Cardiology

Using Biomarkers to Follow Heart Failure Patients

General description of procedure, equipment, technique

There is well-documented inconsistency in adherence to heart failure (HF) practice guidelines. Indeed, gaps in therapy are common in patients suffering from the diagnosis, with missed opportunities to optimize care toward the optimal goal of guideline-derived medical therapy.

Furthermore, not infrequently, the highest risk HF patients are undertreated. To better deliver care to those patients at highest risk for an adverse outcome due to HF, the focus is now on methods to (1) identify those patients in need of therapy optimization, and (2) stratify risk in an objective manner.

Beyond the clinical judgment supported by the knowledge of clinical trials and practice guidelines for patients with chronic HF, clinicians have few tools to support their judgment on managing such patients.

One option that has been explored is the use of biomarkers to assist in therapeutic decision making in the patient with chronic HF. Biomarkers are an attractive choice for this application, given their availability, easy measurement, and noninvasive nature.

The natriuretic peptides, B-type natriuretic peptide (BNP) and amino terminal proBNP (NT-proBNP), have been shown to provide easily obtainable and meaningful prognostic information in chronic HF. Importantly, this prognostic information is linked directly to the biology of HF, and is additive to other objective means to assess risk in such patients.

Furthermore, both BNP and NT-proBNP appear not only able to identify those at higher risk for adverse outcome, but show interaction with HF therapies, such that their serial measurement may also inform success or failure of therapy changes and thus allow for BNP or NT-proBNP to act as objective targets or “guides” for HF care.

Thus, the use of biomarker testing to follow patients with chronic HF, to “guide” their therapy is an emerging option for clinicians who manage such patients.

The approach is conceptually simple: patients with chronic HF seen in the outpatient setting are treated by standard clinical means, including evaluation of symptoms, signs, and objective data such as weights, heart rate, and blood pressure. Subsequently, laboratory results are integrated into the decision-making process for the patient.

If BNP or NT-proBNP are elevated in an otherwise "apparently stable" patient with HF, the clinician is encouraged to review the clinical status of the patient, evaluate opportunities to improve nonpharmacologic care (including adherence to medications as well as dietary prescription), and also consider adjustment in therapies with proven benefit for patients suffering from HF, with the goal to (1) achieve guideline-derived medical therapy targets, and (2) to reduce BNP or NT-proBNP values below a threshold of risk.

While conceptually simple, a considerable degree of information underlies the approach and will be discussed in order to clarify the important nuances of this strategy.

Physiologically, it is reasonable to consider the concentration of either BNP or NT-proBNP as being a sum total of two separate factors: filling pressure and cardiac structure and function. Regarding the link between natriuretic peptides and filling pressure, clinicians should remember that a significant percentage of natriuretic peptide release is triggered by an elevated filling pressure, particularly when very high values for either peptide are present (for example, BNP >500 pg/mL, NT-proBNP >5,000 pg/mL).

However, it is well established that filling pressure is only one trigger for BNP or NT-proBNP secretion, and a wide variety of structural and functional cardiac abnormalities lead to the release of both natriuretic peptides, including 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 chronic HF.

Therefore, when contemplating drug therapy adjustments to “lower” BNP or NT-proBNP, it is advisable to focus on therapies that address the specific cause of natriuretic peptide elevation and improve prognosis; therapeutic options to lower BNP or NT-proBNP values are detailed in Table 1.

Table 1.

Therapies that may lower natriuretic peptide concentrations.

Through the ability to reflect filling pressure and cardiac abnormalities in HF, both BNP and NT-proBNP provide important independent information regarding risk for progression of HF, ventricular remodeling, hospitalization for HF, need for transplantation, or death. Values of both peptides also predict risk for malignant ventricular arrhythmias as well. Thus their use as a barometer to "guide" HF management is supported by robust links to hard outcomes in the diagnosis.

The prognostic thresholds of BNP or NT-proBNP for adverse outcomes of all types have been identified and tend to be on the lower range than those values seen in patients with acutely decompensated HF. For BNP, below a value of 125 pg/mL, risk is quite low but rises rapidly when above this concentration.

For NT-proBNP, repeated studies have solidly established the risk value as >1,000 pg/mL. When considering these thresholds for risk, the value of serial measurement is clear, as such serial measures provide incrementally unique information.

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 for impending complications. This leads to the logical application for longitudinal monitoring in the outpatient setting.

In clinical trials examining this approach, there have been mixed results, with some studies demonstrating value from natriuretic peptide guided HF care, while others show no clear advantage. Important insights from the positive versus negative trials have been gained, which illuminate a path forward regarding the approach of biomarker-guided care (Table 2).

Table 2.

Insights into positive versus negative trials of natriuretic peptide (NP) guided heart failure (HF) therapy.

Also, considering how small each of these trials have been, it is worthwhile noting that when pooling all available data, two meta-analyses suggest a mortality reduction approaching 20% associated with biomarker-guided care. Thus, until more definitive information becomes available this approach appears reasonable.

Indications and patient selection

Most patients with chronic HF should be considered potentially eligible for biomarker-guided care. Clinicians should be aware that BNP or NT-proBNP “guided” HF care has been shown to be particularly successful in younger patients, and those with HF due to left ventricular systolic dysfunction (LVSD).

Regarding age, the belief that older patients benefit less than younger patients from biomarker-guided care has less to do with the inadequacies of the approach, and more to do with the effects of age on HF care. Compared to the younger HF patient, the elderly patient typically requires a different approach for management, with more gradual and careful drug titration.

Intolerance to therapies is greater in older patients, and target doses of drugs are less likely to be achieved as a consequence. This is not to say that elderly patients absolutely cannot respond to biomarker-guided care; indeed, recent data would imply that elders can respond to biomarker-guided care, as long as more gradual care and careful up-titration is given to achieve the lower natriuretic peptide goals.

As far as the distinction between LVSD and HF with preserved ejection fraction (HFpEF), this speaks less of the inability of BNP or NT-proBNP to identify risk (they are both powerfully prognostic in both LVSD and HFpEF), but may be more about differences in how such patients are managed. In contrast with HF patients with LVSD, where there are compelling data from clinical trials to support several therapies, there are virtually no evidence-based pharmacologic treatments for HFpEF patients.

Given the lack of a proven pharmacologic treatment strategy of care for those with HFpEF, it is reasonable to expect that biomarker-guided therapy may be more effective in patients with LVSD. Irrespectively, when "guided" by a BNP or NT-proBNP value, changes in therapy should be made with the goal to lower values of the biomarker in patients with HFpEF.

Contraindications

There are few, if any, contraindications to biomarker-guided HF care, especially as the approach is deployed using clinical judgment as the foundation of the way patients are managed. In other words, while certain patients may be more vulnerable to azotemia or hypotension from aggressive up-titration of medication driven by an elevated BNP or NT-proBNP, when good clinical judgment is employed, such risks are mitigated.

Indeed, among the various clinical trials of BNP or NT-proBNP-guided HF care, an excess risk for adverse outcome related to treatment intensification was not observed in the biomarker arm.

Details of how the procedure is performed

The recommended approach for integrating biomarkers into the clinical management of a patient with chronic HF is depicted in Figure 1.

Figure 1.

Suggested approach for integrating biomarkers into the management of patients with chronic heart failure.

A BNP or NT-proBNP should be measured at each office visit for the patient with chronic HF. For convenience, electrolytes and a measurement of renal function should be measured at the same time.

At the time of the HF visit, standard office procedures should be undertaken, with clinical evaluation superseding the results of BNP or NT-proBNP. Should an opportunity for treatment intensification to achieve guideline-derived medical therapy goals be recognized, it should be made irrespective of the biomarker result.

Following this, the results for BNP or NT-proBNP should be considered. If the BNP is above 125 pg/mL or the NT-proBNP is above 1,000 pg/mL, evaluation for need of lifestyle modification as well as treatment intensification should be strongly considered.

Many therapies both lower natriuretic peptides and provide benefits in chronic HF (Table 1). These include loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta-blockers, aldosterone antagonists, exercise therapy, and cardiac resynchronization therapy.

Thus, in the absence of obvious congestion, the approach of biomarker- guided care is not to be regarded as a "loop-diuretic first" approach.

Indeed, while very congested patients might benefit from up-titration of a loop diuretic in the face of marked elevation of BNP or NT-proBNP (as above, if over 500 pg/mL or 5,000 pg/mL, respectively), clinicians should add or up-titrate therapies such as ACE inhibitors, ARBs, beta-blockers, or aldosterone antagonists first, and consider referral for exercise therapy as well as reconsider indications for cardiac resynchronization therapy.

Notably, in the face of aggressive biomarker guided care, one trial noted the ability to down-titrate and remove loop diuretics in some patients.

The goals of pharmacologic therapy in chronic HF are no different if guided by BNP or NT-proBNP; target doses for all drugs, as identified by consensus practice guidelines, remain the same.

If a patient is below the BNP or NT-proBNP risk threshold, there is nothing to say that therapy should not be up-titrated, as the approach has not been validated in this manner. It is not infrequent, however, that doses of agents might be increased or adjusted beyond the guideline derived goals; if well-tolerated and associated with reduction in BNP or NT-proBNP, this is reasonable.

One question is how to approach a patient who is already taking guideline compliant doses of medication, but still has an elevated BNP or NT-proBNP.

Such patients are at considerable risk, even if they are on a "good" medication program; in this context, further review and intensification of their program is indicated, even if it results in a program that may be "beyond" the guidelines in terms of its intensity. This might include the addition of mineralocorticoid inhibitors for a patient who is a class I or II, for example.

After a change has been made in therapy, resampling of the biomarker should not be done for approximately 2 weeks. This allows the biomarker to achieve a new plateau after the therapy change.

At the 2-week mark, the concentration of BNP or NT-proBNP tends to achieve its new steady state, and reflects the prognosis associated with the new medical state that the patient may have assumed following therapy adjustment.

Following a therapy change, a common question is how much of a change in natriuretic peptide concentration is expected if a therapy intervention is "successful." This relates to the observation that both BNP and NT-proBNP may change from day to day.

This "biologic variability" relates to changes in the basal secretion of both peptides related to changes in physiology of the patient. This physiology may, in fact, be pathologic (such as changes in intracardiac pressure) but may also be related to shifts in gene synthesis of the proteins.

Based on the knowledge that the biologic variability of BNP is 40% and for NT-proBNP is 25%, any change above this percentage (either rise or fall) should be considered a "significant" change, and signal either a worsening or improving status, depending on the direction of the change.

Following therapy intervention based on either a clinical or biomarker driven indication, if the patient remains above the goal for BNP or NT-proBNP, therapy intensification should continue with 2 week return visits until achievement of an obvious therapeutic limit and/or reach the natriuretic peptide goal in the context of a guideline supported medication program.

Once at a therapeutic limit and/or "dry" BNP or NT-proBNP, the usual follow-up should be made; this might be at 3-month intervals as is commonly used for chronic HF patients. Should a deviation in the "dry" natriuretic peptide value occur, then reentry into the routine of biomarker adjustment may be necessary.

It is clear that the biomarker-guided approach may lead to more visits to achieve the goals as outlined. Nonetheless, this effort has been shown to pay dividends.

Disease management programs, with HF care delivered by nurse clinicians is one method for achieving the close follow-up that it sometimes takes to optimize care using biomarkers. Home visits are another method by which this approach may be delivered.

Interpretation of results

The lowest BNP or NT-proBNP achieved in the context of aggressive HF care is known as the "dry" natriuretic peptide value. Whatever this value ultimately is for each patient, it is very prognostic, with a clear gradient of risk associated with values about the prognostic targets employed with guided therapy.

As noted above, the goal is a BNP below 125 pg/mL or an NT-proBNP below 1,000 pg/mL. In studies of optimally deployed therapy, this goal may be reached in approximately 40% to 50% of patients.

A common scenario is that a patient may have an elevated BNP or NT-proBNP value, but the managing clinician feels “the patient is stable” or "looks fine," and does not adjust the therapy. Experience has taught, again and again, that no matter how stable a patient with HF appears, when BNP or NT-proBNP are elevated above their prognostic threshold, a measurable and imminent risk is present.

Ignoring such a powerful objective signal of risk increases the likelihood for a missed opportunity to improve outcome. Indeed, in most of the negative trials of biomarker-guided care, there was no difference in office visits between guided versus control arms, whereas a trade-off of increased out-patient visits was seen in the successful studies of biomarker-guided care.

Following optimal care, those patients achieving a natriuretic peptide below the target values are likely to be at considerably lower risk than those at intermediate or higher values. Additionally, results from a recent trial (ProBNP Outpatient Tailored Chronic Heart Failure Therapy [PROTECT] study) suggest that those with a falling or stable NT-proBNP value were more likely to show improvements in ventricular remodeling parameters, as well as filling pressure and diastolic function, compared to those with a rising value (Figure 2).

Figure 2.

Echocardiographic ramifications of natriuretic peptide “nonresponse” in the course of heart failure management. Patients that did not achieve an NT-proBNP below 1,000 pg/mL during the course of management had little, if any reverse remodeling in response to their heart failure care. In contrast, “responders” had significant improvement in left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume index (LVEDVi), and left ventricular end-systolic volume index (LVESVi).

Over time, even if a patient shows rises or falls in their BNP or NT-proBNP value, the amount of time spent at or below the therapeutic target value is predictive of outcome. Those constantly below the goal are expected to have better outcomes than those intermittently below, while those constantly above the goal would be expected to have worse outcome.

This concept of “therapeutic time in response” is very similar to that seen with respect to benefits predicted by international normalized ratio testing during vitamin K antagonist therapy, where more time “in range” is associated with a greater benefit. Thus, some lowering is better than no lowering.

Resistance to natriuretic peptide lowering is not without significance. When a patient has a "dry" natriuretic peptide value above the goal, this is referred to as “nonresponse” (whether guided by the natriuretic peptide value or via standard HF care), and is associated with a higher risk than if such patient had achieved the natriuretic peptide goal.

When significant "nonresponse" occurs—keeping in mind that both BNP and NT-proBNP are linear variables, thus patients nearer to the goal values have lower risk than those considerably above the goal—it identifies a patient at higher risk for adverse ventricular remodeling, and at higher risk for HF events, including hospitalization or death.

Accordingly, in the context of "nonresponse," ongoing monitoring—and based on the significance of the "nonresponse"—consideration for alternative therapeutic strategies (including invasive hemodynamic monitors, mechanical support, cardiac transplantation, or palliative care initiation) would be reasonable, given the higher likelihood for an impending adverse outcome.

Outcomes (applies only to therapeutic procedures)

As noted above, if carefully applied, the target natriuretic peptide value may be achieved in approximately 40% to 50% of patients with chronic HF, with a great majority within range of the goal. When optimally managed, the "dry" natriuretic peptide value is very prognostic.

For those with a "dry" BNP or NT-proBNP above the goal value, ventricular remodeling is more common, and risk for worsening HF, HF hospitalization, or death is higher compared to those who achieve lower natriuretic peptide values, even if adjusting for relevant variables such as age or left ventricular function.

In those treated with a biomarker-guided approach, in some studies, patient-reported quality of life was similar between biomarker-guided arms and standard arms, while another study recently showed improvement in quality of life associated with the approach. Thus, in addition to improving outcomes when optimally employed, it is reasonable to expect improvement in quality of life metrics.

While most clinical trials of biomarker-guided heart failure management were underpowered to identify an effect on mortality, those studies where a significant lowering of BNP or NT-proBNP occurred in the context of the approach, outcomes were improved. Interestingly, in meta-analyses incorporating the results of all available data from biomarker-guided approaches, a substantial reduction in mortality was observed, lending further enthusiasm for the approach.

Alternative and/or additional procedures to consider

Beyond the natriuretic peptides, there are several novel biomarkers recently available that might ultimately play a role in the management of patients with chronic HF. These include soluble (s)ST2, galectin-3, highly sensitive troponin, and biomarkers of renal dysfunction (such as cystatin C).

sST2 is a member of the interleukin receptor family, and has intimate associations with cardiac fibrosis and remodeling through interactions with interleukin 33, its ligand. Interleukin 33 reduces fibrosis and hypertrophy in the context of myocardial injury by binding to a membrane bound version of ST2.

The soluble version of the receptor, sST2, is thought to play a role as a "decoy" receptor and interrupts the beneficial effects of interleukin 33. As sST2 is measurable in peripheral blood, it was investigated as a candidate biomarker for predicting risk in HF syndromes.

Concentrations of sST2 are associated with the presence and clinical severity of HF, and are strongly predictive of ventricular remodeling and clinical outcomes, even when adjusted for natriuretic peptides.

An approved assay for measurement of sST2 is now available; however, interactions with therapies for HF and sST2 values remain unknown, so while useful for predicting risk in HF, the use of sST2 to "guide" therapy remains unexplored. Still, as concentrations of sST2 appear to rise and fall with changes in risk profile during serial sampling, it appears to be a potential candidate for an additive role in personalizing health care.

In a similar fashion, an approved assay for galectin-3 (a macrophage product that is secreted in the context of fibrosis) is also recently available to clinicians. Like sST2, concentrations of galectin-3 are markedly prognostic for adverse outcome in chronic HF, and results may be additive to natriuretic peptides for this indication. However, much like with sST2, no data are yet available regarding the therapeutic implications of galectin-3.

Novel assays for troponin, known as "highly sensitive" (hs) troponin assays are becoming more widely available, and have the ability to detect minute concentrations of troponin, even in normal patients. In those with HF, concentrations of troponin are frequently not only measurable, but frankly elevated; and when so, identify a patient at considerable risk for worsened ventricular dysfunction and death.

The ability of hs-troponin assays to detect risk is above and beyond the mere presence of coronary artery disease, which argues for a noncoronary mechanism for necrosis in the context of HF, and the risk prediction afforded by hs-troponin testing is additive to BNP or NT-proBNP. However, it remains unclear if there is a therapeutic implication associated with troponin elevation in chronic HF.

Beyond cardiac specific biomarkers, biomarkers of renal dysfunction should be considered when performing BNP or NT-proBNP-guided care. Whether serum creatinine or the estimated glomerular filtration rate, routine measurement of standard renal parameters is recommended.

Newer assays for assessment of renal function (cystatin C) or damage (neutrophil gelatinase associated lipocalin) may add to the ability of the clinician to safely titrate therapies in the face of chronic kidney disease, but this remains unclear at present.

Complications and their management

As with any technique that leads to therapy intensification, risks associated with treatment may exist. These include potentially increased incidence of hypotension, dizziness, syncope, hyperkalemia or hypokalemia, or renal failure.

This risk may be mitigated when using biomarker-guided care, as the approach should not be used as a replacement for clinical judgment. It should supplement it.

In addition to sampling for changes in natriuretic peptide during active therapy titration every 2 weeks, as noted above, clinicians should closely monitor blood pressure, heart rate, electrolytes, and renal function. In doing so, risk for treatment-related side effects can be carefully monitored and mitigated.

Thus, mindless up-titration in the face of a nonfalling BNP or NT-proBNP should not occur; every therapy adjustment should be made with consideration of the clinical ramifications and potential risks from such medication titration. Depending on clinical judgment, therapy may be adjusted based on the individual patient.

For example, in the context of a markedly elevated natriuretic peptide value, a younger patient may tolerate more aggressive and frequent changes in medication, while an older patient may not; such latter patients might do better with more gradual changes in the context of more frequent office visits.

It bears repeating that across all studies of biomarker-guided care, BNP or NT-proBNP guided therapy did not lead to excessive risk for treatment-related complications; this reassures that clinicians did not use the result of the biomarker ignoring the rest of the information gained at the bedside, such as symptoms and vital signs.

In addition, in some studies quality of life scores were not made worse by more intensive therapy, while in one recent study, quality of life was improved by biomarker-guided care.

Thus, in aggregate, when employed correctly and as part of an entire treatment program supplemented by clinical judgment, BNP or NT-proBNP-guided care is well tolerated.

What’s the evidence?

Fonarow, GC, Albert, NM, Curtis, AB. "Improving evidence-based care for heart failure in outpatient cardiology practices: primary results of the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF)". Circulation,. vol. 122. 2010. pp. 585-96.

(Considerable quality gaps exist in modern chronic heart failure care. This is a contemporary study illustrating that in modern cardiology practices, adherence to recommended treatment guidelines is suboptimal, but can be improved with quality improvement efforts.)

Kim, HN, Januzzi, JL. "Natriuretic peptide testing in heart failure". Circulation,. vol. 123. 2011. pp. 2015-9.

(A "clinician update" that is a comprehensive, up-to-date summary of the application of natriuretic peptides for diagnosis, prognosis, and treatment of heart failure.)

Chen, AA, Wood, MJ, Krauser, DG. "NT-proBNP levels, echocardiographic findings, and outcomes in breathless patients: results from the ProBNP Investigation of Dyspnoea in the Emergency Department (PRIDE) echocardiographic substudy". Eur Heart J,. vol. 27. 2006. pp. 839-45.

(An echocardiographic study showing that natriuretic peptide values correspond to cardiac structure and function, including left ventricular size and function, pulmonary artery pressure and diastolic function.)

Masson, S, Latini, R, Anand, IS. "Prognostic value of changes in N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan Heart Failure Trial)". J Am Coll Cardiol,. vol. 52. 2008. pp. 997-1003.

(The importance of serial measurement of natriuretic peptide for prognosis was illustrated in this important analysis from Val-HeFT. For those patients with a low value at the beginning of the trial who developed a rise in the biomarker, a higher risk was observed;conversely those with a high value that fell over time had a lower risk.)

Araujo, JP, Azevedo, A, Lourenco, P. "Intra-individual variation of amino-terminal pro-B-type natriuretic peptide levels in patients with stable heart failure". Am J Cardiol,. vol. 98. 2006. pp. 1248-50.

(An analysis that demonstrated the biologic variability—that is, how much of a change in BNP or NT-proBNP is needed to declare that a "significant"change beyond day-to-day variability has occurred—for BNP and NT-proBNP is 25-50%.)

Pascual-Figal, DA, Domingo, M, Casas, T. " Usefulness of clinical and NT-proBNP monitoring for prognostic guidance in destabilized heart failure out patients". Eur Heart J,. vol. 29. 2008. pp. 1011-8.

(In this prospective study, the best time for follow-up biomarker resampling after a therapy change was determined to be 2 weeks.)

Richards, AM, Doughty, R, Nicholls, MG. "PlasmaN-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group". J Am Coll Cardiol,. vol. 37. 2001. pp. 1781-7.

Anand, IS, Fisher, LD, Chiang, YT. "Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT)". Circulation,. vol. 107. 2003. pp. 1278-83.

Berry, C, Murphy, NF, De Vito, G. "Effects of aldosterone receptor blockade in patients with mild-moderate heart failure taking a beta-blocker". Eur J Heart Fail,. vol. 9. 2007. pp. 429-34.

Conraads, VM, Beckers, P, Vaes, J. "Combined endurance/resistance training reduces NT-proBNP levels in patients with chronic heart failure". Eur Heart J,. vol. 25. 2004. pp. 1797-805.

Fruhwald, FM, Fahrleitner-Pammer, A, Berger, R. "Early and sustained effects of cardiac resynchronization therapy on N-terminal pro-B-typenatriuretic peptide in patients with moderate to severe heart failure and cardiac dyssynchrony". Eur Heart J,. vol. 28. 2007. pp. 1592-7.

(These five references are a reasonable summary regarding the effects of heart failure therapy on concentrations of BNP or NT-proBNP. As noted, vasodilators (such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), beta-adrenergic blockers, mineralocorticoid inhibitors, exercise therapy and cardiac-resynchronization therapy may reduce concentrations of BNP or NT-proBNP; when such reductions occur, improvements in prognosis are expected. If reduction in natriuretic peptide does not occur after therapy introduction or intensification, it is reasonable to expect benefit has not occurred, and outcomes may not be improved.)

Troughton, RW, Frampton, CM, Yandle, TG. "Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations". Lancet,. vol. 355. 2000. pp. 1126-30.

(This is the first pilot study of biomarker-guided heart failure management. In this small trial performed during an era when beta-blockade was less common, treatment with a goal NT-proBNP value below approximately 1,500 pg/mL was associated with reduced risk.)

Berger, R, Moertl, D, Peter, S. "N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure a 3-arm, prospective, randomized pilot study". J Am Coll Cardiol,. vol. 55. 2010. pp. 645-53.

(An interesting study performed in Austria, where patients suffering from heart failure due to left ventricular systolic dysfunction were randomized to one of three arms: standard clinical management, heart failure care delivered by a nursing program, and biomarker-guided care. The biomarker-guided arm experienced more drug up-titration, and while seen more in the office, patients in this arm did better than the other two treatment groups .

Jourdain, P, Jondeau, G, Funck, F. "Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study". J Am Coll Cardiol,. vol. 49. 2007. pp. 1733-9.

(A multicenter, controlled trial of standard heart failure management versus BNP guidance with a goal value below 100 pg/mL. In STARS, patients in the BNP arm received more aggressive addition or up-titration of therapies with proven value in HF, and in parallel showed better outcomes. Biomarker-guided care was well tolerated.)

Januzzi, JL, Rehman, S, Mohammed, AA. "Use of amino-terminal pro-B typenatriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction". J Am Coll Cardiol,. vol. 58. 2011. pp. 1881-9.

(A recent publication that illustrated the benefits of aggressive NT-proBNP lowering, the PROTECT study demonstrated that substantial lowering of NT-proBNP is possible in a majority of patients with chronic heart failure, and when this lowering occurred, significant reductions in heart failure events occurred and the approach was well-tolerated. Improvement in cardiac structure and function appeared to parallel the more aggressive care delivered in the NT-proBNP arm. Interestingly, among those aged >75 years, substantial NT-proBNP lowering was achieved in the biomarker-guided arm, and in parallel, a benefit was observed, which calls into question the concept that this approach is less effective in the elderly.)

Eurlings, LW, van Pol, PE, Kok, WE. "Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study". J Am Coll Cardiol,. vol. 56. 2010. pp. 2090-100.

(In this negative study of biomarker-guided care, the investigators chose an NT-proBNP target selected as the biomarker concentration at the time of hospital discharge. It is well-recognized that biomarker concentrations at hospital discharge are considerably higher than can be achieved with chronic therapy titration.This suggests that the design of this study was flawed in that an inappropriately high target NT-proBNP value was chosen. This is a similar design and result as the STARBRITE study (Shah MR, CaliffRM, Nohria A, et al, J Card Fail, 2011;17:613-21), a BNP study with an inappropriately high target value that was also negative.)

Lainchbury, JG, Troughton, RW, Strangman, KM. "N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial". J Am Coll Cardiol,. vol. 55. 2009. pp. 53-60.

(In this analysis of patients from Christchurch, New Zealand, biomarker-guided care was associated with significant reduction inmortality for those aged <75 years; for older patients, the benefit of the approach was less clear. Importantly, this study included patients with heart failure and preserved ejection fraction, and the treatment strategy for older versus younger patients was not clearly different.)

Pfisterer, M, Buser, P, Rickli, H. "BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial". JAMA,. vol. 301. 2009. pp. 383-92.

(At 499 subjects, the TIME-CHF study is the largest biomarker-guided heart failure trial to date. In this analysis of elderly patients with mainly heart failure due to left ventricular systolic dysfunction, the achieved NT-proBNP value was far too high to expect a significant benefit from biomarker-guided care. Furthermore, it is not clear that the treatment strategy for the older patients in this study differed from younger patients.)

Felker, GM, Hasselblad, V, Hernandez, AF. "Biomarker-guided therapy inchronic heart failure: a meta-analysis of randomized controlled trials". Am Heart J,. vol. 158. 2009. pp. 422-30.

Porapakkham, P, Zimmet, H, Billah, B. "B-type natriuretic peptide-guided heart failure therapy: A meta-analysis". Arch Intern Med,. vol. 170. 2010. pp. 507-14.

Two recent meta-analyses showing significant mortality reduction related to biomarker-guided heart failure care. As the overall number of patients enrolled in all the currently executed biomarker-guided treatment trials is just over 3,000, such meta-analyses provide further evidence the approach is sound, and that larger multicenter trials are justified.
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