Download Natriuretic Peptide Testing Guidelines

EDITORIAL
Natriuretic Peptide Testing Guidelines: A Need
for Harmony Among the Cacophony
Christopher R. deFilippi1*
In this issue of JALM, Hammerer-Lercher (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-ofcares. 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
the fee-for-service model still predominates. A
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
© 2017 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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Copyright 2017 by American Association for Clinical Chemistry.
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EDITORIAL
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 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 guidelinespecific cutoffs (6). Adding to the confusion, although not reflected in the CARMAGUE survey, is
the question of whether BNP will retain its diagnostic accuracy in patients taking the new chronic
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).
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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EDITORIAL
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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