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EDITORIALS
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Natriuretic Peptide Testing Guidelines: A Need
for Harmony Among the Cacophony
Christopher R. deFilippi1*
In this issue of JALM, Hammerer-Lercher et al. (1)
published the results of the Cardiac Marker Guideline Uptake in Europe (CARMAGUE)2 survey of
European and North American laboratory use of
natriuretic peptide (NP) assays. These survey results were acquired in 2013/2014 and provide insight into the surprisingly modest uptake of NP
assays across both continents. Nearly 15 years
have passed since the seminal Breathing Not
Properly study published in the New England
Journal of Medicine (2). The Breathing Not Properly
study established B-type natriuretic peptide (BNP)
as an accurate diagnostics test (area under the
curve 0.91) for differentiating acute heart failure
from other etiologies of dyspnea (2). Issues aside
that may bias surveys, such as incomplete response rates, there was still only a modest majority
of laboratories (67% of European and 58% of
North American) representing major or university
clinical chemistry laboratories that offered NP testing. This occurrence is despite the availability of
these assays at multiple central laboratories and
point-of-cares. In fact, the authors show in Europe,
where the survey was previously administered in
2006 and 2009, there has been only a modest increase in routine use of NP assays from 56% in
2006 to 67% in 2013/2014. This result is despite
incorporation of NP cutoffs into the 2008, 2012,
and 2016 European Society of Cardiology
guidelines as part of 1 of 2 recommended pathways for the evaluation of possible heart failure
(the other option being direct referral for an echocardiogram) (3–5).
In the most recent versions of both the
American Heart Association/American College of
Cardiology and European Society of Cardiology
guidelines for heart failure, the measurement of
a NP provides a Class I level of evidence, A (strongest level), for the diagnosis of heart failure (5, 6).
Furthermore, the use of BNP or N-terminal pro–
B-type natriuretic peptide (NT-proBNP) as part
of an algorithm to diagnose acute heart failure in
the emergency department is cost-effective
(7, 8). The NP assays also have interpretive advantages because there is relatively good harmonization between NP vendors, particularly
with NT-proBNP, which simplifies identification
of optimal medical decision points.
Why is the penetration of NP assays into clinical
care still not universal? First, it might be the cost of
the reagents, despite overall reduction to the cost
of care. Although counterintuitive, the cost of an
echocardiogram is modestly incremental after acquisition of an echocardiography system, mostly
inclusive of sonographer time. If care is capitated,
there could be budgetary pressure to limit the use
of NP testing. However, this wouldn't explain the
only moderate availability in North America where
1
Inova Heart and Vascular Institute, Falls Church, VA.
*Address correspondence to the author at: Inova Heart and Vascular Institute, Suite 1225, 3300 Gallows Rd., Falls Church, VA 22042.
Fax 703-776-3751; e-mail [email protected].
DOI: 10.1373/jalm.2016.022244
© 2016 American Association for Clinical Chemistry
2
Nonstandard abbreviations: CARMAGUE, Cardiac Marker Guideline Uptake in Europe; NP, natriuretic peptide; BNP, B-type natriuretic peptide;
NT-proBNP, N-terminal pro–B-type natriuretic peptide.
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the fee-for-service model still predominates. A
more likely explanation is the impression that NP
interpretation is complex, which is assumed by
frontline providers who staff emergency departments, urgent care centers, and primary care offices. As Hammerer-Lercher et al. highlight in their
Table 3, there are professional societies endorsing
vastly different cutoffs for a diagnosis of acute
heart failure (1). Most striking are the European
Society of Cardiology 2012 guidelines/recommendations because they provide starkly different cutoffs for the diagnosis of acute heart failure in 2
different documents (4, 9). Clinicians often rely on
their laboratory colleagues for guidance with respect to appropriate cutoffs. At the time of this
survey, little consistency was found in European or
US cardiology society recommendations. This variability must be examined in parallel to the clinical
context by which patients are often evaluated.
Based on the Breathing Not Properly trial, clinicians only had an intermediate uncertainty (between a 21% and 79% pretest probability) of acute
heart failure in 28% of the study participants (10). A
BNP cutoff of 100 pg/mL correctly classified the
diagnosis in 74% of the intermediate-risk subjects
(10). Therefore, many clinicians are potentially confident in their clinical diagnosis of 3 out of 4 patients with dyspnea without NP results. One
metaanalysis questioned whether NP testing in
the emergency department resulted in a meaningful reduction in length of stay and showed no reduction in mortality (11). Clinicians are also aware
there are several cardiac and noncardiac comorbidities that can result in higher NP levels in the
absence of acute heart failure (Table 1) (9). Some
guidelines propose cutoffs that will account for
common comorbidities like chronic kidney disease, but other guidelines do not (4, 5, 9). In the US,
society guidelines have provided a class I recommendation for NP testing, but have intentionally
omitted guideline-specific cutoffs (6). Adding to the confusion, although not reflected in the CARMAGUE survey, is the question of whether BNP will retain its
Table 1. Diseases with an increase in NPs.a
Acute or chronic systolic or diastolic left and right
heart failure
Valvular heart disease
Left ventricular hypertrophy with/without arterial
hypertension
Atrial fibrillation
Pulmonary embolism and severe pulmonary
hypertension
Inflammatory cardiac disease
Acute or chronic renal failure
Advanced liver cirrhosis with ascites
Anemia
Sepsis
Endocrine disorders such as hyperaldosteronism,
Cushing's syndrome, hyperthyroidism
Severe neurological disease, e.g., subarachnoid
hemorrhage, stroke, trauma
a
Reproduced with permission from Thygesen et al. (9).
diagnostic accuracy in patients taking the new
chronic heart failure drug Entresto, which combines a nephrilysin inhibitor (which inhibits the
degradation of BNP) to an angiotensin receptor
blocker. In the Prospective Comparison of ARNI
with ACEI to Determine Impact on Global Mortality
and Morbidity in Heart Failure (PARADIGM-HF)
study (a randomized controlled trial of 8399 patients with chronic systolic heart failure assigned to
the angiotensin-converting enzyme inhibitor enalopril vs Entresto), median levels of BNP rose from
approximately 200 pg/mL to 250 pg/mL when taking Entresto (12). Whether this is clinically meaningful for a patient who presents with acute heart
failure is uncertain. Current efforts are underway
to complete a study in emergency department patients with dyspnea to prospectively determine if
specific age-based cutoffs for NT-proBNP, recommended in the 2012 European Society of Cardiology
working group document (9), can be prospectively
validated. If successful, this would result in a change
of the manufacturer claimed medical decision points
documented in the package insert for at least one US
vendor. Ultimately, we should align NP cutoff
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EDITORIALS
recommendations for consistency across guidelines,
package inserts, and marketing materials to limit
confusion when evaluating patients with dyspnea.
The results of this study are eagerly awaited, as
would a follow-up survey of clinical laboratories
in Europe and the US to determine if consistency
in recommendations results in increased adoption of NP testing.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following
4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b)
drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for
all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately
investigated and resolved.
Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure
form. Employment or Leadership: None declared. Consultant or Advisory Role: C. deFilippi, Roche Diagnostics. Stock Ownership: None declared. Honoraria: C. deFilippi, Siemens. Research Funding: None declared. Expert Testimony: None declared. Patents: None declared.
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