International Journal of Cardiology 170 (2014) e68–e69
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Use of natriuretic-doses of spironolactone for treatment of loop diuretic resistant acute decompensated heart failure Marvin Eng a,1, Shweta Bansal b,⁎,1 a b
Division of Cardiology, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA Division of Nephrology, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA
a r t i c l e
i n f o
Article history: Received 13 September 2013 Accepted 2 November 2013 Available online 12 November 2013 Keywords: Acute decompensated heart failure Loop diuretic resistance Aldosterone antagonists
Loop diuretic resistance occurs in approximately 25%–30% of heart failure (HF) patients and is a common cause of acute decompensated heart failure (ADHF) hospitalizations [1]. Despite using higher doses or intravenous (IV) diuretics in 90% of these patients, approximately 50% lose ≤ 5 lb and 20% gain weight resulting in high readmission rates. In addition, worsening renal function is a common occurrence during these hospitalizations [2]. Moreover, recent trials of mechanical ultrafiltration have demonstrated no benefit over stepped up diuretic regimen in terms of volume removal or elevation of creatinine, leaving no further choice for management of diuretic resistant ADHF patients [3,4]. HF patients share the same pathophysiology of decreased effective arterial blood volume as the cirrhotic patients, with resultant stimulation of sympathetic nervous system (SNS) and renin–angiotensin–aldosterone system (RAAS). In cirrhotic patients, hyperaldosteronism plays a major role in the pathogenesis of ascites and loop diuretic resistance; therefore, high doses of spironolactone (up to 400 mg/day) are commonly used to achieve negative sodium balance. Extremely elevated aldosterone levels are similarly prevalent in patients with diuretic resistant heart failure [5]. Aldosterone antagonism is a standard therapy and proven to provide mortality benefit in HF, however, in those trials the doses of spironolactone utilized were non-natriuretic and the majority of benefit resulted from the anti-fibrotic actions [6]. In context
⁎ Corresponding author at: Division of Nephrology, Department of Medicine, UT Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, MSC 7882, San Antonio, TX 78229, USA. Tel.: +1 210 422 0438; fax: +1 210 567 4712. E-mail address: [email protected] (S. Bansal). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.023
of the similar pathophysiology of diuretic resistance in cirrhosis and HF, aldosterone antagonists in natriuretic-doses (N 25 mg of spironolactone or equivalent dose) may be an alternative diuretic strategy in treating HF. In this report, we describe the utility of natriureticdoses of spironolactone to treat volume overload in patients hospitalized with ADHF and resistance to loop and distal acting diuretics. First case: 56 year old female with obesity, diabetes, hypertension, moderate diastolic dysfunction, severe pulmonary hypertension (Pulmonary artery pressure (PAP) = 55 mm Hg), and chronic kidney disease (CKD) stage IV secondary to diabetic nephropathy (DN) with baseline serum creatinine of 2.11 mg/dl admitted with symptomatic volume overload. Initiation of ultrafiltration was under consideration when she did not achieve negative sodium balance with furosemide 120 mg IV bid and metolazone 5 mg oral bid dosing. At that point spironolactone100 mg oral bid was started. Over the next week she lost 6.3 kg in conjunction with symptom relief. Use of lower dose of furosemide and metolazone with the same dose of spironolactone caused another 9 kg weight loss post-discharge over 7 days. Second case: 58 year old female with obesity, diabetes, hypertension, moderate diastolic dysfunction and severe pulmonary hypertension (PAP = 60 mm Hg), CKD IV secondary to DN with baseline serum creatinine of 3.3 mg/dl admitted with sign and symptoms of volume overload. When no response was achieved with IV furosemide drip at 20 mg/h and oral metolazone 5 mg/daily, oral spironolactone was prescribed at 100 mg bid. She lost 2.7 kg over the next 7 days and discharged on oral furosemide 120 mg bid, metolazone 5 mg a day and spironolactone 100 mg bid, resulting in another 6.3 kg weight loss. In both the cases, serum potassium remained within normal range both as inpatient and outpatient (Fig. 1). Serum creatinine initially elevated but returned to baseline in the first case at follow up and remained elevated in second case. Third case: A 66 year old woman with diabetes, CKD (baseline creatinine of 1.3 mg/dl), left ventricular systolic dysfunction and recent acute coronary syndrome was hospitalized for HF. Diuresis was unsuccessful despite escalation of IV furosemide doses totaling 240 mg/daily. Her creatinine rose to 1.8 mg/dl without any improvement in symptoms or congestion. High-dose spironolactone was instituted and the dose was ramped up to 100 mg bid. Subsequently, the patient experienced 2 kg weight loss (Fig. 2) with resolution of her symptoms and her serum creatinine decreased to 1.5 mg/dl over 4 days. This case series illustrates the potential efficacy of natriuretic-doses of spironolactone in treating diuretic resistant hospitalized ADHF patients with renal insufficiency. HF patients have severe underlying
M. Eng, S. Bansal / International Journal of Cardiology 170 (2014) e68–e69
Serum Potassium (meq/L)
5 4 3
Patient 1 2
Patient 2 Patient 3
1 0
0
5
10
15
Days taking natriuretic-Dose spironolactone Fig. 1. Longitudinal serum potassium measurements in 3 patients with renal insufficiency treated with natriuretic-dose spironolactone.
secondary hyperaldosteronism [5]. Long-term loop diuretic use causes further RAAS activation by inhibiting sodium chloride transport at the macula densa and relative volume depletion. In addition, due to enhanced sodium chloride co-transporter expression at distal collecting tubules, loop diuretics use leads to increased sodium absorption at distal convoluted tubule site resulting in resistance to natriuretic effect [7]. Given similar physiology of diuretic resistance in HF and cirrhotic patients and experience of use in cirrhotic patients, inhibition of RAAS via high dose aldosterone antagonists has potential to induce significant natriuresis in HF patients as well, however, not very well explored. In a small trial of 6 avidly sodium-retaining patients with HF, treatment with spironolactone 200 mg bid demonstrated effective sodium excretion [8]. Weight loss increased from 0.5 kg to 4.5 kg with addition of spironolactone 100 mg daily on the 7th day in an additional study of 21 HF patients with diuretic resistance [9]. In another study of 3 patients, spironolactone 100 mg daily increased sodium excretion without adverse effects [10]. Although, in these studies, the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) was not widely prevalent. Our 3 patients, in total lost 11 kg over 7 inpatient days and additional 15 kg with outpatient use of natriuretic-doses of spironolactone. Nevertheless, the risk of hyperkalemia is high in HF patients treated with high doses of aldosterone antagonists in the presence of ACEIs, and/or ARBs. Creatinine of N 2.5 mg/dl was an exclusion for the RALES
18
Total Weight Loss (Kg)
16 14 12 Patient 1
10
Patient 2
8
Patient 3
6
Mean
4 2 0
Fig. 2. Total weight loss of patients treated with natriuretic-doses of spironolactone during both inpatient and outpatient treatment.
e69
trial based on dose finding studies demonstrating unacceptable rates of hyperkalemia when treating patients with renal insufficiency. However, this case series suggests that inpatient use of high dose spironolactone with frequent electrolyte monitoring is safe. Decrease potassium secretion due to aldosterone inhibition is balanced by the increased potassium secretion caused by loop-diuretic mediated enhanced tubular flow rate. All of our patients achieved satisfactory weight loss with no adverse effect of hyperkalemia with high dose spironolactone despite underlying renal insufficiency and use of an ACEI or ARB. Over the last 10–20 years, several therapies have shown beneficial impact on the clinical course of patients with chronic congestive heart failure; however, similar advances have not occurred for the treatment of ADHF. Use of natriuretic-doses of spironolactone to mitigate congestion in hospitalized ADHF patients in the context of renal insufficiency is a safe potential underutilized therapy and should receive consideration.
References [1] Peacock WF, Costanzo MR, De Marco T, et al. Impact of intravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE registry. Cardiology 2009;113:12–9. [2] Heywood JT, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail 2007;13:422–30. [3] Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675–83. [4] Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296–304. [5] Bansal S, Lindenfeld J, Schrier RW. Sodium retention in heart failure and cirrhosis: potential role of natriuretic doses of mineralocorticoid antagonist? Circ Heart Fail 2009;2:370–6. [6] Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17. [7] Ellison DH. Diuretic therapy and resistance in congestive heart failure. Cardiology 2001;96:132–43. [8] Hensen J, Abraham WT, Durr JA, Schrier RW. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention. Am J Nephrol 1991;11:441–6. [9] van Vliet AA, Donker AJM, Nauta JJP, Verheugt FWA. Spironolactone in congestive heart failure refractory to high-dose loop diuretic and low-dose angiotensinconverting enzyme inhibitor. Am J Cardiol 1993:71. [10] Braunwald E, Plauth Jr WH, Morrow AG. A method for the detection and quantification of impaired sodium excretion: results of an oral sodium tolerance test in normal subjects and in patients with heart disease. Circulation 1965;32:223–31.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Use of natriuretic-doses of spironolactone for treatment of loop diuretic resistant acute decompensated heart failure Marvin Eng a,1, Shweta Bansal b,⁎,1 a b
Division of Cardiology, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA Division of Nephrology, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA
a r t i c l e
i n f o
Article history: Received 13 September 2013 Accepted 2 November 2013 Available online 12 November 2013 Keywords: Acute decompensated heart failure Loop diuretic resistance Aldosterone antagonists
Loop diuretic resistance occurs in approximately 25%–30% of heart failure (HF) patients and is a common cause of acute decompensated heart failure (ADHF) hospitalizations [1]. Despite using higher doses or intravenous (IV) diuretics in 90% of these patients, approximately 50% lose ≤ 5 lb and 20% gain weight resulting in high readmission rates. In addition, worsening renal function is a common occurrence during these hospitalizations [2]. Moreover, recent trials of mechanical ultrafiltration have demonstrated no benefit over stepped up diuretic regimen in terms of volume removal or elevation of creatinine, leaving no further choice for management of diuretic resistant ADHF patients [3,4]. HF patients share the same pathophysiology of decreased effective arterial blood volume as the cirrhotic patients, with resultant stimulation of sympathetic nervous system (SNS) and renin–angiotensin–aldosterone system (RAAS). In cirrhotic patients, hyperaldosteronism plays a major role in the pathogenesis of ascites and loop diuretic resistance; therefore, high doses of spironolactone (up to 400 mg/day) are commonly used to achieve negative sodium balance. Extremely elevated aldosterone levels are similarly prevalent in patients with diuretic resistant heart failure [5]. Aldosterone antagonism is a standard therapy and proven to provide mortality benefit in HF, however, in those trials the doses of spironolactone utilized were non-natriuretic and the majority of benefit resulted from the anti-fibrotic actions [6]. In context
⁎ Corresponding author at: Division of Nephrology, Department of Medicine, UT Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, MSC 7882, San Antonio, TX 78229, USA. Tel.: +1 210 422 0438; fax: +1 210 567 4712. E-mail address: [email protected] (S. Bansal). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.023
of the similar pathophysiology of diuretic resistance in cirrhosis and HF, aldosterone antagonists in natriuretic-doses (N 25 mg of spironolactone or equivalent dose) may be an alternative diuretic strategy in treating HF. In this report, we describe the utility of natriureticdoses of spironolactone to treat volume overload in patients hospitalized with ADHF and resistance to loop and distal acting diuretics. First case: 56 year old female with obesity, diabetes, hypertension, moderate diastolic dysfunction, severe pulmonary hypertension (Pulmonary artery pressure (PAP) = 55 mm Hg), and chronic kidney disease (CKD) stage IV secondary to diabetic nephropathy (DN) with baseline serum creatinine of 2.11 mg/dl admitted with symptomatic volume overload. Initiation of ultrafiltration was under consideration when she did not achieve negative sodium balance with furosemide 120 mg IV bid and metolazone 5 mg oral bid dosing. At that point spironolactone100 mg oral bid was started. Over the next week she lost 6.3 kg in conjunction with symptom relief. Use of lower dose of furosemide and metolazone with the same dose of spironolactone caused another 9 kg weight loss post-discharge over 7 days. Second case: 58 year old female with obesity, diabetes, hypertension, moderate diastolic dysfunction and severe pulmonary hypertension (PAP = 60 mm Hg), CKD IV secondary to DN with baseline serum creatinine of 3.3 mg/dl admitted with sign and symptoms of volume overload. When no response was achieved with IV furosemide drip at 20 mg/h and oral metolazone 5 mg/daily, oral spironolactone was prescribed at 100 mg bid. She lost 2.7 kg over the next 7 days and discharged on oral furosemide 120 mg bid, metolazone 5 mg a day and spironolactone 100 mg bid, resulting in another 6.3 kg weight loss. In both the cases, serum potassium remained within normal range both as inpatient and outpatient (Fig. 1). Serum creatinine initially elevated but returned to baseline in the first case at follow up and remained elevated in second case. Third case: A 66 year old woman with diabetes, CKD (baseline creatinine of 1.3 mg/dl), left ventricular systolic dysfunction and recent acute coronary syndrome was hospitalized for HF. Diuresis was unsuccessful despite escalation of IV furosemide doses totaling 240 mg/daily. Her creatinine rose to 1.8 mg/dl without any improvement in symptoms or congestion. High-dose spironolactone was instituted and the dose was ramped up to 100 mg bid. Subsequently, the patient experienced 2 kg weight loss (Fig. 2) with resolution of her symptoms and her serum creatinine decreased to 1.5 mg/dl over 4 days. This case series illustrates the potential efficacy of natriuretic-doses of spironolactone in treating diuretic resistant hospitalized ADHF patients with renal insufficiency. HF patients have severe underlying
M. Eng, S. Bansal / International Journal of Cardiology 170 (2014) e68–e69
Serum Potassium (meq/L)
5 4 3
Patient 1 2
Patient 2 Patient 3
1 0
0
5
10
15
Days taking natriuretic-Dose spironolactone Fig. 1. Longitudinal serum potassium measurements in 3 patients with renal insufficiency treated with natriuretic-dose spironolactone.
secondary hyperaldosteronism [5]. Long-term loop diuretic use causes further RAAS activation by inhibiting sodium chloride transport at the macula densa and relative volume depletion. In addition, due to enhanced sodium chloride co-transporter expression at distal collecting tubules, loop diuretics use leads to increased sodium absorption at distal convoluted tubule site resulting in resistance to natriuretic effect [7]. Given similar physiology of diuretic resistance in HF and cirrhotic patients and experience of use in cirrhotic patients, inhibition of RAAS via high dose aldosterone antagonists has potential to induce significant natriuresis in HF patients as well, however, not very well explored. In a small trial of 6 avidly sodium-retaining patients with HF, treatment with spironolactone 200 mg bid demonstrated effective sodium excretion [8]. Weight loss increased from 0.5 kg to 4.5 kg with addition of spironolactone 100 mg daily on the 7th day in an additional study of 21 HF patients with diuretic resistance [9]. In another study of 3 patients, spironolactone 100 mg daily increased sodium excretion without adverse effects [10]. Although, in these studies, the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) was not widely prevalent. Our 3 patients, in total lost 11 kg over 7 inpatient days and additional 15 kg with outpatient use of natriuretic-doses of spironolactone. Nevertheless, the risk of hyperkalemia is high in HF patients treated with high doses of aldosterone antagonists in the presence of ACEIs, and/or ARBs. Creatinine of N 2.5 mg/dl was an exclusion for the RALES
18
Total Weight Loss (Kg)
16 14 12 Patient 1
10
Patient 2
8
Patient 3
6
Mean
4 2 0
Fig. 2. Total weight loss of patients treated with natriuretic-doses of spironolactone during both inpatient and outpatient treatment.
e69
trial based on dose finding studies demonstrating unacceptable rates of hyperkalemia when treating patients with renal insufficiency. However, this case series suggests that inpatient use of high dose spironolactone with frequent electrolyte monitoring is safe. Decrease potassium secretion due to aldosterone inhibition is balanced by the increased potassium secretion caused by loop-diuretic mediated enhanced tubular flow rate. All of our patients achieved satisfactory weight loss with no adverse effect of hyperkalemia with high dose spironolactone despite underlying renal insufficiency and use of an ACEI or ARB. Over the last 10–20 years, several therapies have shown beneficial impact on the clinical course of patients with chronic congestive heart failure; however, similar advances have not occurred for the treatment of ADHF. Use of natriuretic-doses of spironolactone to mitigate congestion in hospitalized ADHF patients in the context of renal insufficiency is a safe potential underutilized therapy and should receive consideration.
References [1] Peacock WF, Costanzo MR, De Marco T, et al. Impact of intravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE registry. Cardiology 2009;113:12–9. [2] Heywood JT, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail 2007;13:422–30. [3] Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675–83. [4] Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296–304. [5] Bansal S, Lindenfeld J, Schrier RW. Sodium retention in heart failure and cirrhosis: potential role of natriuretic doses of mineralocorticoid antagonist? Circ Heart Fail 2009;2:370–6. [6] Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17. [7] Ellison DH. Diuretic therapy and resistance in congestive heart failure. Cardiology 2001;96:132–43. [8] Hensen J, Abraham WT, Durr JA, Schrier RW. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention. Am J Nephrol 1991;11:441–6. [9] van Vliet AA, Donker AJM, Nauta JJP, Verheugt FWA. Spironolactone in congestive heart failure refractory to high-dose loop diuretic and low-dose angiotensinconverting enzyme inhibitor. Am J Cardiol 1993:71. [10] Braunwald E, Plauth Jr WH, Morrow AG. A method for the detection and quantification of impaired sodium excretion: results of an oral sodium tolerance test in normal subjects and in patients with heart disease. Circulation 1965;32:223–31.
