CONTROVERSAL QUESTION – Can biomarkers guide the assessment and management of heart failure patients after discharge from hospitals?

Can biomarkers guide the assessment and management of heart failure patients after discharge from hospitals?

1. E. A. Bocchi, Brazil
2. D. A. Brito, Portugal
3. O. Chioncel, Romania
4. A. Fong, Malaysia
5. M. Hülsmann, Austria
6. E. A. Jankowska,Poland
7. M. Loutfi, Egypt
8. A. Lupi, Italy
9. Y. F. M. Nosir, Egypt
10. E. B. Reyes, Philippines
11. S. N. Tereschenko, Russia
12. M. B. Yilmaz,Turkey
13. B. Yoo, Republic of Korea

1. E. A. Bocchi, Brazil

Edimar Alcides BOCCHI, MD, PhD
Associate Professor, Head of the Heart
Failure Department and Heart Failure Team
at InCor (São Paulo)
São Paulo University Medical School
SHIFT National Coordinator
Rua Dr Melo Alves 690, apto 41, São Paulo
BRAZIL CEP 01417-010

Epidemiological data have shown 39.4% of total hospital admissions to be related to decompensated heart failure (HF).1 Despite improvement during in-hospital treatment, HF patients frequently present with severe events after hospital discharge. It has been reported that over a period of 4.7±1.6 months, 36% of discharged decompensated HF patients were readmitted.2 In the EVEREST trial (Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan), of all rehospitalizations, 46.3% were for HF. This immediate postdischarge risk period has been termed the “vulnerable phase” of HF.

Early readmission of discharged patients with HF is challenging to predict. The focus has been primarily on quality improvement measures to assure patient education, checklist discharge, physician adherence to evidence-based HF medications, follow-up appointments within 7 to 14 days of discharge and/or telephone follow-up within 3 days of discharge, and use of clinical risk-prediction tools and/or biomarkers to identify higher-risk patients.3

It is important to recognize that many patients after discharge may be “flying under the radar,” without clinical congestion, but with elevated left ventricular filling pressures or comorbidities leading to a high risk of hospital readmission. Aside from residual clinical impairment with persistent signs and symptoms of congestion, biomarkers have been examined as potential predictors for HF readmission. Measurement of circulating natriuretic peptide (NP) levels seems to add incremental prognostic information to standard clinical risk stratification algorithms for both ambulatory and hospitalized HF patients, with a steady increase in the risk of mortality and recurrent HF hospitalization in relation to increment in NP levels.

Despite the widespread use of B-type NP (BNP) assays for diagnosis of HF, there remains a lack of well-defined and accepted diagnostic and prognostic cutoff values. Additionally, elevations in NP levels can occur as a result of several cardiac and noncardiac disease states, making the negative predictive value of the test most clinically helpful.

A plethora of candidate biomarkers now exist that reflect different aspects of HF pathology, with theoretical roles in diagnosis, risk assessment, and therapeutic tailoring, but data is still required from testing within clinical trials. Serum sodium, BNP levels, net reduction in N-terminal proBNP at discharge, creatinine, albumin, hemoglobin, C-reactive protein, troponin, systolic blood pressure, and heart rate seem to be predictive of 30-day readmission for HF.4 In the EVEREST trial, heart rate values ≥70 beats per minute (bpm) measured at either 1 or 4 weeks after discharge were independently associated with all-cause mortality, with a 13% increase in risk of death for every 5-beat increase in heart rate (P=0.002) measured at 1 week or 12% for such increase in heart rate (P=0.001) measured at 4 weeks. A discharge heart rate greater than 80 bpm was associated with greater risk of all-cause mortality during 1 year of follow-up and an elevated risk of 30-day readmission for HF.5 Reducing heart rate with ivabradine is beneficial in chronic HF, decreasing hospitalization and HF mortality.6

1. Bocchi EA, Guimarães G, Tarasoutshi F, Spina G, Mangini S, Bacal F. Cardiomyopathy, adult valve disease and heart failure in South America. Heart. 2008;95: 181-189.
2. Bocchi EA, Vilas-Boas F, Moreira Mda C, et al. Levosimendan in decompensated heart failure patients: efficacy in a Brazilian cohort. Results of the BELIEF study. Arq Bras Cardiol. 2008;90:182-190.
3. Bocchi EA, Cruz F, Guimarães G, et al. Long-term prospective, randomized, controlled study using repetitive education at six-month intervals and monitoring for adherence in heart failure outpatients: the REMADHE trial. Circ Heart Fail. 2008; 1:115-124.
4. Dunlay SM, Gheorghiade M, Reid KJ, et al. Critical elements of clinical follow-up after hospital discharge for heart failure: insights from the EVEREST trial. Eur J Heart Fail. 2010;12:367-374.
5. Habal MV, Liu PP, Austin PC, et al. Association of heart rate at hospital discharge with mortality and hospitalizations in patients with heart failure. Circ Heart Fail. 2014;7:12-20.
6. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.

2. D. A. Brito, Portugal

Dulce Alves BRITO, MD, PhD, FESC
Professor, Department of Cardiology
Hospital Universitário de Santa Maria
Lisbon Academic Medical Centre, CCUL
Av. Prof. Egas Moniz
1649-035 Lisboa

Most studies on biomarkers in heart failure (HF) report their prognostic value, but their use in clinical practice is not well established and should be based on clinical outcomes. Hospitalized HF patients have high postdischarge mortality and rehospitalization rates even when treated with evidence-based therapies and early postdischarge follow-up.1 The first 2 months after discharge are a particularly vulnerable period, with mortality and readmission rates approaching 15% and 30%, respectively, 30 to 60 days postdischarge; 1 in 4 patients are readmitted within 30 days.2 Recurrent HF and related cardiovascular conditions account for about half of readmissions and, overall, postdischarge readmission and mortality rates for HF remain similar whether ejection fraction (EF) is reduced or preserved. Measures to prevent early readmission or death must begin during hospitalization and extend through the early recovery period to reduce the risk of adverse events.

Some biomarkers, including low serum sodium and high aldosterone and natriuretic peptide (NP) levels, at admission and soon after discharge, help to predict early (within 90 days) readmission and death and to identify a subset of higher-risk patients that may benefit from specific targeted therapies.3 Congestion is the single most important contributor to readmission and a crucial target for therapy. Subclinical congestion (elevated left ventricular [LV] filling pressures in the absence of clinical manifestations) may precede clinical congestion by days to weeks or be present at discharge. Of the HF biomarkers, the B-type NPs—BNP and N-terminal proBNP—have been studied most. High levels of NPs at discharge reflect elevated LV filling pressures and correlate with readmissions in the early postdischarge period.3 NPs are thus useful as a marker for persistent congestion demanding further investigation and changes in diuretic dosing strategies.

Nevertheless, the role of NP levels in routine long-term HF monitoring is still under debate, though meta-analysis of published data suggests that NP-guided treatment as compared with intensive clinical management alone may indeed translate into better outcomes. In chronic HF patients (mainly with reduced EF) receiving optimized pharmacologic HF therapy, NP-guided treatment was associated with a significant and consistent benefit in HF-related hospitalization, the main morbidity outcome in HF patients across all age groups.4 A mortality benefit was also observed, but was confined to younger patients (<75 years of age).4

Overall, published studies tell us that individual tailoring of therapy in chronic HF, guided by NP measurements, allows better adjustment of recommended doses of drugs already proven to favorably affect prognosis. However, close followup by trained HF practitioners able to interpret, integrate, and react to peptide levels in the overall clinical context—particularly in the older (and more vulnerable) patient—may itself promote optimization of proven therapies and prevention of adverse outcomes, independently of biomarker use to guide HF therapy in the long term.5

Although NPs are the most extensively studied biomarkers in HF, several others provide important insights into different aspects of the pathophysiology of the syndrome. These others may provide additional prognostic information to that afforded by NPs and may also play a role in guiding treatment and be useful for therapy selection.6 Galectin-3 (Gal-3), a fibrosis biomarker, is one example, potentially allowing the identification of HF patients who may benefit from specific therapies. Although not yet proven, mineralocorticoid receptor antagonists (MRAs) may confer a greater benefit in HF patients with raised Gal-3 levels than in those with lower levels. MRAs favorably affect prognosis in HF, in both the long and short term, significantly reducing the early readmission rate for HF.

The evaluation of multimarker strategies to guide therapy or to provide a comprehensive understanding of how to select therapy would certainly contribute toward better outcomes in HF patients. ■

1. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol. 2013;61:391- 403.
2. Epstein AM, Jha AK, Orav EJ. The relationship between hospital admission rates and rehospitalizations. N Engl J Med. 2011;365:2287-2295.
3. Gheorghiade M, Pang PS, Ambrosy AP, et al. A comprehensive, longitudinal description of the in-hospital and post-discharge clinical, laboratory, and neurohormonal course of patients with heart failure who die or are re-hospitalized within 90 days: analysis from the EVEREST trial. Heart Fail Rev. 2012;17:485-509.
4. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J. 2014;35:1559- 1567.
5. Schlendorf KH, Kasper EK. Use of novel and conventional biomarkers for management of patients with heart failure. See comment in PubMed Commons. Curr Treat Options Cardiovasc Med. 2011;13:475-488.
6. Schmitter D, Cotter G, Voors AA. Clinical use of novel biomarkers in heart failure: towards personalized medicine. Heart Fail Rev. 2014;19:369-381.

3. O. Chioncel, Romania

University of Medicine Carol Davila
Institute of Emergency for Cardiovascular
Diseases “C.C. Iliescu,” Bucharest

Following hospitalization for heart failure (HF), patients are at a significantly increased risk for adverse outcomes, with mortality rates as high as 10% to 15% and rehospitalization rates up to 30% 3 months after discharge.1 Identifying high-risk patients following hospitalization is essential, given the opportunity to aggressively treat these patients and to improve their outcomes.

Biomarkers may help identify patients at increased risk for postdischarge adverse outcomes, and monitoring serial values in the outpatient setting may allow for early intervention aimed at reducing deaths and readmissions. Natriuretic peptides (NPs)—B-type NP and its N-terminal prohormone— are the most commonly used biomarkers with the potential to guide therapy. Plasma NP concentrations reflect cardiac structure and function and are prognostic in both acute and chronic HF.2 NP variations generally parallel responses to anti- HF therapies, and increasing concentrations are associated with poorer outcomes.2 Using NP levels to guide therapy is attractive, as it offers the possibility to individualize therapy according to an objective measure of function and risk. This strategy targets patients with high NP levels, at higher risk for adverse events, to receive higher doses of medications proven to increase survival.2

The concept of NP–guided HF therapy has been examined in recent trials.3-5 A majority of enrolled patients had a left ventricular ejection fraction (LVEF) under 45%, and patients with significant comorbidities were excluded. Although the trial results suggest a potential benefit in the NP-guided–therapy arm, improving all-cause mortality and decreasing HF-related readmissions, NP-guided care was ineffective in preventing noncardiovascular readmissions.3,4 The target-peptide concentrations, the time point of measurement, and the aggressiveness of therapy adjustment, which varied substantially across the trials, could contribute to the presence or absence of a benefit. Current trial data have shown the benefit of NPguided therapy to be confined to patients under 75 years old. However, with increasing age, a higher proportion of patients with HF will have a preserved LVEF (HFPEF) and multiple associated comorbidities. Although the latest published metaanalysis6 did not report an interaction with LVEF, it should be noted that only 10% of the patients had HFPEF at study enrollment. HFPEF has no pharmacotherapy proven to improve mortality rates and increasing doses of drugs that are ineffective is probably harmful. Although NP-guided therapy facilitates optimization of treatment and improves mortality and HF-related readmissions in selected patients, there are no convincing data to suggest that routine NP-guided therapy should be applied to all HF patients. Serial changes in NPs should be interpreted within the entire clinical context, including age, presence of comorbidities, and accounting for “intrinsic biologic variability.” Though well tolerated in the trial population, without excess risk of adverse outcomes related to therapy intensification,3,5 safety of NP-guided care should be considered in the broad HF population. NP-guided care appears to be cost effective by reducing HF hospitalization,7 but that should be confirmed in different health care systems.

Future research will be needed to clarify the type and magnitude of therapeutic response to the release of biomarkers. Most importantly, what should be done once patients at highest risk for postdischarge adverse events are identified? All advocated interventions—intensification of oral therapies, addition of intravenous medications, follow-up visits—are generic measures, and no supporting evidence has demonstrated any specific intervention to be more effective in lowering target NP levels. Secondly, what would be the most appropriate approach if NPs fail to decrease following intensification of therapy? Thirdly, despite decreasing NP levels, some patients may have other elements of high risk such as high troponin or high cystatin C.

In HF, a single biomarker reflects only one pathophysiological pathway. A multimarker panel investigating multiple pathological processes and probing therapeutic options would be an ideal strategy, but will need further investigation. ■

1. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol. 2009;53:557-573.
2. Richards AM, Troughton RW. Use of natriuretic peptides to guide and monitor heart failure therapy. Clin Chem. 2012;58:62-71.
3. Pfisterer M, Buser P, Rickli H, et al. 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. 2009;301:383-392.
4. Eurlings LW, van Pol PE, Kok WE, et al. 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. 2010;56:2090-2100.
5. Januzzi JL Jr, Rehman SU, Mohammed AA, et al. Use of amino-terminal pro–Btype natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction. J Am Coll Cardiol. 2011;58:1881-1889.
6. Troughton R, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J. 2014;35:1559-1567.
7. Adlbrecht C, Huelsmann M, Berger R, et al. Cost analysis and cost-effectiveness of NT-proBNP-guided heart failure specialist care in addition to home-based nurse care. Eur J Clin Invest. 2011;41:315-322.

4. A. Fong, Malaysia

Clinical Research Centre, Sarawak General
Jalan Hospital, 93586 Kuching, Sarawak

Even in the era of advanced therapeutics, hospital readmission rates for patients admitted with heart failure remain high. Approximately 22% of patients are readmitted within 30 days, and more than 50% are readmitted within 6 months.1,2 The cost of rehospitalization and the clinical morbidity associated with hospitalization generate demand for strategies to improve the management of patients discharged with heart failure. Heart failure clinics in the community have already made a positive impact on improving patient outcomes,3 but with rising numbers of patients being hospitalized with heart failure, quantifiable blood biomarkers are increasingly used to discriminate those at greatest risk of rehospitalization and cardiac death after discharge.

In the last decade, the principle biomarkers that have aided clinical decision making in patients with heart failure were the natriuretic peptides (NPs)—B-type NP (BNP) and N-terminal proBNP. In patients admitted with heart failure, NPs have been shown to be useful in identification of those at highest risk for rehospitalization.4,5 High NP levels, eg, a predischarge BNP level >700 ng/L has been associated with a death or readmission rate of approximately 50% 30 days postdischarge and roughly 80% at 6 months.

Conversely, a predischarge BNP level <350 ng/L was associated with a death or readmission rate of less than 5% 30 days postdischarge and <20% at 6 months. As NPs reflect the physiological status associated with myocardial strain, this information can enable clinicians to adapt the monitoring strategy accordingly, thus adopting a more aggressive strategy in those patients with the highest cardiac event risk in the outpatient clinic setting. NPs can now be reliably measured using validated point-of care devices. These can be placed in hospital wards or in the clinics, allowing the health care professional to obtain a timely result so that a management strategy can be more carefully constructed. In addition to the predischarge NP reading, serial monitoring of NPs provides clinicians with a “biochemical monitoring system” facilitating titration of treatment for heart failure patients. In this way, treatment can be optimized before patients experience decompensation and require subsequent hospital admission. Extending this concept further, a home monitoring program for natriuretic testing is now under investigation, although pilot studies showing encouraging results are already available.6

Of all blood biomarkers in clinical practice, the positive role of NP assessment in patients with heart failure is now clearly defined. The additional information it provides to both the health care provider and the patient empowers all parties to optimize the postdischarge management of heart failure patients. ■

1. Krumholz HM, Merrill AR, Schone EM, et al. Patterns of hospital performance in acute myocardial infarction and heart failure 30-day mortality and readmission. Circ Cardiovasc Qual Outcomes. 2009;2:407-413.
2. Chun S, Tu JV, Wijeysundera HC, et al. Lifetime analysis of hospitalizations and survival of patients newly admitted with heart failure. Circ Heart Fail. 2012;5(4): 414-421.
3. Ducharme A, Doyon O, White M, Rouleau JL, Brophy JM. Impact of care at a multidisciplinary congestive heart failure clinic: a randomized trial. CMAJ. 2005;173 (1):40-45.
4. Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol. 2004;43(4):635-641.
5. Salah K, Kok WE, Eurlings LW, et al. A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal pro- B-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ELAN-HF Score. Heart. 2014;100(2):115-125.
6. Maisel A, Barnard D, Jaski B, et al. Primary results of the HABIT Trial (heart failure assessment with BNP in the home). J Am Coll Cardiol. 2013;61(16):1726-1735.

5. M. Hülsmann, Austria

Univ-Dozent, Medical University of Vienna
Department of Cardiology
Währinger Gürtel 18-20
A-1090 Vienna

Patients admitted for decompensation are very heterogeneous in respect to underlying cause and to severity of disease. More importantly, in-hospital treatment success is a prerequisite of postdischarge outcome. Therefore, risk assessment at discharge is necessary for decision making in the vulnerable phase afterwards. In a time of limited economic resources, there are competing interests between care of high- and low-risk patients. Relatedly, length of hospital stay (LOS), which differs up to threefold between various countries, has already become an end point marker of treatment.1

Currently, LOS correlates neither with the severity of heart failure— reflected by N-terminal pro–B-type natriuretic peptide (NT-proBNP) at entrance—nor with postdischarge outcome, implying that the time of discharge might be more influenced by cost effectiveness than evidence. Thus, there is an imminent need to change LOS policy. NT-proBNP is an excellent surrogate for treatment success, especially in acute heart failure. Bettencourt and colleagues2 proved that NT-proBNP level over time is the most favorable variable to detect treatment success. Compared with a >30% decrease in NT-proBNP during hospital stay, there is a 6-fold increase in worse outcome if NT-proBNP increases more than 30%. These results show the importance of using NT-proBNP monitoring to guide treatment and, consecutively, hospital stay. If there is no significant decrease in NT-proBNP following intervention, treatment should be scrutinized as to the expense of hospital stay. On the other hand, a rapid decrease in NT-proBNP level allows a safe and rapid discharge. Consequently, an uncritical discharge policy influences postdischarge outcome and decreases the cost effectiveness of care, something that can be optimized by a biomarker-guided approach.

Predischarge stability can directly affect postdischarge management. After discharge, there is a need for optimization of oral therapy, which has to be done during postdischarge care. A multidisciplinary approach during this period could be attractive.3 Such an approach would include, in particular, an educational program, aside from intensified collaborative care by nurses and doctors. Just after discharge, patients and their families are open to self-care education, hoping to avoid rehospitalization. Data on the effectiveness of such programs are conflicting and appear to depend on duration of the program and severity of the disease. Predischarge NT-proBNP is directly correlated with postdischarge outcome.2 Thus, preselection of patients according to NT-proBNP level might be useful in this context, to identify those patients most likely to gain the greatest benefit. Biomarker-guided therapy is shown to be effective in various settings.4 Some studies did not prove efficacy, but meta-analysis was very “noisy.” Thus, data from an ongoing large, randomized trial by Felker et al (NCT01685840) are awaited for final answers. One of those studies combined a multidisciplinary approach and guided therapy in patients following discharge.5The investigator used NT-proBNP at discharge as a selection parameter to identify high-risk patients and used it to guide intensity of care and treatment during the following vulnerable phase. Depending on the NT-proBNP level, measured at discharge and over time, consultations by the nurse and by the heart failure specialist were initiated if the level remained elevated or, in the event of a low level at discharge, reduced. This strategy significantly reduced event rates compared with controls and with pure multidisciplinary care, but also had cost-saving effects despite increasing numbers of consultations and drug prescriptions.6 It appears that such a risk-selected treatment approach matches the right intervention to the right patient, thus avoiding under- and overtreatment.

In conclusion, NT-proBNP levels indicate the right moment for discharge following decompensation, which is crucial to further disease management. Furthermore, treatment guided by NT-proBNP levels can ensure the patient receives an appropriate intensity of care, which might save lives and money. ■

1. Mentz RJ, Cotter G, Cleland JG, Stevens SR, et al. International differences in clinical characteristics, management, and outcomes in acute heart failure patients: better short-term outcomes in patients enrolled in Eastern Europe and Russia in the PROTECT trial. Eur J Heart Fail. 2014;16(6):614-624.
2. Bettencourt P, Azevedo A, Pimenta J, et al. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation. 2004;110(15):2168-2174.
3. Sochalski J, Jaarsma T, Krumholz HM, et al. What works in chronic care management: the case of heart failure. Health Aff (Millwood). 2009;28(1):179-189.
4. Felker GM, Hasselblad V, Hernandez AF, O’Connor CM. Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am Heart J. 2009;158(3):422-430.
5. Berger R, Moertl D, Peter S, et al. 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. 2010;55(7):645-653.
6. Adlbrecht C, Huelsmann M, Berger R, et al. Cost analysis and cost-effectiveness of NT-proBNP-guided heart failure specialist care in addition to home-based nurse care. Eur J Clin Invest. 2011;41(3):315-322.

6. E. A. Jankowska, Poland

Laboratory of Applied Research on
Cardiovascular System, Department of
Heart Diseases, Wroclaw Medical University
Cardiology Department, Centre for
Heart Diseases, Military Hospital
Weigla 5, 50-981 Wroclaw

Recurrent hospitalization among patients with heart failure (HF) is unanimously considered the clinically crucial issue in both cardiovascular and general medicine today. Recent years have seen numerous attempts to develop optimally targeted treatment strategies aiming to relieve symptoms and improve in-hospital and long-term prognosis. Unfortunately, most have failed, providing no breakthrough in the management of acute HF.

Despite optimal treatment with life-saving drugs and devices, on discharge from hospitalization for circulatory decompensation, HF patients have an extremely high cardiovascular risk and are characterized by an enormous risk of recurrent hospitalization due to HF progression. Most importantly, the history of HF and related prognosis in these patients is very heterogeneous, and available diagnostic tools are imperfect with regard to precise individualized risk stratification.

Therefore, biomarkers have been put forward as potential additional, measurable (objective) indicators of clinical status and its dynamic changes in patients with acute HF.1,2 In this context, a comprehensive assessment (comprising clinical features and a set of biomarkers) performed after preliminary circulatory stabilization and directly before discharge is a particularly attractive concept.

For the last 20 years, biomarker research has garnered a huge amount of attention.1,2 The vast majority of related publications have concerned different aspects of the potential clinical applicability of various biomarkers in HF patients, including the natriuretic peptides (NPs) and numerous others.1,2 Along with the many publications in this field, a huge amount of scientific data on biomarkers in acute HF has been generated. Several biomarkers were shown to be related to HF severity and to predict short- and long-term outcomes; however, most of these papers provided no unequivocal and practically applicable evidence. Although the concept of the biomarker-guided diagnosis and treatment of patients with HF has been theoretically proposed, particularly for acute HF, there is as yet no hard evidence that any classical biomarker (including the NPs) can be used to guide future therapeutic decisions.

On the other hand, biomarkers allow diagnosis of some comorbidities. According to the European Society of Cardiology guidelines, active screening for comorbidities and their optimal treatment is crucial for patients with HF and could constitute an element of a comprehensive assessment before post decompensation discharge. For example, biomarkers of iron status allow diagnosis of iron deficiency (ID) and identify those who can be effectively supplemented. Of acute HF patients, 37% have ID, which unfavorably affects their 12-month survival3 and could constitute a potential therapeutic target.

Notably, the definition of a biomarker is somewhat open. For example, consider the following 2 approaches. According to the traditional, strict definition, a biomarker is a molecule measured in various samples (blood, urine, etc), which provides a certain specificity and sensitivity for the diagnosis of any pathology and/or for the prediction of a particular event, success/ failure in therapy, etc. However, from a broader perspective, a biomarker can be considered a measure of any quantifiable biological signal/sign.

In this context, a measure of body weight, blood pressure, or heart rate during circulatory decompensation, at discharge, and during follow-up potentially offers prognostic information, but could also be considered a therapeutic target. The prime example here could be resting heart rate. In a study of patients hospitalized for HF with a left ventricular ejection fraction ≤40% and who are not in atrial fibrillation/flutter or pacemaker dependent (participants of the EVEREST trial [Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan]), an increase in heart rate ≥70 beats per min in both 1- and 4-week postdischarge assessment was associated with increased all-cause mortality.4 In order to reverse this unfavorable phenomenon in such patients, it seems reasonable to consider pharmacological treatment to reduce resting heart rate during the early postdischarge phase using a β-blocker and/or ivabradine. ■

1. Troughton R, Michael Felker G, Januzzi JL Jr. Natriuretic peptide-guided heart failure management. Eur Heart J. 2014;35(1):16-24.
2. Ahmad T, Fiuzat M, Pencina MJ, et al. Charting a roadmap for heart failure biomarker studies. JACC Heart Fail. 2014;2(5):477-488.
3. Jankowska EA, Kasztura M, Sokolski M, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J. 2014;35(36):2468-2476.
4. Greene SJ, Vaduganathan M, Wilcox JE, et al; EVEREST Trial Investigators. The prognostic significance of heart rate in patients hospitalized for heart failure with reduced ejection fraction in sinus rhythm: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial. JACC Heart Fail. 2013;1(6):488-496.

7. M. Loutfi, Poland

Assistant Professor of Cardiology
Department of Cardiology
Faculty of Medicine
University of Alexandria

Heart failure (HF) is a chronic disease associated with a high symptom burden, and poor health status is common.1 Cardiac biomarkers, which are objective, reproducible, and accessible, are excellent adjuncts to physical examination and imaging studies in HF diagnosis and risk stratification. With a high prevalence of comorbidities associated with HF, an integrated approach utilizing multiple biomarkers has shown promise in better risk stratification, prediction of mortality, and reduction in rehospitalizations, thus lowering health care costs.

The number of biomarker studies in HF is exploding. Currently, among the available biomarkers, 5 could be used for assessment of HF prognosis, as single markers or clustered in a panel: B-type natriuretic peptide (BNP), N-terminal proBNP, (NT-proBNP), high-sensitivity cardiac troponin (hs-cTn), cystatin C, the tumor marker carbohydrate antigen 125 (CA125), and high-sensitivity C-reactive protein (hs-CRP).

BNPs provide independent prognostic information regarding estimated risk of disease progression, hospital readmission, and mortality.2 Bayes-Genis et al reported that among patients hospitalized with acute HF, those who experienced complications had a smaller percentage reduction in NT-proBNP during admission.2 Apart from the BNPs, hs-cTn assays will improve risk stratification in HF compared with conventional Tn tests. In patients with decompensated HF, serial increases in TnI during the course of hospitalization were associated with higher mortality than stable or decreasing TnI levels.3,4 Cystatin C, aside from its use in estimation of renal function, could also be used as a cardiac marker, as it reflects extracellular matrix pathology of ventricles.5 Recently, increased levels of serum CA125, a marker of congestion that indicates the degree of volume overload, have been documented in patients with HF.6 Finally, the biomarker hs-CRP can be used to evaluate progression of HF, due to the inflammatory etiology of the condition. Patients with acute HF and increased levels of both hs-CRP and NT-proBNP had worse clinical outcomes.7

It is possible that the combination of neurohumoral and inflammatory markers could provide a better strategy for risk stratification of patients with acute HF. Moreover, use of a single biomarker reflects only 1 ongoing pathophysiological pathway. The combination of biomarkers in a multimarker panel reflects several ongoing pathological processes, providing an increasingly clearer risk profile for HF patients.

Biomarkers not only serve as traditional predictors of prognosis, they can also help to identify high-risk patients who need closer monitoring and more aggressive therapy. An integrated approach utilizing multiple biomarkers has shown promise in predicting mortality, in risk stratification, and in reducing rehospitalizations, with subsequent improvement in the effectiveness of HF therapy and patient outcomes. ■

1. Heidenreich PA, Spertus JA, Jones PG, et al. Health status identifies heart failure outpatients at risk for hospitalization or death. J Am Coll Cardiol. 2006;47: 752-756.
2. Bayes-Genis A, Santalo-Bel M, Zapico-Muniz E, et al. N-terminal probrain natriuretic peptide (NT-proBNP) in the emergency diagnosis and in-hospital monitoring of patients with dyspnoea and ventricular dysfunction. Eur J Heart Fail. 2004;6:301-308.
3. Xue Y, Clopton P, Peacock WF, Maisel AS. Serial changes in high-sensitive troponin I predict outcome in patients with decompensated heart failure. Eur J Heart Fail. 2011;13:37-42.
4. Pascual-Figal DA, Manzano-Fernandez S, Boronat M, et al. Soluble ST2, highsensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure. Eur J Heart Fail. 2011;13:718-725.
5. Diez J. Altered degradation of extracellular matrix in myocardial remodelling: the growing role of cathepsins and cystatins. Cardiovasc Res. 2010;87:591-592.
6. Núñez F, Chorro FJ, Bodí V, et al. Clinical utility of antigen carbohydrate125 in heart failure. Heart Fail Rev. 2014;19(5):575-584.
7. Park JJ, Choi DJ, Yoon CH, et al. Prognostic value of C-reactive protein as an inflammatory and N-terminal probrain natriuretic peptide as a neurohumoral marker in acute heart failure (from the Korean Heart Failure Registry). Am J Cardiol. 2014;113(3):511-517.

8. A. Lupi, Italy

Alessandro LUPI,MD, FSCAI
Chief of the Hospital Cath Lab
“Maggiore della Carità” University Hospital
Cso Mazzini 18, 28100 Novara,

Heart failure (HF) is a clinically challenging syndrome, with different etiologies according to patient age and coexisting comorbidities. Such heterogeneity is associated with different HF stages, affecting patient prognosis and therapeutic response.1 However, diagnosis and prognostic stratification based purely on clinical features has shown limited accuracy, often accounting for suboptimal therapy and high rates of hospital readmission and mortality. Thus, the efforts of clinical researchers have been polarized toward the development of more reliable HF laboratory markers.

This research has profoundly benefited from increased knowledge in the pathophysiology of cardiac failure: myocyte derangement caused by oxidative stress, injury and apoptosis, inflammation, neurohumoral upregulation, and excessive proliferation of the extracellular matrix are phenomena that can all be tracked with a multitude of biomarkers. However, despite the recent hyperbolic increase in published studies on HF biomarkers, their actual clinical usefulness is still unclear, accounting for the need of convenient frameworks in which these markers might be used in a cost-effective manner.2

Among the numerous biomarkers proposed for guiding therapeutic optimization and postdischarge management of HF patients, only a few have been extensively studied and can currently be assessed with reasonable practicality. B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are by-products of the myocardial endocrine secretion of mediators in response to left ventricular dysfunction and mechanical stress. Increased levels of NPs at discharge have been associated with higher readmission rates for HF,3 thus measurement of such markers after clinical resolution of HF has been proposed for guidance of therapeutic optimization before and after discharge.

Guided therapy was addressed by a few nonrandomized studies that produced contrasting results. Moreover, these studies did not present enough statistical power to detect any significant difference in hard end points. To overcome these limitations, these studies were pooled into 2 metaanalyses, which suggested a mortality reduction in patients treated with NP-guided therapy (NP-GT),4,5 but no apparent reduction in rehospitalization rates.5

These results cannot be directly translated into daily clinical practice for several reasons. First of all, NP-GT studies preferentially enrolled patients with systolic dysfunction of ischemic origin, excluding HF cases with preserved ejection fraction and nonischemic cardiomyopathies. Moreover, different NP goals influenced the final results of NP-GT studies, with better outcomes in those aiming to lower NP levels. In many patients, NP levels did not respond to NP-GT, generally in subjects aged over 75 years. Actually, no randomized trial with sufficient statistical power using NP guidance in acute HF treatment has been published thus far and we currently do not have firm evidence from prospectively-defined published trials that the addition of NP-GT is beneficial.2 However, taking all the evidence into account, the American Heart Association (AHA)/American College of Cardiology (ACC) 2013 guidelines placed NP-GT in class 2a with a level of evidence B.6 From a practical point of view, it seems reasonable to routinely collect baseline and predischarge NP samples in hospitalized HF patients,with those showing a <30% reduction in NP level from baseline considered to be at higher risk of hospital readmission and thus treated with more aggressive management.2 Other available biomarkers, such as high-sensitivity C-reactive protein (hs-CRP), the tumor marker carbohydrate antigen 125 (CA125), and high-sensitivity cardiac troponins, are increased in HF patients, but their role in optimizing HF therapy and guiding hospital discharge seems to be limited. In conclusion, HF biomarkers could potentially guide therapy in HF patients after hospital discharge on an outpatient basis, but the few studies conducted in this area have conflicting results. A large, prospective, controlled study, statistically powered to look at hard end points such as mortality is warranted before the scientific community can reach any consensus on this approach. ■

1. von Scheidt W, Zugck C, Pauschinger M, et al. Characteristics, management modalities and outcome in chronic systolic heart failure patients treated in tertiary care centers: results from the EVIdence based TreAtment in Heart Failure (EVITA-HF) registry. Clin Res Cardiol. 2014;103:1006-1014.
2. Thygesen K, Mair J, Mueller C, et al. Recommendations for the use of natriuretic peptides in acute cardiac care: a position statement from the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Eur Heart J. 2012;33:2001-2006.
3. Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, Ferreira A. N-terminalpro- brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation. 2004;110:2168-2174.
4. Felker GM, Hasselblad V, Hernandez AF, O’Connor CM. Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am Heart J. 2009;158:422-430.
5. Porapakkham P, Porapakkham P, Zimmet H, Billah B, Krum H. B-type natriuretic peptide-guided heart failure therapy: a meta-analysis. Arch Intern Med. 2010; 170:507-514.
6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147-e239.

9. Y. F. M. Nosir, Egypt

Youssef Fathy Mohamed NOSIR
MD, MSc, PhD
Consultant Cardiologist KFAFH, Jeddah, KSA
Professor of Cardiology, Al-Azhar University
Cairo, EGYPT

Heart failure (HF) prevalence is increasing and remains the leading cause of death worldwide, causing a significant burden on health care systems across the globe. Currently, there is no reliable objective guide to optimal pharmacotherapy in HF. Despite clear treatment guidelines, target doses for medications are often not achieved. Clinical assessment is insensitive and frequently does not identify hemodynamic decompensation.

Biomarkers, with their objectivity and widespread availability, have a promising role in improving HF management. The natriuretic peptides (NPs) are the most widely used biomarkers of myocardial strain. These include B-type NP (BNP) and the N-terminal fragment of its prohormone (NT-proBNP), as well as atrial NP (ANP), and the mid-regional fragment of its prohormone (MR-proANP), and adrenomedullin.1 Cardiac troponin (cTn) levels and their assays (cTnI vs cTnT) have also been evaluated in ambulatory patients with stable coronary artery disease (CAD).2 In many studies, there is a >10-fold increase in the proportion of subjects with detectable cTn levels when utilizing a high sensitivity (hs) assay.2 In randomized controlled trials of statins and angiotensin-converting enzyme inhibitors versus placebo, NPs consistently and independently identified subjects with increased risk. The same was found true of cTnI and cTnT.2

Tailoring HF treatment to achieve a target level of BNP was first tested in the late 1990s.3 Since then, a series of studies using a variety of study designs have addressed this strategy.4 To date, there is little evidence to support using elevated levels of either NPs or cTns to guide therapy. It may be that no 1 biomarker fits all in this heterogeneous population with known CAD.2 However, plasma levels of both peptides reflect cardiac function and filling pressures and are powerful predictors of mortality.4

Serial peptide measurements provide incremental prognostic value in both the in- and outpatient setting, with a fall in peptide levels being associated with better outcomes.4-6 In the largest of these studies, TIMECHF (Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive HF), a higher NT-proBNP level was used as a target for subjects over 75 years of age (800 pg/mL) compared with those ages 60 to 74 years (400 pg/mL). Some significant clinical benefit was shown with biomarker-guided management, at least in younger patients.4

The PRIMA study (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?)5 looked at an individualized NT-proBNP target in 345 patients who had been hospitalized with decompensated HF. The target NT-proBNP level was ≤pg/mL. Additionally, subjects had to achieve a >10% decrease and at least a 850 pg/mL reduction in NT-proBNP during hospitalization. For the 174 subjects randomized to the NT-proBNP– guided group, an individualized target NT-proBNP level was identified based on the lowest NT-proBNP level obtained at discharge or within 2 weeks after discharge. Uptitration of treatment was triggered if the NT-proBNP level at scheduled 3-monthly visits was more than 10% and at least 850 pg/mL above their individual baseline level. For the 171 subjects in the comparator clinically guided group, treatment was uptitrated on the basis of standard clinical assessment. After a median follow-up of 702 days, there was greater uptitration of treatment in the NT-proBNP–guided group at 1-year follow-up. The investigators observed fewer deaths in the NT-proBNP– guided group, particularly in patients under 75 years of age and in those with reduced ejection fraction below 45%.5,6

Currently available data showed usefulness of biomarkers in HF management through achieving target dosage of medication with a trend in reducing mortality. Further data are needed from more robust, adequately powered trials before guidelines can confidently endorse a biomarker-guided strategy in HF management. ■

1. Lenzen MJ, Boersma E, Reimer WJ, et al. Under-utilization of evidence-based drug treatment in patients with heart failure is only partially explained by dissimilarity to patients enrolled in landmark trials: a report from the Euro Heart Survey on Heart Failure. Eur Heart J. 2005;26:2706-2713.
2. Beatty AL, Ku IA, Christenson RH, DeFilippi CR, Schiller NB, Whooley MA. Highsensitivity cardiac troponin T levels and secondary events in outpatients with coronary heart disease from the Heart and Soul Study. JAMA Intern Med. 2013;173: 763-769.
3. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000;355:1126-1130.
4. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIMECHF) randomized trial. JAMA. 2009;301: 383-392.
5. Eurlings LW, van Pol PE, Kok WE, et al. 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. 2010;56:2090-2100.
6. Rogers RK, Stoddard GJ, Greene T, et al. Usefulness of adjusting for clinical covariates to improve the ability of B-type natriuretic peptide to distinguish cardiac from noncardiac dyspnea. Am J Cardiol. 2009;104:689-694.

10. E. B. Reyes, Philippines

Eugenio Borja REYES,MD
Associate Professor
Department of Medicine
University of the Philippines College
of Medicine
Taft Avenue, Manila, 1000

Heart failure (HF) is a syndrome with a wide spectrum of clinical manifestations: from asymptomatic to full blown congestive failure; from normal ejection fraction (EF), ie, HF with preserved EF (HFPEF), to very low EF, ie, heart failure with reduced EF (HFREF); from acute onset to gradual onset and chronic conditions. Etiologies and comorbidities are also diverse, and there can be puzzling differences in response to therapies.

At the end of the spectrum is severe symptomatic systolic HF, which is quite easy to diagnose and prognosticate, with clinical assessment as a key basis for choosing diagnostics and treatment. However, gray zones are found in mild disease (New York Heart Association functional classes I or II), in HFPEF, and in treated patients who have stabilized and are feeling better after discharge.1

Left ventricular EF (LVEF), is a useful parameter in assessing LV pump performance, especially now that echocardiography is readily accessible. When LVEF is reduced (<45%), it is a powerful and useful prognostic and monitoring parameter.1 However, LVEF plateaus over time and has limited utility in HFPEF.

In the last 2 decades, an explosion in research paved the way to the use of biomarkers as clinical guidance in the management for HF—an example of knowledge translation from clinical evidence to patient care—to close the gap emanating from the limitations of using pure clinical assessment in making therapeutic decisions.2 One such gap is the low utilization of guideline-directed therapy to optimize patient care, which may be due to low awareness or competence in applying such therapy.

Biomarkers for HF include markers for myocyte stretch (eg, Btype natriuretic peptide [BNP] and atrial NP), myocyte remodeling (eg, ST2 protein and galactin), inflammation (eg, interleukin 6 and Fas), neurohormonal activation (eg, endothelin), and comorbidities (eg, procalcitonin for infection, and neutrophil gelatinase-associated lipocalin for kidney failure).2 All of these are elevated in clinical HF and can define the presence of HF or other diseases that may mimic HF. The best studied markers are BNP and N-terminal proBNP.

There are at least 11 randomized controlled studies that compared NP-guided therapy vs therapy guided by pure clinical assessment.3 The studies were all small (ranging from 69 to 499 included patients) and results of individual trials, though positive, were not convincing. A meta-analysis showed that the hazard ratio for total mortality was 0.82 (95% confidence interval [CI], 0.62-1.00), with the CI touching the line of unity. However, the hazard ratio for rehospitalization was reduced significantly by 26% (0.74; 95% CI, 0.60-0.90). This reduction could be attributed to a 7% absolute increase in the proportion of patients who received target doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (41% vs 34%), a 2% increase in those that received target-dose aldosterone antagonists (28% vs 26%), and no difference for β-blockers (19% vs 19%) and loop diuretics in patients under NP-guided treatment.3

Clearly, biomarker-guided therapy in HF is possible, but the findings from randomized trials are not convincing enough to recommend its routine use. Its weakness lies in the fact that it does not tell you which medications to adjust and so we go back to clinical assessment. Furthermore, NP testing is costly and target levels and frequency of testing have not been standardized. The latest guidelines on HF recommend the use of biomarkers for risk stratification. The recommendations on the use of biomarkers as a guide in maximizing medical therapy are weak, but do not prohibit physicians from using them as guides.4,5 A large randomized trial is needed to address this gap. ■

1. De Keulenaer GW, Brutsaert DL. The heart failure spectrum: time for a phenotype- oriented approach. Circulation. 2009;119(24):3044-3046.
2. Iqbal N, Wentworth B, Choudhary R, et al. Cardiac biomarkers: new tools for heart failure management. Cardiovasc Diagn Ther. 2012;2(2):147-164.
3. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J. 2014;35(23): 1559-1567.
4. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/ AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.
5. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur Heart J. 2012;33:1787-1847.

11. S. N. Tereschenko, Russia

Sergey Nikolaevich TERESCHENKO,MD
Chief of Heart Failure Department
Tretya Cherepkovskaya ul. 15a
Research Institute for Clinical Cardiology
named after A. L. Myasnikov
Russian Cardiology Research and
Production Complex
121552 Moscow, RUSSIA

Today, maximum personalization of risk assessment in heart failure (HF) patients is important in order to identify those most vulnerable, in whom intensified therapeutic approach is the most warranted. To this end, great attention is paid to biomarkers.

To date, the B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are among the most studied biomarkers. An increased level of NP is directly associated with hemodynamic stress. In HF, a high NP level at hospital discharge is an independent marker of poor prognosis (death and HF decompensation).

The significance of NPs for risk stratification in HF patients has been shown in both inpatients and outpatients. These biomarkers represent a “gold standard” in prognostic evaluation. According to Val-HeFT (the Valsartan in Heart Failure Trial), the cutoff values for BNP and NT-proBNP in stable HF patients are 125 pg/mL and 1000 pg/mL, respectively.1 More prognostic information can be obtained by serial measurements. In general, a reduction in NP levels below a specified value predicts fewer hospital admissions or reduced mortality risk. According to a study by Doust et al, each 100 pg/mL increase in BNP level is associated with a 35% increase in mortality risk.2

A study by Berger et al3 included 278 patients with decompensated HF, who were randomized at discharge using the NT-proBNP cutoff value of >2200 pg/mL into 3 groups: (i) personalized treatment (with NT-proBNP level reduction below 2200 pg/mL), (ii) intensive patient management using the multidisciplinary care (MC) approach, and (iii) conventional treatment. Once the target NT-proBNP level was achieved, patients were treated according to standards of the MC group. However, in case of an increase in NT-proBNP level, patients received NP-guided treatment. Main end points included HF hospitalization, time to death or HF rehospitalization, time to first HF rehospitalisation, and death. During follow-up, the NPguided group received more aggressive therapy than the other 2 groups: a higher proportion of patients were on triple therapy, and doses were ≥50% of target doses. As a result, this group showed the greatest reduction in NT-proBNP level by the end of follow-up. In general, these patients remained clinically more stable throughout the study and had significantly fewer days of hospitalization due to decompensated HF (P=0.0001). Moreover, with the NP-guided approach, risk of the combined end point of death/HF rehospitalization at 18 months was reduced by 37% (vs 50% in the MC group and 65% in the conventional treatment group; P<0.05). The mortality rate in the NP-guided group was the same as in the MC group (22%) and was significantly lower than in the conventional treatment group (39%; P=0.02).

This study is of extreme value. It is well known that HF patients with persistently high NP concentrations at discharge after hospitalization due to decompensated HF have a higher risk of death and HF rehospitalization. Thus, these patients require a particular approach to treatment and control that presupposes, among other things, the reduction in NP level as a result of successful therapy.

Limiting factors include the relatively low stability of the BNP molecule, biological variability, a large “gray zone,” as well as the influence of age, sex, and body weight. Comorbidities can cause mistaken risk stratification of HF patients. In this regard, a multimarker strategy (with copeptin, galectin-3, MR-proadrenomedullin, soluble ST2 receptor, high-sensitivity [hs]-troponin, etc) is attractive, due to potential for better risk stratification of HF patients.

Will these multimarker panels have a real advantage? Will the predictive value from a combination of markers exceed that obtained from each individually and to what extent? How many markers are required, and what combination is optimal for prognostic assessment in HF patients? Nowadays, there are still many more questions than answers. ■

1. Masson S, Latini R, Anand IS, et al; Val-HeFT Investigators. Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Heart Failure (Val-HeFT) data. Clin Chem. 2006;52:1528-1538.
2. Doust JA, Pietrzak E, Dobson A, et al. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ. 2005;330:625.
3. Berger R, Moertl D, et al. N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure. J Am Coll Cardiol. 2010;55:645-653.

12. M. B. Yilmaz, Turkey

Sergey Mehmet Birhan Yilmaz,MD, FESC
Professor, Cumhuriyet University
Faculty of Medicine
Department of Cardiology
Sivas, 58140

Can biomarkers guide the assessment and management of heart failure patients after discharge from hospitals? In the presence of an ideal biomarker, the answer would be “Yes, they can.” What is a biomarker? A biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”1 Hence, anything could be a biomarker. However, in the clinical sense, measurement of a biomarker usually refers to a simple blood or urine test in most cases. Biomarkers could be used in diagnosis, prognostication, monitoring of a therapeutic response, stratification and also for some other reasons.

Heart failure (HF) is a complex, fatal disease, characterized by 2 overlapping subtypes, ie, acute and chronic HF.2 Acute HF represents a major challenge both to the physician and to the hospital and has a high risk of mortality and morbidity in the short term. Patients hospitalized for an attack of acute HF enter a vulnerable period after hospital discharge, during which many patients need close follow-up management.3 After discharge, biomarkers can be used to guide physicians. For example, choice of therapy is already guided by “safety” biomarkers, such as creatinine or potassium, as in the case of mineralocorticoid-receptor antagonist therapy.

With regard to biomarkers in HF, considerable progress has already been made. Natriuretic peptides (NPs), as quantitative biomarkers of ventricular and/or atrial loading, can serve as “near-perfect” biomarkers in the diagnosis of HF. Nevertheless, their performance in daily practice is limited4 despite recent efforts and well controlled studies (eg, GUIDE-IT [GUIDing Evidence based therapy using biomarker Intensified Treatment in heart failure]). First of all, quantitation of NPs is limited by test accuracy.5 Secondly, though a decrease/increase in NPs is linked to improvement/progression of the disease, there is considerable room for biological variation, particularly in patients with mild disease or in patients with recent acute HF.6 Thirdly, an ideal biomarker should either be disease specific or organ specific. However, there is a sizeable list of reasons that lead to elevation of NPs in the absence of HF.7 Furthermore, right ventricular function, independent from left ventricular function, adds complexity to the interpretation of elevated NPs. Last, but not least, in order for information from a biomarker to be meaningful, it should not overlap significantly with otherwise obtained basic clinical information. In the case of NPs, they may provide additional information which is useful for diagnostic purposes; however, their use in guiding therapy during follow-up has not been well established.

In conclusion, there is an unmet need for a biomarker that can help physicians tailor therapy of HF patients after discharge. Despite progress in this area, there are obstacles to overcome before integrating biomarkers into clinical decision making in the HF setting. ■

1. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69(3):89-95.
2. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.
3. Metra M, Gheorghiade M, Bonow RO, Dei Cas L. Postdischarge assessment after a heart failure hospitalization: the next step forward. Circulation. 2010;122 (18):1782-1785.
4. Savarese G, Trimarco B, Dellegrottaglie S, et al. Natriuretic peptide guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials. PloS One. 2013;8:e58287.
5. Morrow DA, Cook NR. Determining decision limits for new biomarkers: clinical and statistical considerations. Clin Chem. 2011;57:1-3
6. Wu AH, Smith A. Biological variation of the natriuretic peptides and their role in monitoring patients with heart failure. Eur J Heart Fail. 2004;6(3):355-358.
7. Zakynthinos E, Kiropoulos T, Gourgoulianis K, Filippatos G. Diagnostic and prognostic impact of brain natriuretic peptide in cardiac and noncardiac diseases. Heart Lung. 2008;37(4):275-285.

13. B. Yoo, Republic of Korea

ByungSu YOO,MD, PhD
Professor, Chief of Cardiology Division
Department of Internal Medicine
Wonju College of Medicine
Yonsei University
Wonju, 220-701

Recently, natriuretic peptide (NP) measurements after discharge from hospital have been used to provide incremental information over clinical presentation or as an end point to assess the efficacy of heart failure therapy, and as a prognostic marker in heart failure.1 However, although commercial assays are currently approved for diagnosis of heart failure, use of NPs in monitoring the success of congestive heart failure (CHF) therapy or as a therapeutic target in heart failure has not as yet been submitted for regulatory approval.2

The first question is whether B-type NP (BNP) or N-terminal proBNP (NT-proBNP) can be a treatment target in HF management. BNP levels correlate positively with cardiac filling pressures and volumes and are inversely related to left ventricular ejection fraction. After treatment, recovery of neurohormonal balance means stabilization of HF status. BNP in follow-up of heart failure patients was considered as a “biochemical Swan-Ganz catheter,” such as glycated hemoglobin (HbA1c ) in patients with diabetes mellitus or alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma. Because BNP levels correlate with atrial and ventricular filling pressures, it is reasonable to ask whether changes in BNP mirror the effectiveness of therapies designed to reduce filling pressures. Therefore, it is possible to accept BNP or NT-proBNP as a good target for treatment of heart failure, one that is objective, reliable, practical, and inexpensive.1

The second question is how results of serial measurements of BNP or NT-proBNP should be interpreted in the outpatient clinic. In the Val-HeFT study (Valsartan in Heart Failure Trial), high baseline values of BNP were related to high mortality, and after 4 months, patients with a large reduction (% change) in BNP had a relatively lower risk than other groups.3 In the outpatient setting, symptoms that suggest early decompensation and a rising BNP level should trigger either a clinic visit or diuretic adjustment. BNP level measured in the outpatient clinic may be a reliable monitoring marker, taking into consideration the following advantages: results are obtained quickly, it is not affected by eating or exercise, it facilitates diuretic adjustment early after discharge, and it reflects exacerbation or success of treatment.1

The final question is about BNP- or NT-proBNP–guided therapy in HF. The dynamic nature of BNP and NT-proBNP relative to therapeutic intervention in HF has led to the concept of using the biomarkers as a “guide” for intensification of HF care. The aim would be not only to achieve guideline-directed medical therapy goals, but to target NP itself, suppressing it below prognostic thresholds.4 During the last decade or more, the concept of biomarker-guided management of HF based on NP targets has been an intriguing and controversial topic.2 Nevertheless, in certain studies of this BNP- or NT-proBNP–guided approach, patients treated with biomarker- guided care had superior outcomes when compared with standard heart failure management alone. This was the case particularly in younger study populations, in patients with left ventricular systolic dysfunction, and when substantial reductions in NPs were achieved in association with biomarker guided care.1

BNP and NT-proBNP can provide significant prognostic information and it is possible that adjustment of anti–heart failure therapy according to serial measurements of BNP (in addition to standard clinical assessment) may lead to improved outcomes.4 However, randomized controlled trials have yielded inconsistent results. A better understanding of unresolved issues, including test variation, cutoff values, acceptable times for check-up, and cost effectiveness is needed before we can effectively use this valuable test in the clinical setting. ■

1. Troughton R, Michael Felker G, Januzzi JL Jr. Natriuretic peptide-guided heart failure management. Eur Heart J. 2014;35:16-24.
2. De Vecchis R, Esposito C, Cantatrione S. Natriuretic peptide-guided therapy: further research required for still-unresolved issues. Herz. 2013;38:618-628.
3. 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. 2003;107:1278-1283.
4. Writing Committee Members. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:e240-e327.