Curr Heart Fail Rep (2014) 11:10–18 DOI 10.1007/s11897-013-0175-3
PHARMACOLOGIC THERAPY (WHW TANG, SECTION EDITOR)
Vasopressin Receptor Antagonists: From Pivotal Trials to Current Practice Ankur Kalra & Valmiki Maharaj & Steven R Goldsmith
Published online: 7 November 2013 # Springer Science+Business Media New York 2013
Abstract Heart failure is a growing health and economic problem in America, and outcomes continue to remain dismal, particularly for those presenting with acute heart failure syndrome (AHFS). In theory, arginine vasopressin antagonists (VRAs) could be useful in both acute and chronic heart failure, depending on which vasopressin receptor is targeted. Most studies of VRAs in heart failure have focused on V2 receptor antagonism, and to a lesser extent on combined V1a/ V2 antagonism, due to the availability of appropriate agents and the unmet need of improving outcomes in AHFS. These agents are particularly attractive as adjunctive or alterative agents in AHFS because of their ability to produce a substantial diuresis without some of the drawbacks intrinsic to loop diuretics. While VRAs have been shown to ameliorate signs and symptoms of congestion when added to standard care, the largest trial of these agents showed no improvement in longterm morbidity, mortality, or hospitalization rates when added to standard care. This article reviews the mechanism of action of VRAs, the relevant clinical trials data, and current recommendations for clinical use, and suggests future directions for study of these agents in patients with heart failure.
Keywords Antidiuretic hormone . Arginine vasopressin . Tolvaptan . Conivaptan
Introduction Heart failure (HF) is a health problem of enormous proportions. More than 5 million Americans suffer with HF, and that number is expected to increase by 25 % by the year 2030 [1]. In 2010, ~1.8 million physician office visits and ~1 million hospital discharges were primarily for HF. The total cost of HF in 2020 may increase to $70 billion from current 2013 estimates of $32 billion. While median survival time after HF diagnosis has increased with improved outpatient treatment, mortality rates at 5 years still approach 50 % for sicker patients [1]. Outcomes after admission for an ‘acute heart failure syndrome (AHFS),’ defined by rapid or gradual change in HF signs and symptoms requiring urgent therapy, have unfortunately not changed appreciably over the last 40 years [2]. Re-admission rates and mortality for AHFS may be as high as or higher than 30 % and 15 % in the 60–90 days post discharge, respectively [3]. Hence, new management therapies are needed in patients with HF and particularly those with AHFS, both to mitigate signs and symptoms of HF and to improve re-admission and post discharge mortality rates. Several studies in recent years have examined the utility and role of vasopressin receptor antagonists (VRAs) in AHFS. While no study has demonstrated outcome benefits from the use of these agents in AHFS, much has been learned about them, and the intent of this brief review is to summarize that information in a concise fashion Table 1. Current Therapies for Acute Heart Failure Syndromes
A. Kalra : S. R. Goldsmith (*) Department of Medicine, Section of Cardiology, Hennepin County Medical Center, 701 Park Ave S, Minneapolis, MN 55415, USA e-mail: [email protected] V. Maharaj : S. R. Goldsmith University of Minnesota Medical School, Minneapolis, MN 55415, USA
Current therapies for AHFS include oxygen, loop diuretics, nitrates, nesiritide and inotropes [2]. These are used to alleviate congestion, reduce preload and left ventricular end-diastolic pressure, and increase cardiac performance. However, the side effects of these medications are common and can be substantial, including electrolyte abnormalities (particularly hypokalemia),
Clinical signs of HF Renal function
Signs and symptoms of congestion
Ambulatory adults >18 yo
DB, RCT
Well-treated on standard HF therapy
LVEF ≤30 %
NYHA Class II/III
N =240
METEOR [35]
On standard HF therapy
LVEF 18 yo
NYHA class III/IV
DB, RCT
Placebo vs. 15, 30, Hemodynamics 60 mg tolvaptan onetime dose
N =181
ECLIPSE [34]
HR and BP
UOP, Body weight
Adults >18 yo
Hospitalized for ADHF
DB, RCT
Patient and clinicianassessed symptom scale
N =170
Goldsmith et al. [33]
Cardiac Index≤2.8 L/(min • m2) Placebo vs. conivaptan (loading dose 2 -mg, then two 24-hr continuous infusions 40, 80, 120 mg)
HR and BP
On standard HF therapy
PCWP≥16 mmHg
Cardiac Output, SVR
PCWP
Renal Function
DB, RCT
Placebo vs. single IV dose conivaptan 10, 20, 40 mg
Conivaptan improves UOP in ADHF without affecting adversely vital signs and renal function.
Conivaptan caused favorable changes in UOP and hemodynamics without affecting vital signs in patients with AHFS.
Conclusion
No difference in tolvaptan group compared to placebo for LVEDI or EF.
Tolvaptan was not associated with a statistically significant decrease in LVEDI or increase in EF.
All doses of tolvaptan resulted in statistically significant Tolvaptan results in decreased filling pressures and increased UOP in patients decreases in PCWP, RA and PA pressure (p
PHARMACOLOGIC THERAPY (WHW TANG, SECTION EDITOR)
Vasopressin Receptor Antagonists: From Pivotal Trials to Current Practice Ankur Kalra & Valmiki Maharaj & Steven R Goldsmith
Published online: 7 November 2013 # Springer Science+Business Media New York 2013
Abstract Heart failure is a growing health and economic problem in America, and outcomes continue to remain dismal, particularly for those presenting with acute heart failure syndrome (AHFS). In theory, arginine vasopressin antagonists (VRAs) could be useful in both acute and chronic heart failure, depending on which vasopressin receptor is targeted. Most studies of VRAs in heart failure have focused on V2 receptor antagonism, and to a lesser extent on combined V1a/ V2 antagonism, due to the availability of appropriate agents and the unmet need of improving outcomes in AHFS. These agents are particularly attractive as adjunctive or alterative agents in AHFS because of their ability to produce a substantial diuresis without some of the drawbacks intrinsic to loop diuretics. While VRAs have been shown to ameliorate signs and symptoms of congestion when added to standard care, the largest trial of these agents showed no improvement in longterm morbidity, mortality, or hospitalization rates when added to standard care. This article reviews the mechanism of action of VRAs, the relevant clinical trials data, and current recommendations for clinical use, and suggests future directions for study of these agents in patients with heart failure.
Keywords Antidiuretic hormone . Arginine vasopressin . Tolvaptan . Conivaptan
Introduction Heart failure (HF) is a health problem of enormous proportions. More than 5 million Americans suffer with HF, and that number is expected to increase by 25 % by the year 2030 [1]. In 2010, ~1.8 million physician office visits and ~1 million hospital discharges were primarily for HF. The total cost of HF in 2020 may increase to $70 billion from current 2013 estimates of $32 billion. While median survival time after HF diagnosis has increased with improved outpatient treatment, mortality rates at 5 years still approach 50 % for sicker patients [1]. Outcomes after admission for an ‘acute heart failure syndrome (AHFS),’ defined by rapid or gradual change in HF signs and symptoms requiring urgent therapy, have unfortunately not changed appreciably over the last 40 years [2]. Re-admission rates and mortality for AHFS may be as high as or higher than 30 % and 15 % in the 60–90 days post discharge, respectively [3]. Hence, new management therapies are needed in patients with HF and particularly those with AHFS, both to mitigate signs and symptoms of HF and to improve re-admission and post discharge mortality rates. Several studies in recent years have examined the utility and role of vasopressin receptor antagonists (VRAs) in AHFS. While no study has demonstrated outcome benefits from the use of these agents in AHFS, much has been learned about them, and the intent of this brief review is to summarize that information in a concise fashion Table 1. Current Therapies for Acute Heart Failure Syndromes
A. Kalra : S. R. Goldsmith (*) Department of Medicine, Section of Cardiology, Hennepin County Medical Center, 701 Park Ave S, Minneapolis, MN 55415, USA e-mail: [email protected] V. Maharaj : S. R. Goldsmith University of Minnesota Medical School, Minneapolis, MN 55415, USA
Current therapies for AHFS include oxygen, loop diuretics, nitrates, nesiritide and inotropes [2]. These are used to alleviate congestion, reduce preload and left ventricular end-diastolic pressure, and increase cardiac performance. However, the side effects of these medications are common and can be substantial, including electrolyte abnormalities (particularly hypokalemia),
Clinical signs of HF Renal function
Signs and symptoms of congestion
Ambulatory adults >18 yo
DB, RCT
Well-treated on standard HF therapy
LVEF ≤30 %
NYHA Class II/III
N =240
METEOR [35]
On standard HF therapy
LVEF 18 yo
NYHA class III/IV
DB, RCT
Placebo vs. 15, 30, Hemodynamics 60 mg tolvaptan onetime dose
N =181
ECLIPSE [34]
HR and BP
UOP, Body weight
Adults >18 yo
Hospitalized for ADHF
DB, RCT
Patient and clinicianassessed symptom scale
N =170
Goldsmith et al. [33]
Cardiac Index≤2.8 L/(min • m2) Placebo vs. conivaptan (loading dose 2 -mg, then two 24-hr continuous infusions 40, 80, 120 mg)
HR and BP
On standard HF therapy
PCWP≥16 mmHg
Cardiac Output, SVR
PCWP
Renal Function
DB, RCT
Placebo vs. single IV dose conivaptan 10, 20, 40 mg
Conivaptan improves UOP in ADHF without affecting adversely vital signs and renal function.
Conivaptan caused favorable changes in UOP and hemodynamics without affecting vital signs in patients with AHFS.
Conclusion
No difference in tolvaptan group compared to placebo for LVEDI or EF.
Tolvaptan was not associated with a statistically significant decrease in LVEDI or increase in EF.
All doses of tolvaptan resulted in statistically significant Tolvaptan results in decreased filling pressures and increased UOP in patients decreases in PCWP, RA and PA pressure (p
