Are Serial BNP Measurements Useful in Heart Failure Management?

Are Serial BNP Measurements Useful in Heart Failure Management?
Controversies in
Cardiovascular Medicine
Are Serial BNP Measurements Useful
in Heart Failure Management?

Serial Natriuretic Peptide Measurements Are Not Useful in
Heart Failure Management: The Art of Medicine
Remains Long
Akshay S. Desai, MD, MPH

N     atriuretic peptides, including B-type natriuretic pep-
      tide (BNP) and N-terminal-proBNP (NT-proBNP),
have emerged as powerful markers of cardiovascular risk in
                                                                        strong predictors of the risk for death or hospital readmission
                                                                        at 6 months.8,10,11
                                                                           In addition to their association with risk for adverse car-
patients with heart failure.1 Circulating natriuretic peptide           diovascular outcomes, circulating levels of NP appear to
(NP) levels add incremental prognostic value to standard                vary in relationship to the biology of heart failure progres-
clinical risk stratification algorithms for both ambulatory and         sion. NP levels tend to rise during acute heart failure decom-
hospitalized heart failure patients, with a steady increase in          pensation and to fall with successful treatment in a pattern
the risk of mortality and recurrent heart failure hospitalization       that mirrors reductions in filling pressure, improvements in
as NT-proBNP levels rise above 1000 pg/mL.2–5 A systematic              left ventricular structure and function,12 and improvements
review of 19 studies of patients with heart failure demon-              in functional capacity.13 Therapies with proven benefit in
strated that for every 100-pg/mL rise in BNP concentration,             heart failure patients with reduced ejection fraction, includ-
there was a corresponding 35% increase in the relative risk             ing angiotensin-converting enzyme inhibitors,14 angiotensin
of death.6                                                              receptor blockers,15 spironolactone,16 β-blockers,17 and car-
                                                                        diac resynchronization therapy,18 appear to reduce NP levels
 Response by Januzzi and Troughton on p 516
                                                                        in parallel with improvements in cardiac remodeling and clini-
   Beyond the prognostic value of a single NP measurement,              cal outcomes.
changes in NP concentrations over time may help to further                 The prognostic importance of NP levels and their potential
stratify risk.2,7 Reductions in NP levels, whether achieved             for modulation with treatment have fueled interest in the use
spontaneously or through application of appropriate medical             of serial NP measurements to guide heart failure therapy. The
therapy, appear to be associated with improvement in clinical           fundamental premise is an alluring one: that patients with
outcomes.8,9 In the Valsartan Heart Failure Trial, subjects with        high biomarker levels (and therefore high risk for adverse
the largest proportional reductions in BNP levels at 4 months           outcomes) should receive more intensive disease-modifying
after randomization experienced the best outcomes, whereas              therapy and those with low or normal biomarker levels (low
those with the greatest increase in BNP levels experienced              risk) should receive less intensive treatment. Advocates of this
the highest event rates.7 Among patients hospitalized with              approach highlight the substantial residual risk for heart failure
decompensated heart failure, both predischarge NP levels and            hospitalization and death in even well-managed populations,
the relative change in NP levels during hospital treatment are          the lack of adherence to guidelines recommending titration

  The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
  From Brigham and Women’s Hospital, Boston, MA.
  This article is Part II of a 2-part article. Part I appears on p 500.
  Correspondence to Akshay S. Desai, MD, MPH, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115.
  (Circulation. 2013;127:509-516.)
  © 2013 American Heart Association, Inc.
  Circulation is available at                                  DOI: 10.1161/CIRCULATIONAHA.112.120493

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510  Circulation  January 29, 2013

of neurohormonal antagonists to maximally tolerated doses,           by comparing measured biomarker values with a reference
the inability of many practitioners to reliably estimate filling     benchmark. The success of an NP-driven strategy turns heav-
pressures or to recognize the signs/symptoms of clinical             ily, therefore, on identification of the appropriate BNP or
decompensation, and the limited sensitivity of weights and           NT-proBNP target. Clinical trials of NP-guided therapy have
vital signs for monitoring heart failure progression. The hope       generally tested 1 of 2 general approaches: a uniform strategy
is that by providing an objective and responsive measure of          in which treatment for all patients is adjusted to target a single
heart failure severity, NP levels will prompt providers to titrate   absolute level of BNP or NT-proBNP or an individualized
disease-modifying heart failure therapies more appropriately         strategy in which different targets are defined for different
and to improve clinical outcomes.                                    patients based on a measured baseline value.
                                                                        Identification of a single NP target for all heart failure
       Risk Marker or Therapeutic Target?                            patients is challenging. Levels of BNP and NT-proBNP
Implementation of an effective biomarker-guided strategy             vary in relation to heart failure severity but may also be
depends on fulfillment of 4 basic assumptions. First, a clini-       influenced by several other factors. Age,35 sex,36 body mass
cally relevant biomarker target must be easily defined for each      index,37 and genetic factors38–40 are important confounders,
patient. Second, a therapeutic strategy to adjust biomarker          as are concomitant conditions such as atrial fibrillation,
levels to reach the target should be available. Third, the addi-     pulmonary hypertension, myocardial ischemia, pulmonary
tional treatments triggered by serial biomarker assessments          embolism, and chronic kidney disease.41 Patients with heart
should improve clinical outcomes. Finally, to be truly valu-         failure and preserved EF tend to have lower NP levels than
able, a biomarker-driven treatment strategy must provide dif-        those with heart failure and reduced EF, even when the
ferent content and superior benefits compared with routine           severity of heart failure is similar.42 Furthermore, NP levels
heart failure management guided by the clinical assessment.          correlate imperfectly with measured filling pressures43,44 and
   Even the most potent markers of cardiovascular risk               may remain elevated in those with more advanced or end-
are not necessarily suitable targets for therapy. The serum          stage disease even in the absence of significant congestion.11
sodium concentration varies in parallel with heart failure           The marked interpatient and intrapatient variability of NP
severity and the degree of neurohormonal activation and is           levels has substantially limited the utility of these assays
an accurate predictor of short- and long-term outcomes in            for heart failure diagnosis and has similarly challenged the
heart failure patients.19–22 Treatments directed at normal-          design of trials of NP-guided treatment. Six trials testing the
ization of serum sodium levels, however, have not been               value of an absolute NP target (Table 1) all used a different
associated with improvements in clinical outcomes among              threshold NP value, with NT-proBNP targets ranging widely
hospitalized heart failure patients.23 Moreover, even for            from 400 to 2200 ng/L. Paradoxically, the trials that have
parameters that show a graded association with risk such             demonstrated benefit for NP-guided therapy have not been
as blood pressure, lower may not always be better. For               those with the most stringent NP targets, arguing against the
example, in the Action to Control Cardiovascular Risk in             notion that more aggressive efforts to reduce NP levels are
Diabetes–Blood Pressure (ACCORD-BP) trial, a strategy                necessarily better.
of intensive treatment to aggressive blood pressure targets             In the face of these limitations of uniform NP targets,
among diabetic patients was associated with no benefit and           some have advocated instead for individualizing NP targets.
a higher rate of adverse events.24                                   The reference point for this approach is typically set as the
   Uncertainty about the incremental value of serial BNP             BNP or NT-proBNP nadir at or shortly after hospital dis-
assessment in routine heart failure management has spawned           charge, with treatment targeted at maintaining NP levels at
a number of randomized, controlled trials of NP-guided treat-        or near this value. Although this approach has the virtue of
ment with a wide range of study designs and treatment tar-           acknowledging the inherent between-patient variability in NP
gets25–33 (see Tables 1 and 2). The overall results are mixed,       levels, the challenge is the need to define both an appropri-
with the largest studies showing no clear evidence of bene-          ate reference baseline and the amount of deviation from this
fit but recent positive trials resurrecting enthusiasm for this      baseline that should trigger intervention. Because the long-
approach. Although some have leveraged meta-analytic tech-           term within-patient variability in BNP levels exceeds 30%
niques to infer mortality benefit from the biomarker-guided          even in stable heart failure patients,45 the amount of change
approach,34 the considerable between-trial heterogeneity             in NP levels that is clinically relevant is particularly difficult
makes it difficult to interpret the results of a pooled analy-       to discern. In the Can Pro-Brain-Natriuretic Peptide Guided
sis. In the discussion that follows, the evidence supporting the     Therapy of Chronic Heart Failure Improve Heart Failure
efficacy of an NP-targeted strategy against the 4 assumptions        Morbidity and Mortality? (PRIMA) study,30 the NT-proBNP
outlined above is reviewed.                                          target was based on the lowest plasma level within 2 weeks of
                                                                     hospital discharge, resulting in a median target value of 2491
      Can We Define an Optimal NP Target?                            pg/mL, well above the absolute threshold used in any of the
The core premise of a biomarker-guided approach is that heart        trials using uniform BNP targets. Uptitration of therapy was
failure patients can be efficiently risk stratified for treatment    recommended for patients in the biomarker-guided arm when
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Desai   NP-Guided Therapy is Not Useful   511

Table 1.      Trials of Natriuretic Peptide–Guided Management Using a Fixed Natriuretic Peptide Target
                                                                         Mean             Target for              Comparator           Follow-up          Primary          NP-Guided
                           n              Inclusion Criteria             Age, y         NP-Guided Arm              Group(s)             Duration        End Point(s)       Treatment
Troughton et al  25
                           69     HF hospitalization, LVEF
512  Circulation  January 29, 2013

Table 3. Absolute Reductions in Natriuretic Peptide Levels and Percent Achieving Set Targets in Trials of Natriuretic
Peptide–Guided Heart Failure Therapy
                                         Absolute Reduction in NP* Levels,    Absolute Reduction in NP* Levels,    Achieving Target, NP-Guided      Achieving Target,
                                             NP-Guided Group, pg/mL                Control Group,† pg/mL                    Group, %                Control Group, %†
Trials with uniform NP Targets
  Troughton et al25                                     668                                   25                                  …                          …
  STARS-BNP26                                        68 (BNP)                                 …                                   33                         …
  TIME-CHF   28
                                                        …                                     …                               Minority                   Minority
  BATTLESCARRED29                                       463                                  399                                  49                         32
  PROTECT31                                            1219                                  102                                  44                         36
  Berger et al32                                        …                                     …                               Majority                   Majority
Trials with individualized NP targets
  STARBRITE27                                        40 (BNP)                             −31 (BNP)                               68                         63
  PRIMA30                                               432                                  572                                  80                         80
  SIGNAL-HF33                                           301                                  362                                  19                         22
   BATTLESCARRED indicates NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death; BNP, B-type natriuretic peptide; NP, natriuretic peptides;
PRIMA, Can Pro-Brain-Natriuretic Peptide Guided Therapy of Chronic Heart Failure Improve Heart Failure Morbidity and Mortality?; SIGNAL-HF, Swedish Intervention
Study–Guidelines and NT-ProBNP Analysis in Heart Failure; PROTECT, Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting; STARBRITE,
Strategies for Tailoring Advanced Heart Failure Regimens in the Outpatient Setting: Brain Natriuretic Peptide Versus the Clinical Congestion Score; STARS-BNP, Systolic
Heart Failure Treatment Supported by BNP; and TIME-CHF, Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure.
   *All numbers reflect values of NT-proBNP unless specified otherwise.
    For trials with 2 control groups, data reflect the intensive clinical management arm.

reach the target. Although many therapies with proven benefit                          events, 56% of patients in the NP-guided arm and 64% of those
in heart failure patients reduce circulating NP concentrations,                        in the standard care arm failed to reach the target NT-proBNP
it is not clear that “ideal” NP levels are achievable in every                         of
Desai   NP-Guided Therapy is Not Useful   513

Score (STARBRITE) trial,27 discordance between BNP mea-              therapies varies according to heart failure severity or NP lev-
surements and the clinical assessment of congestion was infre-       els. In fact, trials of β-blockers,49 renin-angiotensin system
quent, suggesting that NP levels often do not add information        antagonists,50 and cardiac resynchronization therapy51 have
to what clinicians already know.                                     shown benefits that are largely independent of baseline NP
   In most trials, persistently high NP levels obligated more        concentrations. Accordingly, the vast majority of those with
frequent follow-up visits. Superior outcomes with NP-guided          chronic heart failure who do not have markedly elevated NP
therapy in selected trials could therefore be attributable in        levels43 should still derive benefit from uptitration of proven
large measure to the more intensive clinical support provided        therapies. In addition, for the nearly 50% of patients with
to patients with persistently elevated NP levels rather than         heart failure and preserved ejection fraction for whom there
success in reducing NP levels to target. In the Systolic Heart       is little evidenced-based treatment, it is unclear how elevated
Failure Treatment Supported by BNP (STARS-BNP) trial,26              NP levels should influence clinicians to adapt their approach.
patients in the BNP-guided arm had twice the number of                  Advocates of the NP-guided approach point out that
physician visits and more frequent medication changes than           adherence to published guidelines is suboptimal in clinical
those in the standard care arm, even though only 33% reached         practice52 and note that serial NP measurement may be an
the target BNP of 2200 pg/mL were deliberately triaged               tion reduces the “guidance” provided by serial NP measure-
to a heart failure specialist for more intensive management,         ment to little more than an “intellectual crutch” to practice
and the remainder of patients were managed either by primary         evidence-based medicine.53 Moreover, if NP levels truly
care physicians or a nurse-led multidisciplinary team. The           facilitate more appropriate medication titration, the greatest
NT-proBNP-Assisted Treatment to Lessen Serial Cardiac                opportunity for NP-guided treatment would be expected in
Readmissions and Death (BATTLESCARRED) trial29                       the hands of inexperienced clinicians who are less aware of
specifically tested the incremental value of the NP-guided           guidelines and for whom the assessment of volume status or
approach relative to both a positive control of intensive,           heart failure stability is especially difficult. However, the 1
standardized clinical care that directed medication titration        trial examining the benefits of such a strategy in a primary
based on a clinical score and a usual-care arm that received         care population (Swedish Intervention Study–Guidelines and
routine primary care follow-up. Relative to usual care, both         NT-ProBNP Analysis in Heart Failure [SIGNAL-HF]33) sug-
treatment groups experienced similar reductions in NP                gested no significant difference in drug titration or clinical
levels, intensification of medical therapy, and reductions in        outcomes between routine care and an NP-guided approach.
the composite of death or heart failure hospitalization. No             Ultimately, serial NP measurements are an inadequate sur-
overall difference in survival was seen between the NP-guided        rogate for good clinical judgment. Routine titration of neuro-
strategy and intensive clinical follow-up.                           hormonal antagonists or other heart failure therapies in some
                                                                     patients with persistently elevated NP levels may be harmful.
         Should Patients With Elevated NP                            Excessive reliance on NP levels to assess volume status might
          Levels Be Treated Differently?                             prompt inappropriate dose escalation of loop diuretics among
Most trials of NP-guided therapy have not defined a specific         patients without significant congestion and increase the rate
algorithm to address elevated NP levels but have encouraged          of hypotension, renal dysfunction, and other adverse events.
clinicians to respond to elevated NP levels by further titrating     Low NP levels may provide false reassurance that treatment
drugs with established benefit in heart failure to recommended       is adequate, even as other clinical parameters suggest other-
targets. Acknowledging the association among loop diuretics,         wise.43 Aggressive medication titration to manage high NP
neurohormonal activation, and adverse outcomes in heart fail-        values may also be poorly tolerated in the elderly or those
ure,47 more recent trials have in addition discouraged titration     with significant renal dysfunction (who were systematically
of loop diuretics in patients with high NP levels and have even      excluded from most trials). In the TIME-CHF28 trial, which
recommended dose reduction in stable patients. Because high          overall showed no incremental benefit to NP-guided therapy,
NP levels frequently direct intensification of therapy even in       a strong interaction with age was noted in secondary analyses.
patients who may be clinically asymptomatic, the NP-guided           Although patients 75
use of angiotensin-converting enzyme inhibitors, β-blockers,         years of age derived no benefit and experienced a higher rate
angiotensin receptor blockers, and spironolactone over stan-         of adverse events from NP-guided drug titration. Similar vari-
dard, symptom-guided care.                                           ation in the benefits of NP-guided treatment according to age
   Guideline-based recommendations for heart failure man-            noted in other trials29 suggests that this is not a spurious result.
agement emphasize titration of neurohormonal antagonists             This signal of potential harm among older patients within the
to maximally tolerated doses and minimization of diuretic            context of a well-managed clinical trial raises serious con-
dosing in all heart failure patients with reduced ejection frac-     cerns for the generalization of the NP-guided approach to
tion.48 There is little evidence that the benefit of heart failure   unselected patients in real-life practice, in which an increasing
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514  Circulation  January 29, 2013

proportion of heart failure patients are elderly with substantial     with normal NP levels and those with advanced age, preserved
comorbid medical illness. Indeed, the most compelling study           ejection fraction, and significant medical comorbidities, who
favoring NP-guided treatment to date31 also has the distinction       make up the growing majority of the heart failure burden, will
of enrolling a much younger population of patients (median            continue to rely on the best clinical judgment of physicians
age, 63 years) than other trials.                                     skilled in the art of medicine.

      Conclusion: Serial NP Levels Are Not                                                          Disclosures
      Useful for Most Heart Failure Patients                          Dr Desai reports having been a paid consultant to Novartis, Reata,
In an era of increasing concern about both the clinical and           Boston Scientific, and Intel.
economic consequences of the growing heart failure burden,
there is an imperative to design new approaches to longitudi-                                        References
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                                                                  Response to Desai
                                              James L. Januzzi, Jr, MD; Richard Troughton, MD, PhD

    We appreciate the elegant comments of Dr Desai; unfortunately, he did not make a strong case against biomarker-guided
    therapy (BGT) and was factually incorrect on several important points, only the most important of which we highlight
    because of space constraints. Raising concern about potential harm from BGT is a tired and incorrect argument, as is sug-
    gesting the risk of undertreatment in those with low natriuretic peptide (NP) values. Not 1 trial has demonstrated safety con-
    cerns of BGT, and no trial withheld treatment for those with low NPs: in fact, achieved doses of therapies in BGT studies are
    more often equivalent to those in landmark trials. Is this not important? The assertion that benefit from BGT has not come
    from stringent NP targets is totally incorrect. In addition, the argument that the inability to always achieve NP targets limits
    the value of the approach is flawed: Outcomes are significantly associated with the lowest achieved NP value; some lowering
    is better than none; and higher-risk patients may thus be better identified to correctly receive precious resources in this cost-
    conscious healthcare environment. The laughable argument of using an immovable/irrelevant parameter such as height to
    guide HF therapy ignores the prognostic value of NPs and the value of their lowering. These are only a few of the incorrect
    statements made in Dr Desai’s commentary. However, there is a common reassuring theme in both of our arguments: Best
    care is needed for our patients with HF. Routinely combining biomarkers with clinical judgment helps achieve this goal.

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Are Serial BNP Measurements Useful in Heart Failure Management?: Serial Natriuretic
Peptide Measurements Are Not Useful in Heart Failure Management: The Art of Medicine
                                  Remains Long
                                  Akshay S. Desai

                                     Circulation. 2013;127:509-516
                            doi: 10.1161/CIRCULATIONAHA.112.120493
    Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
                     Copyright © 2013 American Heart Association, Inc. All rights reserved.
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