Aeshah Al-Azmi

Pharm.D candidate
Decmebr,14,2010
•Patient case objective
•Introduction

•Naturetic peptide

•BNP (pathophysiology and action)

•Role in HF (clinical trial)

•Conclusion
 Patient case
HPI:
71 years old man numerous hospitalized for management of heart failure (SOB,
orthopnea), renal failure. He has end stage ischemic cardiomyopathy. Left
ventricular systolic function was severely decreased with EF range (25%-30%).
Denies chest discomfort, palpitations, dizziness, or syncope
Medication:

Albuterol, allopurinol,amiodaron, aspirin, bumetanide, carvedilol, furosemide,

glipizide, rosuvastatin, spironolactone
PMH:
• HF
• ARF (contrast, aggressive diuresis)
• Hypothyroidism
• DM
• Peripheral vascular disuse
 Lab finding
12/07 12/08 12/09

Na 134 136 137

BP:121/70, RR: 16
Vital signs: neck vein distention noted
K 3.8 4 3.9
Heart: sounds were heard with decreased intensity
BUN 60 70 74 Lungs: diffuse wheezing bilaterally
Abdomen: Obese, soft, non-tender
SCr 2 2.2 2.2 No significant ankle edema

GFR 33 30 30

BNP 1060 1790 819

 Heart failure (HF ) is the major cardiovascular disorder and a leading cause of death,
hospitalization, and re-hospitalization
 The incidence and prevalence increases as the population ages
 Management of HF includes use of therapies based on symptoms, signs
 HF is difficult to diagnose in the ED as the symptoms may be nonspecific, and physical
findings are not sensitive enough to use as a basis for an accurate diagnosis
 Despite advances in medical treatment, deaths due to HF have increased 145% in the
last 20 years
 HF classification
NYHA
Description
Levels
Cardiac disease without resulting
limitations of physical activity.
I A
Slight limitation of physical activity -
comfortable at rest, but ordinary physical
activity results in fatigue, dyspnea, or
II anginal pain.
Marked limitation in physical activity -
comfortable at rest, but less than
III ordinary physical activity causes fatigue,
dyspnea, or anginal pain.
Inability to carry on any physical activity
without discomfort of symptoms at rest.
IV
ACC = American College of Cardiology
AHA = Americal Heart Association
NYHA = New York Heart Association
HF = Heart Failure
ACC/AHA
Description
Stages
Patients at high risk of developing HF because of the presence of
conditions that are strongly associated with the development of HF. Such
patients have no identified structural or functional abnormalities of the
pericardium, myocardium or cardiac valves and have never shown signs or
symptoms of HF
Patients who have developed structural heart disease that is strongly
B associated with the development of HF but who have never shown signs or
symptoms of HF.
C Patients who have current or prior symptoms of HF associated with
underlying structural heart disease
Patients with advanced structural heart disease and marked symptoms of
HF at rest despite maximal medical therapy and who require specialized
D interventions.
Diagnostic studies:

Echocardiography is considered the gold standard for the detection of LVD:

 expensive
not always easily accessible
not always reflect an acute condition

LAB: BNP, C-reactive protein, HCT/Hgb (anemia), electrolytes, TSH, BUN/Creatinine, LFTs
(right-sided), Cardiac enzymes, HIV
CXR: pulmonary edema, pleural effusions, heart enlargement.
EKG: Non-specific changes, arrhythmias, ischemic changes
CT/MRI, and Cardiac catheterization

**BNP, has been investigated in numerous studies and found that it has potentially important
diagnostic, therapeutic, and prognostic implications.
 Natriuretic Peptides:

Neurohormones Internal compensatory mechanism for

intravascular volume changes
Three types:
– Atrial Natriuretic Peptide (ANP)
– Brain-type Natriuretic Peptide (BNP)
– C-type Natriuretic Peptide (CNP)
 Natriuretic Peptides

Natriuretic Where When Secreted Actions

Peptide Manufactured

ANP Atria Atrial Stretch Natriuresis, Diuresis,

BP, Renin

BNP Ventricles Ventricular Stretch Natriuresis, Diuresis,

BP, Renin

CNP Endothelium Local Response Potent Venodilator

BNP actions
 ANP BNP

Plasma half-life 3 Minute 21 Minute

Release stimulus Atrial transmural tension Ventricular wall tension

Synthesis site Cardiac atrium Cardiac ventricle

Physiological actions Natriuresis Natriuresis
vasodepression vasodepression
inhibition, RAA system inhibition, aldosterone ?
antimitogenesis antimitogenesis

 the major source of plasma BNP is cardiac ventricles, suggesting that BNP may be a more
sensitive and specific indicator of ventricular disorders than other natriuretic peptides

 In case of fluid overload may cause rapid BNP production in both heart chambers, and
production in the atrium may exceed the amount of ANP.

BNP Consensus Panel 2004

 BNP
• B-type natriuretic peptide (BNP) is a cardiac neurohormone that is produced and synthesized from heart
muscle cells, mainly in the left ventricular myocardium but also in the atrial myocardium, as a pro-
hormone and released into the cardiovascular system in response to ventricular dilation and pressure
overload
• secreted amounts increased as we age
• women secreting more than men.
• Normal levels are less than 100 pg/m
• Measured at admission, discharge, or any major change in treatment
 BNP Levels with Different Heart Failure Classes

HF Class/Stage BNP Levels (pg/mL)

Mild (NYHA Class I) 83-152

Mild to moderate (NYHA Class II) 235-322

Moderate to severe (NYHA Class III) 459-590

Severe (NYHA Class IV) 960-1119

 BNP role in HF

 Diagnosis
 The Breathing Not Properly study
Study design and method:

large, multinational, prospective study using BNP to evaluate dyspnea in 1586 ED patients.

BNP levels were measured on arrival, BNP cut point is 100 pg/mL and physicians

assessed the probability of the patient having HF. Two cardiologists, blinded to the BNP

level, reviewed all data after hospitalization to produce a "gold standard" clinical diagnosis

Maisel A, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N
Engl J Med. 2002;347(3):161–167
Result:

BNP levels alone more accurately predicted the presence or absence of HF than any

other finding. The 100 pg/mL cutpoint had a 90% sensitivity and 76% specificity for a HF

diagnosis

Conclusion:

BNP levels contributed to the diagnosis, even after considering features of the history

and physical examination

Maisel A, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N
Engl J Med. 2002;347(3):161–167
BHP Consensus Panel. CHF. 2004; 10[5 suppl 3]:1–30)2004
 BNP role in HF

 Diagnosis

 Prognosis
How well does B-type natriuretic peptide predict death and
cardiac events in patients with heart failure: systemic review

Objective
To assess how well B-type natriuretic peptide (BNP) predicts prognosis
in patients with heart failure.
Design :
Systematic review of 19 studies used BNP to estimate the relative risk of
death or cardiovascular events in heart failure patients and five studies
in asymptomatic patients.
Results:
In heart failure patients, each 100 pg/ml BNP increase was associated
with a 35% increase in the relative risk of death.

Conclusion:
results of the studies in this review show that BNP is a strong prognostic
indicator for both asymptomatic patients and for patients with heart
failure at all stages of disease.
 BNP role in HF

 Diagnosis

 Prognosis

 Guide HF therapy
 STARS-BNP trial

Aim:
to demonstrate improved outcomes using a natriuretic peptide guided approach in
patients with HF, goal of decreasing BNP plasma levels <100 pg/ml

Study design and method:

Randomize, open study, parallel group include 220 (1:1) patients enrolled with LVEF
< 45% and NYHA class II or III, were randomly assigned to standard care or
standard care plus BNP reduction to < 100 ng/l. Enrollment with follow up duration
of 6 month. Titration of medication in both treatment arms was left to the physician's

Primary end point: CHF-related death or hospital stay for CHF

Jourdain P, Jondeau G, Funck F, Gueffet P, Le Helloco A, Donal E, Aupetit JF, Aumont MC, Galinier M, Eicher JC, Cohen-Solal A, Juillière Y. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure:
the STARS-BNP Multicenter Study.. J Am Coll Cardiol 2007;49:1733-9
 Clinical outcomes after at least six months of therapy (median, 15
months)

Jourdain P, Jondeau G, Funck F, Gueffet P, Le Helloco A, Donal E, Aupetit JF, Aumont MC, Galinier M, Eicher JC, Cohen-Solal A, Juillière Y. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure:
the STARS-BNP Multicenter Study.. J Am Coll Cardiol 2007;49:1733-9
Treatment modifications in the STARS-BNP trial
Changes in per-patient use of evidence-based medical therapy during first
three months (mean % of recommended dosage received)

Jourdain P, Jondeau G, Funck F, Gueffet P, Le Helloco A, Donal E, Aupetit JF, Aumont MC, Galinier M, Eicher JC, Cohen-Solal A, Juillière Y. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure:
the STARS-BNP Multicenter Study.. J Am Coll Cardiol 2007;49:1733-9
Comment:
BNP-guided management showed a significant
decrease in the primary end point of death or unplanned
hospitalization due to heart failure, fewer HF-related
hospitalizations, and better event-free survival

Jourdain P, Jondeau G, Funck F, Gueffet P, Le Helloco A, Donal E, Aupetit JF, Aumont MC, Galinier M, Eicher JC, Cohen-Solal A, Juillière Y. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure:
the STARS-BNP Multicenter Study.. J Am Coll Cardiol 2007;49:1733-9
Identification and guided treatment of ventricular dysfunction in general

practice using blood B-type natriuretic peptide

Aim:
To assess the practical implications and potential clinical benefit of measuring
BNP to identify and guide the treatment of undiagnosed or under treated
ventricular dysfunction in at-risk patients

Br J Gen Pract. 2008 June 1; 58(551): 393–399.

 Study design and method

Br J Gen Pract. 2008 June 1; 58(551): 393–399.

 Medication prescribed at the beginning and end of BNP-guided
treatment titration (n = 76)

n%
Angiotensin inhibitor Beta-blocker Both beta- Neither beta- Spironolactone Furosemide
without beta-blocker without blocker and blocker nor
angiotensin angiotensin angiotensin
inhibitor inhibitor inhibitor

Entryª 12 (15.8) 24 (31.6) 30 (39.5) 10 (13.2) 3 (3.9) 17 (22.4)

Exit 11 (14.5) 5 (6.6) 56 (73.7) 4 (5.3) 9 (11.8) 19 (25.0)

aAngiotensin inhibitors on entry were ramipril ( n = 11), lisinopril (n = 11), enalapril (n = 4), other ACE inhibitors (n = 5), angiotensin II receptor blockers
(n = 11); beta-blockers on entry were atenolol ( n = 32), bisoprolol (n = 10), metoprolol (n = 5), sotalol (n = 5), carvedilol (n = 1), nebivolol (n = 1).

Br J Gen Pract. 2008 June 1; 58(551): 393–399 .

About 10% (76) of patients with diabetes or cardiovascular disease registers
have a persistently raised plasma BNP concentration. Simple adjustment of their drug
treatment has the potential to reduce their BNP concentration and associated mortality
risk significantly

Br J Gen Pract. 2008 June 1; 58(551): 393–399

 B-Type Natriuretic Peptide–Guided Heart Failure Therapy

Aim:
Examine the overall effect of BNP-guided drug therapy on cardiovascular outcomes in
patients with chronic HF
Methods:
Meta-analysis of prospective randomized controlled trials.
Eight studies involving 1,726 patients, published internationally from 2005-2009
comparing of BNP-guided drug therapy vs usual clinical care of the patient with chronic
HF in an outpatient setting
Study sizes ranged from 41 to 499 patients, (3-24 month) follow-up
Patients had NYHA class II or greater heart failure, with ejection fractions <50%

Arch Intern Med. 2010;170(6):507-514

 Results

• All-cause mortality was significantly lower in BNP-guided therapy compared with

clinical-guided therapy (RR=0.76; 95% CI, 0.63-0.91; P=0.003), specifically in
patients younger than 75 years old (RR=0.52; 95% CI, 0.33-0.82; P=0.005).

• there was no reduction in mortality with BNP-guided therapy in patients 75 years or

older (RR, 0.94; 95% CI, 0.71-1.25; P = .70)

Arch Intern Med. 2010;170(6):507-514

 Conclusion

B-type natriuretic peptide–guided therapy reduces all-cause

mortality in patients with chronic HF compared with usual
clinical care, especially in patients younger than 75 years.

Arch Intern Med. 2010;170(6):507-514

 Trial name and Natriuretic peptide
N Study population Control group(s) Follow-up Primary endpoint(s)
reference target
Enrolled at hospital discharge
The Christchurch New NT-proBNP <1,691 Framingham HF score Cardiovascular death
69 LVEF <40% 9.5 months (median)
Zealand pilot trial[41] ng/l <2 or hospitalization
NYHA class III–IV
Stable outpatients
BNP <100 ng/l for first Unplanned HF
Optimal background therapy LVEF
STARS-BNP[42] 220 3 months after Clinical judgment 15 months (months) hospitalization or HF
<45%
randomization death
NYHA class II–III
Enrolled at hospital discharge
BNP<2x hospital Standardized Hospitalization-free
STARBRITE[43] 130 LVEF ≤35% 90 days
discharge congestion score survival
NYHA class III–IV

Age ≥60 years

LVEF ≤45% NT-proBNP <400 ng/l
Hospitalization-free
NYHA class II–IV if <75 years old or
TIME-CHF[45] 499 NYHA class I or II 18 months survival and quality of
Hospitalized with HF in past year <800 ng/l if ≥75 years
life
NT-proBNP >2x upper limit of old
normal

Symptomatic HF with preserved or

reduced LVEF Total mortality and
NT-proBNP <1,300 Standardized HF
BATTLESCARRED [46]
364 Recent hospitalization with HF (<2 2.8 years (median) death or HF
ng/l score or standard care
weeks) hospitalization
NT-proBNP >400 ng/l

Hospitalized with HF
Preserved or reduced LVEF
NT-proBNP at
NT-proBNP >1,700 ng/l at hospital Hospitalization-free
PRIMA [47]
345 discharge or at 2 Clinical judgment 1.9 years (median)
admission survival
weeks' follow-up
NT-proBNP drop by >10% before
hospital discharge
 PROTECT trial
study design:

small, single-center, randomized trial supports the strategy of

heart-failure medication adjustment guided by assessments of
natriuretic-peptide levels
151 patients enrolled all received standard therapy (75
adjusted medication guided by BNP)

P = .03 for SOC follow-up versus NT-proBNP follow-up 44.3% of NT-proBNP subjects 1000 pg/mL
 methods
Inclusion Criteria
• Age > 21 years of age
• Left ventricular ejection fraction ≤ 40%
• New York Heart Association class II-IV symptoms
• Hospitalization, ED visit, or outpatient therapy for ADHF within 6 months
Exclusion criteria
• Serum creatinine > 2.5 mg/dl
• Inoperable aortic valve disease
• Life expectancy <1 year due to causes other than HF
• Cardiac transplantation or revascularization expected within 6 months
• Severe obstructive or restrictive pulmonary disease
• PCI or CABG within the previous 3 months
• Subject unable or unwilling to provide written informed consent

P = .03 for SOC follow-up versus NT-proBNP follow-up 44.3% of NT-proBNP subjects 1000 pg/mL
 Baseline characteristic

Characteristic NT-proBNP (N=75) SOC (N=76) P

Age, years 63.0 ± 14.5 63.5 ± 13.5 .41

LV ejection fraction (%) 28.0 ± 8.7 25.9 ± 8.3 .52
NYHA Class II or III (%) 65 (85.5) 64 (84.2) .46
Male gender (%) 67 (88.2) 61 (81.3) .24
Caucasian (%) 65 (85.5) 66 (88.0) .65

Cause of heart failure

Ischemic (%) 40 (53.3) 45 (60.0)
.17
Non-ischemic (%) 25 (33.3) 18 (24.0)
Other (%) 10 (13.3) 12 (16.0)

Past medical history

Hypertension (%) 40 (52.6) 39 (52.0) .94
Coronary artery disease (%) 42 (55.3) 50 (66.7) .09
Myocardial infarction (%) 28 (36.8) 30 (40.0) .69
Atrial fibrillation (%) 31 (40.8) 30 (40.0) .92
Ventricular tachycardia (%) 23 (30.3) 21 (28.0) .76
Obstructive airways disease (%) 15 (19.7) 16 (21.3) .81
Diabetes mellitus (%) 30 (39.5) 32 (42.7) .19

Implanted devices
Cardioverter-defibrillator (%) 52 (69.3%) 50 (65.8%) .70
Biventricular pacemaker (%) 30 (40.0%) 30 (39.4%) .68

P = .03 for SOC follow-up versus NT-proBNP follow-up 44.3% of NT-proBNP subjects 1000 pg/mL
 HF baseline therapy
Baseline
Medication
NT-proBNP (N=75) SOC (N=76) P

ACE Inhibitors (%) 53 (70.7) 47 (61.8) .21

.11
Angiotensin receptor blocker (%) 8 (10.7) 15 (19.7)

β blocker (%) 74 (98.7) 71 (93.4) .19

Aldosterone antagonist (%) 37 (49.3) 26 (34.2) .10
Loop Diuretics (%) 67 (89.3) 71 (93.4) .27
Thiazide Diuretic (%) 5 (6.7) 3 (4.0) .48
Digoxin (%) 22 (29.3) 25 (32.9) .89
Hydralazine (%) 4 (5.3) 4 (5.3) .89
Nitrates (%) 8 (10.7) 16 (21.1) .07
P = .03 for SOC follow-up versus NT-proBNP follow-up 44.3% of NT-proBNP subjects 1000 pg/mL
 HF therapy follow up
Medication Follow-up
NT-proBNP (N=75) SOC (N=76) P

ACE Inhibitors (%) 56 (74.7) 46 (60.5) .20

.05
Angiotensin receptor blocker (%) 9 (12.0) 17 (22.4)

β blocker (%) 73 (97.3) 73 (96.1) .56

Aldosterone antagonist (%) 47 (62.7) 34 (44.7) .001
Loop Diuretics (%) 64 (85.3) 73 (96.1) .05
Thiazide Diuretic (%) 5 (6.7) 3 (3.9) .42
Digoxin (%) 23 (30.7) 23 (30.3) .90
Hydralazine (%) 2 (2.7) 4 (5.3) .12
Nitrates (%) 7 (9.3) 14 (18.4) .06
P = .03 for SOC follow-up versus NT-proBNP follow-up 44.3% of NT-proBNP subjects 1000 pg/mL
 HF titration of therapy
Medication Titration
NT-proBNP (N=75) SOC (N=76) P
ACE Inhibitors (%) +25.4% +18.1% .15
Angiotensin receptor blocker (%) +5.8% +22.3% .01
β blocker (%) +46.0% +34.5% .05
Aldosterone antagonist (%) +22.7% +5.8% <.001
Loop Diuretics (%) +23.7% +25.6% .65
Thiazide Diuretic (%)* -16.7% -12.5% .88
Digoxin (%)* -10.9% +2.0% .78
Hydralazine (%)* +27.5% -50.0% .20
Nitrates (%)* +59.4% -3.7% .08

P = .03 for SOC follow-up versus NT-proBNP follow-up 44.3% of NT-proBNP subjects 1000 pg/mL
 NT-Pro naturetic peptide concentration
Baseline Follow-up P

Overall 2118 [1122-3831] 1321 [554-3197] .02

By treatment allocation
Treatment Baseline Follow-up P

SOC 1946 [951-3488] 1844 [583-3603] .61

NT-proBNP 2344 [1193-4381] 1125 [369-2537] .01

P = .03 for SOC follow-up versus NT-proBNP follow-up 44.3% of NT-proBNP subjects 1000 pg/mL
 Pharmacist role

Care of patients with HF requires both inpatient acute care and outpatient chronic
care. Pharmacists can play an important role in appropriate therapy selection,
monitoring, and education in both settings. It is important for pharmacists caring for
patients both in the acute setting and in the chronic setting to be updated and
knowledgeable on the recommendation changes in HF care.
 Conclusion
•BNP is secreted by the heart in response to increased volume, useful in the diagnosis heart failure

•BNP plasma levels strongly associated with the presence and severity of H

•levels be decreased by treatment with proven heart failure medications and associate with favorable outcome

•BNP can be used as guided HF therapy

 References
• Jourdain, P. et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP
Multicenter Study. J. Am. Coll. Cardiol. 49, 1733-1739 (2007)
• Levin ER, Gardner DG, Samson WK. Mechanisms of diseases. Natriuretic peptides. NEJM 1998; 339:321-8.
• Pfisterer, M. 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 301, 383-392 (2009)
• Richards, A. M., Lainchbury, J. G., Troughton, R. W. & Strangman, K. NT-proBNP-guided treatment for chronic heart
failure: results from the Battlescarred trial [abstract 5946]. Circulation 118, S_1035-S_1036 (2008).
• Eurlings, L. et al. Can pro-brain natriuretic peptide-guided therapy of heart failure improve heart failure morbidity and
mortality? Main outcome of the PRIMA study [abstract 402-14]. Presented at the ACC 58th Annual Scientific Session
(Orlando, USA; 29-31 March 2009
• Troughton, R. W. et al. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP)
concentrations. Lancet 355, 1126–1130 (2000).
Aeshah Al-Azmi
Pharm.D candidate
Decmebr,14,2010