Systematic review/meta-analysisHuman Atrial Natriuretic Peptide Treatment for Acute Heart Failure: A Systematic Review of Efficacy and Mortality
Introduction
Heart failure affects more than 23 million people and continues to be a significant cause of morbidity worldwide.1 By some estimates, 3% of those 45 years and older suffer from the disease, with a rising prevalence as populations continue to age.2, 3 Despite the development of many well-established therapies available for treating heart failure,4 the incidence of heart failure did not change between 1970 and 1999.5 In the last decade, the new pharmacotherapeutics that have been developed to treat acute heart failure have met with mixed results. Tolvaptan, a competitive arginine vasopressin receptor 2 antagonist, was used with initial success in the treatment of hyponatremia6 and was later studied for the treatment of heart failure. However, it has failed to improve long-term mortality and acute heart failure-related morbidity.7, 8, 9 Relaxin, a human peptide with multiple vascular control functions, had favourable effects on clinical outcomes in a pilot study, but it requires further study.10 Levosimendan, a phosphodiesterase inhibitor, may not reduce the mortality associated with acute heart failure.11 The continued interest in new therapeutics underscores the need for more effective preventative and therapeutic strategies for acute heart failure.
Infused human B-type natriuretic peptide (hBNP; nesiritide) is a promising therapy for heart failure that began to attract interest a decade ago. In an early meta-analysis, hBNP had been shown to improve the hemodynamic function and clinical status of patients with acute heart failure12 but not to significantly decrease mortality at 30 days.13 In a subsequent meta-analysis, however, 30-day mortality was shown to be slightly increased. Moreover, a recent large-scale, randomized, controlled trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial, or ASCEND) also showed improved dyspnea scores, although there were no benefits seen in all-cause mortality or rehospitalization.14 Given the balance between its probable benefits in short-term symptomatic treatment and its possible adverse effects on outcomes, hBNP use remains controversial in the US and has not been included in the standard of care for acute, decompensated heart failure.
Carperitide, a human atrial natriuretic peptide (hANP), is similar to hBNP in structure and exhibits a variety of regulatory effects on cardiovascular homeostasis.15 Most pronounced are its diuretic and vasodilating effects, both of which reduce cardiac preload, while after load reduction is achieved through inhibition of the renin-angiotensin axis.16 Before coming to market, hANP was shown to improve hemodynamic parameters in an animal model of heart failure.17 In Japan, hANP was first used to treat heart failure in 198718 and received national approval in 1995. Since its approval 15 years ago, hANP has seen widespread use throughout the country. Its reported sales of more than 9.5 billion yen (100 million US dollars) in 2009 represent the largest market share among heart failure therapies.19 Because hANP was first developed and continues to be used almost exclusively in Japan, it is less well known in other countries. Given Japan's extensive experience with this therapy, an analysis of its efficacy and disease outcomes may prove useful for acute, decompensated heart-failure patients worldwide.
Despite its extensive use in Japan and its evaluation in several randomized controlled trials (RCTs), there are no systematic reviews exploring the short- or long-term effects of hANP.20 In the current study, we conducted a systematic search of the literature to review the effect of hANP on hemodynamic parameters and mortality compared with placebo in patients with acute heart failure.
Section snippets
Protocol and registration
We conducted a systematic review that followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement for reporting results of systematic reviews of RCTs.21
Eligibility criteria
Our systematic review targeted patients with acute, decompensated heart failure who were treated with hANP. We included studies for any dosage, duration of treatment, and follow-up period. We limited the publication type to RCTs and included studies in any language.
Information sources
We searched for articles published in any
Study selection
We retrieved 347 studies using our initial selection strategy. Of these, 102 studies overlapped. Two of the authors independently reviewed the titles and abstracts of the remaining 245 studies and screened their reference sections. A total of 208 studies were either irrelevant or did not meet the inclusion criteria outlined in the Methods section (above), leaving a remaining 37 studies. These studies underwent a thorough and independent review, and 33 were subsequently excluded due to problems
Summary of evidence
In our study, carperitide tended to improve hemodynamic parameters compared with placebo, although the RAP and patient mortality rates were not different when compared with placebo. While our study demonstrated that carperitide appears to act favourably on important hemodynamic parameters, it was difficult to assess its effect on mortality due to an insufficient pooled sample size. However, these findings corroborate previous studies of hBNP that found improvements in parameters measuring the
Conclusions
In this systematic review, hANP appeared to improve several hemodynamic parameters, including the PCWP reduction and CIN. Although no differences in mortality were found, the data from the studies included in our analysis were insufficient to definitively assess long-term mortality with hANP use. Given the potential benefits of hANP, further high-quality RCTs in a variety of populations are warranted.
Disclosures
The authors have no conflicts of interest to disclose.
References (37)
- et al.
Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study
Lancet
(2001) - et al.
Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study
Lancet
(2009) - et al.
Short and long-term mortality with nesiritide
Am Heart J
(2006) - et al.
Assessing the quality of reports of randomized clinical trials: is blinding necessary?
Control Clin Trials
(1996) - et al.
Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis
J Clin Epidemiol
(2001) Natriuretic peptides for treatment of congestive heart failure
Am Heart J
(1999)- et al.
Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials
Lancet
(2007) - et al.
Practice patterns and outcomes in patients presenting to the emergency department with acute heart failure
Can J Cardiol
(2009) The Prevention of Heart Failure
- et al.
Prevalence of heart failure and systolic ventricular dysfunction in older Australians: the Canberra Heart Study
Med J Aust
(2006)
ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society
Circulation
Long-term trends in the incidence of and survival with heart failure
N Engl J Med
Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia
N Engl J Med
Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial
JAMA
Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials
JAMA
Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program
Am Heart J
Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial
JAMA
Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failureNesiritide Study Group
N Engl J Med
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2019, Journal of Critical CareCitation Excerpt :Third, we did not collect detailed data on cardiac function because measurement of cardiac indices of all patients in the 13 ICUs with reasonable quality had been adjudicated impracticable. Prior studies of hANP in acute congestive heart failure patients suggested the favorable effect on stroke volume or cardiac index [11,12]; however, data were scant, and the quality of the studies was low. Since a cohort study has implied increased mortality with using hANP for acute heart failure [45], the hemodynamic effect of hANP in critically ill patients should be explored in a future study.
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2017, International Journal of CardiologyCitation Excerpt :However, the duration of carperitide usage and total number of vials of carperitide used were inversely associated with large hospital case volumes. Although a previous small randomized clinical trial revealed the efficacy of carperitide on mortality in patients with AHF [9], a recent meta-analysis and retrospective study revealed that carperitide could not improve survival rates and was rather associated with increased in-hospital mortality, which was consistent with our results [3,4]. In spite of these background, our national registry data revealed that the usage of carperitide was up to 58.2%, which was much higher than nesiritide usage in hospitals in the United States (15.4% in 2005 and 1.2% in 2010) [10].
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