Cardiac biomarkers that reflect myocardial stretch, injury, and remodeling have been recognized for their potential to aid in the diagnosis, prognosis, risk stratification, and management of heart failure (HF).1 Specifically, these biomarkers (see Table) have 3 key utilities: (1) to assess the diagnosis of patients presenting to the emergency department (ED) and primary care settings with nonspecific symptoms; (2) to establish disease prognosis and severity based on biomarker levels; and (3) to screen patients with risk factors for HF to determine appropriate interventions for the prevention of disease development.1–16 Thus, these biomarkers are a valuable tool, contributing to the objective, noninvasive, and clinical assessment of patients with HF.17
The significance of these biomarkers has been underscored by recommendations in the joint American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) clinical practice guidelines for the management of HF18 and in the 2017 American College of Cardiology (ACC)/AHA/Heart Failure Society of America (HFSA) update.1 Specifically, measurements of B-type natriuretic peptide (BNP) and the N-terminal proBNP (NT-proBNP) are recommended in the ambulatory setting and upon admission in hospitalized patients with acute HF to support or exclude the diagnosis of HF and to determine the prognosis or severity of HF. In addition, measurement of these natriuretic peptides (NPs) can be performed in hospitalized patients before discharge for prognosis; they can also be used to prevent HF by screening patients at risk and subsequently providing team-based care. As a result of inconsistent evidence for the improvement of clinical outcomes, specific recommendations cannot be made at this time regarding the use of NPs to guide therapeutic management. Notably, the type of NP assay used and the potential impact of HF medications must be taken into consideration when interpreting concentrations.1
Biomarkers that reflect myocardial injury, including cardiac troponin T (cTnT), cTnI, high-sensitivity (hs)-cTnT, and high-sensitivity cardiac troponin I (hs-cTnI), are also recommended in the ACCF/AHA guidelines and in the ACC/AHA/HFSA 2017 update for additive risk stratification in ambulatory patients with chronic HF.1,18 In addition, measurements of biomarkers that reflect myocardial fibrosis, such as soluble suppression of tumorigenicity 2 (ST2) and galectin-3, are recommended for additive risk stratification in ambulatory patients.1,18 Although not part of the ACC/AHA/HFSA recommendations, assessing atrial NP17 and C-type NP19 may also be useful for HF management.
This review will provide information on the use of the ACC/AHA/HFSA guideline–recommended biomarkers in HF. A patient case study is included to illustrate the clinical applications of these biomarkers. As biomarker levels may be influenced by factors other than HF itself, such as patient characteristics, comorbidities, and HF therapies, the effects of these aspects will also be discussed.
APPLICATION OF BIOMARKERS TO AID IN DIAGNOSIS, PROGNOSIS, AND RISK STRATIFICATION
Acute HF cannot be diagnosed accurately with the use of routine laboratory tests, and the typical signs of acute HF (ie, dyspnea, congestion, peripheral edema, hepatojugular reflux, and jugular venous distension) overlap with those of other conditions, impeding the clinician’s ability to achieve an accurate diagnosis.20 Although the ACCF/AHA guidelines include the recommendation that patients with suspected HF, acute HF, or new-onset HF should receive a chest x-ray,18 up to 20% of patients with acute HF will not show congestion.20 As illustrated in the Patient Encounter below, measurements of biomarkers are particularly useful in uncertain situations in which a chest x-ray does not confirm a suspicion of HF as suggested by medical history and symptoms.
Patient Encounter No 1
A 68-year-old white, male retired construction worker presented to the ED, complaining of dyspnea and fatigue for the past week that seemed to have worsened within the past few hours prior to arrival. His medical history included hypertension and a myocardial infarction (MI) 2 years prior. His blood pressure was 146/86 mm Hg, and his heart rate was 80 beats per minute. His medications included 50 mg of atenolol daily, 81 mg of aspirin daily, and 20 mg of atorvastatin at bedtime. Findings from the chest x-ray revealed no congestion. Biomarker tests indicative of HF were ordered, and the patient’s BNP level was 775 pg/mL. This was much higher than the normal level of <100 pg/mL, which supported a suspicion of HF. Well above the assay cutoff point of 14 ng/L, his hs-cTnT level was 22 ng/L, which was suggestive of myocardial injury.
BNP and NT-proBNP
BNP is a 32-amino acid protein that is released from the ventricle in response to cardiac chamber wall stretch that results from volume overload.4 It mediates natriuresis, diuresis, vasodilation, and smooth-muscle relaxation.4 BNP levels are low under normal conditions21; however, in HF, BNP levels increase as a compensatory mechanism to promote the restoration of fluid balance and systemic hemodynamics.4 BNP levels also play a counterregulatory role by antagonizing the overactivation of the renin–angiotensin–aldosterone system, the sympathetic nervous system, and endothelin-1.4 BNP is inactivated by an endopeptidase known as neprilysin, which is primarily concentrated in the kidneys, but can also be found in other tissues.22 Because of increasing degradation by neprilysin and loss of its effectiveness with HF progression, BNP cannot adequately compensate for the overactivation of other neurohormonal factors in the presence of HF.4
Instead of measuring BNP levels, some institutions measure NT-proBNP, which is the biologically inactive 76-amino acid N-terminal fragment produced from the proteolytic cleavage of the precursor prohormone of BNP, proBNP.4,23 The value of BNP and NT-proBNP as biomarkers in HF is well established.17,23 Compared with traditional HF assessment methods, biomarkers are not limited by costly subjective interpretation or invasive measurement, requiring only a blood sample.24 The half-life of BNP is approximately 20 minutes and that of NT-proBNP is approximately 120 minutes, which explains why NT-proBNP values are roughly 6 times higher than BNP values.21 Furthermore, biomarker stability varies with storage conditions, which affects the quality of laboratory results.25
Using BNP and NT-proBNP measurements can provide high diagnostic accuracy and can assist with excluding other diagnoses; when levels of BNP and NT-proBNP are low, they can be used to exclude HF (Figure 1).1,26,27 Unlike BNP, NT-proBNP is not a substrate for neprilysin; therefore, its concentration is not affected by changes in neprilysin enzymatic activity.23 In the Breathing Not Properly Multinational Study, a prospective study performed at 5 sites in the United States and 2 sites in Europe, the impact of BNP testing on the evaluation of acute dyspnea was evaluated by measuring the BNP levels of 1586 patients presenting to the ED with dyspnea.3 Patient diagnoses were made by physicians who were blinded to the results of the BNP measurements. The patients were classified as having dyspnea due to congestive HF (n = 744; 47%), dyspnea due to noncardiac causes (with a history of left ventricular (LV) dysfunction [n = 72; 5%]), and no congestive HF (n = 770; 49%).2 Comparing the mean BNP levels in each group revealed that those in the congestive HF group had significantly higher levels than those in the other 2 groups (P < 0.001).2 Results also suggested that BNP levels increased with New York Heart Association (NYHA) functional class.2 It was determined that a BNP cutoff value of 100 pg/mL had 83% accuracy for the diagnosis of acute HF in this population, which was more accurate than the National Health and Nutrition Examination Survey (NHANES) criteria (67%), the Framingham diagnostic criteria (73%),2 or clinical judgment (74%).3
The ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study was a prospective, single-site study that compared the value of NT-proBNP levels with clinical assessment for the diagnosis of acute HF in 599 patients presenting to the ED with dyspnea.5 The study design and findings were similar to those of the Breathing Not Properly Study. Clinical diagnoses were categorized as acute HF (n = 209; 35%) or not acute HF (n = 390; 65%).5 When the mean NT-proBNP levels in each of these groups were compared, those with acute HF had significantly higher levels than those without acute HF (P < 0.001).5 In addition, NT-proBNP levels increased with NYHA functional class.5 The optimal cutoffs for ruling in acute HF were 450 and 900 pg/mL for patients aged <50 and ≥50 years, respectively, and the use of NT-proBNP alone was superior to clinician estimation alone.5 In the International Collaborative of NT-proBNP (ICON) Study, a multicenter pooled analysis of studies (including the PRIDE study) containing 1256 patients with a clinical diagnosis of acute HF (n = 720; 57%) and without acute HF (n = 536; 43%), findings confirmed the value of NT-proBNP levels in the diagnosis and exclusion of acute HF and their relationship with NYHA functional class.28
Measuring BNP and NT-proBNP levels is also useful for dynamic risk stratification in HF, as changes in serum concentrations are significant predictors of clinical outcome. An analysis of the PRIDE study found that a higher NT-proBNP level was the strongest independent risk factor for mortality within 60 days of presentation (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.2–2.0),29 and a concentration of NT-proBNP >986 pg/mL at presentation to the ED was the single strongest predictor of mortality by 1 year (HR, 2.88; 95% CI, 1.64–5.06).30 The ICON study analyses also showed that NT-proBNP values were informative in the short-term estimation of mortality risk in acute HF. Patients presenting with NT-proBNP values >5180 pg/mL had a 5.2-fold increased risk for death by 76 days compared with those presenting with lower values.28 In an analysis of the Acute Decompensated Heart Failure National Registry (ADHERE; NCT00366639), in 48,629 patients with BNP levels measured within 24 hours of presentation, BNP values ≥1730 pg/mL were associated with a 2.23-fold increase of in-hospital mortality compared with values <430 pg/mL.31 In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF; NCT00344513) registry, in 7039 patients aged ≥65 years, BNP concentrations at discharge—compared to admission—were most predictive of 1-year mortality (HR, 1.34; 95% CI, 1.28–1.40) and second-most predictive (after history of chronic obstructive pulmonary disease) of 1-year death or rehospitalization (HR, 1.15; 95% CI, 1.12–1.18).32 An analysis of data from the Veterans Affairs Health Care System for more than 50,000 veterans hospitalized with a primary diagnosis of HF revealed a correlation between BNP levels and readmission for HF. In this study, 30-day HF readmission was associated with elevated discharge BNP levels, elevated admission BNP levels, and smaller percentage change in BNP level from admission to discharge. Patients with admission or discharge BNP levels ≥1000 pg/mL were 2 to 3 times more likely to be readmitted for HF within 30 days than patients with admission or discharge BNP levels <200 pg/mL.33
In addition to risk stratification in patients given a diagnosis of HF, the measurement of NPs may be used as a screening method to identify patients at high risk of developing LV dysfunction.1 When followed by multidisciplinary HF management for patients identified as high risk, it is possible that HF may be effectively prevented.1 The St. Vincent’s Screening to Prevent HF (STOP-HF; NCT00921960) randomized trial assessed the efficacy of a screening program using BNP measurements and subsequent collaborative care for the prevention of the development of HF and LV dysfunction in 1374 patients.34 Compared with patients treated with routine primary care physician management, patients who received collaborative HF management based on screening BNP concentrations were less likely to develop LV dysfunction and HF (odds ratio, 0.55; 95% CI, 0.37–0.82; P = 0.003),34 supporting the recommendation that assessment of NP levels may be useful for disease prevention.1
cTnI or cTnT
In the prior Patient Encounter, the patient’s hs-cTnT level was elevated at 12 ng/L, which is suggestive of myocardial injury.9 Troponins are proteins involved in the contraction of striated muscle.9 cTn exists as a complex of proteins that includes TnI, TnT, and troponin C (TnC).9 Elevated levels of cTnI and cTnT specifically reflect myocardial injury because they are not expressed in skeletal muscle; consequently, these biomarkers are highly sensitive.9,10 To determine the underlying cause of the injury, further diagnostic tests in combination with other assessments (eg, patient history, physical examination, electrocardiography) are required.35 Elevations in cTn levels may result from various mechanisms—such as oxidative stress, increased wall stress (such as in worsening HF), epicardial coronary artery disease, neurohormonal activation, inflammatory cytokines, and altered calcium handling—which may lead to reversible injury, myocyte necrosis, troponin degradation, and myocyte apoptosis (ie, programmed cell death).9
Elevated cTn levels are associated with worse outcomes in HF. In the ADHERE Registry, 4240 (6.2%) hospitalized HF patients positive for troponins, as measured by elevated cTnI (≥1000 ng/L) or cTnT (≥100 ng/L), required more cardiac procedures and had a longer duration of hospitalization compared with the 63,684 patients who were troponin negative (P < 0.001).6 Tn-positive patients had a significantly higher rate of in-hospital mortality compared with Tn-negative patients (8% vs 2.7%, respectively; P < 0.001), with an adjusted odds ratio of 2.55 (95% CI, 2.24–2.89; P < 0.001).6 In the ICON study, among the 720 patients given a diagnosis of acute HF, a cTnT level >30 ng/L was identified as a significant independent predictor for 76-day mortality (odds ratio, 3.4; 95% CI, 1.6–5.2).28 In the Valsartan Heart Failure Trial (Val-HeFT), which was performed in 4053 patients with chronic HF, hs-cTnT levels were detected in 92% of patients, and increasing concentrations were associated with an increased risk for mortality (HR for baseline +50 ng/L, 1.2; 95% CI, 1.1–1.3) and hospitalization (HR for baseline +50 ng/L, 1.1; 95% CI, 1.0–1.2).36 Ambulatory patients with chronic HF whose levels of hs-cTnT increased over 3–4 months had the highest risk of all-cause mortality in Val-HeFT (HR, 1.59; 95% CI, 1.39–1.82)36 and in another large trial (N=1231), the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca–Heart Failure (GISSI-HF) trial (HR, 1.88; 95% CI, 1.50–2.35).37
The Cardiovascular Health Study (CHS; NCT00005133) was a prospective observational cohort study of older adults (aged ≥65 years) without HF who had low levels of biomarkers at baseline (N=2008). In this study, the 123 individuals who experienced significant increases in both cTnT and NT-proBNP levels in a 10-year period had an adjusted relative risk (RR) of 3.56 (95% CI, 2.56–4.97) for incident HF and 2.98 (95% CI 2.09–4.26) for cardiovascular mortality compared with the 1322 individuals with no significant increase in either cTnT or NT-proBNP levels.38 Correspondingly, patients with an increase in only cTnT or NT-proBNP had more modest adjusted risks of incident HF (RR, 1.37; 95% CI, 1.04–1.80; and RR, 1.56; 95% CI, 1.18–2.08; respectively) and cardiovascular mortality (RR, 1.16; 95% CI, 0.85–1.59; and RR, 1.37; 95% CI 1.00–1.87; respectively) compared with patients with no significant increase in cTnT or NT-proBNP levels.38
Soluble ST2 is a protein biomarker of myocardial stress that correlates with cardiac remodeling and myocardial fibrosis, such as in MI, acute coronary syndrome, and HF.23,39 The membrane-bound form of ST2 is a receptor for the inflammatory cytokine, interleukin (IL)-33. In response to cardiac disease or injury, IL-33 binds to the ST2 receptor on the cell membrane and provides a cardioprotective effect to preserve cardiac function. However, when circulating levels of soluble ST2 are increased, it binds to IL-33 in the circulation, which makes IL-33 unavailable to bind to ST2 on the cell membrane. This blocks the beneficial antihypertrophic, antifibrotic, and antiapoptotic effects of IL-33.39 Soluble ST2 levels are increased in a number of disorders, specifically autoimmune diseases and cardiovascular diseases involving myocardial stretch.40 Soluble ST2 has also shown promise as a biomarker in HF.23,39 In experimental models, excessive ST2 secretion led to progressive myocardial fibrosis and hypertrophy; specifically, in a mouse model of MI, the beneficial effects of IL-33 administration (ie, cardioprotection, improved cardiac function, and increased survival) were not observed in the mice lacking ST2.12 ST2 assessments may be used to identify patients with HF at high risk for increased mortality or hospitalization41 and to identify which patients are likely to respond to therapies that reverse myocardial fibrosis.42 The Critical Diagnostics Presage ST2 Assay (Critical Diagnostics, San Diego, CA) is widely accessible and commonly used in clinical practice, with a reference interval of 4–31 ng/mL for men and 2–21 ng/mL for women.11
In the PRIDE study, patients in the acute HF group had significantly higher concentrations of ST2 than those who did not have acute HF (P < 0.001), and levels were directly related to disease severity based on NYHA functional class.13 Concentrations of ST2 above normal limits were predictive for death at 1 year in all patients with dyspnea (HR, 5.6; 95% CI, 2.2–14.2; P < 0.001) and in patients in the acute HF group (HR, 9.3; 95% CI, 1.3–17.8; P = 0.03); however, ST2 was calculated to be inferior to NT-proBNP as a diagnostic marker.13 Furthermore, a pooled analysis of data from 3 trials containing 447 patients with acute HF showed that an elevated ST2 concentration is an independent predictor of mortality in patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), with significantly increased risk per ng/mL for HFrEF (P < 0.001) and for HFpEF (P = 0.002).43
In a post hoc analysis of the Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting (PROTECT; NCT00351390), 151 patients with chronic HF who had an ST2 level >35 ng/mL for 1 year had the highest rates of cardiovascular events, and a decrease in ST2 concentration was shown to correlate with improved prognosis.39,40 Another post hoc analysis of PROTECT showed that ST2 assessments may be used as a tool to identify patients who would benefit from beta blocker uptitration, as patients with high ST2 levels who received the highest doses of beta blockers had lower rates of cardiovascular events than those who received lower doses.44 In the Multinational Observational Cohort on Acute Heart Failure (MOCA) study of 5036 patients hospitalized with acute HF, ST2 measurements provided added value to clinical variables (age, gender, blood pressure on admission, estimated glomerular filtration rate <60 mL/min/1.73 m2, sodium levels, hemoglobin levels, and heart rate) for risk stratification for 30-day and 1-year mortality.45 A study in 66 patients hospitalized with acute HF and renal insufficiency found a significant positive correlation between ST2 and BNP levels at admission (P = 0.007) and at discharge (P = 0.009).26 In addition, higher ST2 levels at discharge compared to admission were independently associated with death or HF readmission during the 3 months after discharge in multivariate analysis (HR, 1.038; 95% CI, 1.011–1.066; P = 0.006).26
Galectin-3 is a mediator of myocardial fibrosis, collagen production, and cardiac remodeling that leads to altered cardiac function.15 In a transgenic rat model of decompensated HF, the expression of galectin-3 increased prior to progression to overt HF; and in healthy rats, intrapericardial infusion of galectin-3 induced cardiac dysfunction and increased the collagen volume fraction of the LV myocardium.46 In HF, galectin-3 is secreted by activated macrophages, and increased levels of galectin-3 are associated with poor prognosis.15 In the PRIDE study, the median concentration of galectin-3 was significantly higher in patients with acute HF than in those without (9.2 ng/mL vs 6.9 ng/mL; P < 0.001).14 Other studies in patients with chronic HF have shown that levels of plasma galectin-3 are (1) also significantly higher than in patients without HF;16,47 (2) increased proportionately with NYHA functional class; (3) positively correlated with diastolic left atrial diameter and LV end-diastolic diameter; and (4) negatively correlated with LVEF.16 Although not widely accessible, galectin-3 and other biomarkers of myocardial fibrosis may be used in conjunction with NPs to provide additive prognostic value.1
In a prospective study of patients with chronic HF (n=150) and coronary heart disease (n=261), increased galectin-3 levels in patients with HF were an independent predictor of all-cause mortality and rehospitalization within a 12-month follow-up period, with a cutoff level of 17.78 ng/mL.47 Similar findings were reported in a prospectively designed substudy of the Coordinating Study of Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH; NCT02674438) trial of patients hospitalized for HF and followed for 18 months.48 When patients were divided into quartiles by baseline galectin-3 levels (Quartile 1: 5.0–15.2 ng/mL; Quartile 2: 15.2–20 ng/mL; Quartile 3: 20–25.9 ng/mL; Quartile 4: 25.9–66.6 ng/mL), an increased level of galectin-3 was a predictive factor for poor outcome (death or HF readmission), with Quartile 2 having an HR of 1.98 (95% CI, 1.29–3.02; P = 0.0016), Quartile 3 having an HR of 2.66 (95% CI, 1.76–4.03; P < 0.001), and Quartile 4 having an HR of 3.34 (95% CI, 2.23–5.01; P < 0.001) compared with Quartile 1.48 In both studies, the level of galectin-3 had a stronger predictive value in patients with HFpEF than in patients with HFrEF.47,48 In a pooled analysis of 3 trials of patients hospitalized for HF, a threshold galectin-3 level of 17.8 ng/mL at discharge was identified as predictive of near-term rehospitalization (within 30, 60, 90, and 120 days after discharge) for HF.49 In the PRIDE study, the galectin-3 level was the best independent predictor of 60-day mortality, with patients who died by 60 days of follow-up having significantly higher levels of galectin-3 than patients who survived; the optimal cutoff point was 9.42 ng/mL.14
A head-to-head comparison for long-term risk stratification in 876 ambulatory patients with HF examined ST2 and galectin-3, which both reflect cardiac fibrosis and remodeling.50 This study found that the assessment of galectin-3 was inferior to that of ST2.50 However, when considered along with BNP assessment, elevated galectin-3 levels at discharge after an episode of acute HF in 83 patients with chronic HF were strongly predictive of outcomes at 18 months. Patients with BNP levels ≥500 pg/mL and galactin-3 levels ≥17.6 ng/mL had a much higher likelihood of cardiovascular events (death by any cause, cardiac transplantation, worsening HF requiring readmission to the hospital) during 18 months of follow-up compared with patients with BNP levels <500 pg/mL and galactin-3 levels <17.6 ng/mL (log rank = 5.65; P = 0.017).51
Among 3353 healthy participants in the community-based Framingham Offspring Cohort study during a mean follow-up of 11.2 years, increased levels of galectin-3 were associated with an increased risk for developing incident HF, with a 1-standard deviation increase in logarithmic galectin-3 values associated with a 28% increase in the risk for incident HF (95% CI, 1.14–1.43; P < 0.0001).52 In addition, a 1-standard deviation increase in logarithmic galectin-3 values was associated with a 24% increased risk for mortality (95% CI, 1.12–1.38; P < 0.0001). These findings suggest that this biomarker may also be useful in identifying healthy individuals who are more likely to develop HF.52
Patient Encounter No 2
Given the biomarker results for this patient, a bedside echocardiogram was performed to reveal an EF of 35%. He was given a diagnosis of HFrEF and admitted to the hospital. A stress test was negative for ischemic changes at rest and with exercise.
In the case study, ongoing monitoring of the patient’s biomarker levels throughout his HF hospitalization can provide important information about his treatment response and residual risk; however, biomarker-guided HF therapy is not currently recommended in clinical practice due to insufficient supporting evidence.1,23 Biomarker-guided therapy has focused primarily on the use of the well-established and validated NPs.
With most therapies for acute HF, treatment can be guided based on “dry” and “wet” BNP levels. A dry BNP value represents the baseline euvolemic low BNP level, while a wet BNP value represents the elevated BNP level resulting from volume overload.53 Wet BNP levels can be used to determine the need for titration of HF therapy and/or use of diuretics.53 In Val-HeFT, patients in the placebo arm whose NT-proBNP values increased from <1078 pg/mL at baseline to >1078 pg/mL over 4 months had a mortality rate of 21.1% compared with 8.9% for patients whose NT-proBNP values remained below <1078 pg/mL.54 However, in prospective studies, continual outpatient assessments and uptitration of HF medications to achieve decreases in NP levels have shown conflicting results regarding benefits over standard HF management.55,56 Results from 2 meta-analyses demonstrated a 20% to 30% reduction in all-cause mortality with BNP- or NT-proBNP-guided therapy versus standard HF care.57,58 An individual patient meta-analysis found that NP-guided therapy provided a significant benefit over clinically guided treatment with regard to all-cause mortality (HR, 0.62; 95% CI, 0.45–0.86; P = 0.004), and when data were stratified by age, the benefit was restricted to patients aged <75 years.59 Another individual patient meta-analysis by an independent group is planned, with a primary outcome of time-to-all-cause mortality.60
The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT; NCT01685840) study was designed to determine the role of NP-guided therapy in patients with HF.61 The goal of this prospective, randomized, controlled trial was to compare the effects of an NP-guided strategy to maintain a target NT-proBNP level of <1000 pg/mL with usual care in ≈1100 patients with HF and LVEF ≤40%.61 Endpoints included a composite of time to cardiovascular death or first HF hospitalization (primary endpoint), time to cardiovascular death, time to first HF hospitalization, all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, health-related quality of life, resource utilization, costs, cost-effectiveness, and safety (secondary endpoints).61 The study was stopped early for futility, because no significant differences were found between NT-proBNP–guided therapy and usual care for the primary endpoint, or for the other clinical endpoints.62
CONSIDERATIONS FOR THE INTERPRETATION OF BIOMARKER LEVELS
Patient Characteristics and Comorbidities
In addition to the pathology of HF itself, patient characteristics and comorbidities may affect biomarker levels. A retrospective observational study found that higher LVEF levels were significantly associated with lower levels of BNP and NT-proBNP, while advancing age, lower hemoglobin levels (<12.0 g/dL), and decreased creatinine clearance (<60 mL/min) were significantly associated with higher levels of BNP (≥100 pg/mL) and NT-proBNP (≥300 pg/mL).63 An analysis of 20 studies has shown the following: increased body mass index and LVEF decrease the levels of BNP and NT-proBNP; nonwhite race decreases the levels of NT-proBNP, while its effect on BNP levels vary; pulmonary embolism/hypertension increase the levels of both BNP and NT-proBNP; female gender has no effect on the levels of both BNP and NT-proBNP; and renal insufficiency and age increase the levels of BNP and NT-proBNP.20 Other noncardiac factors that increase NP levels include obstructive sleep apnea, severe pneumonia, critical illness, bacterial sepsis, severe burns, and toxic/metabolic insults.18
Novel Pharmacological Therapy
The use of the novel angiotensin receptor/neprilysin inhibitor (ARNI) pharmacological class increases BNP levels by inhibiting the neprilysin enzyme that degrades endogenous vasoactive peptides, including BNP.22 In contrast, NT-proBNP is not a substrate of neprilysin, and, therefore, the levels of NT-proBNP continue to represent HF severity, even if a patient is receiving ARNI therapy.64 The net effect of this combination is to augment the positive effects of NPs while inhibiting the unfavorable effects of renin–angiotensin–aldosterone system activation.22 Therefore, treatment with ARNI therapy has contrasting effects on levels of BNP versus those of NT-proBNP, with NT-proBNP levels—but not necessarily BNP levels—being reflective of HF severity and the therapeutic effects of the drug.64
When patients are receiving therapy with the first-in-class ARNI, sacubitril/valsartan, biomarkers other than BNP—such as NT-proBNP or troponin, which are not affected by neprilysin inhibition—should be measured to establish baseline biomarker levels. Establishing a baseline for BNP and NT-proBNP levels in these patients will be critical because ratios of BNP:NT-proBNP concentrations have the potential to guide treatment. If guidelines recommend the NP-guided HF therapy in the future, a new algorithm will be needed to monitor biomarkers in patients with HF who are using ARNI combination products.
Patient Encounter No 3
When the patient was discharged from the hospital, his beta blocker was changed to carvedilol 6.25 mg twice daily. In addition, the patient was initiated on the angiotensin receptor blocker (ARB) valsartan, at the starting dose of 40 mg twice daily for 2 weeks. If the patient tolerates valsartan, his clinician will switch the ARB to the ARNI, sacubitril/valsartan (at an initial dose of 24/26 mg twice daily), to further reduce mortality. This regimen change is consistent with the 2016 and 2017 ACC/AHA/HFSA Focused Update to the ACCF/AHA Pharmacologic Therapy for Heart Failure guidelines, which recommends replacement of angiotensin-converting enzyme inhibitor/ARB by ARNI in patients with NYHA class 2 or 3 HFrEF who are able to tolerate these initial therapies.1,65–67 The stepwise strategy to initiate ARNI therapy was based on the design of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF; NCT01035255) clinical trial.65–67 If appropriate, an aldosterone antagonist may be added prior to discharge, per guideline recommendations.18 In accordance with guidelines, his HF medications will be titrated upward over 3 to 6 months until the desired maintenance doses are reached. The patient’s NT-proBNP level was measured and recorded at discharge so that it could be monitored throughout the course of his outpatient treatment. The NT-proBNP level was measured instead of the BNP level because sacubitril/valsartan increases BNP concentrations. It is expected that effective HF treatment will be reflected by decreases in NT-proBNP levels. Future increases in the levels of biomarkers may prompt a change in the dose of the patient’s medications or a change in HF therapy.
Biomarkers have become increasingly useful in HF for various applications; those recommended in the 2017 ACC/AHA/HFSA guideline update1 are BNP, NT-proBNP, cTn, ST2, and galectin-3. Clinicians must be aware that in patients with HF treated with ARNI combination products, or neprilysin inhibitors, increases in BNP concentrations will not necessarily be indicative of pathology or risk, and NT-proBNP or another marker not affected by neprilysin inhibition should be used, along with a physical examination and symptom assessment. Biomarker assessments can be used to help confirm the diagnosis of HF and to prevent the development of HF. Further research regarding the nuances of biomarker-guided therapy will provide clinicians with evidence-based data to improve patient care.
Medical writing assistance was provided by Marcel Kuttab, PharmD, of Oxford PharmaGenesis Inc., which was funded by Novartis Pharmaceuticals Corporation.
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