- Email: [email protected]
Natriuretic Peptides as Therapy for Heart Failure – Unfulfilled Promise?
Accepted Manuscript Natriuretic peptides as therapy for heart failure – unfulfilled promise? Tien M.H. Ng, PharmD PII:
S1071-9164(15)01034-9
DOI:
10.1016/j.cardfail.2015.08.338
Reference:
YJCAF 3624
To appear in:
Journal of Cardiac Failure
Received Date: 28 August 2015 Revised Date:
28 August 2015
Accepted Date: 31 August 2015
Please cite this article as: Ng TMH, Natriuretic peptides as therapy for heart failure – unfulfilled promise?, Journal of Cardiac Failure (2015), doi: 10.1016/j.cardfail.2015.08.338. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Natriuretic peptides as therapy for heart failure – unfulfilled promise? Tien M.H. Ng, PharmD, University of Southern California, Los Angeles, CA
Correspondence:
RI PT
Tien M.H. Ng, PharmD University of Southern California School of Pharmacy 1985 Zonal Ave Los Angeles, CA 90033
SC
Tel: 323-442-1840 Fax: 323-442-1681 Email: [email protected]
M AN U
Disclosures: The author has no conflicts of interest to declare. Short title:
AC C
EP
TE D
Natriuretic peptides as therapy for heart failure
ACCEPTED MANUSCRIPT
Neurohormonal activation was first recognized as an important mediator of heart failure (HF) in the early 1990s. The neurohormonal model of HF helped explain the hemodynamic alterations of the cardiorenal and cardiocirculatory models, and built upon them by providing a mechanism for the progressive nature of the syndrome.1 Since then, development of novel HF therapies has focused on antagonizing or counteracting the effects of so-called vasoconstrictive neuorhormonal pathways.
SC
RI PT
Granules located in human atria were first recognized in the early 1960s, but it wasn’t until 1981 that the contents of these granules was described as atrial natriuretic peptide (ANP), originally known as atrial natriuretic factor.2-4 Related natriuretic peptides were subsequently identified. B-type or braintype natriuretic peptide (BNP) was identified in humans in 19895, and C-type natriuretic peptide (CNP) in 1990.6 Experimental studies demonstrated that these peptides exerted important cardiac and renal physiologic effects, essentially being the natural physiologic antagonists to the renin-angiotensinaldosterone-system. In addition, they have a multitude of other actions that would be beneficial to the failing heart including being antiinflammatory, antifibrotic, lusitropic, antioxidative, and antitrophic.7 Naturally, these peptides would be studied as therapeutic agents for HF.
AC C
EP
TE D
M AN U
Recombinant human ANP (carperitide, hANP) and BNP (nesiritide, hBNP), which have greater affinity for natriuretic peptide receptor-A compared to CNP, have been studied in patients hospitalized for HF and as intermittent outpatient infusion therapy for advanced chronic HF. Early clinical studies demonstrated bolus and short-term continuous infusions of either hANP or hBNP effectively reduced left and rightsided cardiac filling pressures, while improving or having a neutral effect on cardiac output and urine output. However, considering the advances in our understanding of the pathophysiology of HF, it’s not surprising that hemodynamic improvements have become insufficient and the ultimate goal has become improved clinical outcomes for both chronic and acute HF. Nesiritide was approved based on hemodynamic improvement, while lacking studies demonstrating a clear advantage on outcomes such as dyspnea improvement, re-hospitalization for HF, and survival. Its trials and tribulations have been well chronicled.8 Post-hoc and pooled analyses found associations to increased risk of acute worsening of renal function and mortality. However, registry data suggested nesiritide was associated with improved outcomes when assessed using propensity-matched cohorts. Inevitably, the question of safety and efficacy of nesiritide was finally evaluated prospectively in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.9 This trial considered the question of whether the addition of nesiritide to standard therapy would improve short-term dyspnea, risk of renal dysfunction, and re-hospitalization or death from any cause at 30 days. Despite the study concluding nesiritide was safe and associated with a small but non-significant improvement in patient self-reported dyspnea, the lack of benefit on re-hospitalization or death has rendered this agent an after-thought in the minds of many practitioners who manage hospitalized HF patients. Although carperitide was in clinical use earlier (approved in Japan in 1995) than nesiritide (approved in the United States in 2001), the story is eerily similar. Current evidence for the effect of carperitide on clinical outcomes in decompensated HF patients is derived from an open-label registry10, a prospective observational study, and two small comparative trials with less than 60 patients each.11, 12 The impression from the registry and observational study is carperitide is safe and that most patients respond, but there were no comparators. In acute HF patients with pulmonary artery catheter monitoring treated with either carperitide or nitroglycerin, changes in hemodynamics and BNP levels at discharge favored nitroglycerin, however no difference was detected in total number of cardiac events after 1 year of follow-up.11 The Prospective Trial of cardiopro-tective Effect of Carperitide Treatment (PROTECT) study randomized 49 patients hospitalized for acute decompensated HF to carperitide (median dose 0.01 mcg/kg/min) as initial therapy or standard medical treatment.12 Patients were all
ACCEPTED MANUSCRIPT
RI PT
New York Heart Association functional class III or IV, with left ventricular ejection fraction less than 45%. Importantly, there was increased use of intravenous vasodilators in the control group, but no other significant differences in use of diuretics or other HF medications at discharge or during longitudinal follow-up. The purpose of this study was to compare effects on biomarkers for left ventricular wall stress and myocardial damage, renal function, and mechanisms possibly influencing long term prognosis. The major findings were a reduction in the ratio of heart-type fatty acid-binding protein to serum creatinine and a significant reduction in 180 day re-hospitalizations and all-cause mortality. Although noteworthy, the limited sample sizes render the question of safety and efficacy with carperitide equivocal.
M AN U
SC
This brings us to the current study by Matsue et al. published in this issue of the Journal. This study compiled data from 1,038 patients hospitalized with acute HF of which 402 (38.7%) were treated with carperitide within the first 48 hours of admission. Propensity-score matching was performed with 367 of these patients. Patients tended to be older than those in contemporary US based acute HF registries, fewer with ischemic etiology, and lower rates of established HF with reduced ejection fraction (HFrEF) medications prior to admission. In their analysis, carperitide was associated with a two-fold increase in all-cause in-hospital mortality. Although retrospective in design, it is an important addition to the limited literature related to carperitide. The 367 propensity-score matched pairs represent the largest sample size used in any comparative analysis with carperitide for acute HF. Once again the question of whether short-term therapy with a recombinant natriuretic peptide is truly safe and effective has been raised.
AC C
EP
TE D
How should this study be interpreted? Notwithstanding the inherent limitations of a retrospective study, there are additional limitations to the association of carperitide to increased mortality risk. The analysis fails to provide clues to possible mechanisms for increased mortality. Although the authors propose hypotension as a plausible explanation, vital statistics were not available during the course of therapy and the subgroup analysis failing to show an interaction based on admission systolic blood pressure doesn’t support this supposition. Established predictors of poor prognosis such as renal function were also not assessed. In addition, dose-dependent effects of carperitide were not considered despite being a major limitation of the nesiritide post-hoc analyses. Finally, the analysis was limited to carperitide use within the first 48 hours of hospitalization while the median length of stay was 15 days. There may be important differences in the management of HF in different parts of the world as well, as carperitide is commonly used in Japan as monotherapy and it’s unclear if all patients received concomitant diuretics although mean intravenous furosemide doses were similar between the carperitide and non-carperitide groups. Recognizing these limitations, the authors correctly conclude that a prospective randomized clinical trial is needed to evaluate the safety and efficacy of carperitide in acute HF. On the surface this may be true. However, following in the footsteps of nesiritide may not be the best approach. This study adds to mounting evidence that short term administration of recombinant natriuretic peptides may not be the optimal approach if the goal is to improve short and long term outcomes. Many reasons have been postulated for the failure of exogenous natriuretic peptides to alter the natural history of HF, including resistance to natriuretic peptide response, inadequate levels to completely counteract detrimental neurohormonal activation, and the risk of hypotension. Perhaps the beneficial effects of natriuretic peptides depend on duration of exposure. This is logical considering many of the beneficial effects of natriuretic peptides are unrelated to acute effects on ventricular loading conditions. Very preliminary data with serial carperitide infusions in the outpatient setting for advanced HF has been positive.13 Additional evidence can be derived from a proof of concept study
ACCEPTED MANUSCRIPT
SC
RI PT
evaluating serial subcutaneous injections of BNP in symptomatic chronic HFrEF.14 In this randomized, double-blind study, BNP administered twice daily for 8 weeks reduced left ventricular remodeling and filling pressures, while preserving glomerular filtration rate compared to placebo. Although the FollowUp Serial Infusions of Nesiritide (FUSION II) study was considered a negative trial, the study population was limited to advanced HFrEF patients, nesiritide was administered only once or twice weekly, and the study was underpowered to detect a difference in the primary endpoint of all-cause mortality or cardiovascular or renal hospitalization.15 The most compelling data that extended exposure is required to modify disease progression is highlighted by the success of neprilysin inhibition and LCZ696.16 Although it is difficult to separate whether the synergistic benefits of combining sacubitril to an angiotensin receptor blocker are due primarily to boosting of natriuretic peptides or other vasodilatory peptides such as adrenomedullin, bradykinin, and angiotensin 1-7, the premise of augmenting natriuretic peptides chronically to improve long term outcomes has finally come to fruition. The concept is not new, as the search to prolong the actions of natriuretic peptides had been considered several times in the past by combining BNP with phosphodiesterase inhibition and vasopeptidase inhibition.17, 18
References
EP
TE D
M AN U
So will recombinant natriuretic peptide therapy ever fulfill its promise of improved longitudinal outcomes in HF? Isolating the chronically beneficial natriuretic and neurohormonal effects from the acute vasodilatory potentially hypotensive effects (CD-NP) has been modestly successful but has not been studied beyond acute application.19 Similarly, ularitide (the recombinant renal pro-atrial natriuretic peptide urodilatin), is currently being evaluated in a Phase III trial for acute decompensated HF (TRUE-AHF, NCT01661634). Considering the evidence with carperitide and nesiritide, one could question the likelihood of a 48 hour ularitide infusion to improve 180 day mortality despite more selective inclusion criteria. Perhaps most promising, but most naïve in clinical evaluation, are the attempts to prolong the actions of natriuretic peptides by fusing with albumin.20, 21 In experimental studies, the half-lives of these synthetic peptides are extended to hours instead of minutes, while retaining their inherent biologic activity. This renders them more attractive for extended therapy. If the bar for acute HF therapies has been set at improved longitudinal outcomes such as 30 day rehospitalization and 180 day mortality, perhaps shifting towards more extended duration of therapy may increase the chances of success. The unfulfilled promise of natriuretic peptide therapy in HF is case in point.
AC C
1. Packer M. How should physicians view heart failure? The philosophical and physiological evolution of three conceptual models of the disease. The American journal of cardiology 1993;71:3C-11C. 2. Rosenzweig A, Seidman CE. Atrial natriuretic factor and related peptide hormones. Annual review of biochemistry 1991;60:229-55. 3. Jamieson JD, Palade GE. Specific Granules in Atrial Muscle Cells. The Journal of cell biology 1964;23:151-72. 4. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life sciences 1981;28:89-94. 5. Sudoh T, Maekawa K, Kojima M, Minamino N, Kangawa K, Matsuo H. Cloning and sequence analysis of cDNA encoding a precursor for human brain natriuretic peptide. Biochemical and biophysical research communications 1989;159:1427-34. 6. Sudoh T, Minamino N, Kangawa K, Matsuo H. C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochemical and biophysical research communications 1990;168:863-70.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
7. de Sa DD, Chen HH. The role of natriuretic peptides in heart failure. Current cardiology reports 2008;10:182-9. 8. Burnett JC, Jr., Korinek J. The tumultuous journey of nesiritide: past, present, and future. Circulation Heart failure 2008;1:6-8. 9. O'Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of nesiritide in patients with acute decompensated heart failure. The New England journal of medicine 2011;365:32-43. 10. Suwa M, Seino Y, Nomachi Y, Matsuki S, Funahashi K. Multicenter prospective investigation on efficacy and safety of carperitide for acute heart failure in the 'real world' of therapy. Circulation journal : official journal of the Japanese Circulation Society 2005;69:283-90. 11. Mizutani T, Inomata T, Watanabe I, Maekawa E, Yanagisawa T, Shinagawa H, et al. Comparison of nitrite compounds and carperitide for initial treatment of acute decompensated heart failure. International heart journal 2011;52:114-8. 12. Hata N, Seino Y, Tsutamoto T, Hiramitsu S, Kaneko N, Yoshikawa T, et al. Effects of carperitide on the long-term prognosis of patients with acute decompensated chronic heart failure: the PROTECT multicenter randomized controlled study. Circulation journal : official journal of the Japanese Circulation Society 2008;72:1787-93. 13. Nishi K, Sato Y, Miyamoto T, Toma M, Taniguchi R, Fukuhara R, et al. Intermittent infusions of carperitide or inotoropes in out-patients with advanced heart failure. Journal of cardiology 2012;59:36673. 14. Chen HH, Glockner JF, Schirger JA, Cataliotti A, Redfield MM, Burnett JC, Jr. Novel protein therapeutics for systolic heart failure: chronic subcutaneous B-type natriuretic peptide. Journal of the American College of Cardiology 2012;60:2305-12. 15. Yancy CW, Krum H, Massie BM, Silver MA, Stevenson LW, Cheng M, et al. Safety and efficacy of outpatient nesiritide in patients with advanced heart failure: results of the Second Follow-Up Serial Infusions of Nesiritide (FUSION II) trial. Circulation Heart failure 2008;1:9-16. 16. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. The New England journal of medicine 2014;371:993-1004. 17. Chen HH, Huntley BK, Schirger JA, Cataliotti A, Burnett JC, Jr. Maximizing the renal cyclic 3'-5'guanosine monophosphate system with type V phosphodiesterase inhibition and exogenous natriuretic peptide: a novel strategy to improve renal function in experimental overt heart failure. Journal of the American Society of Nephrology : JASN 2006;17:2742-7. 18. Chen HH, Lainchbury JG, Harty GJ, Burnett JC, Jr. Maximizing the natriuretic peptide system in experimental heart failure: subcutaneous brain natriuretic peptide and acute vasopeptidase inhibition. Circulation 2002;105:999-1003. 19. Lieu HD, Young J, Elkayam U, Katz A, Darius H, Goldstein S, et al. A phase II, dose-ranging study with CD-NP, a chimeric natriuretic peptide, in acute decompensated heart failure patients with renal compromise. Journal of the American College of Cardiology 2011;57:E2029. 20. Wang W, Ou Y, Shi Y. AlbuBNP, a recombinant B-type natriuretic peptide and human serum albumin fusion hormone, as a long-term therapy of congestive heart failure. Pharmaceutical research 2004;21:2105-11. 21. de Bold MK, Sheffield WP, Martinuk A, Bhakta V, Eltringham-Smith L, de Bold AJ. Characterization of a long-acting recombinant human serum albumin-atrial natriuretic factor (ANF) expressed in Pichia pastoris. Regulatory peptides 2012;175:7-10.
S1071-9164(15)01034-9
DOI:
10.1016/j.cardfail.2015.08.338
Reference:
YJCAF 3624
To appear in:
Journal of Cardiac Failure
Received Date: 28 August 2015 Revised Date:
28 August 2015
Accepted Date: 31 August 2015
Please cite this article as: Ng TMH, Natriuretic peptides as therapy for heart failure – unfulfilled promise?, Journal of Cardiac Failure (2015), doi: 10.1016/j.cardfail.2015.08.338. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Natriuretic peptides as therapy for heart failure – unfulfilled promise? Tien M.H. Ng, PharmD, University of Southern California, Los Angeles, CA
Correspondence:
RI PT
Tien M.H. Ng, PharmD University of Southern California School of Pharmacy 1985 Zonal Ave Los Angeles, CA 90033
SC
Tel: 323-442-1840 Fax: 323-442-1681 Email: [email protected]
M AN U
Disclosures: The author has no conflicts of interest to declare. Short title:
AC C
EP
TE D
Natriuretic peptides as therapy for heart failure
ACCEPTED MANUSCRIPT
Neurohormonal activation was first recognized as an important mediator of heart failure (HF) in the early 1990s. The neurohormonal model of HF helped explain the hemodynamic alterations of the cardiorenal and cardiocirculatory models, and built upon them by providing a mechanism for the progressive nature of the syndrome.1 Since then, development of novel HF therapies has focused on antagonizing or counteracting the effects of so-called vasoconstrictive neuorhormonal pathways.
SC
RI PT
Granules located in human atria were first recognized in the early 1960s, but it wasn’t until 1981 that the contents of these granules was described as atrial natriuretic peptide (ANP), originally known as atrial natriuretic factor.2-4 Related natriuretic peptides were subsequently identified. B-type or braintype natriuretic peptide (BNP) was identified in humans in 19895, and C-type natriuretic peptide (CNP) in 1990.6 Experimental studies demonstrated that these peptides exerted important cardiac and renal physiologic effects, essentially being the natural physiologic antagonists to the renin-angiotensinaldosterone-system. In addition, they have a multitude of other actions that would be beneficial to the failing heart including being antiinflammatory, antifibrotic, lusitropic, antioxidative, and antitrophic.7 Naturally, these peptides would be studied as therapeutic agents for HF.
AC C
EP
TE D
M AN U
Recombinant human ANP (carperitide, hANP) and BNP (nesiritide, hBNP), which have greater affinity for natriuretic peptide receptor-A compared to CNP, have been studied in patients hospitalized for HF and as intermittent outpatient infusion therapy for advanced chronic HF. Early clinical studies demonstrated bolus and short-term continuous infusions of either hANP or hBNP effectively reduced left and rightsided cardiac filling pressures, while improving or having a neutral effect on cardiac output and urine output. However, considering the advances in our understanding of the pathophysiology of HF, it’s not surprising that hemodynamic improvements have become insufficient and the ultimate goal has become improved clinical outcomes for both chronic and acute HF. Nesiritide was approved based on hemodynamic improvement, while lacking studies demonstrating a clear advantage on outcomes such as dyspnea improvement, re-hospitalization for HF, and survival. Its trials and tribulations have been well chronicled.8 Post-hoc and pooled analyses found associations to increased risk of acute worsening of renal function and mortality. However, registry data suggested nesiritide was associated with improved outcomes when assessed using propensity-matched cohorts. Inevitably, the question of safety and efficacy of nesiritide was finally evaluated prospectively in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.9 This trial considered the question of whether the addition of nesiritide to standard therapy would improve short-term dyspnea, risk of renal dysfunction, and re-hospitalization or death from any cause at 30 days. Despite the study concluding nesiritide was safe and associated with a small but non-significant improvement in patient self-reported dyspnea, the lack of benefit on re-hospitalization or death has rendered this agent an after-thought in the minds of many practitioners who manage hospitalized HF patients. Although carperitide was in clinical use earlier (approved in Japan in 1995) than nesiritide (approved in the United States in 2001), the story is eerily similar. Current evidence for the effect of carperitide on clinical outcomes in decompensated HF patients is derived from an open-label registry10, a prospective observational study, and two small comparative trials with less than 60 patients each.11, 12 The impression from the registry and observational study is carperitide is safe and that most patients respond, but there were no comparators. In acute HF patients with pulmonary artery catheter monitoring treated with either carperitide or nitroglycerin, changes in hemodynamics and BNP levels at discharge favored nitroglycerin, however no difference was detected in total number of cardiac events after 1 year of follow-up.11 The Prospective Trial of cardiopro-tective Effect of Carperitide Treatment (PROTECT) study randomized 49 patients hospitalized for acute decompensated HF to carperitide (median dose 0.01 mcg/kg/min) as initial therapy or standard medical treatment.12 Patients were all
ACCEPTED MANUSCRIPT
RI PT
New York Heart Association functional class III or IV, with left ventricular ejection fraction less than 45%. Importantly, there was increased use of intravenous vasodilators in the control group, but no other significant differences in use of diuretics or other HF medications at discharge or during longitudinal follow-up. The purpose of this study was to compare effects on biomarkers for left ventricular wall stress and myocardial damage, renal function, and mechanisms possibly influencing long term prognosis. The major findings were a reduction in the ratio of heart-type fatty acid-binding protein to serum creatinine and a significant reduction in 180 day re-hospitalizations and all-cause mortality. Although noteworthy, the limited sample sizes render the question of safety and efficacy with carperitide equivocal.
M AN U
SC
This brings us to the current study by Matsue et al. published in this issue of the Journal. This study compiled data from 1,038 patients hospitalized with acute HF of which 402 (38.7%) were treated with carperitide within the first 48 hours of admission. Propensity-score matching was performed with 367 of these patients. Patients tended to be older than those in contemporary US based acute HF registries, fewer with ischemic etiology, and lower rates of established HF with reduced ejection fraction (HFrEF) medications prior to admission. In their analysis, carperitide was associated with a two-fold increase in all-cause in-hospital mortality. Although retrospective in design, it is an important addition to the limited literature related to carperitide. The 367 propensity-score matched pairs represent the largest sample size used in any comparative analysis with carperitide for acute HF. Once again the question of whether short-term therapy with a recombinant natriuretic peptide is truly safe and effective has been raised.
AC C
EP
TE D
How should this study be interpreted? Notwithstanding the inherent limitations of a retrospective study, there are additional limitations to the association of carperitide to increased mortality risk. The analysis fails to provide clues to possible mechanisms for increased mortality. Although the authors propose hypotension as a plausible explanation, vital statistics were not available during the course of therapy and the subgroup analysis failing to show an interaction based on admission systolic blood pressure doesn’t support this supposition. Established predictors of poor prognosis such as renal function were also not assessed. In addition, dose-dependent effects of carperitide were not considered despite being a major limitation of the nesiritide post-hoc analyses. Finally, the analysis was limited to carperitide use within the first 48 hours of hospitalization while the median length of stay was 15 days. There may be important differences in the management of HF in different parts of the world as well, as carperitide is commonly used in Japan as monotherapy and it’s unclear if all patients received concomitant diuretics although mean intravenous furosemide doses were similar between the carperitide and non-carperitide groups. Recognizing these limitations, the authors correctly conclude that a prospective randomized clinical trial is needed to evaluate the safety and efficacy of carperitide in acute HF. On the surface this may be true. However, following in the footsteps of nesiritide may not be the best approach. This study adds to mounting evidence that short term administration of recombinant natriuretic peptides may not be the optimal approach if the goal is to improve short and long term outcomes. Many reasons have been postulated for the failure of exogenous natriuretic peptides to alter the natural history of HF, including resistance to natriuretic peptide response, inadequate levels to completely counteract detrimental neurohormonal activation, and the risk of hypotension. Perhaps the beneficial effects of natriuretic peptides depend on duration of exposure. This is logical considering many of the beneficial effects of natriuretic peptides are unrelated to acute effects on ventricular loading conditions. Very preliminary data with serial carperitide infusions in the outpatient setting for advanced HF has been positive.13 Additional evidence can be derived from a proof of concept study
ACCEPTED MANUSCRIPT
SC
RI PT
evaluating serial subcutaneous injections of BNP in symptomatic chronic HFrEF.14 In this randomized, double-blind study, BNP administered twice daily for 8 weeks reduced left ventricular remodeling and filling pressures, while preserving glomerular filtration rate compared to placebo. Although the FollowUp Serial Infusions of Nesiritide (FUSION II) study was considered a negative trial, the study population was limited to advanced HFrEF patients, nesiritide was administered only once or twice weekly, and the study was underpowered to detect a difference in the primary endpoint of all-cause mortality or cardiovascular or renal hospitalization.15 The most compelling data that extended exposure is required to modify disease progression is highlighted by the success of neprilysin inhibition and LCZ696.16 Although it is difficult to separate whether the synergistic benefits of combining sacubitril to an angiotensin receptor blocker are due primarily to boosting of natriuretic peptides or other vasodilatory peptides such as adrenomedullin, bradykinin, and angiotensin 1-7, the premise of augmenting natriuretic peptides chronically to improve long term outcomes has finally come to fruition. The concept is not new, as the search to prolong the actions of natriuretic peptides had been considered several times in the past by combining BNP with phosphodiesterase inhibition and vasopeptidase inhibition.17, 18
References
EP
TE D
M AN U
So will recombinant natriuretic peptide therapy ever fulfill its promise of improved longitudinal outcomes in HF? Isolating the chronically beneficial natriuretic and neurohormonal effects from the acute vasodilatory potentially hypotensive effects (CD-NP) has been modestly successful but has not been studied beyond acute application.19 Similarly, ularitide (the recombinant renal pro-atrial natriuretic peptide urodilatin), is currently being evaluated in a Phase III trial for acute decompensated HF (TRUE-AHF, NCT01661634). Considering the evidence with carperitide and nesiritide, one could question the likelihood of a 48 hour ularitide infusion to improve 180 day mortality despite more selective inclusion criteria. Perhaps most promising, but most naïve in clinical evaluation, are the attempts to prolong the actions of natriuretic peptides by fusing with albumin.20, 21 In experimental studies, the half-lives of these synthetic peptides are extended to hours instead of minutes, while retaining their inherent biologic activity. This renders them more attractive for extended therapy. If the bar for acute HF therapies has been set at improved longitudinal outcomes such as 30 day rehospitalization and 180 day mortality, perhaps shifting towards more extended duration of therapy may increase the chances of success. The unfulfilled promise of natriuretic peptide therapy in HF is case in point.
AC C
1. Packer M. How should physicians view heart failure? The philosophical and physiological evolution of three conceptual models of the disease. The American journal of cardiology 1993;71:3C-11C. 2. Rosenzweig A, Seidman CE. Atrial natriuretic factor and related peptide hormones. Annual review of biochemistry 1991;60:229-55. 3. Jamieson JD, Palade GE. Specific Granules in Atrial Muscle Cells. The Journal of cell biology 1964;23:151-72. 4. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life sciences 1981;28:89-94. 5. Sudoh T, Maekawa K, Kojima M, Minamino N, Kangawa K, Matsuo H. Cloning and sequence analysis of cDNA encoding a precursor for human brain natriuretic peptide. Biochemical and biophysical research communications 1989;159:1427-34. 6. Sudoh T, Minamino N, Kangawa K, Matsuo H. C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochemical and biophysical research communications 1990;168:863-70.
ACCEPTED MANUSCRIPT
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EP
TE D
M AN U
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