3). Further, initiation of mineralocorticoid receptor antagonist therapy (n=73) was not associated with increased odds for WRF (p=0.52) or low DE (p=0.90). The rate of a discharge systolic blood pressure < 80 mmHg, 85 mmHg, or 90 mmHg was not significantly changed with in-hospital titration of either ACE/ARB or beta blocker therapy (p≥0.19 for all comparisons) and the odds for high diuretic efficiency with new start or uptitration of ACE/ARB were unaffected by adjustment for discharge systolic blood pressure (OR=1.7, 95% CI 1.3-2.4, p<0.001).
Table 3.
Association between initiation or titration of neurohormonal antagonists and blood pressure reduction, worsening renal function, and diuretic efficiency
| Medication started or dosage increased: | ||||||
|---|---|---|---|---|---|---|
| ACE/ARB (n=320) | Beta blocker (n=253) | ACE/ARB and Beta blocker (n=150) | ||||
| OR (95% CI) | p | OR (95% CI) | p | OR (95% CI) | p | |
| Unadjusted | ||||||
| Systolic blood pressure reduction | 1.6 (1.2-2.2) | 0.002 | 1.4 (1.0-1.9) | 0.04 | 1.5 (1.0-2.1) | 0.04 |
| Worsening renal function | 1.0 (0.6-1.5) | 0.90 | 1.1 (0.7-1.7) | 0.62 | 0.8 (0.5-1.3) | 0.39 |
| High diuretic efficiency | 1.7 (1.3-2.4) | 0.001 | 1.1 (0.8-1.5) | 0.57 | 1.5 (1.0-2.1) | 0.04 |
| Adjusted | ||||||
| Systolic blood pressure reduction | 1.1 (0.8-1.6) | 0.59 | 0.8 (0.6-1.2) | 0.35 | 0.7 (0.5-1.2) | 0.20 |
| Worsening renal function | 1.0 (0.6-1.6) | 0.99 | 1.2 (0.8-2.0) | 0.41 | 0.8 (0.4-1.4) | 0.39 |
| High diuretic efficiency | 1.5 (1.0-2.1) | 0.03 | 0.9 (0.6-1.3) | 0.66 | 1.3 (0.8-2.0) | 0.32 |
Systolic blood pressure reduction defined as relative decline in blood pressure from admission to discharge greater than the median value (>9.9% reduction). High diuretic efficiency defined as a value greater than the median (480 ml/40mg).
Discussion
The primary findings of the current analysis are that: 1) Despite the strong relationship between blood pressure reduction and worsening renal function, blood pressure reduction was not negatively associated with a wide range of metrics of diuresis and decongestion. 2) Initiation or uptitration of neurohormonal antagonists such as ACE/ARB or beta blockade did not appear to increase the rate of worsening renal function. 3) Initiation or uptitration of ACE/ARB was associated with a significant improvement in diuretic efficiency. 4) Only with moderate to severe hypotension (systolic blood pressure <80 mmHg) was the absolute level of blood pressure linked to a higher rate of WRF or worse diuresis. While these results are observational and causality cannot be concluded, they do provide reassurance that current guideline recommendations to utilize and ADHF admission as an opportunity to titrate potentially lifesaving chronic oral therapy is not antagonistic to the short-term goal of decongestion.
The observed differences between patients with and without SBP reduction were similar to findings previously reported from the ESCAPE trial, where notable difference in baseline characteristics between patients with and without SBP reduction included better metrics of renal function and higher blood pressure.4 The observation that reduction in blood pressure is strongly associated with a higher rate of WRF has been reported in several populations.4-7 Notably, changes in blood pressure have been shown to be significantly more important than change in invasively determined cardiac index, right atrial pressure, and pulmonary capillary wedge pressure.5 However, beyond these well documented effects on glomerular filtration, little is known about the consequences of reducing blood pressure on other domains of renal function such as sodium and water handling. Diuretic therapy represents the mainstay of therapy for decongestion in ADHF and thus the kidney serves as the conduit for volume removal in the majority of patients. Therefore, factors that affect kidney function could in theory compromise successful decongestion. However, in the current analysis, we found that across a diverse spectrum of markers of diuresis and decongestion there was no negative impact of reduction in blood pressure. These findings add to a growing literature suggesting that treatment induced changes in serum creatinine of small to moderate magnitude may have limited clinical importance.21 Among this literature is the DOSE trial, which found that use of high-dose compared to low-dose loop diuretics did not result in worsened outcomes despite a significantly increased rate of WRF.22
Another important finding of the current analysis was that initiating or increasing the dose of neurohormonal antagonists, in the context of careful selection of patients by the treating physician, did not lead to a detectable diminution in diuresis and decongestion. Notably, a new start or uptitration of ACE/ARB or beta blockade occurred in over half of the population. Although blood pressure was reduced to a greater extent in these patients, the absolute change in blood pressure was modest and the signal largely eliminated with adjustment for baseline confounders. This likely contributed to the absence of a statistically significant increase in the rate of WRF with initiation or uptitration of neurohormonal antagonists. However, many of the mechanisms by which hemodynamic perturbations and diuretic therapy lead to worsening renal function and diuretic resistance are mediated via neurohormonal activation.11, 12, 23 Although renin-angiotensin-aldosterone system inhibitors are often considered to have detrimental renal effects, there are potent positive direct renal effects. Specifically, inhibition of the renin-angiotensin-aldosterone system can lead to attenuation of renal angiotensin II-induced sodium reabsorption and increased renal blood flow, which may enhance diuresis and/or preserve GFR.23, 24 Illustrating this point, in an elegant study by Chen et al. administration of losartan simultaneously with a dose of furosemide resulted in preservation of glomerular filtration rate, renal plasma flow, and improved sodium excretion compared to furosemide administered alone.11 As a result, it is plausible that the improved diuretic efficiency and the absence of an increase in WRF with initiation/titration of ACEI or ARB in the current analysis was in part driven by direct positive renal neurohormonal and hemodynamic effects of the medications.
The finding of a J-shaped relationship between both WRF and diuretic efficiency with the absolute level of discharge blood pressure provides an important caveat in interpreting the above results. As the absolute level of discharge blood pressure approached 80 mmHg, the odds for both WRF and low diuretic efficiency sharply increased. Reassuringly this was a relatively uncommon scenario as only 10% of the population had a discharge blood pressure <90 mmHg and only 3% less than 80 mmHg and over the remainder of the spectrum above this range discharge blood pressure was unrelated to both WRF and diuretic efficiency. However, these findings do highlight the common sense fact that caution should be exercised in starting or titrating antihypertensive therapies such as neurohormonal antagonists when significant hypotension is present.
Limitations
Given the post-hoc retrospective nature of this analysis, uncontrolled confounding cannot be excluded and causality is impossible to conclude. Importantly, patients in this study were not randomized to a decrease in blood pressure or titration of neurohormonal antagonists. Rather, physicians who were not blinded to blood pressure, renal function, or metrics of diuresis made clinical decisions in part based upon the aforementioned parameters. As a result, the observations presented here are in the context of the clinical assessment and patient selection of a treating physician who felt it was safe/advantageous to carry out the treatment plan such as titration of the ACE inhibitor. Therefore, it should not be assumed that titration of neurohormonal antagonists or reduction in blood pressure in unselected patients will produce the same results. Further, net fluid balance is known to be difficult to track accurately even in ideal clinical conditions, and therefore point estimates resulting from this metric should be viewed in context of this limitation.25
Although an average of three admission and three discharge values were taken to calculate change in blood pressure, blood pressure may have been labile throughout the hospitalization in many patients. As a result, the effect of transient changes in blood pressure on renal function and diuresis remains unknown. Further, the exact time of each blood pressure measurement was not recorded; as a result, we are unable to exclude confounding by the length of time over which average admission and discharge SBP was determined. Additionally, transient worsening in renal function can result specifically from coadministration of multiple drugs (such as in the morning), and confounding due to this effect cannot be excluded.
Conclusion
Reduction in blood pressure during the treatment of ADHF is strongly associated with worsening renal function, but this was not associated with a worsening of diuresis. Titration of neurohormonal antagonists is associated with a modest decrease in blood pressure, however this did not translate into a significant increase in the rate of WRF and diuretic efficiency was actually improved. These results provide reassurance that the guideline recommended practice of titrating chronic oral medication during the treatment of ADHF, in appropriately selected patients, is likely not antagonistic to the short-term goal of decongestion. Additional research is warranted to investigate if routine uptitration of ACE/ARB during the treatment of ADHF can be recommended to improve diuresis.
Supplementary Material
Clinical Perspective.
Current guidelines recommend using heart failure hospitalization as an opportunity to optimize chronic oral medications, including neurohormonal antagonists. However, initiation or uptitration of these medications can cause a fall in blood pressure, which has been associated with worsening renal function in several studies. Since the kidney is the major conduit for fluid and sodium removal during treatment of decompensated heart failure, it is unclear whether the optimization of chronic oral medical therapy is antagonistic to the short-term goal of achieving decongestion. In this study, we investigated the relationship between significant blood pressure reduction and metrics of renal function and diuretic efficiency. We found that blood pressure reduction was strongly related to worsening renal function, but did not appear to impede successful diuresis by a number of different metrics. Initiation/uptitration of neurohormonal antagonists was associated with a modest decrease in blood pressure. However, this did not translate into a statistically significant increase in the rate of worsening renal function. Moreover, diuretic efficiency was actually superior in patients that had initiation or uptitration of neurohormonal antagonists. Overall, these results provide reassurance that titration of neurohormonal antagonists during heart failure hospitalization is not likely to hinder decongestion in appropriately selected patients, despite associated reduction in blood pressure. Furthermore, prospective research is needed to determine if intensification of neurohormonal antagonism during the treatment of decompensated heart failure is a strategy that can actually improve diuretic responsiveness.
Acknowledgments
Sources of Funding
NIH Grants, K23HL114868, L30HL115790 (JT), K24DK090203 (CP), and K23DK097201 (FPW): The funding source had no role in study design, data collection, analysis or interpretation.
Footnotes
Disclosures
None.
References
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