Natriuretic Peptide in CHF & ACS

Dr Virbhan Balai

Overview

• 4 human natriuretic peptides1. Brain natriuretic peptide (BNP) 2. Atrial natriuretic peptide (ANP) 3. C-type natriuretic peptide (CNP) 4. Dendroaspis natriuretic peptide (DNP)

• BNP is a member of a family of 4 human natriuretic peptides

• Shares a common 17-peptide ring structure.• Discovered over 15 years ago

• BNP, important biomarker in the diagnosis of CHF.

• Its utility has also been explored in-1. Myocardial ischemia and infarction 2. Right-sided heart failure (eg, cor pulmonale)3. Acute pulmonary embolism.

• Currently clinical trials are under way to determine if serial BNP measurements have a role in guiding the titration of CHF therapies.

• Recombinant BNP (nesiritide)- evaluated and approved for adjunctive therapy for acute CHF.

• Although questions about its safety have diminished its use for this indication.

• >10%• Hypotension (4-35% )• Serum creatinine

raised (17-28% )

• 1-10%• Nausea (4-13% )• Ventricular tachycardia (3-10% )• Headache (7-9% )• Dizziness (3-6% )• Insomnia (2- 6% )• Back pain (4%)• Ventricular premature beats (3-4% )• Anxiety (3%)• Angina (2%)• Atrial fibrillation (1% or greater )• Atrioventricular node (1% or greater )• Bradycardia (1%)• Somnolence (1%)• Tremor (1%)

Normal Activity of Natriuretic Peptides

• The first NP was identified in 1983 - named atrial natriuretic peptide (ANP).

• ANP is a 28-amino acid polypeptide • ANP is secreted in response to atrial stretching• Normal hearts secrete extremely small

amounts of ANP • Elevated levels are found in patients with LVH

and mitral valve disease.

• BNP was first identified in pig brains in 1988 and therefore named BNP.

• Subsequently discovered to be present in high concentrations in cardiac tissues, particularly the ventricles.

• C-type natriuretic peptide (CNP)-act in the peripheral vasculature

• Dendroaspis natriuretic peptide (DNP)- atria.

• Before its activation, BNP is stored as a 108–amino acid polypeptide precursor

• Pro BNP, in secretory granules in both ventricles and, to a lesser extent, in the atria.

• After pro BNP is secreted in response to volume overload and resulting myocardial stretch

• It is cleaved to the 76-peptide, biologically inert N -terminal fragment NT-pro BNP and the 32-peptide, biologically active hormone BNP.

• High ventricular filling pressures stimulate the release of ANP and BNP.

• Both peptides have diuretic, natriuretic, and antihypertensive effects, which they exert by inhibiting the renin-angiotensin-aldosterone system.

• They also have systemic and renal sympathetic activity. • BNP may provide a protective effect against the

detrimental fibrosis and remodelling that occurs in progressive heart failure.

• Although ANP was identified first, concentrations of BNP in the myocardial tissue were found to be higher than those of ANP.

• Therefore, BNP has been studied more intensely than ANP as a clinically useful marker of increased ventricular filling pressure.

• An elevated BNP level is a marker of increased LV filling pressures and LV dysfunction.

• Natriuretic peptide receptors and plasma endo peptidases actively clear BNP from the circulation; the plasma half-life is thus short, approximately 20 minutes.

• No receptor-mediated clearance of NT-pro BNP is known to occur, and NT-pro BNP has a correspondingly prolonged half-life of 60-120 minutes.

• As a result, plasma levels of NT-pro BNP tend to be 3-5 times higher than BNP levels.

• Clearance of NT-pro BNP is primarily renal. • Therefore, the renal clearance of NT-pro BNP confounds its diagnostic utility

in patients with renal insufficiency.• As a laboratory specimen, NT-pro BNP is more stable during storage than

BNP. • NT-pro BNP samples are stable at room temperature for 72 hours, versus less

than 4 hours for BNP samples.

BNP and NT-pro BNP Assay Methods

• First-generation assays for BNP were competitive radio immunoassays that required extraction and purification of the plasma sample.

• Second-generation assays were based on monoclonal antibodies and radioisotope labels.

• Commercial versions of the monoclonal antibody assay first appeared in 1994 and initially required 12-36 hours to complete.

• Third-generation assays, which provided results in as little as 15 minutes, became available in 2000.

• These rapid assays used immunofluorescent methods. • All of the assays for BNP and NT-proBNP that are commercially

available for clinical use in the United States are rapid immunoassays.

BNP and NT-pro BNP Levels in LV Dysfunction

• NT-pro BNP levels - sensitivity of 75% and a negative predictive value of 99% in diagnosis of CHF.

• NT-pro BNP levels were compared with LV function in 3051 patients pooled from 3 large European data sets.

• Median values for patients with- – Normal LV function- 20– LV dysfunction -117– Acute CHF -270 pg/mL

Recombinant BNP

• Recombinant BNP- nesiritide • Nesiritide - US FDA approved for the

treatment of acute decompensated heart failure with dyspnea in 2001.

• Nesiritide is a BNP measured by the BNP assay.

• Measurement of BNP is not indicated in patients who are receiving nesiritide.

BNP and NT-pro BNP Evaluation in the ED

• BNP testing in the acute care setting is derived from the landmark Breathing Not Properly study and later studies.

•  Breathing Not Properly multicenter prospective study involved 1586 patients presenting to the ED with acute dyspnea.

• Establish the diagnosis of CHF when the clinical presentation is ambiguous or when confounding comorbidities are present.

Factors affecting BNP/NT-pro BNP assays

• Renal clearance of NT-pro BNP and, to a lesser degree BNP

• BNP levels were inversely correlated with estimated GFRs.

• BNP rule-out CHF cut offs GFR 60-89 = 290 pg/mL15-29mL/min = 515pg/mL

• For NT-pro BNP assays, optimal cut offs were 1360 and 6550pg/mL, respectively.

• BNP - inversely correlated with BMI.• Mean BNP values are 3 times higher for lean

patients with CHF than for obese patients with CHF (517 vs 176mg/mL).

• Obese patients with BMIs ≥ 25 kg/m2 had median BNP levels below the recommended rule-in threshold of 500pg/mL.

• AF confounds the utility of BNP assay for diagnosing acute CHF exacerbation.

• AF was associated with increased BNP levels in the absence of acute CHF.

• A high cut off value to exclude CHF is required.

BNP versus NT-pro BNP assays

• Similar confounding effects of age, sex, and renal insufficiency.

• NT-pro BNP is most sensitive for the detection of mild LV dysfunction and structural heart disease.

• BNP is less sensitive to the effects of renal insufficiency than NT-pro BNP.

Evidence-Based BNP and NT-pro BNP Cut off Values for Diagnosing Heart Failure

Likelihood ratios

• BNP levels very reliable in differentiating heart failure from pulmonary disease.

• < 100pg/mL to rule out heart failure and > 500pg/mL to rule in heart failure.

• LR-negative = 0.13 and LR-positive = 8.1. • Intermediate range of 100-500pg/mL with LR-

positive of only 1.9. • Therefore, an intermediate BNP result alone

cannot be used to rule in or rule out heart failure.

• Any 2 or more clinical features, a heart failure history, and a mid-range BNP level - Had a cumulative LR-positive of 10

• A mid-range BNP level, no history of heart failure, and 0 or 1 clinical criterion - Had an intermediate cumulative LR-negative of 0.7, which was not clinically useful.

• Serial BNP measurements for monitoring the treatment of heart failure is not well established.

Risk Stratification and Outcome Prediction

• Direct correlation between BNP and NT-pro BNP levels and clinical outcomes in patients with CHF.

• Useful as triage instruments to help guide the emergency physician.

Framingham Heart Study

• Prospective study, 3346 patients without heart failure • To determine the usefulness of BNP in predicting the risks for all-cause

mortality.• Patients were followed up for a mean period of 5.2 years.• After adjustment for known cardiovascular risk factors, high levels of BNP

were associated with a – 27% increase in risk of all-cause mortality– 28% increase in risk for a first cardiovascular event– 77% increase in the risk of CHF– 66% increase in the risk of AF– 50% increase in the risk of stroke or TIA.

• BNP levels were not predictive of coronary heart disease. • ? ? BNP testing has a role in risk stratification and screening for cardiovascular

& cerebrovascular disease in asymptomatic populations.

REDHOT study

• Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) to examine the prognostic role of BNP in the ED.

• Multicenter• Undertaken by Breathing Not Properly investigators.• This investigation indicated that BNP level is a

strong predictor of 90-day patient outcome with regard to cardiac mortality and subsequent ED visits and/or re hospitalization for acute CHF.

BASEL study

• B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study

• Patients were randomly assigned to undergo standard evaluation or evaluation aided with rapid bedside BNP measurement.

• BNP measurement significantly decreased rates of admission (75% vs 85%) and admission to the ICU (15% vs 24%).

• Length of hospitalization was also significantly shortened with BNP measurement.

Copenhagen Hospital Heart Failure study

• NT-pro BNP level was predictive of 1-year mortality in patients with heart failure.

• LVEF provided no additional prognostic value over NT-pro BNP values in this small subset of patients with heart failure.

Rothenburger et al study

• German researchers evaluated NT-pro BNP levels in 550 extremely ill patients with severe DCMP in whom cardiac transplantation was being considered.

• At 1 year, patients with levels less than 1000pg/mL had a less than 1% mortality rate

• Patients with levels of 1000-5000 pg/mL had a 2% mortality rate

• Patients with levels greater than 5000 pg/mL had a 28% mortality rate.

O’Brien et al study

• Did not reveal a statistically significant relationship between the admission NT-pro BNP level and outcome.

• However, the discharge NT-pro BNP level was a statistically significant predictor of adverse outcome.

Bettencourt et al study

• In this study, change in NT-pro BNP level was the strongest predictor of death and/or hospital readmission in hospitalized patients with CHF.

• Levels of NT-pro BNP were measured on admission and again at hospital discharge.

• Patients were stratified as those whose NT-pro BNP levels decreased ≥30% between admission and discharge, those with an increase ≥30%, and those with any change < 30%.

NT-pro BNP for Monitoring Therapeutic Response

• Data from a Spanish study suggested that serial NT-pro BNP—or BNP—levels may be useful adjuncts in monitoring therapeutic responses in patients admitted to the hospital with acute CHF.

• NT-pro BNP levels were highly predictive of LV dysfunction.• Patients with complete symptom resolution had mean

decreases in NT-pro BNP values of 56%. • Patients whose conditions were stabilized but still

symptomatic had intermediate mean decreases of 37%. • Patients whose decompensation persisted at 7 days had

decreases of 21%.

Acute coronary syndrome

• BNP levels as a marker of left LV dysfunction associated with myocardial ischemia in ACS.

• However, BNP levels do not enable sufficient discrimination on their own to rule ACS in or out.

• In patients with confirmed ACS, the natriuretic peptides may have a role in risk stratification.

• After adjustment for other risk factors, a baseline NT-pro BNP level of greater than 250pg/mL was associated with an adverse cardiac event.

• Patients with persistently elevated NT-pro BNP levels over 72 hours had a worsened 30-day prognosis.

• In patients with non–ST-elevation ACS.• BNP levels > 80pg/mL were predictive of

adverse cardiac outcomes.[beyond those predicted on the basis of troponin levels alone (even after as long as 6 months)].

• However, treatment strategies did not significantly differ when retrospectively stratified by BNP level.

• The NT-pro BNP level had prognostic information beyond conventional risk factors.

RV dysfunction and pulmonary disease

• Patients with primary pulm. HTN had NT-pro BNP concentrations 40 times higher than those of patients with terminal parenchymal lung disease.

• NT-pro BNP Levels also useful in predicting uncomplicated clinical courses of patients with a diagnosis of acute PE.

• NT-pro BNP < 500pg/mL had a NPV of 97% for complications due to PE.

• The NT-pro BNP level remained an independent predictor for adverse outcome even after the analysis was adjusted for age, sex, history of CHF, and severity of PE.

• NT-pro BNP levels are significantly higher in patients with RV dysfunction.

Clinical Uses of BNP and NT-proBNP Testing

• General recommendations• Care must be taken to interpret results in the context of the assay

being used (BNP vs NT-pro BNP) and the patient’s confounding factors and comorbidities (including obesity and renal insufficiency).

• BNP levels < 100pg/mL & > 500pg/mL have a 90% NPV & PPV for the diagnosis of CHF.

• For intermediate levels between 100- 500pg/mL, clinicians must also consider underlying LV dysfunction, effects of renal insufficiency, or RV dysfunction secondary to corpulmonale or acute PE.

• If clinical suspicion is high for CHF but the natriuretic peptide levels are lower than expected, obesity or flash pulmonary edema should be considered.

• BNP and NT-pro BNP levels are increased in the presence of renal insufficiency, NT-pro BNP levels more so than BNP.

• NT-pro BNP levels can be elevated simply on the basis of the normal age-related decline in GFR.

• When the calculated GFR < 60mL/min, NT-pro BNP levels can be extremely elevated.

• For BNP, increasing the rule-out cut off value to 200pg/mL is recommended when the GFR < 60mL/min.

• Natriuretic peptide levels may be elevated in the intermediate range in chronic pulmonary disease when RV overload occurs.

• NT-pro BNP and BNP levels may also be elevated in acute PE.• Although elevations are not diagnostic for PE, high levels are predictive

of a worsened prognosis, particularly when in conjunction with elevated troponin levels.

• In about 20% of patients with pulmonary disease, natriuretic peptide levels are elevated.

• Elevations in this context imply CHF, combined CHF and lung disease, corpulmonale, or acute PE.

• BNP and NT-pro BNP may be used to identify patients with diastolic dysfunction, but cut off points remain to be age adjusted and subsequently related to diastolic filling abnormalities.

• Patients with BMI > 30kg/m2 have low levels of BNP and NT-pro BNP.

• Although serial determinations are likely to be useful, a diagnosis of CHF must be carefully considered in the appropriate context, even when levels are below cut off levels.

• Natriuretic peptides are independent predictors of mortality in CHF.

• Increased or persistent elevation in natriuretic peptide levels despite treatment suggests progression of disease or resistance to treatment.

• In the acute setting, failure of BNP or NT-pro BNP levels to decrease with treatment is a poor prognostic factor that requires intensification of treatment.

• Natriuretic peptide levels should not be measured daily. • One suggested algorithm is to measure levels on admission,

after 24 hours of treatment, and at discharge. • Decreased natriuretic peptide levels are predictive of excellent

outcomes.• BNP levels should not be measured while patients are

receiving recombinant infusions of BNP (eg, nesiritide). • However, NT-pro BNP levels are not affected by nesiritide.

• In ACS, troponin, CK-MB, and myoglobin are markers of myocardial necrosis and are highly predictive of adverse cardiac events.

• As a marker of LV dysfunction, natriuretic peptides are not helpful in diagnosing myocardial ischemia and ACS.

• However, BNP and NT-pro BNP levels may be useful for risk stratification in patients with ACS.

• BNP or NT-pro BNP screening is not appropriate for low-risk, asymptomatic patients.

• Screening may have some value in populations with certain risk factors (eg, previous MI, diabetes, long-standing uncontrolled HTN)

ACCF/AHA recommendations

• Guidelines from the ACCF and the AHA list as a class I recommendation the use of BNP or NT-pro BNP values in the diagnosis of heart failure in ambulatory patients with dyspnea, especially when the diagnosis is uncertain, as well as their use in establishing the prognosis or disease severity in ambulatory patients with chronic heart failure.

• The guidelines assign a class IIa recommendation to the use of BNP or NT-pro BNP in determining optimal dosing for select ambulatory patients who are clinically euvolemic and are undergoing medical therapy in a well-structured heart-failure management program.

• For hospitalized/acute patients, the ACCF/AHA guidelines list as a class I recommendation the use of BNP or NT-pro BNP in the diagnosis of acutely decompensated heart failure, especially when the diagnosis is uncertain, as well as the use of BNP or NT-pro BNP and/or cardiac troponin in establishing the prognosis or disease severity of acutely decompensated heart failure in such patients.

• However, the guidelines state that the usefulness of BNP or NT-pro BNP in guiding therapy in hospitalized/acute patients with acutely decompensated heart failure has not been well established.

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