Summary
The care of patients with heart failure can be challenging, with few objective tools available to assist in therapy decision-making. Natriuretic peptides are powerfully prognostic biomarkers in patients with heart failure and may represent an objective target for therapy. Accordingly, the use of biomarker-guided care with either B-type natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) has been recently explored. Over the past few years, a number of studies with heterogeneous inclusion criteria, methods and results have been performed. We have reviewed the available literature, summarizing the results of biomarker-guided heart failure trials and deriving recommendations for optimal application of biomarker-guided heart failure care based on the experience gained. In general, positive studies had low BNP or NT-proBNP target concentrations (∼100 pg/mL and ∼1000 pg/mL, respectively) and achieved lower natriuretic peptide concentrations compared with standard care. Patients in the biomarker-guided arms of the studies typically received more aggressive heart failure care and had no excess adverse outcomes. In the recent ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study, patients treated with biomarker-guided care also had improved quality of life and significantly better reverse remodeling on echocardiography compared with patients who received standard care. In conclusion, heart failure therapy guided by a goal to reduce natriuretic peptide concentrations below prognostically-meaningful levels results in more aggressive heart failure care, is well tolerated and is associated with superior outcomes.
Résumé
La prise en charge des patients en insuffisance cardiaque peut être difficile avec la faible disponibilité des moyens pour guider le traitement et la décision thérapeutique. Les peptides natriurétiques sont des biomarqueurs ayant un impact sur l’évaluation du pronostic des patients en insuffisance cardiaque et pourraient être utiles pour guider le traitement. Ainsi, cette hypothèse a été testée, en évaluant les résultats concernant le peptide natriurétique de type B (BNP) ou le proBNP (NT-proBNP). Dans les années écoulées, de nombreuses études avec cependant des critères d’inclusion, des méthodes et des résultats hétérogènes ont été réalisées. Nous avons revu les données disponibles de la littérature et résumé les résultats concernant la prise en charge de l’insuffisance cardiaque guidée par la prise en compte du taux de peptide natriurétique, et ainsi proposer des recommandations afin de prendre en considération ces données biologiques pour orienter de façon optimale le traitement. De façon globale, les études positives avaient des objectifs de concentration de BNP ou de NT-proBNP bas (respectivement 100 pg/mL et 1000 pg/mL) et ont atteint des concentrations de peptide natriurétique plus bas, comparativement à la prise en charge standard. Les patients inclus dans le bras guidé par le taux de biomarqueurs, dans ces études, étaient traités de façon plus agressive et n’avaient pas d’augmentation du risque de survenue d’évènements cardiovasculaires. Dans l’étude la plus récente, ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT), les patients en insuffisance cardiaque traités en prenant en considération le taux de peptide natriurétique avaient également une amélioration de la qualité de la vie, ainsi qu’une correction significative du remodelage ventriculaire gauche évaluée par échocardiographie comparativement aux patients pris en charge dans une stratégie thérapeutique conventionnelle, ne prenant pas en considération les taux de biomarqueurs. En conclusion, le traitement de l’insuffisance cardiaque orienté et guidé par la prise en compte des concentrations de peptides natriurétiques, en visant un objectif de la concentration la plus basse conduit à une prise en charge optimale car plus agressive de l’insuffisance cardiaque, et est bien tolérée et est associée à un moindre risque de complication cardiovasculaire lors du suivi.
Background
In modern practice, there are numerous challenges to be faced when trying to deliver optimal care to patients with chronic HF. Among these are the fact that it is a major challenge to achieve an optimal medical programme that minimizes HF symptoms and potential side effects while achieving the pre-specified goal doses of these therapies. Further, it is a challenge to easily identify when those goal doses are achieved. Frequent office visits with constant evaluation and management are often needed to optimize care; this, more often than not, requires great skill in recognizing opportunities to titrate therapies and the acumen to implement such changes.
Despite clearly defined targets for HF care worldwide, there is well-documented inconsistency in adherence to HF practice guidelines , with eligible patients being undertreated and opportunities to optimize care frequently being missed. This has led to a considerable focus on methods to identify those patients in need of therapy titration and to stratify risk in an objective manner, in order to better deliver care to those patients at highest risk of an adverse outcome. Very few tools for this exist, beyond clinical judgment, and the everyday clinician has very few easily-obtainable, inexpensive and widely-available resources to draw on to support their judgment regarding the management of a patient with chronic HF. Several emerging options are listed in Table 1 .
| Non-invasive | Invasive |
|---|---|
| Echocardiography | Transthoracic impedance monitoring |
| Bio-impedance vector monitoring | Left atrial pressure monitoring |
| Auditory S3 monitoring | Pulmonary artery pressure monitoring |
| Non-invasive cardiac output monitoring | |
| Biomarker-guided monitoring |
Haemodynamic monitoring devices offer promise but almost universally require invasive placement, while non-invasive haemodynamic and impedance monitors require validation and lack substantial data regarding their usefulness in guiding therapy . One intriguing option is the use of biomarkers to assist in therapeutic decision-making, which is attractive, given their wide availability and easy measurement, and the non-invasive nature of the approach. Indeed, the natriuretic peptides — BNP and its amino-terminal propeptide equivalent (NT-proBNP) — have been shown to provide easily-obtainable and meaningful prognostic information in chronic HF, which is linked directly to the biology of the diagnosis and is additive to other objective means of assessing risk. Importantly, as will be discussed, both BNP and NT-proBNP appear not only to be able to identify those at higher risk of adverse outcome but also to show interaction with HF therapies, such that their serial measurement may also provide information about the success or failure of therapy changes, thus allowing BNP or NT-proBNP to act as targets for HF care, in a similar manner to blood pressure or heart rate.
In order to better understand the potential role of BNP or NT-proBNP in guiding HF management, a brief summary of the important topics relating to their release, their prognostic value and methods for interpreting their values is worthwhile. This will be followed by a review of studies examining “biomarker-guided” therapy, an interpretation of their results and recommendations for application of BNP or NT-proBNP for HF care.
Interpretation of natriuretic peptide concentrations in ambulatory heart failure (HF)
Triggers for B-type natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) release
While the topic of natriuretic peptide release in patients with chronic HF is extensive and exceeds the scope of this document, certain concepts are worthwhile discussing in detail.
Physiologically, it is reasonable to consider the concentration of either BNP or NT-proBNP as being the sum of two separate components: fluid and function.
It is well established that myocardial stretch consequent to volume status is an important trigger for the release of natriuretic peptides . When interpreting results for either BNP or NT-proBNP, clinicians should remember that a significant percentage of their release is triggered by filling pressures, particularly when there are very high concentrations of either peptide (e.g. BNP > 500 pg/mL or NT-proBNP > 5000 pg/mL).
Importantly, however, it is well established that filling pressures are only one trigger for BNP or NT-proBNP secretion . Of the wide variety of structural and functional cardiac abnormalities leading to the release of both natriuretic peptides (detailed in Table 2 ), it is fair to assert that the prognostic importance of each is known and that potential therapeutic interventions exist for their treatment. Such abnormalities of cardiac structure and function include left ventricular systolic and diastolic dysfunction, pulmonary artery hypertension, abnormal right ventricular size and function, valvular heart disease and heart rhythm abnormalities that are prevalent in patients with compensated HF. Therapeutic interventions to address each are considered below.
| Characteristic |
|---|
| Myocardial processes |
| Systolic dysfunction |
| Diastolic dysfunction |
| Fibrosis/scar |
| Hypertrophy |
| Infiltrative diseases |
| Valvular abnormalities |
| Mitral stenosis, regurgitation |
| Aortic stenosis, regurgitation |
| Tricuspid regurgitation |
| Pulmonic stenosis |
| Cardiac chamber size |
| Ventricular enlargement |
| Atrial enlargement |
| Filling pressures |
| Atrial, ventricular |
| Pulmonary |
| Ischaemic heart disease |
| Coronary artery ischaemia |
| Heart rhythm abnormalities |
| Atrial fibrillation, flutter |
| Pericardial diseases |
| Constriction, tamponade |
| Congenital abnormalities |
| Shunts, stenotic lesions |
Natriuretic peptides and prognosis in ambulatory heart failure (HF)
This topic has been recently reviewed in detail . Both BNP and NT-proBNP represent the biomarker “gold standard” for prognostication in chronic HF, providing independent information regarding risk of progression of HF, ventricular remodeling, hospitalization for HF, need for transplantation or death. Concentrations of both peptides also predict the risk of arrhythmias , underscoring their value to prognosticate across a wide range of adverse outcomes in HF, from pump complications to heart rhythm abnormalities.
While a single measurement of BNP or NT-proBNP provides useful prognostic data for such adverse outcomes, it is well established that serial measurement provides incrementally unique information . Indeed, compared with a single point measurement, the addition of subsequent analysis of BNP or NT-proBNP allows for the identification of changes in risk over time: some patients have a falling natriuretic peptide, which predicts a lower risk than a baseline value might suggest, while others develop a rising pattern, which predicts a higher likelihood of impending complications ( Fig. 1 ).
The link between these secular trends in natriuretic peptide concentrations and outcome is quite important, as it implies a potential value of BNP or NT-proBNP for “monitoring” patients at each office visit. Indeed, recent guidelines stress the importance of serial measurement of BNP or NT-proBNP for this indication . Logically, one recognizes the importance of a stable natriuretic peptide concentration for identifying those patients who are less likely to have progressive HF, while in those with a high or changing concentration, such complications are more likely and more careful monitoring would be recommended.
The prognostic thresholds of BNP or NT-proBNP for adverse outcomes of all types have been identified and tend to be at the lower end of the scale of what is expected relative to concentrations seen in patients with acutely decompensated HF. For BNP, as indicated by Masson et al. , it would appear that a concentration of ∼125 pg/mL represents the inflection point for risk, while repeated studies have more solidly established a concentration of 1000 pg/mL for NT-proBNP. Above these risk thresholds, one may see a higher risk of adverse outcome, while below these concentrations, the risk tends to be considerably lower.
When a patient is truly optimally managed, their BNP or NT-proBNP concentration may be considered as the “dry” value. This “dry” natriuretic peptide value — ostensibly the best result a patient can reach — may then be used to assess risk of mortality and morbidity, if still elevated above prognostic thresholds, as will be discussed next.
Interpreting B-type natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations in the office: understanding changes and timing of measurement
When measuring biomarkers, it is common to see a rise and/or fall in multiple measures of physiological function; when in the absence of an obvious pathological process, this change in the biomarker is known as biological variability. In the case of natriuretic peptides, biological variability is likely to be related to subtle changes in BNP synthesis, as well as to dynamic changes in cardiac filling pressures, pulmonary pressure, haemodynamics and changes in the clearance of BNP or NT-proBNP.
While biological variability is considerably higher at low concentrations of BNP and NT-proBNP, at the ranges seen in HF, a biological variability of 25% for NT-proBNP and 40% for BNP is more to be expected . NT-proBNP has a longer half-life, which may be responsible for lower biological variability than BNP. Thus, a rise or fall of 25% (NT-proBNP) to 40% (BNP) implies a significant change in physiology. This point is particularly important to know when making decisions about changing drug therapy based on BNP or NT-proBNP concentrations. Given that BNP (with its shorter half-life) is more likely to be labile compared with NT-proBNP (with its longer half-life), differences in monitoring (and treatment approaches) using the two peptides are likely to exist, with greater day-to-day excursions with the former peptide and a smoother integration of daily physiology with the latter. How this relates to decisions about timing and method of intervention with BNP versus NT-proBNP remains somewhat less clear.
Another important topic relevant to serial testing is the amount of time it takes after a physiological change for BNP or NT-proBNP to achieve a new “steady state”. While biological data are largely lacking in this regard, on a clinical level it has been suggested that the largest prognostic value relative to changes in NT-proBNP concentration is observed 2 weeks after a therapy change .
Effect of heart failure (HF) therapies on natriuretic peptide concentrations
Therapies for HF directly affect the processes that contribute the rise of BNP or NT-proBNP and are likely to affect the biological variability of natriuretic peptides. Thus, it is well established that many HF therapies lower the concentrations of BNP and NT-proBNP ( Table 3 ). These include, of course, loop diuretics, but also ACE inhibitors, ARBs, beta-blockers, aldosterone antagonists, exercise therapy and cardiac resynchronization therapy .
