Diuretic resistance in patients with heart failure: Clinical characteristics and predictors of outcome

Mesfin Tasew; Tamirat Moges Aklilu; Senbeta Guteta Abdissa

doi:10.4103/jcls.jcls_1_20

ORIGINAL RESEARCH REPORT

Year : 2020 | Volume : 17 | Issue : 3 | Page : 66-73

Diuretic resistance in patients with heart failure: Clinical characteristics and predictors of outcome

Mesfin Tasew¹, Tamirat Moges Aklilu¹, Senbeta Guteta Abdissa²
¹ Department of Pediatrics and Child Health, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
² Department of Internal Medicine, Division of Cardiology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia

Date of Submission	01-Jan-2020
Date of Acceptance	21-May-2020
Date of Web Publication	04-Jul-2020

Correspondence Address:
Dr. Senbeta Guteta Abdissa
Department of Internal Medicine, Division of Cardiology, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 28287/1000, Addis Ababa
Ethiopia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jcls.jcls_1_20

Abstract

Background: Our aim was to study the clinical characteristics and predictors of mortality in heart failure (HF) with diuretic resistance. Methods: We conducted a 5-year retrospective study on 119 HF patients with diuretic resistance at Tikur Anbessa Specialized Teaching Hospital. The primary endpoint was mortality. We compared baseline characteristics and assessed association in patients who received high-dose (≥120 mg) versus low-dose (<120 mg) furosemide. Bivariate and multivariate logistic regression analyses were done. Results: Patients receiving high-dose diuretic had significantly higher mean values for age and in New York Heart Association Class IV HF and received a larger dose of hydrochlorothiazide than low-dose patients. They also had significantly higher mean values for systolic blood pressure (SBP), hemoglobin, and serum creatinine. There was no significant difference in mortality between the two groups. On multivariate analysis, association with the high-dose diuretic group remained significant for the higher mean value for SBP and serum creatinine. Independent predictors of mortality were anemia (adjusted odds ratio [AOR]: 4.1, 95% confidence interval [CI]: 1.1–15.2, P = 0.04), infective endocarditis (AOR: 4.9, 95% CI: 2.1–25.7, P = 0.01), and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (AOR: 3.1, 95% CI: 1.1–9.9, P = 0.04). The use of digoxin was associated with lower mortality (AOR: 0.21, 95% CI: 0.06–0.78, P = 0.01). Conclusions: In HF patients with diuretic resistance, anemia, infective endocarditis, and the use of NSAIDs were independently associated with increased mortality, whereas the use of digoxin was associated with reduced mortality. Early identification and treatment of the risk factors could play a role in reducing mortality.

Keywords: Diuretic resistance, heart failure, prognosis

How to cite this article:
Tasew M, Aklilu TM, Abdissa SG. Diuretic resistance in patients with heart failure: Clinical characteristics and predictors of outcome. J Clin Sci 2020;17:66-73

How to cite this URL:
Tasew M, Aklilu TM, Abdissa SG. Diuretic resistance in patients with heart failure: Clinical characteristics and predictors of outcome. J Clin Sci [serial online] 2020 [cited 2023 Jun 2];17:66-73. Available from: https://www.jcsjournal.org/text.asp?2020/17/3/66/288902

Introduction

In the management of patients with heart failure (HF), loop diuretics are the cornerstone of congestion relief and are widely used for acute management (up to 90% of patients) as well as for chronic stabilization.^[1],[2],[3] Despite the fact that diuretics themselves are not linked to increased survival,^[4],[5] diuretic efficacy has been shown to prolong event-free survival, regardless of glomerular filtration rate.^[5],[6]

Different studies have shown that low systemic blood pressure, elevated blood urea nitrogen (BUN), HF of ischemic origin, and diabetes are predictors of diuretic resistance.^{[3],[6],[7],[8]} These studies, which were primarily done in a patient population with ischemic heart disease (IHD) as an underlying cause for HF, also found that diuretic resistance is an independent predictor of worse inhospital outcomes for HF, early postdischarge mortality, and increased HF-related rehospitalization.^{[2],[7],[8],[9]}

In patients with HF, the assessment of clinical characteristics and estimation of mortality risk are important for clinical management and in triage for special interventions.^{[1],[2],[3],[10]} The prognostic value of various clinical or laboratory parameters has been demonstrated in numerous HF studies.^{[4],[5],[11],[12],[13]} One of the indicators used to guide treatment in clinical practice is congestive symptoms and signs. The other most commonly used parameters include left ventricular (LV) dysfunction, reduced exercise capacity, hypotension, azotemia, and arrhythmias.^[1],[3],[10]

Medical therapy for HF must be intensified as the disease progresses, and this is particularly true of diuretics.^[1] Diuretic treatment options in HF are primarily loop diuretics. However, some patients do not respond well to diuretic treatment, hence developing diuretic resistance.^[9]

Diuretic resistance in patients with HF has been explained by various pharmacokinetic and pharmacodynamic changes. These factors include cardiac pump failure, hyperaldosteronism, dietary indiscretion, gastrointestinal edema, drug–drug interactions, and insufficient concentrations of diuretics in HF patients with renal insufficiency.^{[14],[15],[16]}

The understanding of diuretic resistance is limited, particularly in low-income settings where rheumatic heart disease is the most common underlying cause of HF.^[17],[18] In addition, factors that affect the prognosis of HF patients with diuretic resistance are not well studied in these settings. In this study, we aimed to describe the baseline clinical characteristics and predictors of mortality in HF patients with diuretic resistance.

Methods

Study design and clinical setting

This is a 5-year (September 1, 2012, to August 31, 2017) retrospective study that was done at Tikur Anbessa Specialized Hospital (TASH) in Addis Ababa, Ethiopia, to assess the clinical characteristics and outcome of HF patients with diuretic resistance. TASH is an institution where specialized clinical services are rendered to the whole nation. TASH provides specialized cardiac care to patients referred from hospitals and health institutions from all regions of the country.

Study population and sample size

The study population consisted of patients with HF who were diagnosed with diuretic resistance. The primary outcome of interest was all-cause mortality. From a total of 560 patients with HF and with complete medical records, 119 fulfilled the inclusion criteria. Prior data that compared mortality in the high- versus low-dose diuretic treatment group of patients with HF showed a hazard ratio of 1:1.45 in the high-dose furosemide group. The total mortality rate in the low-dose group was 31% versus 44.8% in the high-dose group.^[9] Considering type I error probability of 5%, we eventually recruited medical records of 119 patients based on inclusion criteria.

Inclusion criteria

All HF patients above the age of 18 years and who were on follow-up at TASH cardiac clinics with the diagnosis of diuretic resistance.

Exclusion criteria

Hypertensive or other patients who were started on hydrochlorothiazide (HCT) simultaneously with or before furosemide^[4]
Incomplete data.

Operational definitions

Diuretic resistance was defined as:

Persistent congestion despite taking furosemide >80 mg/day or >3 mg/kg/day^[9],[19]
The addition of HCT as a diuretic after lack of improvement or worsening congestion despite an escalated dose of diuretics.

The high- and low-dose diuretic groups were defined according to the daily dose of loop diuretic (high-dose furosemide was defined as dose >120 mg/day or dose >6 mg/day).^[20]

Anemia diagnosis was made if the hemoglobin level was <12 g/dL.^[21]

HF was defined based on the presence of cardiologist-documented diagnosis of HF. HF was classified into groups based on the New York Heart Association (NYHA) Functional Classification.^[22]

Hypertension was defined based on cardiologist-registered diagnosis on the medical record. Patients were diagnosed to have hypertension if systolic blood pressure (SBP) was ≥140 mmHg, and/or diastolic blood pressure (BP) was ≥90 mmHg, or were taking antihypertensive medications.

IHD was defined based on the cardiologist-registered diagnosis of IHD on the medical record. The diagnosis of IHD was made based on a history of chest pain or shortness of breath or fatigue and echocardiography findings of regional wall motion abnormality.

Data collection

Data were collected from the patients' registry by trained nurses using a pretested structured questionnaire. From a total of 560 medical records, 119 fulfilled the inclusion criteria.

The questionnaire contained sociodemographic variables (age, sex, and residence), presenting signs and symptoms, type and dose of diuretics and other drugs, laboratory tests of full blood count, urea, plasma creatinine, and electrolytes. Data on comorbidities (cardiac or noncardiac), history and frequency of hospital admission, and survival were collected.

Data analysis

Data were entered into an electronic database using SPSS Statistics for Windows, Version 23.0 (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp), and then, data analysis was done. Categorical variables were reported as frequencies (%) and continuous variables were reported using mean (standard deviation). Baseline characteristics of patients in the high- and low-dose diuretic groups were compared with the Chi-square test for categorical variables and with the use of t-tests and analysis of variance (ANOVA) for continuous variables. Relationships of medication doses and other baseline variables to total mortality were evaluated by bivariate (for unadjusted event rates) analysis. Multivariate analysis was performed with the use of logistic regression (to determine adjusted odds ratios [AORs]). Variables entered into the regression analysis were age, sex, HF cause, NYHA class, laboratory data, baseline doses of diuretics, and the use of digoxin, HCT, spironolactone, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal anti-inflammatory drugs. In addition, variables included systolic and diastolic BP and heart rate, jugular venous distention, rales, and edema, as well as levels of serum sodium, potassium, chlorine, creatinine, BUN, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), and bilirubin. In cases of missing data, the “Exclude cases pairwise” option was used during analysis. This excludes the cases (persons) only if they are missing the data required for the specific analysis. A 5% significance level was adopted for all tests, and all tests were two-sided.

Ethical considerations

Ethical clearance was obtained from the Ethics and Review Committee of School of Medicine, College of Health Sciences, Addis Ababa University. As the data collection was from patients' registry, waiver of consent was requested and permission was obtained from the committee (Ref: PD/MF/354/11). All procedures were followed in accordance with the ethical standards.

Results

Medication use

All HF patients with diuretic resistance were taking furosemide as the primary diuretic (n = 119). The median daily dose was 160 mg (range: 40–480 mg/day). Most of the patients were taking other diuretic agents in combination that included HCT (n = 94, 74%, median daily dose 25 mg [range: 12.5–50]) and spironolactone (n = 115, 90.6%, median daily dose 25 mg [range 6.3–75]).

Group characteristics

The characteristics of patients receiving high versus low doses of loop diuretics are shown in [Table 1]. Patients under the age of 25 years constituted 38.7% of the overall HF patients with diuretic resistance. Mean daily doses of loop diuretics in the high- and low-dose groups were 234.9 (±86.0) versus 99.0 (±23.2).

Table 1: Demographic and clinical characteristics of patients with diuretic resistance by loop diuretic treatment group

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Patients receiving high-dose diuretics were older (40 years and above), with significantly higher mean values for age and in NYHA Class IV HF, and received a larger dose of HCT than low-dose patients. Significantly more patients (28 [84.8%]) with chronic rheumatic valvular heart disease received low-dose (28 [84.8%] low dose vs. 55 [64.0%] high dose), whereas those with dilated cardiomyopathy (1 [3.0%] low dose vs. 13 [15.1%] high dose) received high-dose diuretics.

HF patients who received high-dose diuretic also had significantly higher mean values for systolic BP, hemoglobin, and serum creatinine. They had significantly lower mean values for pulse rate and respiratory rate. There was no significant difference in mortality between the two treatment dose groups.

On multivariate analysis, the association with the high-diuretic group remained significant for the higher mean value for SBP and serum creatinine [Table 2].

Table 2: Clinical characteristics: Bivariate and multivariate analyses for the high-dose furosemide group

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Mortality: Clinical characteristics and outcome

As shown in [Table 3] and [Table 4], there was no significant baseline demographic and clinical characteristic difference in those patients who died.

Table 3: Baseline demographic characteristics of heart failure patients with diuretic resistance by mortality

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Table 4: Baseline clinical characteristics of heart failure patients with diuretic resistance by mortality

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Mortality was significantly higher in patients who had anemia, infective endocarditis, or two or more noncardiac comorbidities at baseline [Table 5]. Baseline mean SGOT and SGPT were also higher in those who died. In those patients who died, the use of digoxin was significantly lower, whereas the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was significantly higher.

Table 5: Comorbidity, baseline laboratory, and treatment characteristics of heart failure patients with diuretic resistance by mortality

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Unadjusted mortality rates

The univariate relation of patient characteristics to mortality is shown in [Table 6]. Anemia (crude odds ratio [COR]: 3.4, 95% confidence interval [CI]: 1.5–7.6, P = 0.03), infective endocarditis (COR: 3.7, 95% CI: 1.1–13.8, P = 0.04), and use of NSAIDs (COR: 2.2, 95% CI: 1.1–4.8, P = 0.04) were significantly associated with total mortality. The total mortality was lower in those who took digoxin (COR: 0.3, 95% CI: 0.1–0.7, P = 0.01) and spironolactone (COR: 0.2, 95% CI: 0.1–0.8, P = 0.02).

Table 6: Predictors of mortality: Bivariate and multivariate analysis

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Independent predictors of mortality

To correct for baseline differences between the treatment groups, multivariable analysis was performed [Table 6]. Independent predictors of mortality were anemia (AOR: 4.1, 95% CI: 1.1–15.2), infective endocarditis (AOR: 4.9, 95% CI: 2.1–25.7), and use of NSAIDs (AOR: 3.1, 95% CI: 1.1–9.9). The use of digoxin was associated with lower mortality (AOR: 0.2, 95% CI: 0.03–0.6).

Subgroup analysis in patients who had anemia

A one-way between-group ANOVA was conducted to explore the association of age groups with levels of hemoglobin. Participants were divided into three groups according to their age (Group 1: under 25 years; Group 2: 25–39 years; and Group 3: 40 years and above). There was a statistically significant difference at the P < 0.05 level in hemoglobin for the three age groups: F (2, 120) = 5.0, P = 0.008. The actual difference in mean scores between the groups was medium. The effect size, calculated using eta squared, was 0.08. Post hoc comparisons using the Tukey's honestly significant difference test indicated that the mean score for Group 1 (M = 10.91 ± 2.77) was significantly lower when compared to Group 3 (M = 13.75 ± 4.11). Group 2 (M = 12.72 ± 3.58) did not differ significantly from either Group 1 or 3.

Discussion

In this study of HF patients with diuretic resistance, we found that independent predictors of the overall mortality were anemia, infective endocarditis, and the use of NSAIDs. In the group of patients who died, anemia was significantly higher in patients under the age of 25 years when compared to those above the age of 40 years. We also found that mortality was significantly low in patients who were taking digoxin.

Our finding of anemia as an independent predictor of mortality was consistent with what was reported by Barlera et al. in their study of patients with chronic HF.^[23] In patients with HF, anemia may lead to ischemia of myocardium, myocardial stunning, apoptosis, and necrosis.^[24] The increased mortality with the use of NSAIDs is similar to a study done by Gislason et al. in patients with HF.^[25] The use of NSAIDs may as well contribute to diuretic resistance by impairing renal function and the ability of the kidney to excrete sodium chloride. In addition, they can cause hyperkalemia, particularly when used in combination with potassium-sparing diuretics or ACE inhibitors.^{[26],[27],[28]}

The finding of our study indicates a significantly lower mortality in patients who were taking digoxin, and this is in agreement with findings of the Digitalis Investigation Group (DIG) trial. A comprehensive post hoc analysis of data from the DIG trial indicates that at low doses, which is likely to achieve low (<0.9 ng/ml) serum digoxin concentration (SDC), digoxin reduces mortality and hospitalization in a broad spectrum of ambulatory men and women with chronic systolic or diastolic HF. At higher SDC, digoxin reduces HF hospitalizations but has no effect on mortality or all-cause hospitalizations.^[29] It has to also be noted that there are conflicting data regarding the mortality benefit of digoxin in patients with HF even though most suggest that it has a neutral effect.^[30]

We did not find a significant association between doses of loop diuretics and mortality in our study. This is in contrast to a study done by Neuberg et al. where they found that high doses of loop diuretics were independent predictors of mortality in patients with advanced HF.^[9] Neuberg et al. and the Diuretic Optimization Strategies in Acute HF (DOSE-AHF) trial also explained that there was a potential patient selection bias in their study, whereby patients who received higher diuretic doses were sicker than others, as evidenced by numerous prognostic characteristics such as NYHA Class IV HF and higher serum creatinine.^[1],[9]

We also found that high doses of loop diuretics were more likely to be given to HF patients with diuretic resistance in the following clinical conditions: NYHA Class IV HF, diagnosis of dilated cardiomyopathy, higher SBP, higher hemoglobin, higher serum creatinine, lower pulse rate and lower respiratory rate. Those patients who received high-dose loop diuretics were also more likely to be given a larger dose of HCT. Patients under the age of 25 years and those diagnosed with chronic rheumatic valvular heart disease were more likely to receive a lower dose of diuretics in our study. The association with NYHA Class IV HF and high serum creatinine is in agreement with the study by Neuberg et al. and the DOSE-AHF.^[1],[9] These findings of higher functional class and poor baseline renal function in the high diuretic group are consistent with a study done by Voors et al.^[8] Analyses in other studies suggest that higher doses of diuretics are necessary in severe cases with more impaired renal function, and thus, adverse effects may result from disease severity, more than from the dose of diuretics.^[3],[31] However, the high-dose loop diuretic and the concomitant use of a large-dose HCT are potentially deleterious. Because of its side effects, the combination therapy of high-dose loop diuretic with HCT needs to be accompanied with close follow-up. It has to be reserved for a selected group of patients who fail to respond to loop diuretics.^[10]

One possible mechanism for diuretic resistance in patients with chronic HF is that diuretic dose requirements tend to increase as the disease progresses because of worsening fluid retention.^{[32],[33],[34]} These phenomena are related by overlapping mechanisms. The mechanisms include decreased renal blood flow resulting from a low cardiac output, renin–angiotensin system activation and vasoconstriction, excess sodium and fluid intake, and the use of NSAIDs. Other mechanisms of diuretic resistance described in patients with HF include decreased drug absorption and renal adaptation to chronic therapy.^[28],[35]

Conclusions

We found that anemia, infective endocarditis, and the use of NSAIDs were independently associated with mortality in HF patients with diuretic resistance, whereas the use of digoxin was associated with lower mortality. Early identification and treatment of the risk factors could play a role in reducing mortality. When digoxin is used in the treatment of patients with HF and diuretic resistance, the administration of proper dosage needs to be ensured to maintain the mortality benefit. A multisite prospective study on HF with diuretic resistance at a larger scale needs to be conducted to have consistent evidence.

Limitations

The retrospective nature of our study remains the principal limitation of the current analysis. It is a single-center study with a relatively limited sample size. Thus, the results need to be evaluated with respect to other studies in the same field. The other limitation comes from the lack of data on daily urine output, fluid balance, weight measurements, and LV function. We applied multivariate analysis to reduce the potential confounding effects, but this could still be inadequate because of the relatively small sample size.

Acknowledgment

This study would not have been possible without the staff of cardiology outpatients and wards, Black Lion Hospital, and the registration and archives department workers. The Department of Internal Medicine and Pediatrics and Child Health, Addis Ababa University, also deserves gratitude for facilitating the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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