The Potential Role of Natriuretic Peptide–Guided Management for Patients Hospitalized for Heart Failure

Journal of Cardiac Failure Vol. 21 No. 3 2015

Review Article

The Potential Role of Natriuretic PeptideeGuided Management for Patients Hospitalized for Heart Failure ALAN MAISEL, MD,1 YANG XUE, MD,1 STEPHEN J. GREENE, MD,2 PETER S. PANG, MD,3 JAMES L. JANUZZI, MD,4 ~ MD, MPH,5 CHRISTOPHER DEFILIPPI, MD,6 AND JAVED BUTLER, MD, MPH7 ILEANA L. PINA, San Diego, California; Chicago, Illinois; Indianapolis, Indiana; Boston, Massachusetts; New York and Stony Brook, New York; and Baltimore, Maryland

ABSTRACT There are O1 million hospitalizations for heart failure (HF) in the United States annually. After discharge, 25% of these patients are rehospitalized within 30 days, and 30% are dead within 1 year. To date, all trials in patients with acute HF (AHF) have failed to improve post-discharge outcomes. There remains a need for an effective objective risk stratification strategy that is capable of reliably identifying patients at heightened risk for readmission and informing discharge decision making. Natriuretic peptide (NP) levels during and after AHF hospitalization can provide valuable information regarding congestion status and chronic remodeling stress. The lack of sensitivity and inter-rater reliability of physical examination, and failure to achieve dry weight in many patients before discharge, renders the use of NP to guide therapy to prevent readmission an attractive option. NP levels can be used across the spectrum of AHF care settings, ranging from the emergency department and inpatient stay to post-discharge follow-up and chronic management. This review summarizes available data and provides an expert opinion on the potential role of NPs to reduce HF readmissions. (J Cardiac Fail 2015;21:233e239) Key Words: Heart failure, natriuretic peptides, readmission, hospitalization.

There are O 1 million hospitalizations for heart failure (HF) in the United States each year, accounting for the majority of the w$40 billion spent annually on HF care.1,2 Hospitalization represents an inflection point in the natural

history of the HF syndrome and is an independent predictor of mortality.3e5 After discharge, 25% of these patients are rehospitalized within 30 days and 30% are dead within 1 year.6,7 To date, randomized trials in patients with acute HF (AHF) have consistently failed to show an improvement in post-discharge outcomes.8e11 Consequently, most interventions targeting HF readmissions are generic (eg, patient education) and without specific consideration of underlying pathophysiology. These interventions have either failed or have led to only modest improvement at high costs.12e14 Intriguingly, the correlation between post-discharge mortality and readmission is not strong.15,16 Many disease management strategies rely on risk stratification tools to identify high-risk patients; however, these tools were developed to predict mortality and are less effective in predicting readmissions.3,17 Randomized trials testing whether use of risk scores leads to improved outcomes have yet to be performed. There remains an unmet need for an effective objective risk stratification strategy that is capable of reliably identifying patients at heightened risk for readmission and informing discharge decision making. Biomarkers, with their objectivity, reproducibility, and widespread

From the 1Division of Cardiology, Department of Medicine, University of California San Diego and San Diego Veterans Administration Medical Center, San Diego, California; 2Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 3 Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana; 4Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; 5Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, New York, New York; 6Department of Medicine, University of Maryland, Baltimore, Maryland and 7Division of Cardiology, Department of Medicine, Stony Brook University, Stony Brook, New York. Manuscript received April 6, 2014; revised manuscript received October 11, 2014; revised manuscript accepted November 17, 2014. Reprint requests: Javed Butler, MD, MPH, Division of Cardiology, Stony Brook University, Health Sciences Center, T-16, Room 080, Stony Brook, New York 11794. Tel: þ1 631-444-1066; Fax: þ1 631-444-1054. E-mail: [email protected] See page 237 for disclosure information. 1071-9164/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2014.11.009

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234 Journal of Cardiac Failure Vol. 21 No. 3 March 2015 availability, may play a role. In this space, natriuretic peptides (NPs) have moved from diagnostic and prognostic roles to representing a potential guide for therapy. NP levels during and after AHF hospitalization can provide valuable information regarding ventricular filling pressures, intravascular volume, and chronic remodeling stress. The lack of sensitivity and inter-rater reliability of physical examination,18 and failure to achieve dry weight in many patients prior to discharge,19 renders the use of NPs to guide therapy to prevent readmission an attractive option. NP levels can be used across the spectrum of AHF care settings, ranging from the emergency department (ED) and inpatient stay to post-discharge follow-up and chronic management. B-Type- (BNP) or N-terminal proeB-type (NT-proBNP) NP may complement clinical assessment in AHF, representing an individualized approach with the potential to improve patient engagement as well.20 The present review summarizes available data and provides an expert opinion on the potential role of NPs for reducing HF readmissions. Biomonitoring With Natriuretic Peptides The value of a biomarker relies not only on diagnostic or prognostic value, but also in the potential to guide therapy. NPs are one of the most well studied biomarkers in HF, with an established role for diagnosis and prognosis.21e23 Several smaller studies have been conducted to assess the role of NP-guided therapy in chronic HF, leading to an ongoing definitive trial.24e26 NPs have been studied in nearly every setting important to HF readmissions, from ambulatory clinic, ED, and hospital to post-discharge follow-up. The reproducibility and objectivity of NP make it a valuable tool to be used across the spectrum of HF care settings. With inpatient medicine moving towards ‘shift work’ by hospitalists, biomarker measurements can help provide objective information during patient handoffs. NPs should not take the place of history and examination; they should be used in conjunction with clinical judgment. The value of NP-guided therapy would be enhanced if it occurs within an overall structure or process of care rather than in isolation. Emergency Department

In the United States, w80% of patients hospitalized with AHF are initially managed in the ED.27 Nearly 4 out of 5 patients who present to the ED with AHF are admitted.28,29 Although many admissions are necessary, the literature suggests that up to 50% of AHF patients may be safely discharged from ED or managed in an observation unit.30,31 Conversely, the lack of validated risk prediction models for short-term outcomes is reflected in studies showing that patients discharged from ED are often at higher risk for adverse outcomes than admitted AHF patients.31 Accurate identification of low-risk patients safe for discharge after ED treatment represents a unique opportunity to reduce admissions. Prompt and accurate diagnosis is a critical step

for managing these patients. NPs have an established role in aiding diagnosis of AHF, owing to their high sensitivity and specificity (NT-proBNP: sensitivity 90%, specificity 84%; BNP: sensitivity 90%, specificity 76%), and guidelines give NP the highest level of evidence for aiding AHF diagnosis.21e23,32,33 Routine NP measurement in the initial evaluation of AHF is now a class I indication.34 For recently hospitalized patients, a pre-discharge NP level may be particularly valuable as a point of reference (ie, optivolemic NP level) when the patient re-presents to the ED and the clinician is deciding on the diagnosis and decision to admit the patient. NP assessment in the ED can result in increased efficiency, decreased costs, and improved resource utilization.35,36 The argument against broad NP assessment is that HF is a clinical diagnosis.34 However, studies consistently show improved diagnostic accuracy with the use of NP. As clinicians’ diagnostic accuracy may vary, NP testing can often improve the diagnosis and triage of AHF patients.36 NPs may also help to avoid treatment delays, which are associated with worse outcomes.37,38 Prompt NP measurement can improve time to treatment, and in a subset of patients it may facilitate ED discharge and improve outcomes. Reducing the rate of admission for AHF hinges on the accurate identification of low-risk patients in the ED. NP levels discriminate risk better than physician impression.33 Specifically, NPs may more accurately identify lower-risk patients, eg, patients with BNP !200 pg/mL have a very low 30-day mortality risk.33 Patients with BNP !230 pg/ mL have a !2.5% risk for repeated ED visits, hospitalization, or death in 6 months.39 For simplicity, an ageindiscriminate cutoff of NT-proBNP of !1,800 pg/mL can be used to identifies patients at lower risk for mortality.22 Furthermore, comparison of patients’ ‘‘wet’’ NP (acute) with their ‘‘dry’’ NP level (chronic or optivolemic), may inform treatment decisions, particularly for patients recently discharged from the hospital.32 Pre-discharge NP level may be compared with the re-visit ED NP level, providing an objective assessment of disease severity. Figure 1 represents a proposed ED evaluation algorithm stratifying patients into low, intermediate, and high risk, incorporating NP and other common clinical characteristics. It is important to note that this algorithm requires prospective testing and validation. However, we think it is a reasonable and practical approach with the potential to optimize patient disposition from the ED. In the setting of ED presentation with at least minimal signs and symptoms compatible with AHF, patients with BNP levels O1,000 pg/mL, NTproBNP O1,800 pg/mL, or O25% increase from ‘‘dry or optivolemic’’ NP levels following recent HF admission represent high risk and likely warrant inpatient therapy. Patients with a BNP level from 400 pg/mL to 1,000 pg/ mL, NT-proBNP level from 900 pg/mL to 1,800 pg/mL, or !25% increase from ‘‘dry or optivolemic’’ NP levels after a recent admission for HF are at intermediate risk. Triage to an observation unit with intensive HF therapy should be

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Fig. 1. Proposed algorithm for natriuretic peptide (NP) leveleguided risk stratification and management in the emergency department (ED). With the use of NP as an initial stratification biomarker and subsequent use of other common clinical parameters, patients can potentially be divided into low, intermediate, and high risk groups and managed accordingly. AHF, acute heart failure; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal proeB-type natriuretic peptide; SBP, systolic blood pressure; SCr, serum creatinine; BUN, blood urea nitrogen.

considered. Patients who respond to therapy in the observation unit can be safely discharged with plans for early follow-up (within 7 days). Patients who do not improve in the observation unit should be admitted for further therapy. There is a subset of the intermediate-risk patients with high-risk features who should be directly admitted to the hospital instead of going to the observation unit. Reasonable examples of high-risk features include systolic blood pressure !115 mm Hg, acute kidney injury, troponin release, or oxygen saturation !93%.5,40,41 Patients with BNP !400 pg/mL or NT-proBNP !900 pg/mL are considered to be at low risk, and, pending clinical and psychosocial assessment and absolute NP elevations within this range, discharge from the ED with close outpatient follow-up may be considered. Use of NPs in this manner may prevent unnecessary admissions for AHF. Hospitalization and Before Discharge

Congestion drives hospitalization for the significant majority of AHF patients,42,43 and relief of congestion is associated with improved outcomes.44e46 Weight is an important correlate of congestion, but almost 50% of patients are discharged without appreciable weight loss.47,48 Symptoms are often sufficiently alleviated but decongestion is incomplete. Even with symptom relief, readmission and mortality risk remains high if NP levels stay elevated.49e51 NPs are markers of ventricular wall stretch,32,52 and may be better surrogates for congestion than clinical signs owing to the lack of sensitivity and low inter-rater reliability of

examination.53 Baseline and changes in NP levels are associated with changes in filling pressures, and changes in levels during hospitalization are associated with outcomes, with best outcomes seen when NP levels decrease by O30% in hospital.49,50,53e56 Valle et al showed that treating to a BNP level of !250 pg/mL before discharge was associated with favorable outcomes.54 Whether treatment should be directed toward a proportional decrease in NP or below a certain threshold requires further study. A prospective trial evaluating inpatient NP-guided therapy targeting a O30% reduction before discharge is actively enrolling (PRIMA II, NTR3279).57 Discharge NP levels are useful for risk stratification22,51,58 and appear to be superior to admission levels or change in NP levels during hospitalization (Table 1).59 A discharge NP level that has not decreased or is discordant with the clinical picture requires careful consideration including further inpatient observation or diagnostic evaluation. Several studies demonstrate how clinical impression, and risk defined by NP level, may differ significantly.34,51 Decreased NP levels with treatment may identify patients at lower risk, but, regardless of the decrease, higher levels at discharge still portend worse outcomes. These patients may warrant priority for close outpatient follow-up. Discharge NP levels may facilitate management when patients present to clinic or to the ED again. Routine daily NP measurements in the hospital are not recommended, because NP levels may not reflect acute changes in enddiastolic pressure, but repeated measurements can be considered in patients whose clinical improvement is not

236 Journal of Cardiac Failure Vol. 21 No. 3 March 2015 Table 1. Associated Prognostic Value of Natriuretic Peptide Level Based on Timing of Measurement During Index Hospitalization Author

Year

n

Outcome

Bettencourt50 Logeart58 Verdiani56 Bayes-Genıs55 Waldo66 SURVIVE67 ESCAPE68 Noveanu69 Kociol59 RELAX-AHF70

2004 2004 2005 2005 2008 2009 2010 2011 2011 2013

182 202 100 74 164 1,038 255 171 7,039 1,161

6-mo M/R 6-mo M/R 30-d R 12-mo CVM 90-d M 6-mo M 6-mo M 12-mo M 12-mo M 6-mo M

Natriuretic Peptide

Admission*

NT-proBNP BNP BNP NT-proBNP NT-proBNP BNP BNP NT-proBNP/BNP BNP NT-proBNP

Nonsignificant 0.69 Significant Not assessed 0.79 Not assessed Nonsignificant 0.67 0.68 Not assessed

Before-Discharge* Significant 0.80 Significant/Most prognostic Not assessed 0.83 0.70 0.76 0.77 0.69 Not assessed

In-Hospital Change* Significant/Most prognostic 0.76 Not assessed 0.78 Not assessed 0.71 Not assessed Not assessed 0.68 Significant

M, mortality; R, readmission; NT-proBNP, N-terminal proeB-type natriuretic peptide; BNP, B-type natriuretic peptide; CVM, cardiovascular mortality. *Values are area under the receiver operating characteristic curve/c-index.

adequate. Changes in NP levels during hospitalization may identify patient subgroups that may benefit from tailored therapies.60 Post-Discharge Ambulatory Care Setting

The use of biomonitoring at the time of discharge provides an ideal transition to the outpatient arena, where the assessment of clinical stability may be challenging. Biomarkers offer a common mode of assessment between the hospital and outpatient clinic. Along with clinical assessment, NP levels may facilitate care optimization while allowing identification of early subclinical decompensation. Although there are limited prospective data specifically addressing NP-guided therapy during the early post-discharge period,61 pooled analyses of ambulatory HF trials favor efficacy of NP-guided therapy (Fig. 2).25,62 The aforementioned large-scale definitive trial of NP-guided outpatient management is currently underway (Guiding EvidenceBased Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840).26 Although this trial will further define the utility of ambulatory NP

trajectory as a target for therapy, existing data consistently support the association with rising NP levels and risk for decompensation, even in the absence of symptoms.63 For patients discharged from the hospital, a repeated NP measurement should be considered during the postdischarge visit. If it is elevated to O75% of admission NP level, this observation should prompt strong consideration for escalation of guideline-directed and decongestive medical therapies. Those with rising NP compared with admission or discharge levels should be followed closely for medication adjustments to prevent readmission. For patients whose ‘‘dry’’ NP levels are known, management after discharge should aim to reduce levels back to ‘‘dry’’ levels. NP levels measured 30 days after discharge may predict outcomes better than levels at discharge.64 This highlights the value of NP assessment as part of a continuum. Therefore, a low discharge NP level, although better than a high level, does not mean that further care and follow-up NP measurements are not useful. For stable outpatients, a recent consensus statement has outlined the role of NP levels as part of a monitoring program.32 For patients with weight gain and symptoms, diuretics are adjusted. For those without symptomatic change, the degree of NP level change from baseline may aid management. Patients with !25% change should be evaluated for other causes of weight gain. Management of patients with a rise in NP level of 25%e50% is based on the clinical picture. Patients with O50% increases in NP levels are at risk for decompensation and should have diuretics adjusted. In this setting, NP levels are an excellent adjunct to clinical evaluation because there is often discordance between NP levels and physical signs.65 Home Monitoring

Fig. 2. Forest plot of all-cause mortality from selected clinical trials of patients with chronic heart failure randomized to biomarkerguided therapy versus control. The size of the marker for the point estimate (diamond ) is proportional to the sample size for each study. Horizontal lines show 95% confidence intervals. Adapted with permission from Felker at al.25

Similar to home monitoring for diabetes mellitus and hypertension, home-monitored NP levels may be useful in chronic management. Home monitoring may alert patients and physicians to early decompensation and allow for timely intervention. A pilot study demonstrated home NP monitoring to be safe and capable of identifying signals where early intervention may have significant impact.20 Because this is a nascent field, no specific guidelines on

Natriuretic Peptides and Hospitalized Heart Failure

home monitoring of NP are available. Follow-up home NPebased interventional studies have been proposed, but the threshold for action and protocols for intervention need to be defined. It is currently unknown which patients would be best served with home monitoring. Different patients and varying HF phenotypes will likely express unique characteristics in the degree of variation of home NP levels, suggesting that tailored approaches may be necessary. Home monitoring of NP levels may become another important component of improving outcomes for HF patients. Conclusion Reducing preventable HF hospitalizations is an important national healthcare goal. Available data support the use of NPs in the diagnosis, prognosis, and treatment of AHF patients across the care spectrum. Although further prospective studies are needed before NPs can be widely recommended for all AHF patients, integration of NPs into current structures and processes of care holds promise to reduce HF hospitalizations and should be strongly considered.

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Disclosures Alan Maisel, MD, has received research support from Alere, Abbott, BG Medicine, and Brahms; is a consultant to Alere, Critical Diagnostics, Sphingotect, BG Medicine, and EFG Diagnostics; has had speaking engagements for BG Medicine and Alere; and is a cofounder of Cardero Therapeutics and My Life Diagnostics. Yang Xue, MD, has received travel grants from Alere, Brahms, and BG Medicine. Stephen J. Greene, MD, has no potential conflicts. Peter S. Pang, MD, reports consultancies and honoraria from Janssen, Medtronic, Novartis, Otsuka, Trevena, scPharmaceuticals, Cornerstone Therapeutics, and BG Medicine; and has has received research support from Alere. James L. Januzzi, MD, has received research support from Roche, Critical Diagnostics, Siemens; and is a consultant to Amgen, Novartis, Zensun, Critical Diagnostics, and Sphingotec. Ileana L. Pi~ na, MD, MPH, has no potential conflicts. Christopher DeFilippi, MD, has received research support from Roche and Alere; is a consultant to Roche; and has received an honorarium from Siemens. Javed Butler, MD, MPH, has received research support from the National Institutes of Health, European Union, and Health Resources and Services Administration; has participated in clinical trials supported by Amgen, Gambro, Otsuka, and Bio Control; is a consultant to Amgen, BG Medicine, Celladon, Harvest, Gambro, Ono Pharma, Trevena, Bayer, Medtronic, Stemedica, and GE Healthcare; and has stock options with Stemedica.

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