Natriuretic peptides testing and survival prediction models for chronic heart failure: a systematic review of added prognostic value

Brain (B-type) natriuretic peptide (BNP) is a 32 amino acid peptide that is synthesized and released predominantly from ventricular myocardium in response to myocyte stretch. Like atrial natriuretic peptide (ANP), BNP seems to have almost exclusively beneficial physiological properties, including balanced vasodilation, natriuresis, and inhibition of both the sympathetic nervous system and the renin-angiotensin-aldosterone axis. Attempts to exploit these properties for therapeutic benefit has led to the development of recombinant human BNP (nesiritide) for the acute treatment of decompensated heart failure, and also of novel compounds that inhibit neutral endopeptidase, an enzyme that is partially responsible for BNP degradation. See p 2913 In patients with heart failure, the cardiac neurohormonal system is activated, and circulating plasma levels of ANP, BNP, and the N-terminal fragments of their prohormones (N-proANP and N-proBNP) are elevated. Compared with ANP and N-proANP, BNP and N-proBNP undergo a greater proportional rise in disease states (ie, higher “signal-to-noise” ratio), and thus have emerged as the preferred biomarkers for clinical development. With commercially available assays now available, measurement of BNP or N-proBNP can be integrated readily into the care of patients with suspected heart failure. Although data are limited, BNP and N-proBNP seem to provide qualitatively similar information, and for purposes of this editorial, will be referred to interchangeably. Incorporation of BNP measurement into the clinical evaluation facilitates the diagnosis of heart failure due to either left ventricular (LV) systolic or diastolic dysfunction; a normal BNP level virtually rules out the diagnosis of decompensated heart failure, whereas a markedly elevated BNP has a high positive predictive value for heart failure.1 Although BNP levels are correlated with age, sex, intracardiac filling pressures, LV mass and ejection fraction (LVEF), renal function, and symptoms, BNP provides prognostic information in patients with heart failure that is independent of these variables.2 …

### A. Context of Biochemical Marker Testing in Heart Failure Biochemical marker testing has revolutionized the approach to diagnosis and management of heart failure over the past decade. There is an unsurpassed excitement in the heart failure community that significant advances in our understanding of currently available and future cardiac biomarkers will facilitate improved characterization of heart failure disease states and promote individualized therapy in heart failure and beyond. However, like most novel diagnostic tests, the promising findings from pivotal trials have met with ongoing challenges when applied in the clinical setting. The material discussed in this guidelines document addresses clinical use of BNP/NT-proBNP and cardiac troponin testing in the context of heart failure diagnosis, risk stratification and management, including therapeutic guidance in adult (>18 year-old) patients. Together with the associated document titled “ National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure ”, …

Measuring risk in end-stage renal disease: Is N-terminal pro brain natriuretic peptide a useful marker?

Article, see p 1671 Heart failure (HF) hospitalization presents a substantial burden to patients, hospitals, and payors. Hospitals face competing incentives from government payors because prolonged lengths of stay risk unreimbursed costs beyond the fixed reimbursement, whereas premature discharge increases the risk of 30-day readmission, for which hospitals can be penalized on a much broader scale. Clinicians have struggled to define the objective criteria regarding readiness for discharge from a HF hospitalization, which should address not only relief of congestion, but also evaluation of etiology, enhancement of guideline-directed therapies, review of disease trajectory, and consolidation of outpatient management. Once gaps in the transition process have been closed, the major cause of readmission is recurrent congestion. Regardless of how congestion is documented,1–3 patients who go home “wet” are likely to return “wetter”. Quality improvement and cost containment efforts are converging to design care pathways that begin early during hospitalization to ensure adequate decongestion by discharge. Employment of brain natriuretic peptide (BNP) levels as targets for therapy arose naturally from the robust predictive value of BNP levels and changes in levels, further supported by their close relationship with elevated cardiac filling pressures4,5 and recognized as a hemodynamic determinant of outcomes. Utility of a biomarker as a target for therapy requires not only clinical relevance, but also timely responsiveness to the therapy titration, and unique information beyond usual clinical assessments. Multiple trials have used natriuretic peptides as targets for adjustment of chronic outpatient therapy with neurohormonal antagonists6–10 (Figure). When uptitration was aggressive in response to persistently high levels of natriuretic peptides, outcomes were better than without such uptitration.9 However, when the design encouraged vigorous …

Cardiac myosin-binding protein C as a candidate biomarker in heart failure: rational but not revolutionary.

The prognostic significance of N-terminal pro B-type natriuretic peptide (NT-proBNP) in heart failure with preserved ejection fraction (HFpEF) has been well established. HFpEF and atrial fibrillation (AF) commonly coexist, and each contributes to poor outcomes independently. Nevertheless, the ability of NT-proBNP to predict AF in HFpEF patients remains uncertain. A total of 367 HFpEF patients without baseline AF from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were included. The Cox proportional hazard model was used to assess the association of NT-proBNP with the risk of AF. The C-statistic, categorical net reclassification index (NRI), and integrated discrimination improvement (IDI) were used to evaluate the ability of NT-proBNP in new-onset AF prediction. During a median follow-up of 2.91years, 17 (4.63%) new-onset AF cases occurred. Every 1000pg/mL increase in NT-proBNP was associated with a 16% increase in the risk of AF occurrence after adjustments (hazard ratio, 1.16 [95% CI, 1.02-1.32]). NT-proBNP showed a moderate performance for new-onset AF at 3years (C-statistic, 0.67). Adding NT-proBNP to CHADS2/R2CHADS2/CHA2DS2-VASc/C2HSET scores improved their predictive performance for AF risk (CHADS2: C-statistic, 0.63, CHADS2+NT: C-statistic, 0.69, NRI, 47.46%, IDI, 1.18%; R2CHADS2: C-statistic, 0.65, R2CHADS2+NT: C-statistic, 0.70, NRI, 48.03%, IDI, 0.51%; CHA2DS2-VASc: C-statistic, 0.67, CHA2DS2-VASc+NT: C-statistic, 0.72, NRI, 49.41%, IDI, 0.86%; C2HSET: C-statistic, 0.77, C2HSET+NT: C-statistic, 0.80, NRI, 50.32%, IDI, 1.58%). Among patients with HFpEF, the NT-proBNP level was positively associated with the incidence of new-onset AF and may be a promising predictor.

Circulating levels of natriuretic peptides (NP) are inversely related to body mass index (BMI), and obese patients with heart failure (HF) have lower brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations than nonobese patients.1,2 These observations have raised concerns about the prognostic value of NP in patients with HF with an elevated BMI. Prior observational studies suggested that NP may retain their capacity to predict mortality across all BMI categories in HF with individuals with reduced ejection fraction.3,4 Nevertheless, these studies included a relatively small number of events and did not evaluate additional cardiovascular end points. Because it remains uncertain whether BMI may influence the prognostic utility of NP in patients with HF, we examined the influence of BMI on the predictive value of NT-proBNP and BNP in patients with reduced ejection fraction from the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255). The design and primary results of the PARADIGM-HF trial have been previously described.5 The patients randomized in the trial (n=8399) were required to have a plasma BNP ≥150 pg/mL or an NT-proBNP ≥600 pg/mL or, if they were hospitalized for HF within the previous …

BackgroundNatriuretic peptides are recognized as important predictors of cardiovascular events in patients with heart failure, but less is known about their prognostic importance in patients with acute coronary syndrome. We sought to determine whether B‐type natriuretic peptide (BNP) and N‐terminal prohormone B‐type natriuretic peptide (NT‐proBNP) could enhance risk prediction of a broad range of cardiovascular outcomes in patients with acute coronary syndrome and type 2 diabetes mellitus.Methods and ResultsPatients with a recent acute coronary syndrome and type 2 diabetes mellitus were prospectively enrolled in the ELIXA trial (n=5525, follow‐up time 26 months). Best risk models were constructed from relevant baseline variables with and without BNP/NT‐proBNP. C statistics, Net Reclassification Index, and Integrated Discrimination Index were analyzed to estimate the value of adding BNP or NT‐proBNP to best risk models. Overall, BNP and NT‐proBNP were the most important predictors of all outcomes examined, irrespective of history of heart failure or any prior cardiovascular disease. BNP significantly improved C statistics when added to risk models for each outcome examined, the strongest increments being in death (0.77–0.82, P<0.001), cardiovascular death (0.77–0.83, P<0.001), and heart failure (0.84–0.87, P<0.001). BNP or NT‐proBNP alone predicted death as well as all other variables combined (0.77 versus 0.77).ConclusionsIn patients with a recent acute coronary syndrome and type 2 diabetes mellitus, BNP and NT‐proBNP were powerful predictors of cardiovascular outcomes beyond heart failure and death, ie, were also predictive of MI and stroke. Natriuretic peptides added as much predictive information about death as all other conventional variables combined.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01147250.

N-Terminal Pro-B-Type Natriuretic Peptide as an Indicator of Disease Severity in a Heterogeneous Group of Patients With Chronic Precapillary Pulmonary Hypertension

Heart failure (HF) is a prevalent syndrome with considerable disease burden, healthcare utilization and costs. Timely diagnosis is essential to improve outcomes. This study aimed to compare the diagnostic performance of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) in detecting HF in primary care. Our second aim was to explore if personalized thresholds (using age, sex, or other readily available parameters) would further improve diagnostic accuracy over universal thresholds. A retrospective study was performed among patients without prior HF who underwent natriuretic peptide (NP) testing in the Amsterdam General Practice Network between January 2011 and December 2021. HF incidence was based on registration out to 90 days after NP testing. Diagnostic accuracy was evaluated with AUROC, sensitivity and specificity based on guideline-recommended thresholds (125 ng/L for NT-proBNP and 35 ng/L for BNP). We used inverse probability of treatment weighting to adjust for confounding. A total of 15,234 patients underwent NP testing, 6,870 with BNP (4.5 % had HF), and 8,364 with NT-proBNP (5.7 % had HF). NT-proBNP was more accurate than BNP, with an AUROC of 89.9 % (95 % CI: 88.4-91.2) vs. 85.9 % (95 % CI 83.5-88.2), with higher sensitivity (95.3 vs. 89.7 %) and specificity (59.1 vs. 58.0 %). Differentiating NP cut-off by clinical variables modestly improved diagnostic accuracy for BNP and NT-proBNP compared with a universal threshold. NT-proBNP outperforms BNP for detecting HF in primary care. Personalized instead of universal diagnostic thresholds led to modest improvement.

A New Signal From B-Type Natriuretic Peptide in ST-Elevation Myocardial Infarction

Sacubitril/valsartan and B-type natriuretic peptide value: recalculating route.

Current biochemistry, molecular biology, and clinical relevance of natriuretic peptides

This article refers to ‘The prevalence and clinical associations of ultrasound measures of congestione in patients at risk of developing heart failure’ by J.J. Cuthbert et al., published in this issue on pages 1831–1840. Signs and symptoms related to congestion are the predominant cardiac reason why patients with heart failure are being admitted to the hospital. Congestion is a setting in which a culmination of a wide range of cardiac structural or functional abnormalities together with changes in intravascular volume or venous capacitance function lead to symptoms of breathlessness and fatigue or signs of extravascular volume accumulation.1-3 Data from implantable haemodynamic sensors have taught us that slight elevations in filling pressures can occur weeks before an acute decompensation in heart failure and in the early stages often occur without symptoms or signs of heart failure, being termed subclinical congestion.4, 5 Furthermore, subclinical congestion has long been recognized to herald an ominous prognosis in heart failure patients awaiting cardiac transplantation or in patients being discharged after an acute heart failure episode.6 Targeted ultrasound evaluation of extra-cardiac structures including lung tissue, venous structures and the kidneys allows to determine the presence of systemic congestion and is becoming increasingly integrated in the ultrasound evaluation of patients with established heart failure.7 This is further driven by the appreciation that congestion itself is a perpetuating mechanism driving disease progression in heart failure. Indeed, the recent universal definition of heart failure recognizes this important role of congestion, defining heart failure as a clinical syndrome with current or prior symptoms and/or signs caused by structural and/or functional cardiac abnormalities being corroborated by either an elevated natriuretic peptide (NP) level or objective evidence of cardiogenic pulmonary or systemic congestion by diverse diagnostic modalities (however not specifically naming lung ultrasound, jugular vein diameter analysis or renal vein Doppler analysis).8 This definition of heart failure requires current or past symptoms of heart failure. However, population-based registries indicated that up to 40–50% of the adult population can be categorized as having stage A (risk factors for) or stage B (pre) heart failure.9 This being related to the high prevalence of disease conditions such as diabetes, hypertension and coronary artery disease. However, this also begs the question if all those patients need to be defined as having heart failure and which patient end up progressing to clinical overt heart failure. Clearly choosing the right preventive strategies in selected stage A patients such a diuretic-based antihypertensive therapies or angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in hypertensive patients or sodium–glucose co-transporter 2 (SGLT2) inhibitors in diabetic patients, can reduce the occurrence of symptomatic heart failure. Additionally, the St Vincent's Screening to Prevent Heart Failure (STOP-HF) illustrated that using a NP biomarker approach in patients with stage A heart failure allows to better diagnose and manage the transitioning towards more clinically overt heart failure than classic preventive strategies for stage A (at-risk heart failure).10 In the STOP-HF trial, 41.6% of patients had an elevated NP in the intervention group and these patients underwent more cardiac investigations and were more often treated with renin–angiotensin–aldosterone system-based therapies at follow-up than patients undergoing classic preventive strategies (standard of care approach in stage A patients). Such approach ultimately leads to a lower occurrence of left ventricular (LV) dysfunction with or without heart failure, asymptomatic LV dysfunction, or emergency hospitalization for major cardiovascular events. Not surprisingly, the recent universal definition of heart failure recognizes this finding and more broadly defines stage B heart failure (Figure 1) incorporating the role of elevated NPs.8 However, the potential role of dedicated ultrasound congestion evaluation remains unstudied in this population of at-risk (stage A) and pre- (stage B) heart failure. In this issue of the Journal, Cuthbert and colleagues report on an interesting prospective sub-study of the Heart OMics in AGEing (HOMAGE).11 This prospective trial included patients at risk for heart failure (≥1 of: diabetes, hypertension, a previous myocardial infarction or coronary artery revascularization) and excluded patients with clinical suspected heart failure, atrial fibrillation or grossly elevated NPs [B-type natriuretic peptide (BNP) >280 ng/L or N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1000 ng/L] or presence of isolated systolic dysfunction defined as a LV ejection fraction <45%. Patients underwent ultrasound evaluation of congestion at two study sites using a same approach of lung ultrasound, jugular vein analysis at rest and during Valsalva manoeuvre and vena cava analysis. However, Doppler analysis of the renal veins was not performed. Additionally, echocardiographic assessment of LV systolic and diastolic function was performed and NPs were measured, with cutoffs for abnormality being aligned with the European Society of Cardiology guidelines or the recent universal definition for pre- (stage B) heart failure (NT-proBNP >125 ng/L or BNP >35 ng/L). A total of 238 patients with stage A heart failure were prospectively included and enrolled in this analysis. Of these patients, a total of 73% patients had an elevated NP and, according to the universal definition of heart failure, can be deemed to have stage B or pre-heart failure. This percentage is higher in comparison to the screening of stage A patients in the STOP-HF trial (41.6% vs. 73%), but the STOP-HF trial used a higher BNP cutoff (>50 ng/L).10 Interestingly, of the total patient population with all ultrasound evaluations present (n = 214), a total of 30% (n = 64) had ≥1 ultrasound congestion marker and these patients more often had a dilated left atrium (92%) or elevated NP (75%). If ultrasound congestion imaging is a reliable indicator of elevated filling pressures, one-fourth of patients were missed to be reclassified from at-risk (stage A) to pre- (stage B) heart failure if NPs were only used. Indeed, building on the question of the incremental value of ultrasound congestion imaging on top of NPs, authors show only a moderate correlation of ultrasound congestion imaging with NPs. Furthermore, 19% of patients (n = 12 of 64) only had congestion on ultrasound imaging and no abnormal NPs, no structural abnormalities (e.g. left atrial volume index <34 mL/m2) or functional abnormalities (E/e′ <13). Taken together potentially suggesting incremental information being gained by ultrasound congestion imaging. In a purely hypothesis generating (underpowered) analysis, the addition of presence of congestion on ultrasound imaging on top of NPs in patients at risk for heart failure better identified patients developing a post-hoc defined combined endpoint (unplanned cardiovascular admission, prescription of a loop diuretic, diagnosis of atrial fibrillation, diagnosis of heart failure, or death). This interesting analysis raises several questions. Can ultrasound congestion imaging help us better define those with pre- (stage B) heart failure at risk (Figure 1)? Can identification of a different mechanism (ultrasound congestion imaging) help us identify patients in need of potentially different treatment strategies (e.g. more emphasis on diuretic-based hypertensive instead of calcium antagonists, better follow-up and diagnosis like in the STOP-HF trial, SGLT2 inhibitors even in the absence of diabetes, and so on)? Can ultrasound congestion imaging help us better restage patients with at-risk (stage A) heart failure in settings where NP testing is not available? Next to the questions raised, several limitations need to be taken into account: (i) these ultrasound evaluations have never been validated in at-risk patients to reflect increased filling pressures (arguably one of the most important perpetuation mechanism in the transition between stages of heart failure) and therefore need invasive haemodynamic validation; (ii) this study is not powered to determine if adding ultrasound congestion imaging can better detect the transitioning to clinical overt (stage C) heart failure; (iii) absence of other biomarkers (soluble CD146 or carbohydrate antigen-125) potentially also reflecting a more vascular/systemic phenotype of congestion could have been informative as one-fourth of patients with congestion on ultrasound imaging had a normal NT-proBNP. Clearly, additional studies are necessary to further define the place of ultrasound congestion imaging in patients with at-risk (stage A) and pre- (stage B) heart failure, but Cuthbert and colleagues should be congratulated on their effort in paving the way. Pieter Martens is supported by a grant from the Belgian American Educational Foundation (BAEF) and from the Frans Van de Werf Fund. Conflict of interest: none declared.

NT-proBNP as a tool to stratify disease severity in pulmonary arterial hypertension