June 28, 2016 Overview & Update on the Utilization of the ... · BNP and NT-proBNP Physiology...

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Overview & Update on the Utilization of theNatriuretic Peptides in Heart Failure

June 28, 2016

Linda C. Rogers, PhD, DABCC, FACB

Restricted © Siemens Healthcare Diagnostics Inc., 2015 All rights reserved.

Agenda

• Overview of the Natriuretic Peptides and Efficacy studies• Similarities and Differences• Confounders• Clinical Studies of Entresto and Implications for

Measurement of the Natriuretic Peptides

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Cardiac Natriuretic Peptides

Physiological role:

• Natriuresis, i.e., discharge of sodium by urinary excretion

• Regulates blood volume through osmotic hemodynamics

Peptide Stimulus for ReleaseANP Atrial DistensionBNP Ventricular OverloadCNP Endothelial Stress

ANPANP

BNPBNP

CNP

Weber, et al. Heart 2006;92:843-9.


Physiology of BNP control

Na+

Na+

Na+

Renin-angiotensin-aldosteronesystem (RAAS)

Weber, et al. Heart 2006;92:843-9.

Restricted © Siemens Healthcare Diagnostics Inc., 2015 All rights reserved.5 Unrestricted © Siemens Healthcare Diagnostics Inc. 2014 All rights reserved. Artifact #A91DX CAI-140459-UC1-4A00

BNP32 aa½ life = 20 minEnzymatic, receptor, and renal clearancePhysiologically active

NT-proBNP76 aa½ life = 120 minRenal clearancePhysiologically inactive

—COOH H2N

Cardiac myocyte

Natriuretic Peptides

Pre-proBNP (134 aa)

80

90

100

108—COOH

S P K M V Q G S GCF

CRK

M D R I S SSSG

LCC K V L R R H

Hemodynamic StressIschemia

CardiotoxicitySepsis

ProBNP (108 aa)

Blood stream

Enzymaticcleavage

Martinez-Rumayor et al. Am J Cardiol 2008;101[suppl]:3A-8ABoerrigter, et al. Heart Fail Clin. Oct 2009; 5(4): 501–514.

H2N1

10 70

76

H P L G S P G S A S Y T L R A P R

Signal peptide(26 aa)


6 Siemens Healthcare Diagnostics

Elimination Paths of BNP and NT-proBNP Impacts Half Life

BNP NT-proBNP

Half-Life = 60 – 120 minutes

+ +

Half-Life = 20 minutesWeber, et al. Heart 2006;92:843-9.


Decision Cut Points for Ruling Out Heart Failure

NT-proBNP BNP

Age < 75 yrs: ≤ 125 pg/mLAge ≥ 75 yrs: ≤ 450 pg/mL

< 100 pg/mL

These are the only accepted cut points,regardless of manufacturer.

Source: Siemens IFU’s


BNP and NT-proBNP Physiology

Pre-proBNP

Dilation of the left ventricle increases cardiacpre-proBNP gene expression.

The amount of pre-proBNP released into thecirculation is directly proportional to the extentof heart wall stretch.

Thus, natriuretic peptide levels are an accuratereflection of the severity of heart failure.



Breathing Not Proper Study: BNP

• BNP is a useful test to distinguish patients with heart failure from thosewithout heart failure.

• BNP is useful for both systolic and nonsystolic heart failure, even thoughnonsystolic heart failure diagnosis is more difficult to make and is ofternincorrectly excluded in the presence of normal left ventricular systolicfunction.

• BNP cannot reliably distinguish systolic dysfuncion from nonsystolicdysfunction: a measurement of left ventricular dysfunction is required tomake this distinction and guide therapy accordingly.

Maisel, et al. J Am Coll Cardiol. 2003;41:2010-7.



PRIDE Study Supports the Clinical Utility of NT-proBNP

• NT-proBNP testing alone was superior to clinical judgment alone fordiagnosing acute CHF.

• NT-proBNP plus clinical judgment was superior to NT-proBNP or clinicaljudgment alone.

• NT-proBNP measurement is a valuable addition to standard clinicalassessment for the identification and exclusion of CHF in theemergency department setting.

Januzzi, Am J Cardiol 2005;95:948-954

Restricted © Siemens Healthcare Diagnostics Inc., 2015 All rights reserved.11 Unrestricted © Siemens Healthcare Diagnostics Inc. 2014 All rights reserved. Artifact #A91DX CAI-140459-UC1-4A00

a. McCullough PA, et al. Circulation. 2002;106:416-22.b. Januzzi JL, et al. Am J Cardiol. 2005;95:948-54.

ROC Curves Estimating Clinical Probability of Heart Failure

1 − Specificity

BNP Studya PRIDE Studyb

Sen

sitiv

ity

0.0 0.60.4 0.8 1.00.20.00.1

0.3

0.6

0.40.5

0.70.80.91.0

0.2

0.0 0.60.4 0.8 1.00.20.00.1

0.3

0.6

0.40.5

0.70.80.91.0

0.2BNP + clinical assessment, AUC = 0.93 NT-proBNP + clinical assessment, AUC = 0.96

Clinical assessment alone, AUC = 0.86 Clinical assessment alone, AUC = 0.90

BNP alone, AUC = 0.90 NT-proBNP alone, AUC = 0.94



Clinical Confounders to NP Interpretation

AFib

High BMICKD

Age-associated increases



NP’s in CKD

• BNP and NT-proBNP were elevated in kidney dysfunction even in theabsence of systolic heart failure (SHF).

• NT-proBNP elevated more than BNP.

• Further research and association guidelines are necessary for clinicalguidance.

Jafri, et al. BMC Nephrol. 2013;14:117-26



Impact of NPs in Patients with Renal Dysfunction and Dyspnea

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

> 89 89-60 59-30 < 30

NT-

proB

NP

(pg/

mL)

eGFR (mL/min/1.73m2)

0

250

500

750

1,000

1,250

1,500

1,750

2,000

2,250

> 89 89-60 59-30 < 30

BN

P(p

g/m

L)

eGFR (mL/min/1.73m2)

Chenevier-Gobeaux et al. Clin Chim Acta 2005;361:167-75.

NT-proBNPBNP

Non-cardiac dyspneaCardiac dyspnea

Manufacture decision cut-points are unchanged



Natriuretic Peptides in Obese Patients with CHF

Krauser, et al. Am Heart J. 2005;149:744-50.

BNP

Weight Categories (BMI)

1000

500

2000

0

BN

P(p

g/m

L) 2500

3000

3500

1500

£ 25 25-29.9 ³ 30

p < 0.001NT-proBNP

£ 25 25-29.9 ³ 30Weight Categories (BMI)

NT-p

roBN

P(p

g/mL)

10000

5000

20000

0

25000

30000

15000

p < 0.001

Manufacture decision cut-points are unchanged



1.01.3 1.5

2.6

1.0

2.0

2.9

4.5

0.0

0.51.01.52.0

2.53.03.54.04.5

5.0

Q1 Q2 Q3 Q4

Adj

uste

dR

isk

Rat

ion

BNP NT-proBNP

Association Between Natriuretic Peptides and 1-Year Mortality

N = 383

De Filippi, et al. Clin Chem 2007; 53:1511-19.

QuartileBNP

pg/mLNT-proBNP

pg/mLQ1 < 88 < 472Q2 88 – 333 472 – 1728Q3 334 – 800 1729 – 6000Q4 > 800 > 6000


Comparing BNP versus NT-proBNP

Similarities DifferencesBoth show similar clinical diagnostic performancefor HF.

NT-proBNP appears more impacted by age(requiring age-specific cut-points).

Both demonstrate prognostic performance(although NT-proBNP may outperform BNP).

NT-proBNP has greater analytical stability (24hours at room temp vs. 4 hours for BNP and NT-proBNP may have greater stability when storedfrozen).

Studies for both suggest potential utility fortherapeutic monitoring.

Absolute values are very different due to alternatemechanisms of clearance.

Performance of both may be impacted by CKD(although NT-proBNP perhaps more so).

BNP values are typically in the hundreds whileNTproBNP can be in the thousands.

Both may have clinical utility outside of HF (likeACS).


Intended Use

LCZ696*A combination of sacubitril, a neprilysin inhibitor, and valsartan,an angiotensin II receptor blocker, indicated to reduce the risk ofcardiovascular death and hospitalization for heart failure in patients withchronic heart failure (NYHA Class II–IV) and reduced ejection fraction.Usually administered in conjunction with other heart failure therapies,in place of an ACE inhibitor or other ARB.

*trade name Entresto

ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker

http://www.drugs.com/imprints/nvr-l11-23381.html


Mechanism of Action of LCZ696

ValsartanBlocks the angiotensin II type-1 (AT1) receptor, inhibitingangiotensin II and the release of aldosterone.

NeprilysinAn endopeptidase that breaks down vasoactive peptides(BNP, bradykinin, and adrenomedullin); its inhibition maytherefore reduce remodeling, vasoconstriction, and renalsodium retention and improve outcomes in HFrEF.

Inhibition of neprilysin by LBQ657, the active metaboliteof sacubitril, increases the levels of these peptides,decreasing vasoconstriction, sodium retention, andmaladaptive remodeling.

LCZ696

AngiotensinReceptor Blocker

Inhibitionof Neprilysin

SacubitrilValsartan


The PARAMOUNT Trial

The angiotensin receptor-neprilysin inhibitor LCZ696 in heart failure withpreserved ejection fraction: a phase 2 double-blind randomized controlled trial.

Prospective comparison of ARNI (angiotensin receptor-neprilysin inhibitor)with ARB (angiotensin receptor blocker) on Management Of heart failUre withpreserved ejectioN fracTion (PARAMOUNT).

Solomon SD, Zile M, Pieske B, et al.Lancet. 2012;380(9851):1387–1395.


PARAMOUNT Trial: Inclusion and Exclusion Criteria

Key Inclusion Criteria

• Age ≥40 years

• Documented stable chronic heart failure (NYHAII–IV) with signs and symptoms of HF (dyspnea onexertion, orthopnea, paroxysmal nocturnaldyspnea, peripheral edema)

• LVEF ≥45%

• Plasma NT-proBNP >400 pg/mL at screening

• On diuretic therapy prior to visit 1, controlledsystolic BP (<140 mmHg, or <160 mmHg ifon three meds)

• eGFR ≥30 mL/min/1.73 m2 (MDRD)

• Patients with a K ≤5.2 mmol/L at visit 1

Key Exclusion Criteria

• Patients with a prior LVEF <45% at ANY time

• Patients who required treatment with both an ACEinhibitor and an ARB

• Isolated right HF due to pulmonary disease

• Dyspnea and/or edema from noncardiac causes,such as lung disease, anemia, or severe obesity

• Presence of valvular heart disease, hypertrophiccardiomyopathy, infiltrative cardiomyopathy, restrictivecardiomyopathy, or pericardial disease

• Coronary disease requiring revascularizationduring the study


PARAMOUNT TrialPrimary Endpoint: Significant Reduction of NT-proBNP at 12 Weeks

HR = 0.77 (0.64–0.92)P = 0.005

• Patients with HFpEF taking ENTRESTO reducedNT-proBNP to a greater extent than valsartan after 12weeks of therapy.

• This reduction became evident at 4 weeks and wassustained to 36 weeks, although the between-groupdifference was no longer significant.

• There was also a reduction in left atrial size, indicative ofreverse left atrial remodeling and improvement in NYHAclass in patients randomly assigned to ENTRESTO after 36weeks compared with those randomly assigned tovalsartan.

• ENTRESTO was well tolerated.

• These findings suggest that ENTRESTO may havebeneficial effects in patients with HFpEF and that furthertesting of this drug may be warranted in patients with thiscondition.


PARADIGM-HF Trial

N Engl J Med 2014; 371:e15September 11, 2014


Aim of the PARADIGM-HF Trial

Prospective Comparison of ARNI with ACEI to Determine Impacton Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF)

400 MG DAILY

Specifically designed to replace current use of ACE inhibitors and angiotensinreceptor blockers as the cornerstone of the treatment of heart failure.

ARNI: Angiotensin receptor-neprilysin inhibition; ACEI: angiotensin-converting enzyme inhibition

LCZ69620 MG DAILY

Enalapril


PARADIGM-HF Trial Was Designed toShow Incremental Effect on Cardiovascular Death

Primary Endpoint

• Primary endpoint was cardiovascular death or hospitalizationfor heart failure, but PARADIGM-HF was designed as acardiovascular mortality trial.

• The sample size of the trial was determined by effect oncardiovascular mortality, not the primary endpoint.

• The Data Monitoring Committee was allowed to stop the trialonly for a compelling effect on cardiovascular mortality (inaddition to the primary endpoint).

• Difference in cardiovascular mortality of 15% betweenLCZ696 and enalapril was prospectively identified as beingclinically important.

Secondary Endpoints

• All-cause mortality.

• Change from baseline in the clinicalsummary score of the Kansas CityCardiomyopathy Questionnaire (KCCQ)at 8 months.

• Time to new onset of atrial fibrillation.

• Time to first occurrence of a protocol-defined decline in renal function.


PARADIGM-HF

558 (13.3%)

693 (16.5%)

914 (21.8%)

1117 (26.5%)

N Engl J Med. 2014 Sep 11;371:e15.

HR = 0.80 (0.73–0.87)P = 0.0000002

Number needed to treat = 21

HR = 0.80 (0.71–0.89)P = 0.00004

Number needed to treat = 32


537 (12.8%)

658 (15.6%)

711 (17.0%)

835 (19.8%)

PARADIGM-HF

N Engl J Med 2014; 371:e15September 11, 2014


PARADIGM-HF: Cause of Death and Hospitalization Data

PARADIGM-HF Cause of Death and Hospitalization Datavs. Current Standard of Care ACEi Enalapril

McMurray et al. NEJM 2014;371:993–1004; Packer et al. Circulation 2015;131:54-61


Change in KCCQ Score at 8 Months

LCZ696

Enalapril

LCZ696 improved the symptoms and physical limitationsof heart failure more than enalapril, p = 0.001.


PARADIGM-HF: Conclusions

In comparison with guideline-recommended doses of an ACE inhibitor, combinedinhibition of both the angiotensin receptor and neprilysin was more effective not only inreducing all-cause and cardiovascular mortality, but also in reducing the risks and rates ofmultiple manifestations of clinical deterioration of surviving patients with heart failure. Theeffect of LCZ696 to stabilize the course of heart failure is likely to have importantramifications for both quality of life and resource utilization in this disorder.


PARADIGM-HF Trial

Circulation. 2015;131:54–61.


The Effect of LCZ696 on NT-proBNP and BNP

In contrast, in comparison with enalapril,patients receiving LCZ696 had consistentlylower levels of NT-proBNP (reflecting reducedcardiac wall stress) and troponin (reflectingreduced cardiac injury) throughout the trial.

The contrasting effects of LCZ696 on thetwo types of natriuretic peptides represent animportant finding, because the levels of thetwo peptides characteristically parallel eachother during the course of heart failure.

However, because BNP (but not NT-proBNP)is a substrate for neprilysin, levels of BNP willreflect the action of the drug, whereas levelsof NT-proBNP will reflect the effects of thedrug on the heart.

LCZ696 Enalapril


Summary

PARAMOUNT Trial

• Patients with HFpEF taking ENTRESTO ascompared to valsartan reduced NT-proBNP to agreater extent than valsartan after 12 weeks oftherapy.

• This reduction became evident at 4 weeks and wassustained to 36 weeks, although the between-groupdifference was no longer significant.

• There was also a reduction in left atrial size,indicative of reverse left atrial remodeling andimprovement in NYHA class in patients randomlyassigned to ENTRESTO after 36 weeks comparedwith those randomly assigned to valsartan.

• ENTRESTO was well tolerated.

• These findings suggest that ENTRESTO may havebeneficial effects in patients with HFpEF and thatfurther testing of this drug may be warranted inpatients with this condition.

• ENTRESTO is not currently approved for treatmentof patients with HFpEF.

PARADIGM-HF Trial

• LCZ696 was more effective than enalapril for patients withHFrEF in reducing the risk of CV death and HFhospitalization, reducing the risk of CV death, reducingthe risk of HF hospitalization, reducing all-cause mortality,and incrementally improving symptoms and physicallimitations.

• LCZ696 was better tolerated than enalapril and less likelyto cause cough, hyperkalemia, or renal impairment.

• Less likely to be discontinued due to an adverse event.

• More hypotension, but no increase in discontinuations.

• Not more likely to cause serious angioedema.

• However, because BNP (but not NT-proBNP) is asubstrate for neprilysin, levels of BNP will reflect theaction of the drug, whereas levels of NT-proBNP willreflect the effects of the drug on the heart.

• ENTRESTO was FDA-approved to treat chronic HFpatients with reduced HFrEF.


• Linda C. Rogers, PhD, DABCC, FACBSenior Clinical Consultant

• Siemens Healthcare

• Scientific & Clinical Affairs

• Phone: (949)421-9101Email: [email protected]

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