Title Page
2nd Revision. February 2015 Invited “Point-Counterpoint” manuscript: Intravenous furosemide for acute decompensated congestive heart failure; what is the evidence? Word count 1599 (excluding title page and references)
Authors: David RJ Owen1, Raymond MacAllister2, Reecha Sofat2.
1
Division of Brain Sciences, Imperial College, Hammersmith Hospital, London W12 0NN, UK
2
Centre for Clinical Pharmacology, University College London, London, UK
Running Title: Furosemide in decompensated heart failure
Corresponding Author: David RJ Owen 2nd revision. February 2015.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/cpt.120
This article is protected by copyright. All rights reserved.
Use of intravenous (IV) furosemide in preference to oral administration in acute decompensated congestive cardiac failure (ADCCF) is universally recommended in international guidelines (1, 2), although the justification is largely unreferenced. The Heart Failure Society of America guidelines (2) recommend this switch on the basis that oral bioavailability is highly variable within the same patient, and substantially reduced during cardiac decompensation. However, no evidence to support this advice is cited.
In patients with acute respiratory distress, IV furosemide offers rapid improvement that is due, at least in part, to direct effects on vasculature that precede diuresis (3, 4). Whilst these same vascular effects (that also precede diuresis) occur also with oral administration (5), administering furosemide IV in acutely compromised patients is rational because of the more rapid onset of action (5). However, in patients who present with fluid overload without respiratory compromise, we argue that the rationale for the use of IV rather than oral furosemide is less clear, and that the evidence base does not support its preferred use. Here, we present pharmacokinetic data suggesting that there is little evidence to support the claim that furosemide absorption is substantially altered by fluid overload. There is no pharmacodynamic data available that directly compares oral and IV administration for a given furosemide exposure. However, we present pharmacodynamic data suggesting that the high peak concentrations obtained with IV bolus doses (that oral administration would not be able to achieve) do not appear to be a major determinant of overall clinical response. We therefore propose that the role of oral furosemide should be reassessed in patients with fluid overload but without respiratory distress. Improved evidence in this field may have substantial impact on the ways in which patients with ADCCF are treated, leading to a reduction in hospital admissions due to greater use of oral diuretic therapy in primary care.
Pharmacokinetics
Two studies have addressed the specific question of whether furosemide pharmacokinetics are altered in the presence of ADCCF. In 1985, Vasko et al studied 11 patients with ADCCF, administering a single dose of oral furosemide during an acute admission and then subsequently when the patient was euvolaemic (6). The pharmacokinetic profile of furosemide differed between the two volume states (figure 1); when euvolaemic, drug absorption was faster and the peak plasma concentration was higher compared with acute decompensation . However, there was no significant change in area under the plasma furosemide curve (AUC) between either state. Therefore in acute decompensation and euvolaemia, there was no difference in the amount of drug that reached the circulation for a given oral dose of furosemide. Analogous results were reported in a subsequent study in 1998 (7). Here, 37 patients with ADCCF were administered an oral dose of furosemide (n=18) or torsemide (n=19), and administration was repeated when the patients were euvolaemic. With furosemide, there were no significant
This article is protected by copyright. All rights reserved.
differences in time to peak furosemide concentration or maximum furosemide concentration when the patients were acutely decompensated compared with euvolaemia. Again, there was no significant difference in AUC between the two volume states; median relative bioavailability in the decompensated state was 94% that of the euvolaemic state. However, in a small subset the AUC increased by > 30% when euvolaemic. The results for torsemide AUC were similar; there was no significant difference between the two states, with median relative bioavailability in the decompensated state 95% that of the euvolaemic state. These two studies therefore do not support the commonly held view that absorption of loop diuretics is substantially reduced in patients with ADCCF. Within-subject variability of furosemide absorption has not been assessed in patients with ADCCF, but has been measured in stable heart failure patients (8). In this study 25 euvolaemic heart failure patients and 25 healthy volunteers were administered a single IV dose of 40mg furosemide and, the following day, a single oral dose of 40mg furosemide. A subset of patients received further daily oral doses for up to 6 consecutive days. No difference in oral bioavailability was found between patients and controls. Whilst there was high between-subject variability in both controls and patients (coefficient of variation 0.85), within-subject data was much more consistent (CoV 0.33). These 3 studies suggest there is little change in furosemide exposure during ADCCF compared with euvolaemia, and that furosemide absorption is relatively consistent within the same subject.
Pharmacodynamics
Might it be that IV furosemide delivered as a bolus is superior to oral, for a given AUC, because it achieves much higher peak concentrations? There are no randomised controlled trials (RCTs) which specifically address this question. Such a study would need to be carefully designed so that both arms are matched for furosemide AUC. However, trials comparing IV bolus to IV infusions provide relevant information. Boluses produce high peak concentrations whereas infusions produce a near constant concentration. If furosemide efficacy is driven by high peak concentrations then boluses should be superior to infusions, whereas if efficacy is driven by AUC there should be little difference between the two. This very specific question has been addressed in numerous studies, most recently a double-blind RCT (9). In this study, 308 ADCCF patients received furosemide either as an IV bolus twice per day or an infusion. The primary endpoint was a composite score combining patient wellbeing and dyspnoea, and in this primary endpoint there were no differences between the two groups. Nor were there differences in numerous secondary endpoints including length of hospital admission, change in B natriuretic peptide, or change in weight. A 2005 Cochrane review (10) showed similar results, specifically that that there was no difference in hospital stay between bolus dosing and infusions. Together, this data tentatively suggests that efficacy is driven more by AUC rather than by peak concentration. Clearly, however, further trials are required to enable more definitive conclusions to be drawn.
Discussion
This article is protected by copyright. All rights reserved.
The available pharmacokinetic data suggests that, for the vast majority of patients, decompensated heart failure does not cause a major reduction in the bioavailability of furosemide. Furthermore, clinical trials tentatively suggest that high peak concentrations associated with IV bolus dosing are not a necessary requirement for an adequate clinical effect, and rather efficacy is more likely driven by a parameter related to AUC. In neither the pharmacokinetics nor the pharmacodynamics is there sufficient data to produce clarity. However, the available data certainly does not support the commonly held assertion stated in guidelines that the route of administration of furosemide should be changed from oral to IV during acute decompensation. Indeed, given the wide between-subject variability but narrower within-subject variability of furosemide bioavailability, it would be more rational, during decompensation, to select an oral furosemide dose that is based on the patient’s routine oral dose. For example, doubling the oral dose during decompensation would be expected to produce a predictable approximate doubling in furosemide exposure. However, if the route of administration is changed to IV, the increase in furosemide exposure will be unpredictable, because oral bioavailability is highly variable between subjects. The fact that the AUC tended to increase with euvolaemia, and that the datasets are small, suggest a type II error may have occurred and that a larger study might reveal significant differences in bioavailability between the two volume states. However, even if this is the case, the absolute changes are small (the median AUC ratio prediuresis/postdiuresis was 0.94), and hence of little consequence given the oral dose can be comfortably increased. This data also suggests that there may be a small subset of patients whose loop diuretic bioavailability does meaningfully reduce during acute decompensation. Even in this small subset, further increases in oral furosemide would be expected to overcome the reduction in AUC. It is tempting to speculate that this subset of patients, in whom an IV switch will likely induce a large clinical effect despite a poor response to oral, may be the source of the anecdotal evidence favouring the IV switch. It remains possible that IV furosemide may yet prove to be a more efficacious treatment than oral. Because the appropriate data does not exist comparing IV and oral, we have had to base the pharmacodynamic argument on a comparison between boluses and infusions, both of which are of course IV routes. There are two reasons why this is important. Firstly, IV furosemide has been shown to have various extra renal actions, including effects on vasculature, prostaglandins, and the neurohumoral axis (3, 4). It may be that some of these actions only occur with IV dosing. However, to our knowledge, there is no evidence that these effects do not occur following oral dosing. Indeed, as previously discussed, oral dosing does induce changes in venous capacitance to a degree similar to that induced by IV dosing (5). Secondly, orally administered furosemide will be subject to possible metabolism in enterocytes and hepatocytes during the first pass effect, both of which IV furosemide bypasses. Again, however, there is no empirical evidence for this theoretical difference.
We therefore suggest that the use of oral furosemide in the context of ADCCF requires reevaluation, and that our current threshold for switching to IV delivery may be too low. When patients are admitted to hospital for ADCCF, their management involves more than just furosemide
This article is protected by copyright. All rights reserved.
administration. However, weaning the patient from IV to oral is often the rate limiting step in discharge. If such patients can be managed by increasing oral doses rather than converting to IV then this could reduce length of admission, and in many cases might reduce the need for admission in the first place.
Figure 1 Representative patient (from (6)) showing difference in the furosemide plasma curve during euvolaemia (dotted line) and decompensated heart failure (black line)
This article is protected by copyright. All rights reserved.
References 1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-327. 2. Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. Journal of cardiac failure. 2010;16(6):e1-194. 3. Dikshit K, Vyden JK, Forrester JS, Chatterjee K, Prakash R, Swan HJ. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. The New England journal of medicine. 1973;288(21):1087-90. 4. Jhund PS, McMurray JJ, Davie AP. The acute vascular effects of frusemide in heart failure. British journal of clinical pharmacology. 2000;50(1):9-13. 5. Johnston GD, Nicholls DP, Leahey WJ. The dose-response characteristics of the acute nondiuretic peripheral vascular effects of frusemide in normal subjects. British journal of clinical pharmacology. 1984;18(1):75-81. 6. Vasko MR, Cartwright DB, Knochel JP, Nixon JV, Brater DC. Furosemide absorption altered in decompensated congestive heart failure. Annals of internal medicine. 1985;102(3):314-8. 7. Gottlieb SS, Khatta M, Wentworth D, Roffman D, Fisher ML, Kramer WG. The effects of diuresis on the pharmacokinetics of the loop diuretics furosemide and torsemide in patients with heart failure. The American journal of medicine. 1998;104(6):533-8. 8. Brater DC, Seiwell R, Anderson S, Burdette A, Dehmer GJ, Chennavasin P. Absorption and disposition of furosemide in congestive heart failure. Kidney international. 1982;22(2):171-6. 9. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, et al. Diuretic strategies in patients with acute decompensated heart failure. The New England journal of medicine. 2011;364(9):797-805. 10. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. The Cochrane database of systematic reviews. 2005(3):Cd003178.
This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
2nd Revision. February 2015 Invited “Point-Counterpoint” manuscript: Intravenous furosemide for acute decompensated congestive heart failure; what is the evidence? Word count 1599 (excluding title page and references)
Authors: David RJ Owen1, Raymond MacAllister2, Reecha Sofat2.
1
Division of Brain Sciences, Imperial College, Hammersmith Hospital, London W12 0NN, UK
2
Centre for Clinical Pharmacology, University College London, London, UK
Running Title: Furosemide in decompensated heart failure
Corresponding Author: David RJ Owen 2nd revision. February 2015.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/cpt.120
This article is protected by copyright. All rights reserved.
Use of intravenous (IV) furosemide in preference to oral administration in acute decompensated congestive cardiac failure (ADCCF) is universally recommended in international guidelines (1, 2), although the justification is largely unreferenced. The Heart Failure Society of America guidelines (2) recommend this switch on the basis that oral bioavailability is highly variable within the same patient, and substantially reduced during cardiac decompensation. However, no evidence to support this advice is cited.
In patients with acute respiratory distress, IV furosemide offers rapid improvement that is due, at least in part, to direct effects on vasculature that precede diuresis (3, 4). Whilst these same vascular effects (that also precede diuresis) occur also with oral administration (5), administering furosemide IV in acutely compromised patients is rational because of the more rapid onset of action (5). However, in patients who present with fluid overload without respiratory compromise, we argue that the rationale for the use of IV rather than oral furosemide is less clear, and that the evidence base does not support its preferred use. Here, we present pharmacokinetic data suggesting that there is little evidence to support the claim that furosemide absorption is substantially altered by fluid overload. There is no pharmacodynamic data available that directly compares oral and IV administration for a given furosemide exposure. However, we present pharmacodynamic data suggesting that the high peak concentrations obtained with IV bolus doses (that oral administration would not be able to achieve) do not appear to be a major determinant of overall clinical response. We therefore propose that the role of oral furosemide should be reassessed in patients with fluid overload but without respiratory distress. Improved evidence in this field may have substantial impact on the ways in which patients with ADCCF are treated, leading to a reduction in hospital admissions due to greater use of oral diuretic therapy in primary care.
Pharmacokinetics
Two studies have addressed the specific question of whether furosemide pharmacokinetics are altered in the presence of ADCCF. In 1985, Vasko et al studied 11 patients with ADCCF, administering a single dose of oral furosemide during an acute admission and then subsequently when the patient was euvolaemic (6). The pharmacokinetic profile of furosemide differed between the two volume states (figure 1); when euvolaemic, drug absorption was faster and the peak plasma concentration was higher compared with acute decompensation . However, there was no significant change in area under the plasma furosemide curve (AUC) between either state. Therefore in acute decompensation and euvolaemia, there was no difference in the amount of drug that reached the circulation for a given oral dose of furosemide. Analogous results were reported in a subsequent study in 1998 (7). Here, 37 patients with ADCCF were administered an oral dose of furosemide (n=18) or torsemide (n=19), and administration was repeated when the patients were euvolaemic. With furosemide, there were no significant
This article is protected by copyright. All rights reserved.
differences in time to peak furosemide concentration or maximum furosemide concentration when the patients were acutely decompensated compared with euvolaemia. Again, there was no significant difference in AUC between the two volume states; median relative bioavailability in the decompensated state was 94% that of the euvolaemic state. However, in a small subset the AUC increased by > 30% when euvolaemic. The results for torsemide AUC were similar; there was no significant difference between the two states, with median relative bioavailability in the decompensated state 95% that of the euvolaemic state. These two studies therefore do not support the commonly held view that absorption of loop diuretics is substantially reduced in patients with ADCCF. Within-subject variability of furosemide absorption has not been assessed in patients with ADCCF, but has been measured in stable heart failure patients (8). In this study 25 euvolaemic heart failure patients and 25 healthy volunteers were administered a single IV dose of 40mg furosemide and, the following day, a single oral dose of 40mg furosemide. A subset of patients received further daily oral doses for up to 6 consecutive days. No difference in oral bioavailability was found between patients and controls. Whilst there was high between-subject variability in both controls and patients (coefficient of variation 0.85), within-subject data was much more consistent (CoV 0.33). These 3 studies suggest there is little change in furosemide exposure during ADCCF compared with euvolaemia, and that furosemide absorption is relatively consistent within the same subject.
Pharmacodynamics
Might it be that IV furosemide delivered as a bolus is superior to oral, for a given AUC, because it achieves much higher peak concentrations? There are no randomised controlled trials (RCTs) which specifically address this question. Such a study would need to be carefully designed so that both arms are matched for furosemide AUC. However, trials comparing IV bolus to IV infusions provide relevant information. Boluses produce high peak concentrations whereas infusions produce a near constant concentration. If furosemide efficacy is driven by high peak concentrations then boluses should be superior to infusions, whereas if efficacy is driven by AUC there should be little difference between the two. This very specific question has been addressed in numerous studies, most recently a double-blind RCT (9). In this study, 308 ADCCF patients received furosemide either as an IV bolus twice per day or an infusion. The primary endpoint was a composite score combining patient wellbeing and dyspnoea, and in this primary endpoint there were no differences between the two groups. Nor were there differences in numerous secondary endpoints including length of hospital admission, change in B natriuretic peptide, or change in weight. A 2005 Cochrane review (10) showed similar results, specifically that that there was no difference in hospital stay between bolus dosing and infusions. Together, this data tentatively suggests that efficacy is driven more by AUC rather than by peak concentration. Clearly, however, further trials are required to enable more definitive conclusions to be drawn.
Discussion
This article is protected by copyright. All rights reserved.
The available pharmacokinetic data suggests that, for the vast majority of patients, decompensated heart failure does not cause a major reduction in the bioavailability of furosemide. Furthermore, clinical trials tentatively suggest that high peak concentrations associated with IV bolus dosing are not a necessary requirement for an adequate clinical effect, and rather efficacy is more likely driven by a parameter related to AUC. In neither the pharmacokinetics nor the pharmacodynamics is there sufficient data to produce clarity. However, the available data certainly does not support the commonly held assertion stated in guidelines that the route of administration of furosemide should be changed from oral to IV during acute decompensation. Indeed, given the wide between-subject variability but narrower within-subject variability of furosemide bioavailability, it would be more rational, during decompensation, to select an oral furosemide dose that is based on the patient’s routine oral dose. For example, doubling the oral dose during decompensation would be expected to produce a predictable approximate doubling in furosemide exposure. However, if the route of administration is changed to IV, the increase in furosemide exposure will be unpredictable, because oral bioavailability is highly variable between subjects. The fact that the AUC tended to increase with euvolaemia, and that the datasets are small, suggest a type II error may have occurred and that a larger study might reveal significant differences in bioavailability between the two volume states. However, even if this is the case, the absolute changes are small (the median AUC ratio prediuresis/postdiuresis was 0.94), and hence of little consequence given the oral dose can be comfortably increased. This data also suggests that there may be a small subset of patients whose loop diuretic bioavailability does meaningfully reduce during acute decompensation. Even in this small subset, further increases in oral furosemide would be expected to overcome the reduction in AUC. It is tempting to speculate that this subset of patients, in whom an IV switch will likely induce a large clinical effect despite a poor response to oral, may be the source of the anecdotal evidence favouring the IV switch. It remains possible that IV furosemide may yet prove to be a more efficacious treatment than oral. Because the appropriate data does not exist comparing IV and oral, we have had to base the pharmacodynamic argument on a comparison between boluses and infusions, both of which are of course IV routes. There are two reasons why this is important. Firstly, IV furosemide has been shown to have various extra renal actions, including effects on vasculature, prostaglandins, and the neurohumoral axis (3, 4). It may be that some of these actions only occur with IV dosing. However, to our knowledge, there is no evidence that these effects do not occur following oral dosing. Indeed, as previously discussed, oral dosing does induce changes in venous capacitance to a degree similar to that induced by IV dosing (5). Secondly, orally administered furosemide will be subject to possible metabolism in enterocytes and hepatocytes during the first pass effect, both of which IV furosemide bypasses. Again, however, there is no empirical evidence for this theoretical difference.
We therefore suggest that the use of oral furosemide in the context of ADCCF requires reevaluation, and that our current threshold for switching to IV delivery may be too low. When patients are admitted to hospital for ADCCF, their management involves more than just furosemide
This article is protected by copyright. All rights reserved.
administration. However, weaning the patient from IV to oral is often the rate limiting step in discharge. If such patients can be managed by increasing oral doses rather than converting to IV then this could reduce length of admission, and in many cases might reduce the need for admission in the first place.
Figure 1 Representative patient (from (6)) showing difference in the furosemide plasma curve during euvolaemia (dotted line) and decompensated heart failure (black line)
This article is protected by copyright. All rights reserved.
References 1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-327. 2. Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. Journal of cardiac failure. 2010;16(6):e1-194. 3. Dikshit K, Vyden JK, Forrester JS, Chatterjee K, Prakash R, Swan HJ. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. The New England journal of medicine. 1973;288(21):1087-90. 4. Jhund PS, McMurray JJ, Davie AP. The acute vascular effects of frusemide in heart failure. British journal of clinical pharmacology. 2000;50(1):9-13. 5. Johnston GD, Nicholls DP, Leahey WJ. The dose-response characteristics of the acute nondiuretic peripheral vascular effects of frusemide in normal subjects. British journal of clinical pharmacology. 1984;18(1):75-81. 6. Vasko MR, Cartwright DB, Knochel JP, Nixon JV, Brater DC. Furosemide absorption altered in decompensated congestive heart failure. Annals of internal medicine. 1985;102(3):314-8. 7. Gottlieb SS, Khatta M, Wentworth D, Roffman D, Fisher ML, Kramer WG. The effects of diuresis on the pharmacokinetics of the loop diuretics furosemide and torsemide in patients with heart failure. The American journal of medicine. 1998;104(6):533-8. 8. Brater DC, Seiwell R, Anderson S, Burdette A, Dehmer GJ, Chennavasin P. Absorption and disposition of furosemide in congestive heart failure. Kidney international. 1982;22(2):171-6. 9. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, et al. Diuretic strategies in patients with acute decompensated heart failure. The New England journal of medicine. 2011;364(9):797-805. 10. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. The Cochrane database of systematic reviews. 2005(3):Cd003178.
This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
