Diuretic Response in Acute Heart Failure
Diuretic Response in Acute Heart Failure
We showed that poor diuretic response is associated with more advanced HF, renal impairment, diabetes, atherosclerotic disease, and in-hospital worsening HF, and independently predicts HF rehospitalization and mortality.
Current definitions of diuretic resistance are all similar—failure to diurese (or decongest) in response to escalating doses of diuretics. Diuretic absorption and efficacy is reduced in HF patients, and response is blunted further in AHF. This is the result of numerous pathophysiological processes present in HF, including reduced renal perfusion due to haemodynamic impairment, increased congestion, and neurohormonal activation, which contribute to renal impairment, WRF and cardiorenal syndromes, all highly prevalent in AHF. Yet despite a solid pathophysiological understanding of the underlying mechanisms, data examining both diuretic dose and effects in HF populations are scarce. Most studies have focused on diuretic dosage and outcomes, while the prognostic significance of effects on body weight or urinary output—as proxies for volume status—has not been examined prospectively in HF. Post hoc analyses from the DOSE trial indicate weight loss is associated with a better outcome, though Hasselblad et al. found no association between diuretic dose and weight loss in a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial. Van der Meer et al. have shown that haemoconcentration—a marker for intravascular decongestion—correlates with weight loss, lower diuretic doses, and lower mortality. In a recent study, Testani et al. retrospectively investigated what they termed diuretic efficiency in two AHF populations—net fluid output indexed to diuretic dose, and dichotomized into high and low efficiency. Similarly to our analyses, they found an independent prognostic effect on survival.
The proposed diuretic response metric—weight loss indexed to diuretic dose—reflects a 'dose–response' effect that can be understood intuitively. On a conceptual level, it can limit the bias intrinsic to each individual component; weight loss, for example, is not merely a marker for diuretic responsiveness, which may in part explain the inconsistent associations between weight loss and outcomes in past studies—better in DOSE and PROTECT, no differences in ESCAPE. A sicker patient may have accumulated more weight, and thus have the potential to loose more weight, but correction for diuretic dose should allow for 'correct' classification. Similarly, diuretic dose reflects a variety of patient and physician-related factors, so examining dose without its effect can lead to bias. While diuretic response does not capture an individual patient's (non-linear) dose–response curve, it does allow identification of patients with blunted response. This is supported by the observations that haemoconcentration was more common in good responders, that thiazides—often used to address loop diuretic resistance—were prescribed more often to less responsive patients, and that metozalone use independently predicted a poor diuretic response.
The value on Day 4 was chosen to reflect the fact resistance to diuretics is a dynamic process, not a static one, as outlined below. Sensitivity analyses showed consistent patterns in baseline characteristics and outcomes irrespective of high vs. low diuretic dose. We did note that patients who developed worsening diuretic response over time had a greater risk of rehospitalization outcomes in particular; while the initial diuretic response after 1 day of treatment is already predictive of outcome, responsiveness at a later time provides more accurate prognostic information. From a clinical perspective, examination of diuretic response is best suited for patients with manifest volume overload rather than those with redistribution HF alone. The findings in the congested group bear this out, with higher HRs and lower P-values on all endpoints in multivariable models and a slightly better model fit. Based on various measures for model performance (Harrell's C-index, AIC, and continuous NRI), diuretic response essentially provided the same prognostic information as the component variables in our population, even outperforming them for the prediction of HF rehospitalization. We believe this equivalence may be accepted, considering diuretic response provides a 'cleaner' signal for the matter under investigation. Further research will be necessary to confirm this.
In our study, patients with a poor diuretic response showed signs of more advanced HF and worse renal function. Comorbid conditions underlying both HF and renal impairment—including diabetes, atherosclerosis, and low haemoglobin levels—were also more common. The complex underlying physiology is reflected in the strong overlap with these and other clinical characteristics ( Table 1 ). Most were not independently predictive, suggesting strong colinearity with many of these variables; diuretic response may therefore merely reflect the confluence of these factors. The recent study by Testani et al. examining a fluid output-based diuretic efficiency metric showed some similarities to our results; diabetes, elevated BUN levels and a reduced eGFR were more common in poor responders. However, these analyses were limited in part by incomplete data on diuretic doses, examination of a dichotomized rather than continuous metric, and a lack of analyses examining independent predictors of efficiency, making meaningful comparisons difficult.
Diuretics exert their effects via the kidney, relying on secretion and to a minor degree on glomerular filtration to achieve therapeutic concentrations in the tubule. Diabetes and atherosclerosis can both cause glomerular damage and glomerulosclerosis, affecting GFR, while the Renin-Angiotensin system activation and inflammation common to both conditions likely also contributes to a reduced response. Haemodynamic impairment in HF causes congestion and reduced renal perfusion, while feedback mechanisms designed to preserve renal blood flow, GFR, and sodium levels lead to WRF and further congestion. In untreated HF, short-term decongestion with diuretics can acutely lower certain neurohormone levels. However, chronic diuretic use may cause structural changes in the tubular epithelium, resulting in sodium retention, worsening congestion, and neurohormonal activation, necessitating higher diuretic doses, with the potential for more renal damage. As a result of these effects, patients with AHF display a steeper dose–response curve than healthy controls or HF patients in a compensated state.
An intriguing finding in our study was the relatively small difference in renal function between good and poor responders—a difference of only 9 mL/min/1.73 m in estimated GFR, 0.2 mg/dL in creatinine, and 7 mg/dL in BUN between bottom and top quintiles of diuretic response. Except BUN, none of these renal function parameters independently predicted diuretic response outright, and there were no interactions with diuretic response in survival models. This is in contrast with the traditional view of diuretic resistance, in which renal function is the primary determinant. The explanation may lie in the limitations of creatinine (and creatinine-based GFR estimates) as a marker for renal function, as it provides no direct information about tubular function or injury. Novel tubular or combined (urinary) markers, such as cystatin C, NGAL, NAG, or KIM-1, may provide better insights into diuretic resistance phenomena. Another interesting finding was the relatively high incidence of WRF in the best quintile of diuretic response, despite better long-term outcomes. This is consistent with findings by Metra et al. indicating that effective decongestion is more important than (transient) WRF.
Interestingly, rolofylline independently predicted diuretic response. As this effect was driven by weight loss, not diuretic dose, it suggests either a direct diuretic effect, or potentiation of diuretics via improved haemodynamics, consistent with findings from earlier trials. Metra et al. previously noted an association between improvement in dyspnoea and rolofylline, though it should be noted that overall, rolofylline's effects on clinical outcomes were neutral, which, combined with safety concerns, resulted in discontinuation of the development programme. In PROTECT, patients received diuretics based on clinical assessment, and those with a poor diuretic response received higher doses and had worse outcomes. Although rolofylline did not prevent WRF, there is still a strong need for adjuvant therapies that improve diuresis without compromising renal function.
Loop diuretic therapy remains the cornerstone of decongestive treatment in AHF, despite a lack of convincing evidence or consensus on optimal dosage, and mixed evidence on survival impact. Alternative decongestive treatments, such as ultrafiltration, may be effective, but remain unproven.
We feel the simple measure of weight change per unit of diuretic provides better insight into patient response to therapy than examining weight loss or diuretic dose independently; diuretic dose provides insufficient information, as higher doses with adequate weight loss will be misclassified, while weight loss alone does not reflect the degree of resistance. Once validated and investigated further, diuretic response could be used in clinical research settings to help identify patients who might benefit from alternative or adjuvant decongestive therapies.
This study is a post hoc analysis of a randomized clinical trial, with all attendant limitations. The excluded subpopulation differed significantly from the analysed group, with higher incidences of multiple co-morbidities and worse outcomes. Multivariable modelling alone may not be sufficient to account for the differences, and our findings should be considered hypothesis-generating. Furthermore, available data did not allow extensive investigation of differences in diuretic responsiveness in HF with reduced vs. preserved ejection fraction. The true degree of volume overload in the congested subgroup also cannot be ascertained with certainty, as both oedema and rales may have other causes or be due to redistribution. Additionally, diuretic response as defined in this study is a linear relationship, while the dose–response relationship in vivo is S-shaped, and dependent on individual patient characteristics, making it difficult to model accurately post hoc.
Given the focus on diuretic response, data on urinary output and fractional sodium excretion would be preferred, although body weight is easily measured and recommended for monitoring volume status. The results from Testani et al. indicate indexed net fluid output contains similar prognostic information, and validation and comparison of both metrics in the same populations would be valuable. The study protocol did not specify how to assess weight, which could affect data quality. Serial measurements of these variables should be considered for all future AHF trials.
Discussion
We showed that poor diuretic response is associated with more advanced HF, renal impairment, diabetes, atherosclerotic disease, and in-hospital worsening HF, and independently predicts HF rehospitalization and mortality.
Current definitions of diuretic resistance are all similar—failure to diurese (or decongest) in response to escalating doses of diuretics. Diuretic absorption and efficacy is reduced in HF patients, and response is blunted further in AHF. This is the result of numerous pathophysiological processes present in HF, including reduced renal perfusion due to haemodynamic impairment, increased congestion, and neurohormonal activation, which contribute to renal impairment, WRF and cardiorenal syndromes, all highly prevalent in AHF. Yet despite a solid pathophysiological understanding of the underlying mechanisms, data examining both diuretic dose and effects in HF populations are scarce. Most studies have focused on diuretic dosage and outcomes, while the prognostic significance of effects on body weight or urinary output—as proxies for volume status—has not been examined prospectively in HF. Post hoc analyses from the DOSE trial indicate weight loss is associated with a better outcome, though Hasselblad et al. found no association between diuretic dose and weight loss in a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial. Van der Meer et al. have shown that haemoconcentration—a marker for intravascular decongestion—correlates with weight loss, lower diuretic doses, and lower mortality. In a recent study, Testani et al. retrospectively investigated what they termed diuretic efficiency in two AHF populations—net fluid output indexed to diuretic dose, and dichotomized into high and low efficiency. Similarly to our analyses, they found an independent prognostic effect on survival.
The proposed diuretic response metric—weight loss indexed to diuretic dose—reflects a 'dose–response' effect that can be understood intuitively. On a conceptual level, it can limit the bias intrinsic to each individual component; weight loss, for example, is not merely a marker for diuretic responsiveness, which may in part explain the inconsistent associations between weight loss and outcomes in past studies—better in DOSE and PROTECT, no differences in ESCAPE. A sicker patient may have accumulated more weight, and thus have the potential to loose more weight, but correction for diuretic dose should allow for 'correct' classification. Similarly, diuretic dose reflects a variety of patient and physician-related factors, so examining dose without its effect can lead to bias. While diuretic response does not capture an individual patient's (non-linear) dose–response curve, it does allow identification of patients with blunted response. This is supported by the observations that haemoconcentration was more common in good responders, that thiazides—often used to address loop diuretic resistance—were prescribed more often to less responsive patients, and that metozalone use independently predicted a poor diuretic response.
The value on Day 4 was chosen to reflect the fact resistance to diuretics is a dynamic process, not a static one, as outlined below. Sensitivity analyses showed consistent patterns in baseline characteristics and outcomes irrespective of high vs. low diuretic dose. We did note that patients who developed worsening diuretic response over time had a greater risk of rehospitalization outcomes in particular; while the initial diuretic response after 1 day of treatment is already predictive of outcome, responsiveness at a later time provides more accurate prognostic information. From a clinical perspective, examination of diuretic response is best suited for patients with manifest volume overload rather than those with redistribution HF alone. The findings in the congested group bear this out, with higher HRs and lower P-values on all endpoints in multivariable models and a slightly better model fit. Based on various measures for model performance (Harrell's C-index, AIC, and continuous NRI), diuretic response essentially provided the same prognostic information as the component variables in our population, even outperforming them for the prediction of HF rehospitalization. We believe this equivalence may be accepted, considering diuretic response provides a 'cleaner' signal for the matter under investigation. Further research will be necessary to confirm this.
Determinants of Diuretic Response
In our study, patients with a poor diuretic response showed signs of more advanced HF and worse renal function. Comorbid conditions underlying both HF and renal impairment—including diabetes, atherosclerosis, and low haemoglobin levels—were also more common. The complex underlying physiology is reflected in the strong overlap with these and other clinical characteristics ( Table 1 ). Most were not independently predictive, suggesting strong colinearity with many of these variables; diuretic response may therefore merely reflect the confluence of these factors. The recent study by Testani et al. examining a fluid output-based diuretic efficiency metric showed some similarities to our results; diabetes, elevated BUN levels and a reduced eGFR were more common in poor responders. However, these analyses were limited in part by incomplete data on diuretic doses, examination of a dichotomized rather than continuous metric, and a lack of analyses examining independent predictors of efficiency, making meaningful comparisons difficult.
Diuretics exert their effects via the kidney, relying on secretion and to a minor degree on glomerular filtration to achieve therapeutic concentrations in the tubule. Diabetes and atherosclerosis can both cause glomerular damage and glomerulosclerosis, affecting GFR, while the Renin-Angiotensin system activation and inflammation common to both conditions likely also contributes to a reduced response. Haemodynamic impairment in HF causes congestion and reduced renal perfusion, while feedback mechanisms designed to preserve renal blood flow, GFR, and sodium levels lead to WRF and further congestion. In untreated HF, short-term decongestion with diuretics can acutely lower certain neurohormone levels. However, chronic diuretic use may cause structural changes in the tubular epithelium, resulting in sodium retention, worsening congestion, and neurohormonal activation, necessitating higher diuretic doses, with the potential for more renal damage. As a result of these effects, patients with AHF display a steeper dose–response curve than healthy controls or HF patients in a compensated state.
An intriguing finding in our study was the relatively small difference in renal function between good and poor responders—a difference of only 9 mL/min/1.73 m in estimated GFR, 0.2 mg/dL in creatinine, and 7 mg/dL in BUN between bottom and top quintiles of diuretic response. Except BUN, none of these renal function parameters independently predicted diuretic response outright, and there were no interactions with diuretic response in survival models. This is in contrast with the traditional view of diuretic resistance, in which renal function is the primary determinant. The explanation may lie in the limitations of creatinine (and creatinine-based GFR estimates) as a marker for renal function, as it provides no direct information about tubular function or injury. Novel tubular or combined (urinary) markers, such as cystatin C, NGAL, NAG, or KIM-1, may provide better insights into diuretic resistance phenomena. Another interesting finding was the relatively high incidence of WRF in the best quintile of diuretic response, despite better long-term outcomes. This is consistent with findings by Metra et al. indicating that effective decongestion is more important than (transient) WRF.
Interestingly, rolofylline independently predicted diuretic response. As this effect was driven by weight loss, not diuretic dose, it suggests either a direct diuretic effect, or potentiation of diuretics via improved haemodynamics, consistent with findings from earlier trials. Metra et al. previously noted an association between improvement in dyspnoea and rolofylline, though it should be noted that overall, rolofylline's effects on clinical outcomes were neutral, which, combined with safety concerns, resulted in discontinuation of the development programme. In PROTECT, patients received diuretics based on clinical assessment, and those with a poor diuretic response received higher doses and had worse outcomes. Although rolofylline did not prevent WRF, there is still a strong need for adjuvant therapies that improve diuresis without compromising renal function.
Clinical Perspectives
Loop diuretic therapy remains the cornerstone of decongestive treatment in AHF, despite a lack of convincing evidence or consensus on optimal dosage, and mixed evidence on survival impact. Alternative decongestive treatments, such as ultrafiltration, may be effective, but remain unproven.
We feel the simple measure of weight change per unit of diuretic provides better insight into patient response to therapy than examining weight loss or diuretic dose independently; diuretic dose provides insufficient information, as higher doses with adequate weight loss will be misclassified, while weight loss alone does not reflect the degree of resistance. Once validated and investigated further, diuretic response could be used in clinical research settings to help identify patients who might benefit from alternative or adjuvant decongestive therapies.
Limitations
This study is a post hoc analysis of a randomized clinical trial, with all attendant limitations. The excluded subpopulation differed significantly from the analysed group, with higher incidences of multiple co-morbidities and worse outcomes. Multivariable modelling alone may not be sufficient to account for the differences, and our findings should be considered hypothesis-generating. Furthermore, available data did not allow extensive investigation of differences in diuretic responsiveness in HF with reduced vs. preserved ejection fraction. The true degree of volume overload in the congested subgroup also cannot be ascertained with certainty, as both oedema and rales may have other causes or be due to redistribution. Additionally, diuretic response as defined in this study is a linear relationship, while the dose–response relationship in vivo is S-shaped, and dependent on individual patient characteristics, making it difficult to model accurately post hoc.
Given the focus on diuretic response, data on urinary output and fractional sodium excretion would be preferred, although body weight is easily measured and recommended for monitoring volume status. The results from Testani et al. indicate indexed net fluid output contains similar prognostic information, and validation and comparison of both metrics in the same populations would be valuable. The study protocol did not specify how to assess weight, which could affect data quality. Serial measurements of these variables should be considered for all future AHF trials.
