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As more patients are diagnosed with heart failure each year, heart failure management has become a growing public health issue. The development of new therapies and effective implementation of existing therapies for heart failure remain a challenge. Biomarkers, such as natriuretic peptides, offer consistent and cost-effective means of monitoring response to therapy. There is growing interest in using biomarkers to guide heart failure therapy due to their objectivity, reproducibility, and accessibility. There have been several trials to date, including the New Zealand Natriuretic Peptide-Guided Heart Failure Therapy study, the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure Studies, the NT-proBNP–Assisted Treatment to Lessen Serial Cardiac Readmissions and Death trial, and the Plasma Brain Natriuretic Peptide–Guided Therapy to Improve Outcome in Heart Failure trial, that examined the effectiveness of biomarker-guided heart failure therapy with very promising results. When compared with intensive medical management, natriuretic peptide-guided heart failure therapy was shown to be noninferior in general and slightly superior in certain patient populations. Although larger trials are required to validate their results, these studies have provided evidence for the effectiveness of biomarker-guided heart failure therapy and paved the way for the integration of biomarkers into routine evaluation and management of patients with heart failure. Congest Heart Fail. 2010;16(4)(suppl 1):S62–S67. ©2010 Wiley Periodicals, Inc.
Heart failure is one of the major public health challenges in the United States. Approximately 4.9 million individuals in the United States have a diagnosis of heart failure and the number is growing. It is the fastest-growing cardiac diagnosis in North America, with an annual incidence of 10 cases per 1000 people in individuals older than 65.1 Heart failure is a complex clinical syndrome that can result from a variety of structural and functional cardiac disorders that prevent the left ventricle from properly filling and ejecting blood. In spite of major improvements in prevention and treatment, prognosis remains poor.2 The development of new therapies for heart failure remains a challenge, as it is difficult to predict which patients will benefit or deteriorate from novel therapies. Biomarkers representing different pathophysiologic processes have been used extensively in the diagnostic evaluation and risk stratification of heart failure patients. With the emergence of new biomarkers and further understanding of existing ones, there is great potential for using biomarkers as a tool to objectively guide therapy in heart failure patients. Among the many biomarkers available today, natriuretic peptides such as B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are perhaps the most extensively studied biomarkers in heart failure (Table I). Their role in the diagnosis of acute heart failure and risk stratification of heart failure patients are very well-established.3–5 Besides screening and risk stratification, natriuretic peptides have also been proposed as an objective guide for heart failure therapy. This interest in using natriuretic peptides to guide heart failure therapy stems from the observation that natriuretic peptide levels rise with worsening heart failure and fall with heart failure treatment and optimization.4–8
Table I. Characteristics of BNP and NT-proBNP
|Components||BNP molecule||NT fragments (1–76) NT-proBNP (1–108)|
|Molecular weight||4 kd||8.5 kd|
|Genesis||Cleavage from NT-proBNP||Release from ventricular myocytes|
|Half-life||20 min||120 min|
|Clearance mechanism||Neutral endopeptidase Clearance receptors||Renal clearance|
|Increase with normal aging||+||++++|
|Correlation with estimated glomerular filtration rate||−0.20||−0.60|
|Approved cutoff(s) for CHF diagnosis||100 pg/mL||Age <75: 125 pg/mL Age >75: 450 pg/mL|
|Studies completed, No.||1370||39|
|Entry on US market||November 2000||December 2002|
To understand the rationale for using natriuretic peptides in guiding heart failure therapy, we must start with the underlying physiology. It is well-known that natriuretic peptides are markers for myocardial wall stress and preload, which is based on extensive studies correlating elevations of natriuretic peptides levels with increased central venous pressure, elevated pulmonary capillary wedge pressure (PCWP), and increased left ventricular wall stress.9–13 For example, in a study by Ikeda and colleagues9 that examined patients undergoing aortic valve replacement for aortic stenosis, BNP levels correlated extremely well with left ventricular wall stress in both preoperative and postoperative patients, demonstrating that BNP is a good surrogate marker for left ventricular wall stress. In a separate study by Yoshimura and colleagues, significantly elevated natriuretic peptide levels were seen in patients with dilated cardiomyopathy. In addition, BNP levels correlated very well with PCWP.10 In heart failure patients, elevated PCWP is an objective marker of fluid overload, especially left ventricular preload. Elevated PCWP is associated with increased mortality in this population.14 The strong correlation between elevations of BNP and left ventricular wall stress and preload highlights the role of BNP as a surrogate marker for these processes, which are crucial pathophysiologic components of congestive heart failure.15 The reason BNP correlates so well with increased left ventricular wall stress and preload lies in its origin. BNP is produced mostly by the ventricles, with the left ventricle being the predominant source.11,12 Increased BNP production in patients with elevated ventricular wall stress and preload is the result of up-regulation of BNP in the ventricular myocytes. This up-regulation can be demonstrated histologically in patients with hypertrophic cardiomyopathy, which results in markedly elevated left ventricular wall stress.13 The strong correlation between elevated BNP and increased PCWP and left ventricular wall stress provides the physiologic basis for using BNP for guided therapy in heart failure patients. To date, there have been several studies conducted to evaluate the utility of using natriuretic peptide levels to guide heart failure therapy16–19 (Table II). While these studies have shown promising results, the incorporation of biomarker-guided heart failure therapy into routine clinical practice is still controversial. Additional studies with novel strategies and multimarker approaches are required before the widespread use of biomarker-guided heart failure therapy becomes a reality.
Table II. Existing Biomarker-Guided Therapy Studies
|Study||Study Population||Outcome Measures||Main Strengths||Main Limitations||Main Conclusion/Findings|
|TIME-CHF Randomized Trial||499 patients ≥60 y with systolic heart failure NYHA class of II or greater, Prior hospitalization for HF within 1 y NT-proBNP levels of 2 or more times the upper limit of normal||8-month survival free of all-cause hospitalizations Quality of life as assessed by structured validated questionnaires||Largest randomized studyto date High-risk older patientpopulation||Inability to determinewhich single drug addedto the findings Age-specific findings aresubgroup findings only Patient recruits from onlyclinics of small/largehospitals||Improved primary outcomes in patients aged 60–75 y but not in those older than 75 (P<.02) Survival free of hospitalization for HF higher among those receiving BNP-guided therapy|
|Randomized arms: (1) Symptom-guided therapy (2) NT-proBNP–guided therapy Symptom guided: targeted reduction of symptoms to dyspnea NYHA class of II or less NT-proBNP–guided: targeted NT-proBNP levels to less than 2 times the upper limit of normal≤400 pg/mL in patients younger than 75 y and <800 pg/mL in patients aged 75 y or older and NYHA class of II or less|
|New Zealand study||69 patients with impaired systolic function (left ventricular ejection fraction <40%) Symptomatic HF||Total cardiovascular events (cardiovascular death plus hospital admission for any cardiovascular event) NT-proBNP concentration Left-ventricular ejectionfraction Functional capacity Quality of life||Differences in event ratesbetween study groupsindependent of baselinevariables Concordance of standardized treatment mortality rates to prior related studies Concordance of HFstandardized treatmentreadmission rates withinother demographic studies||Small sample size Minor variations betweengroups in baselinevariables Low rate of β-blocker andspironolactone use||Fewer total cardiovascular events (death, hospital admission, or HF decompensation) in the BNP group than in the clinical group (19 vs 54; P=.02) NT-proBNP–guided treatment or delayed time to a first event compared with an intensive clinically guided approach|
|Randomized arms: (1) Standard clinical assessment (2) NT-proBNP concentration–guided therapy Standard group: targeted treatment of decompensated HF according to an objective score (HF score <2) NT-proBNP group: targeted NT-proBNP <200 pmol/L|
|BATTLE-SCARRED Trial||366 patients ≥18 y Symptomatic congestive HF Prerandomization plasmaNT-proBNP levels ≥50 pmol/L (400 pg/mL)||All-cause mortality and thecomposite of death plushospitalization for HF Death plus hospital admis- sion for any cardiovascularevent plus episodes of outpatient decompensated HF requiring increasedmedications Any episode of HFdecompensation Total admissions tohospital Changes in NT-proBNPlevels||Large sample size Comparison of usual carewith intensive standard- ized care with NT-proBNP–guided care Long follow-up periods of1, 2, 3, 5 y ||Use of a single plasmaNT-proBNP (150 pmol/L)as a target for pharmacotherapy independent of patient age Recruitment of patientsfrom only specialty clinics||1-year mortality was lowerin both the hormone-(9.1%) and clinicallyguided (9.1%) groupscompared with usual care(18.9%; P=.03) 3-year mortality wasselectively reduced inpatients >75 y receivinghormone-guided treat- ment (15.5%) comparedwith their peers receivingeither clinically managedtreatment (30.9%;P=.048) or usual care(31.3%; P=.021)|
|Randomized arms: (1) Usual care (2) Intensive standardized clinical management 3) NT-proBNP–guided therapy Usual care: no treatment from research team Only 3-month clinical info documentation Intensive: targeted HF score >2.0 NT-proBNP: targeted NT-proBNP >150 pmol/L and/or HF score >2.0|
|STAR-BNP Trial||220 patients ≥18 y Symptomatic NYHA functional class II to III systolic HF defined by left ventricular ejection fraction <45% Stable condition Treated by optimal medical therapy according to the European guidelines at the time of the study||Unplanned hospital staysfor HF or death related toHF All-cause death, deathrelated to HF, all-causehospital stay, and hospitalstay for HF||Lower baseline left ventricular ejection fraction in the BNP group to increase number of clinical events Large sample size||BNP-guided strategy testedafter medical therapy hadbeen optimized by highlyqualified cardiologists Sample size was young, mostly male, and limited to systolic dysfunction||During follow-up (median15 months), significantlyfewer patients reachedthe combined end point inthe BNP group (24% vs52%; P=.001) Mean dosages of angio- tensin-converting enzymeinhibitors and β-blockerswere significantly higherin the BNP group (P=.05)|
|Randomized arms: (1) Standard clinical care (2) BNP-guided therapy Standard group: adjustment of therapy based on standard clinical care, physical examination, and opinion of investigator BNP group: targeted BNP <150 pg/mL|
One of the earliest studies exploring the concept of natriuretic peptide–guided heart failure therapy is a New Zealand study by Troughton and colleagues16 published in 2000. This small study included 69 patients with systolic dysfunction (left ventricular ejection fracture <40%) and symptomatic heart failure (New York Heart Association [NYHA] class II–IV). Therapy guided by plasma concentrations of BNP was compared with treatment guided by standard clinical assessment. The patients included in this trial were between the ages of 35 and 85 and were either referred by outpatient cardiology clinics or recruited after admission for decompensated heart failure. The patients were randomized to 1 of the 2 treatment arms and evaluated every 3 months in a specialized cardiology clinic for a median duration of 9.5 months. Treatment within the standard clinical therapy arm targeted a goal of compensated heart failure according to an objective symptom score, while the BNP-guided arm targeted a previously studied treatment goal of BNP <200 pmol/L.3 If these treatment goals were not reached in either arm, therapy with angiotensin-converting enzyme (ACE) inhibitors, loop diuretics, spironolactone, digoxin, isosorbide mononitrate, and felodipine was intensified to achieve the treatment goals. The primary end point for the study was cardiovascular death and admission for any cardiovascular event. By the end, this study found fewer total cardiovascular events in the BNP-guided group when compared with the clinical assessment–guided group (19 vs 54, P=.02). Despite the small size of the study, post-study regression analyses confirmed that differences in event rates between the 2 groups were independent of any baseline patient characteristic differences. It is also worthwhile to point out that the event rates in the standard clinical assessment arm in this study compare well to the event rates in other contemporary heart failure treatment studies and local observational data from New Zealand, adding further credibility of this study’s treatment arm comparisons.20–22 One obvious limitation of this study is its small sample size, which not only calls into question its accurate reflection of different patient populations but also highlights the necessity of additional large scale studies to confirm its findings. Nevertheless, the results from this study sparked great interest in the heart failure community and prompted several large scale follow-up studies (STARBRITE, NT-proBNP–Assisted Treatment to Lessen Serial Cardiac Readmissions and Death [BATTLESCARRED] trial), Plasma Brain Natriuretic Peptide–Guided Therapy to Improve Outcome in Heart Failure [STAR-BNP], and Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure Studies (TIME-CHF).17–19,23
We will start our discussion with STAR-BNP, which is the first large-scale follow-up study to the study by Troughton and colleagues. The STAR-BNP trial was a multicenter study comparing the outcomes of BNP-guided therapy against standard clinical therapy according to current guidelines. A total of 220 NYHA class II and III patients optimally treated with ACE inhibitors, β-blockers, and diuretics were involved in the study. The patients were randomized to receive either BNP-guided therapy with a goal BNP of <100 pg/mL or standard clinical therapy according to current clinical guidelines. The patients were followed every 3 months with a median follow-up of 15 months. The primary end point was CHF-related death or admission. Both treatment arms had similar baseline demographic and clinical characteristics. By the end of the study, the authors found that the BNP-guided arm had significantly fewer patients reaching the primary end point than the standard clinical therapy arm (24% vs 52%; P<.001), confirming the results by Troughton and colleagues. An interesting observation from this study was that ACE inhibitors and β-blockers were up-titrated more frequently and to higher average doses in the BNP-guided therapy arm, while average diuretic doses were similar in the 2 treatment arms, suggesting that biomarker-guided therapy leads to more aggressive up-titration of medications with proven prognostic benefits than standard clinical therapy. The comparable diuretic doses in the 2 treatment arms also suggested that when used to guide outpatient therapy, BNP is not just a marker of the patient’s symptoms but a marker of the severity of the patient’s disease.23
The STAR-BNP study was followed by the BATTLESCARRED study, which was a large and well-designed study with a novel approach of comparing 3 different treatment arms. The goal of the study was to compare the clinical outcomes in patients with chronic symptomatic heart failure randomized to receive NT-proBNP–guided therapy, intensive clinical management, or usual care. In all, 366 patients admitted to a single medical center were included in the study. The patients were evenly randomized to the 3 treatment arms with the treatment strategies applied for 2 years and a total follow-up time of up to 3 years. The study found that 1-year mortality was significantly less in both the NT-proBNP–guided therapy arm (9.1%) and the intensified clinical management arm (9.1%) when compared with usual care (18.%; P=.03). Moreover, the study found that in patients younger than 75, the 3-year mortality is significantly lower in the NT-proBNP–guided arm (15.5%) when compared with both the intensive clinical management arm (30.9%; P=.048) and the usual care arm (31.3%; P=.021). The results from this study are quite remarkable in several ways. First of all, it again demonstrated that biomarker-guided therapy is noninferior to intensive clinic management. In addition, NT-proBNP–guided therapy has shown superiority over intensive clinical management in the subgroup of patients younger than 75. More important, it included a usual care group. It is well-known that the intensive treatment arm described in clinical studies is difficult to uniformly apply to “real-world” clinical practice. Most patients in the real world are receiving usual care, which is less uniform and less aggressive the intensive clinical management described in clinical trials. This study underscores the superiority of biomarker-guided therapy over the usual care that most heart failure patients receive in the real world.18
Last, we come to the TIME-CHF trial, which is the largest prospective randomized study evaluating the effectiveness of natriuretic peptide–guided therapy to date. A total of 499 chronic heart failure patients were included. It compared outcomes of NT-proBNP–guided therapy against symptom-guided therapy in a patient population aged 60 years or older with systolic heart failure (ejection fraction ≤45%), NYHA class of II or greater, prior hospitalization for heart failure within 1 year, and NT-proBNP levels 2 or more times the upper limit of normal.4 The study focused on an older patient population since evaluation based on symptoms is less reliable in this population, thus potentially lending greater attractiveness to the concept of natriuretic pep-tide–guided therapy.5 The trial was a multicenter study that was conducted between January 2003 and June 2008. All patients were followed for 18 months. In the symptom-guided treatment arm, guideline-based treatments were intensified as needed to reduce symptoms to NYHA class of II or less, while the natriuretic peptide-guided therapy arm targeted natriuretic peptide levels of 2 times or less than the upper limit of normal and a reduction of symptoms to NYHA class of II or less. The primary end point of the study was survival free of all-cause hospitalization and quality of life as assessed by structured validated questionnaires. The study found similar rates of survival free of all-cause hospitalizations between the natriuretic peptide–guided therapy arm and symptom-guided therapy arm (41% vs 40% respectively; hazard ratio, 0.91; 95% confidence interval, 0.72–1.14; P=.39). In addition, natriuretic peptide–guided heart failure therapy led to higher rates of survival free of all-cause hospitalizations in patients aged 60 to 75 years but not in those older than 75 (P<.02). This study, with the large sample size, again demonstrated the noninferiority of natriuretic peptide–guided therapy when compared with symptom-guided therapy and demonstrated superiority of natriuretic peptide–guided therapy in the subgroups of patients younger than 75.19
When taken as a whole, these studies confirm the feasibility and utility of using natriuretic peptides to guide therapy in heart failure patients. These studies demonstrated that natriuretic peptide–guided therapy was at least comparable to intensive symptom-guided therapy if not slightly better. By comparing natriuretic peptide–guided therapy to both intensive medical therapy and usual care, BATTLESCARRED added an additional dimension to the comparison. While the results of natriuretic peptide–guided therapy were comparable to intensive medical therapy, it was significantly better than usual care, which represents the most likely mode of therapy a typical heart failure patient would receive in the real world. In these “real world” patients, the intensive medical therapy described in the study may not be available due to lack of local expertise and limited resources, while biomarkers such as BNP or NT-proBNP are relatively cheap and easily assessable to the typical primary care physician. In these patients, natriuretic peptide–guided therapy may be an especially attractive alternative based on the results of these studies. It is also important to point out that biomarkers have the distinct advantage of objectivity and reproducibility, while symptom–guided therapy is very subjective and suffers from wide interphysician variability, which in real life practice may not reach the level of effectiveness demonstrated in these studies.
While the studies described above have shown promising results and sparked increasing interest in biomarker-guided therapy, a significant amount of work is still required to further define the role of biomarkers in guiding heart failure therapy. In addition, the current approach of using a single biomarker to guide therapy has significant limitations. Heart failure is a complex disease process, where dysfunctions in multiple physiologic processes are involved in its pathogenesis. As a result, a single biomarker is unlikely to be sufficient to guide its therapy. Thus, a combination of several biomarkers representing different pathophysiologic processes may be required in future biomarker-guided therapy trials. Finally, one also has to keep in mind that biomarker-guided therapy in heart failure is a nascent field. It has been limited to natriuretic peptides, which are the only well-studied biomarkers in heart failure to date. In recent years, significant efforts have been placed on the discovery and application of new biomarkers. Some of these emerging biomarkers include N-terminal pro-arginine vasopressin (copeptin), pro-adrenomedulin, neopterin, neutrophil gelatinase–associated lipocalin, high-sensitivity troponin, and midregional pro-atrial natriuretic peptide. What distinguishes these new biomarkers is the fact that they are markers of physiologic process not represented by existing biomarkers, offering glimpses into disease processes that are previously invisible to us. However, it is still too early to say what role these biomarkers will have in the management of heart failure patients. On the other hand, with these emerging biomarkers, a multimarker approach will be feasible in future biomarker-guided therapy trials. Biomarkers, with their advantage of objectivity, reproducibility, and accessibility will undoubtedly have a significant role in the future of guided heart failure management.