Natriuretic peptide-guided management of patients with heart failure: a decade of progress but still a controversy
2010; Future Medicine; Volume: 6; Issue: 6 Linguagem: Inglês
10.2217/fca.10.104
ISSN1744-8298
AutoresMotaz Baibars, Ahmed Ibrahim, James C. Fang, İlke Sipahi,
Tópico(s)Cardiac Structural Anomalies and Repair
ResumoFuture CardiologyVol. 6, No. 6 EditorialFree AccessNatriuretic peptide-guided management of patients with heart failure: a decade of progress but still a controversyMotaz Baibars, Ahmed Ibrahim, James C Fang & Ilke SipahiMotaz BaibarsCase Western Reserve University, St Vincent Charity Medical Center, Cleveland, OH, USA, Ahmed IbrahimCase Western Reserve University, St Vincent Charity Medical Center, Cleveland, OH, USA, James C FangHarrington-McLaughlin Heart & Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA: 11100 Euclid Ave, LKS 5038, Cleveland, OH 44106, USA & Ilke Sipahi† Author for correspondencePublished Online:9 Dec 2010https://doi.org/10.2217/fca.10.104AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: biomarkersheart failurenatriuretic peptideHeart failure (HF) is a common disease of high morbidity and mortality worldwide. Despite recent advances in management of HF, it remains a leading cause of morbidity and mortality in the USA [1] with 30% of patients readmitted within 60–90 days following HF hospitalization and approximately 10% dying in the same time span [2].Natriuretic peptide (NP) markers, such as B-type NP (BnP), and its amino-terminal fragment N-terminal proBnP (nt-proBnP), have emerged as important tools for the diagnosis [3,4] and risk stratification of patients with HF [5], but have not been clearly shown to supplement careful clinical assessment for managing HF [6,7]. It is still debatable whether titration of medications guided by NP levels can help to 'personalize' treatment of patients with HF [8] in contrast to standard clinical management.Historical background of NPsIn 1981, de Bold and colleagues demonstrated increased sodium and water excretion after the infusion of atrial muscle extracts in rats [9]. Later in 1984, Kangwa et al. isolated a 28-amino acid peptide from the atria (atrial NP), which was shown to have potent diuretic and vasorelaxant activity [10]. Another NP was isolated from porcine brain in 1988 and was named brain NP, now more commonly referred to as BNP [11].Rationale for use of NP to guide management of heart failureTargeting cut-off numbers is a preferable method in managing common diseases such as low-density lipoprotein levels in hypercholesterolemia, glycosylated hemoglobin (HbA1c) in diabetes mellitus and blood pressure in hypertension. Measuring these parameters at regular intervals and adjusting medications accordingly make it standardized management and ensure delivery of appropriate care based on guidelines.In HF, efforts have been made to develop numerical parameters to follow-up patients with biomarker assays. A good biomarker has to fulfill the following criteria: accuracy, availability, reasonable price and ability to provide additional data that is not obtained by clinical examination [12]. Finally it should have a target range for therapy and should help in improving outcomes by earlier diagnosis and better triage. NP has emerged as an attractive biomarker for HF, but others advocate that BNP cannot be a substitution for the information derived from a good history and physical examination [13]. Different studies have targeted different levels of NP, such as nt-proBnP levels of less than 200 ng/l [14], 1270 ng/l [15], 1000 ng/l [101] or BNP levels of less than 100 ng/l [16].NP assays are cheap and cost an average of US$20 per test [17]. However, since NP has interpatient and intrapatient variability depending on gender, age, renal function, body-mass index and genetic pleomorphism [18–20], the extent of its accuracy has limitations. NP is proven to help in the diagnosis and risk stratification of patients with HF, but one question that remains is will patients with higher NP get more benefit with intensified medical treatment than those with lower levels? [18]. Our armamentarium of medications that are proven to reduce mortality in HF, including angiotensin-converting enzyme (ACE) inhibitors [21], angiotensin-receptor blockers [22], aldosterone antagoniosts [23] and electrical device therapy in the form of biventricular pacemakers [24], also proved to decrease the level of NP, while β-blockers usually follow a more biphasic pattern with an increase NP levels in the first 3 months, followed by a decrease later on, whereas other studies showed no effect of β-blockers on NP levels [25,26]. However, if we use NP for titration of HF medications, it may still be impossible to differentiate whether the improved outcome is due to NP-guided therapy or a result of increased medication doses, which are already proven to have additional benefit regardless of NP levels [18]. Considering the improved outcomes with higher drug doses, at least with ACE inhibitors and angiotensin-receptor blockers [27,28], intensified antineurohormonal treatment should be given to most patients regardless of their BNP levels. The goal would always be to reach the maximum-tolerated doses advocated in the treatment guidelines [6] (in other words, without hypotension, severe bradycardia or renal failure).Clinical trials of NP as a guide for heart failure managementOver the last decade, several randomized-controlled trials (RCTs) have investigated the NP-guided approach in HF patients. Of these, Strategies for Tailoring Advanced Heart Failure Regimens in the Outpatient Setting: Brain Natriuretic Peptide Versus the Clinical Congestion Score (STARBRITE) [29] and Signal-HF [30] failed to show any benefit of the NP-guided approach while nt-proBnP-guided management of chronic heart failure, based on an individual target value (PRIMA) [31] showed a significant decrease in mortality and hospitalization in patients who remained on target NP levels. In addition, the Christchurch New Zealand [14], Systolic Heart Failure Treatment supported by the BNP (STARS-BNP) [16] and BNP-Guided Care in Addition to Multidisciplinary Care [32] trials showed a decrease in hospitalizations as well as mortality in the NP-guided group compared with usual clinical care. The Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study was terminated early after 1 year due to a significant drop in hospitalizations and cardiovascular-related deaths in the NP-guided group [25]. Very recently, two large-scale trials, a nt-proBnP-assisted treatment to lessen serial cardiac readmission and death (BATTLESCARRED) [15] and Trial of Intensified versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) [33] showed better outcomes with NP-guided uptitration of medications only in patients aged under 75 years. There are two studies still recruiting patients: the Improvement of Patients With Chronic Heart Failure Using NT-proBNP (EX-IMPROVE-CHF) [102], which is double-blinded aiming to recruit 400 patients, and a nt-proBnP stratified follow-up in outpatient heart failure clinics (NORTHSTAR) [34], which will involve 1250 patients.Meta-analysis of these trials would have been heterogeneous owing to differences in study populations, cut-off NP targets and inclusion levels, interventions, duration of follow-ups, monitoring algorithms, difficulties with double blinding and different end points. Nevertheless, two groups of investigators one from Duke (NC, USA) [35] and other from Australia [36] performed a meta-analysis of NP-guided therapy trials. The former included all major trials except the signal-HF (six trials with total n = 1627), while the latter meta-analysis added two more small trials (eight trials with total n = 1726) [37,38]. Neither included the BNP-Guided Care in Addition to Multidisciplinary Care trial [32], as this is more recently published. Both meta-analyses concluded that NP-guided therapy could reduce all-cause mortality in patients with chronic HF, particularly in those aged under 75 years. Investigators acknowledged the need for additional well-powered studies with a larger number of patients.Reviewing medication titration and doses achieved in different RCTs would have been helpful to understand the heterogeneity of different results achieved in NP trials. In the older Christchurch New Zealand trial [14], the percentage of patients on β-blockers at follow up was 12.12% in the NP arm, while this was 6.06% in the clinical-guided arm. In the same trial the percentage of target dose of ACE inhibitor achieved in all patients at follow-up was 77 in patients in the NP arm versus 66% in the control arm. In STARS-BNP, the percentage of b-blocker target dose achieved in patients in the NP arm patients at follow-up was 77 versus 66% in the control arm [16]. In addition, the BNP-Guided Care in Addition to Multidisciplinary Care trial showed that b-blocker doses achieved in the NP-guided arm at follow-up was 73% while it was in 38 and 58% in the usual care and multidisciplinary care arms, respectively [32]. The percentage of target dose of the ACE inhibitor achieved at follow-up in STARS-BNP was 106% in the NP-guided arm compared with 98% in the control arm. In the NP arm of BNP-Guided Care in addition to Multidisciplinary Care trial it was 100% versus 54 and 97% in the usual care and multidisciplinary care arms, respectively. It is apparent that medications known to improve outcomes were more aggressively uptitrated in NP-guided arms compared with conventional treatment arms and the necessity of measuring BNP to perform aggressive drug uptitration is questionable.Age of the patient may play an important role in the outcome as shown in TIME-CHF [33] and BATTLESCARRED [15], which showed no significant difference in mortality and hospitalization between NP- and clinical-guided approaches for patients aged 75 years or older. In patients aged under 75 years, TIME-CHF reported that the percentage of the b-blocker target dose achieved was lower in the control arm than in the NP arm (16 vs 28%; p < 0.001), and similarly, in patients aged over 75 years it was 12.5 versus 19%, respectively (p < 0.001). For ACE inhibitors, the target dose achieved was 15% in patients aged less than 75 years in the control arm, while it was 29% in the NP-guided arm (p < 0.001) and in patients aged 75 years or over, it was 16% in the control arm versus 25% in the NP-guided arm. The likely explanation is that older people are likely to be less able to tolerate higher doses of proven-benefit medications. Also, they are more likely to have altered renal function than younger HF populations. In addition, there is a higher proportion of HF with preserved left ventricular ejection fraction type, where standard systolic HF therapy is not effective [39,40]. The Heart Failure End Point Evaluation of Angiotensin II Antagonist Losartan (HEAAL) [28] and Assessment of Treatment with Lisinopril and Survival (ATLAS) [27] trials support the same observation about age, as they have shown that higher doses of losartan and lisinopril were improving outcomes only in the younger patients. Subgroup analysis in the HEAAL trial for patients aged 65 years or older showed no significant difference in outcomes comparing lower (50 mg/day) and higher (150 mg/day) doses of losartan (percentage of patients with events were 14.6 vs 13.7%, respectively; p = 0.18). Also, the ATLAS trial found no significant differences in all-cause mortality in HF patients aged more than 70 years when comparing low- (2.5–5 mg/day) versus high-dose (32.5–35 mg/day) lisinopril regimens. Uptitration of β-blockers in the elderly population might even be a difficult task as shown by the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS-ELD) trial, where the proportion of patients with a mean age over 70 years achieving the target dose of carvidelol and bisoprolol was only 25% [30]. In conclusion, it is likely that higher doses of standard HF medications are less likely to be effective and/or more likely to cause side effects such as hypotension and renal failure in older patient populations.Current heart failure guidelines & NPThe 2009 focused update incorporated into the American College of Cardiology (ACC) and the American Heart Association (AHA) 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults, suggests that using NP to guide HF therapy remains poorly established (Class 2b/level of evidence C) [6]. This can be attributed to the obvious need for larger, better-designed RCTs before adopting the NP-guided approach. Whether the more recently published trials [31,32,101] and the meta-analyses [35,36] will change the guidelines remains to be seen.ConclusionDespite emerging data in the last decade that progressed from small pilot studies to RCTs to meta-analyses, NP-guided therapy for chronic HF remains controversial. The consensus opinion remains that favorable outcomes attained with this approach are due to better adherence and continuous uptitration of medications to maximal-tolerated target doses and due to closer follow-up of these patients [18,103]. We still believe that routine BNP-guided management of HF is not warranted.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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Hurst's The Heart/General Update/Access Medicine. www.accessmedicine.com/updatesContent.aspx?aID=1001580Google ScholarFiguresReferencesRelatedDetailsCited ByBiomarkers in heart failureAshraf Mostafa, Mohamed El-Haddad & Jalal K Ghali26 September 2012 Vol. 6, No. 6 Follow us on social media for the latest updates Metrics History Published online 9 December 2010 Published in print November 2010 Information© Future Medicine LtdKeywordsbiomarkersheart failurenatriuretic peptideFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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