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 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 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 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.
↵2 Nonstandard abbreviations:
- Cardiac Marker Guideline Uptake in Europe
- natriuretic peptide
- B-type natriuretic peptide
- N-terminal pro–B-type natriuretic peptide.
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.
- Received December 12, 2016.
- Accepted December 16, 2016.
- © 2016 American Association for Clinical Chemistry