Heart failure (HF) is currently achieving epidemic proportions, representing the single fastest-growing diagnosis among patients aged >65 years of age and the most common cause for hospitalisation in these patients.1 In addition to having a high incidence and prevalence, HF is associated with substandard clinical outcomes and with high rates of hospitalisation and death.1 Accordingly, great focus has been put on improving therapeutics for affected patients. Significant improvements in patient outcomes have been observed following the introduction of angiotensin-converting enzyme inhibitors (ACEIs), and subsequently of angiotensin-II receptor blockers (ARBs), β-adrenergic blockers, mineralocorticoid inhibitors, automatic implantable cardioverter-defibrillators and biventricular pacemakers.2–7 However, when considering the advances in the understanding of therapeutic options in HF made over the last few decades, it is interesting to note a remarkable discrepancy between the large amount of research that has been performed to introduce new drugs or devices into clinical practice on one hand, and the little effort that has been made to clear up the optimal strategy of how to implement all these new therapies on the other hand.
Accordingly, based on the clinical practice guidelines for HF,8 patients are essentially to be treated with a ‘one size fits all’ approach, physicians basing their decisions regarding the application of many therapies on subjective measurements – such as the severity of dyspnoea – while up-titrating drugs to their maximal tolerated doses. This approach, while based on excellent clinical trial data, unfortunately results in considerable gaps in care, with many patients undertreated despite being eligible for specific therapies, and higher-risk patients, who would benefit most from therapeutic intensification, least likely to receive such therapies.9
The gap in care for a patient suffering from HF depends somewhat on the skills of the physician caring for them, but it is also due to the lack of available tools to assist the physician in judging the severity of disease. In order to be useful to the physician, such tools must be widely available, inexpensive, reproducible and easy to interpret. In addition, any tool used to assist or ‘guide’ therapy in HF must show reciprocity between therapeutics and prognosis; in other words, if it is to be adopted to guide care, the tool used to monitor the response to treatment when an HF therapy is applied should reflect the benefits of that therapy on the patient.
One option that may fit many (if not most) of the requirements of a guide to HF therapy is the measurement of HF biomarkers. While many biomarkers have been examined with respect to their behaviour in the context of HF care, the two natriuretic peptides – B-type natriuretic peptide (BNP) and its amino-terminal cleavage equivalent N-terminal-pro-BNP (NT-proBNP) – have the greatest amount of data regarding their use. Both are potent markers of risk in chronic HF, with higher levels of each predicting an adverse outcome.10–12 Additionally, when the standard therapies for HF are applied, a significant drop in BNP or NT-proBNP may be seen.
Given all this, the concept of natriuretic peptide-guided HF therapy has been examined in recent trials (see Table 1). However, in contrast to the huge number of patients studied with biomarkers over the last decade, the total number of patients enrolled in the various natriuretic peptide-guided trials over the last few years equals that of one medium-sized drug study. Furthermore, while the principle of the natriuretic peptide-guided trials may be straightforward, the protocols differ substantially and the published results are diverse.13–22
Nonetheless, despite this heterogeneity in design and results, two recent meta-analyses pooling all data showed that natriuretic peptide-guided therapy was associated with a significant reduction in the risk of mortality (see Figure 1).23,24 In addition, whether positive or negative, the trials examining the use of BNP or NT-proBNP to guide HF therapy have universally shown the approach to be well tolerated, without excess risk of adverse outcomes related to therapy intensification. In fact, one recent trial suggested that NT-proBNP-guided therapy was associated with an improvement in quality of life, compared with standard HF care.16
Large-scale trials examining the use of biomarker-guided therapy in HF are soon to be launched. However, based on experiences gained and data published thus far,23,24 a clinician who intends to implement natriuretic peptide-guided therapy in his/her practice should be aware of the following considerations:
- What biological and physiological factors may influence the concentrations of BNP and NT-proBNP?
- Which patients will benefit from natriuretic peptide-guided therapy?
- What is the natriuretic peptide target value?
- What should be the strategy to reach the target without causing serious side effects?
What Biological and Physiological Factors May Influence Concentrations of Natriuretic Peptides?
To comprehend all aspects and pitfalls of natriuretic peptide-guided therapy, clinicians should be aware of the several factors that influence the concentrations of these markers. Myocardial stretch is generally accepted to be the most important trigger of BNP and NT-proBNP release, and concentrations of both may therefore be loosely considered to reflect filling pressures.25 However, filling pressures are not the only trigger of BNP or NT-proBNP secretion: besides myocardial stretch, a wide variety of structural and functional cardiac abnormalities may lead to the release of both natriuretic peptides, including ischaemia, pulmonary arterial hypertension, abnormal right ventricular size and function, valvular heart disease and arrhythmias such as atrial fibrillation. Further important extracardiac factors associated with changes in concentrations of BNP or NT-proBNP, such as anaemia (raised concentrations), impaired renal function (raised concentrations) and higher body mass index (lowered concentrations), should also be considered.26
Another important consideration is how much of a change in BNP or NT-proBNP concentrations should be seen to determine whether a significant clinical change has occurred. In other words, following a therapy change, how much of a rise or fall in either natriuretic peptide should occur before the clinician can be assured that the therapy has had a significant effect on the concentrations of that peptide. To understand this concept, it is important to discuss the known biological variability of BNP and NT-proBNP. From day to day or week to week, subclinical changes in cardiovascular physiology may lead to shifts in the concentrations of each of these peptides. In normal patients, this biological variability is high, as very low concentrations of BNP and NT-proBNP can change substantially without clinical import. However, at the natriuretic peptide ranges clinically seen in HF patients, a biological variability of 25 % for NT-proBNP and 40 % for BNP is more expected.27 Thus a rise or fall of at least 25 % for NT-proBNP or at least 40 % for BNP implies a significant change in physiology. This point is particularly important when making decisions about drug therapy based on BNP or NT-proBNP measurements.
Lastly, yet equally importantly, it must be realised that it takes some time for BNP or NT-proBNP concentrations to adapt to the new ‘steady state’ following a clinical change. It has been suggested that the largest prognostic value relative to changes in NT-proBNP concentrations is observed at two weeks after a change in therapy.28 This therefore represents a reasonable time point for follow-up.
Which Patients Will Benefit from Natriuretic Peptide-guided Therapy?
When comparing the results of the positive natriuretic peptide-guided therapy studies with those of the negative ones, important differences in baseline characteristics may be noted. Firstly, guided therapy may be less beneficial in HF with preserved ejection fraction (HFPEF) than in HF with left ventricular systolic dysfunction (LVSD). This is not surprising, and is not so much a limitation of the natriuretic peptides in discriminating the patients at risk than a reflection of our lack of adequate treatment options for patients suffering from HFPEF. At present, specific and adequate therapeutic agents for this subset of patients are lacking, with or without biomarker guidance. That said, the approach may be very different for patients with HFPEF than for those with LVSD, with a more diuretic-based treatment strategy versus vasodilators, β-blockers and so on.
Another important caveat, discussed below, is that, in order for a biomarker-guided HF therapy to be successful, one must aim for a low target value and that target value must be achieved. Among the categories of patients less likely to achieve such a target value are the elderly. The older HF patient is more prone to dose-limiting side effects (e.g., worsening of renal function, hyperkalaemia, hypotension) from the intensification of pharmacological therapy. Older patients typically have higher BNP or NT-proBNP levels than younger patients with similar degrees of HF, and, in the negative studies, the elderly patients did not show anywhere near as significant a natriuretic peptide lowering than the younger ones.17,19 Thus one might be tempted to decry the use of biomarker-guided therapy in the elderly. However, interestingly, in a recent study in which elderly patients achieved substantial NT-proBNP lowering in the biomarker-guided therapy group, clinical events in those elderly patients were considerably reduced.16 Explaining this finding was a more gradual up-titration of treatment and a more assiduous application of therapies in the biomarker-guided group compared with the standard-of-care group – the elderly patients who received standard-of-care treatment showed a rise in NT-proBNP.29 Thus the take-home message is that biomarker-guided HF therapy is expected to be successful in those patients with LVSD in whom a significant lowering of the biomarker used to guide therapy occurs. Whether elderly or not, those showing substantial reductions in BNP or NT-proBNP following HF therapy have a better prognosis.
This raises the question of how to react when a patient has shown to be a natriuretic peptide-guided therapy ‘non-responder’ despite intensified pharmacological treatment. Is this a failure of the biomarker-guided concept, or is this a clear clinical signal that an alternative approach to care is needed? The data are actually clear in this regard; an elevated BNP or NT-proBNP concentration following treatment intensification reflects important information: prognosis in these ‘non-responders’ is usually poor and more invasive therapies, such as (temporary) mechanical support or transplantation, or a more palliative approach, should be considered.21,22
What is the Natriuretic Peptide Target Value?
Various theories have been formed about conceptualising the BNP or NT-proBNP target value for patients treated with a guided approach, ranging from an individualised personal target to an absolute value based on risk inflection – a relative decrease being a compromise between the two. All three options have been studied.
Studies of natriuretic peptide-guided therapy with a positive result typically had a low absolute value as a target, particularly when achieved natriuretic peptide concentrations in the biomarker-guided arm were lower than in the standard-of-care arm. It is well recognised that both BNP and NT-proBNP have values below which the risk in HF is extremely low. For BNP it is approximately 125 pg/ml, while for NT-proBNP it is 1,000 pg/ml.16,30 Interestingly, in contrast to results seen in studies of patients with acutely decompensated HF, the two studies that had chosen an individualised target were both negative.20,21 One explanation for this may be the fact that these two studies had both chosen, as the target value, the natriuretic peptide concentration at hospital discharge for acutely decompensated HF, which is far too high; indeed, it is now well established that BNP or NT-proBNP concentration at hospital discharge for decompensated HF are typically markedly elevated relative to the much lower concentrations that can be achieved when medication is carefully up-titrated. Although only one study used a relative decrease of natriuretic peptide concentrations as its target, that study failed to show that this was a beneficial strategy,18 and consensus is now that the absolute targets listed above should be the treatment goal.
It bears repeating that a biomarker-guided strategy is only effective if significant lowering of BNP or NT-proBNP occurs. Several studies showed no substantial difference in biomarker concentrations from baseline to completion, leaving the hypothesis untested. Further, even in negative studies, when patients responded to HF therapy by showing a robust fall in NT-proBNP concentrations, favourable outcomes were expected.21,22 Lastly, in the course of HF therapy not guided by natriuretic peptides, if substantial reduction in BNP or NT-proBNP occurs, this is a favourable sign – even if not driven by the natriuretic peptide itself.
What Should Be the Strategy to Reach the Target without Causing Serious Side Effects?
To reach an optimal low target, treating physicians should be aware that careful up-titration can only be achieved by increasing the number of patient visits. Interestingly, in most of the negative trials, there was no difference in the number of visits between the biomarker-guided and the standard-of-care arms, in contrast to the positive studies, in which a clear increase in outpatient visits was seen.
As noted, HF therapies including loop diuretics, ACEIs, ARBs, β-blockers, aldosterone antagonists, exercise therapy and cardiac resynchronisation therapy have been shown to decrease natriuretic peptide concentrations.26 However, when titrating therapies to lower BNP or NT-proBNP levels in patients with LVSD who are not obviously congested, it is important to recognise that the approach should not be primarily loop diuretic-driven. Although diuretics have a particularly potent effect in lowering BNP or NT-proBNP (and are therefore a tempting tool to reach the target quickly), titration of other agents listed above with favourable effects on long-term outcomes31 should be considered the first priority in a relatively stable outpatient setting. Indeed, in one study, NT-proBNP-guided therapy even allowed for the downwards titration of loop diuretics,16 probably reflecting a more aggressive application of mineralocorticoid receptor antagonism, as well as greater clinician confidence in patient stability when NT-proBNP was measured in an open setting.
Importantly, and consistently across all studies, biomarker-guided therapy did not result in a significant increase in treatment-related complications. As all studies showed, BNP- or NT-proBNP-guided therapy typically leads to more intensification of therapy (higher number of outpatient visits as well as higher number and/or dosages of drugs prescribed), which implies that the clinical judgement of the study physicians helped to avoid causing complications. Indeed, in clinical practice, biomarker-guided therapy will never replace clinical judgment. It will only aid the treating clinician in his/her judgement and decision-making by providing an easily interpretable, biologically sound, reproducible result reflective of a pathophysiology that may not be recognised at the bedside.
There is now sufficient evidence that natriuretic peptide measurement may enable physicians not only to better stratify risk in chronic HF, but also to better treat patients. When using concentrations of BNP or NT-proBNP, good knowledge of the target value for each is recommended: it is 125 pg/ml for BNP and 1,000 pg/ml for NT-proBNP. When taking into account the array of causes of an elevated BNP or NT-proBNP concentration, as well as the possibilities and limitations regarding how to lower these concentrations, a careful and dedicated implementation of the successful natriuretic peptide-guided treatment trials in daily clinical practice may result in significant reductions in adverse outcomes.