NT-proBNP in Heart Failure Diagnosis: Clinical Delay, Biomarker Limits, and the Need for Diagnostic Reinvention

 

Misconceptions, Misuse, and Missed Diagnoses in the Primary Care Pathway.

Abstract – Misuse of NT-proBNP in Primary Care and Diagnostic Delays

N-terminal pro B-type natriuretic peptide (NT-proBNP) is widely used in the diagnostic pathway for heart failure (HF). While it remains a sensitive marker for excluding HF, particularly in acute settings, its application in primary care—especially for diagnosing heart failure with preserved ejection fraction (HFpEF)—is fraught with challenges. This paper critiques the overreliance on NT-proBNP as a primary diagnostic tool in general practice, highlights the biomarker's high false positive (FP) rates, and examines implications for healthcare systems. Despite updated ESC 2022 guidelines advocating algorithmic and context-aware diagnosis, NT-proBNP continues to be underutilized, with only 17% of UK patients reportedly receiving the test prior to HF diagnosis. We argue for a reevaluation of the biomarker's role in favour of a more integrated diagnostic approach that includes clinical scoring tools, advanced imaging, and emerging biomarkers.

 

Gaps Between Guidelines and Real-World Practice

Heart failure (HF) is a leading cause of morbidity and hospital admissions worldwide, particularly among older adults. Diagnosing HF accurately and early remains a clinical challenge, particularly in primary care, where access to echocardiography and cardiology input is often limited. N-terminal pro B-type natriuretic peptide (NT-proBNP) is a widely recognized biomarker used to detect HF and rule out the condition when levels are low. However, its diagnostic application is more complex than often appreciated. While NT-proBNP provides high sensitivity, its specificity is markedly lower, especially in older adults and those with comorbidities.

Electrocardiography (ECG) and symptom review are typically the first steps in the HF diagnostic pathway in UK primary care. However, NT-proBNP is often underused or applied inconsistently, with only 17% of HF patients reportedly receiving the test prior to diagnosis [1]. This suggests a gap between guideline recommendations and real-world practice, influenced by confusion over interpretation, local test access, and clinical habits.

 

Understanding NT-proBNP: Mechanism and Diagnostic Context

NT-proBNP is an inactive prohormone released from myocardial cells in response to wall stress and pressure overload. It is cleaved into active BNP and the biologically inert NT-proBNP, both of which are used in clinical diagnostics. The molecule's half-life and stability in blood make it an attractive biomarker in both acute and chronic HF settings [2,3].

NT-proBNP levels are influenced by a range of physiological and pathological factors including age, sex, renal function, obesity, and atrial fibrillation [4,5]. As such, interpreting NT-proBNP levels in isolation—particularly without knowledge of comorbid conditions—can lead to diagnostic errors.

 

NT-proBNP Limitations and False Results in GP Settings

In primary care, NT-proBNP is predominantly used as a triage tool. Values below 125 pg/mL in non-acute settings have a high negative predictive value, effectively ruling out HF. However, elevated levels require confirmatory testing, most often echocardiography, which is not immediately available in many general practice settings [6,7].

Elevated NT-proBNP levels can result from:

• Chronic kidney disease (decreased clearance)
• Advanced age (baseline elevation)
• Atrial fibrillation (independent of ventricular dysfunction)
• Pulmonary embolism and hypertension
• Sepsis and systemic inflammation

Conversely, obesity can suppress NT-proBNP levels, potentially leading to false negatives [8,9].

 

Diagnosing HFpEF: Structural Barriers and Imaging Gaps

While the ESC 2022 guidelines recommend combining NT-proBNP testing with validated diagnostic algorithms like the HFA-PEFF or H2FPEF scores, it's important to note that their application in primary care is limited. The HFA-PEFF score, though comprehensive, relies heavily on echocardiographic parameters such as E/e′ ratio, LV mass, and LA volume—measurements typically unavailable to general practitioners without specialist imaging support. Similarly, while the H2FPEF score is simpler and can be partially applied in primary care, it still depends on filling pressure estimates (E/e′ >9) from echocardiography. As a result, both scoring systems are not fully feasible until echocardiographic data is available, often after significant wait times.

This structural dependency delays definitive diagnosis and contributes to suboptimal patient management. A tool like Cardio-HART, which provides echocardiography-equivalent functional and structural assessments, can fill this diagnostic gap by enabling earlier scoring and risk stratification within primary care itself.

 

ESC 2022 Guidelines: Current Diagnostic Recommendations

The European Society of Cardiology's 2022 heart failure guidelines underscore NT-proBNP’s role in excluding HF, but stress that elevated levels require clinical context [13]. They advocate a stepwise diagnostic approach:

1. Clinical assessment
2. NT-proBNP testing
3. Echocardiography
4. Use of HFA-PEFF or H2FPEF scores

This methodology aims to minimize over-diagnosis and reduce unnecessary referrals [14,15].

 

Proposed Diagnostic Framework for Primary Care

An innovative Framework, extending the ESC’s 2022 Guidelines but for use in clinical practice would be to implement the following stepwise diagnostic approach:

1. Clinical assessment
2. Cardio-HART (for echocardiography equivalent findings)
3. NT-proBNP confirmation testing
4. Use of HFA-PEFF or H2FPEF scores (now actionable because of Cardio-HART providing Echo equivalent findings)

This revised methodology aims to further minimize over-diagnosis and reduce unnecessary referrals, but starting in Primary Care on initial patient presentation [14,15].

 

Misuse of NT-proBNP and Echo Overload in UK Healthcare

Data from the UK National Heart Failure Audit suggest that ECG is the most commonly performed initial test, while NT-proBNP is underutilized [1]. In many cases, echocardiography is ordered directly, bypassing NT-proBNP, which contradicts guideline recommendations and contributes to inappropriate use of resources.

In the UK, this has exacerbated into a national crisis in echocardiography capacity.

Where NT-proBNP is used, lack of contextual interpretation has lead to over-referral, this has exacerbated into a national crisis in echocardiography capacity resulting in long delays. Studies indicate that NT-proBNP-driven referrals can result in false positive rates often exceeding 50% in some echocardiography services, particularly when pre-test probability is low [16,17].

According to the British Society of Echocardiography and the Society for Cardiological Science and Technology, prolonged wait times for echocardiography—often several months—are undermining timely heart failure diagnosis and management, resulting in disease progression. This backlog significantly limits the feasibility of relying on echo-dependent tools or confirmation pathways in a timely manner, undermining opportunities for early intervention and prevention.

 

System Strain from NT-proBNP Overuse Without Context

Increased NT-proBNP testing without proper interpretation can overwhelm diagnostic imaging services. This delays care for patients with genuine heart failure and creates bottlenecks in the healthcare system [18,19]. These inefficiencies are compounded in systems like the NHS where access to echocardiography is limited by staffing and infrastructure.

 

Future Diagnostics: Novel Biomarkers and Smart Technologies

Recent studies have highlighted alternative or complementary biomarkers:

• sST2 (soluble suppression of tumorigenicity 2): reflects myocardial fibrosis and remodeling [20]
• Galectin-3: associated with inflammation and fibrosis, elevated in HFpEF [21]
• GDF-15: prognostic in HF with reduced EF [22]

In addition, machine learning models using clinical and echocardiographic data have shown promise in predicting HF subtypes with high accuracy [23]. A most recent innovation is Cardio-HART^TM, a next generation ECG device enhanced with Echocardiography-like capabilities, intended for point of care use, that is non-invasive, quick, requires no specialists, and provides immediate results.

 

Clinical Scoring Tools and Imaging Dependency

While decision tools like the H2FPEF Score and HFA-PEFF Algorithm are valuable for stratifying the probability of HFpEF, their practical application in primary care is limited. The HFA-PEFF algorithm relies on detailed echocardiographic parameters such as E/e′, LV mass, and LA volume—metrics that GPs generally cannot access without specialist referral. Similarly, the H2FPEF score, though designed for use in general settings, still requires echocardiographic estimates of filling pressure (e.g., E/e′ >9), making its full implementation impractical before echocardiography is completed.

Because both scores depend on imaging inputs not readily available at the point of care, their utility is delayed until after often lengthy wait times for echocardiography in secondary care. As such, these tools do not currently fulfill the role of real-time decision aids in primary care. Emerging technologies such as Cardio-HART, which provide echocardiography-equivalent functional and structural data, offer a potential pathway to enable early use of these scoring systems at the GP level, effectively bridging the diagnostic gap.

 

Recommendations to Optimize HF Diagnosis in Primary Care

1. Cardio-HART should be immediately used on initial patient presentation
2. NT-proBNP should remain a rule-out test, especially in primary care.
3. Elevated levels require contextual interpretation, considering age, renal function, and comorbidities.
4. Use of decision support tools (e.g., H2FPEF, ESC guidelines) should be standardized.
5. Echocardiography referral should follow when NT-proBNP elevation only when pre-test probability is high, supported by Cardio-HART findings of severity.

 

Conclusion – Redefining the Role of NT-proBNP with Cardio-HART

Primary care providers face an increasing burden in the early diagnosis and management of heart failure, particularly HFpEF, a condition that continues to grow in prevalence and complexity. NT-proBNP, while invaluable for ruling out HFrEF, lacks the specificity required for nuanced differentiation across HF phenotypes, especially HFpEF. Its interpretation is confounded by factors like renal function, age, obesity, and comorbid conditions that frequently coexist in HF patients.

Advanced decision support tools like the HFA-PEFF and H2FPEF scores offer promising accuracy for HFpEF identification but are fundamentally constrained in primary care due to their reliance on echocardiographic inputs that require secondary care referral. As national wait times for echocardiography continue to grow, this dependency further delays diagnosis, undermining early preventative interventions.

This is where Cardio-HART presents a clinically significant breakthrough. By integrating ECG with echocardiography-equivalent outputs using biosignal analysis, Cardio-HART equips GPs with real-time, interpretable data that mirror many of the core structural and functional inputs needed for HFpEF diagnosis. It can also detect valvular disease—another major HF contributor—currently invisible to both ECG and NT-proBNP.

Together, the synergistic use of Cardio-HART and NT-proBNP transforms the primary care diagnostic pathway from one of uncertainty and delay to one of precision and timeliness. Cardio-HART can direct when NT-proBNP testing is truly warranted and interpret its result in the context of visual structural dysfunction, enhancing both sensitivity and specificity in diagnosis. This integrated approach has the potential to prevent misdiagnoses, reduce unnecessary referrals, and support timely therapeutic decisions before disease progression sets in.

Ultimately, addressing the limitations of NT-proBNP requires augmenting the diagnostic arsenal available to primary care. Cardio-HART exemplifies a solution aligned with ESC 2022's emphasis on structured, context-aware diagnosis—bringing echocardiographic insight and actionable guidance directly to the front lines of patient care.

 

Key Questions in Primary Care Heart Failure Diagnostics

1. Why is NT-proBNP underused in primary care despite ESC guidelines?
   Many GPs still rely on ECG and symptoms due to limited access to NT-proBNP testing and uncertainty about how to interpret elevated results without echocardiography support.
2. What are the main factors that distort NT-proBNP levels?
   Age, renal insufficiency, atrial fibrillation, and obesity can either elevate or suppress NT-proBNP, leading to false positives or false negatives.
3. Why are scoring systems like HFA-PEFF and H2FPEF rarely used in general practice?
   They depend on imaging data (e.g. E/e′ ratio) that are not available without specialist equipment, making them impractical until after a long referral process.
4. How does Cardio-HART improve heart failure diagnosis at the GP level?
   It provides echocardiography-equivalent structural and functional cardiac data in real time, allowing immediate application of diagnostic scores and reducing unnecessary referrals.
5. Should NT-proBNP be removed from the diagnostic pathway?
   No. NT-proBNP remains essential as a rule-out test. However, its role should be contextualized within a broader, structured diagnostic framework that includes clinical data and imaging-like tools.

 

To better understand the context and limitations of NT-proBNP in HFpEF, read the first article in this series:
NT-proBNP in Heart Failure Diagnosis – Challenges and the Need for More Accurate Tools
 

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