Biomarkers in Heart Failure

W. H. Wilson Tang, MD FACC FAHAAssociate Professor of Medicine, Cleveland Clinic Lerner College of MedicineResearch Director & Director of Cardiomyopathy Program, Kaufman Center for Heart FailureMedical Director, Center for Cardiovascular Diagnostics and Prevention

Heart & Vascular Institute

Biomarkers In Heart Failure

Heart Failure Teleconference ● June 25, 2011

Biomarkers in Heart Failure l June 25, 2011 l 2

Biomarker: Definition

A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

NIH Biomarkers Definition Working Group. Atkinson, et al. Clin Pharmacol Ther 2001

Discovery Confirmation Validation & Refinement

Adoption

Identification Established relevance to population Identify clinical utility


Whellan et al, Am Heart J Suppl 2007

Monitoring Heart Failure: Necessary Pre-requisites

• Broadly available

• Accurate and precise

• Consist results

• Responsive to interventions

– Non-pharmacologic

– Pharmacologic

• Reimbursed


Objectives of Biomarker Testing in Heart Failure

Diagnosis:

1. To establish or refute a diagnosis

2. To understand the underlying pathophysiologic processes

Risk Stratification / Screening:

3. To determine the presence or level of severity of disease

4. To detect adverse consequences

Monitoring / Therapeutic Guidance:

5. To guide or monitor responses to treatment.

Condition X

Outcome A

Outcome B

Biomarker

Intervention


Non-Specific Blood Biomarkers in Heart Failure

Tang W, Biomarkers Med 2009; Braunwald, HF Clin NA 2009

• BUN, creatinine, microalbuminuria

• Bilirubin, INR, albumin, AST/ALT

• Fasting cholesterol panel

• Sodium, potassium

• Hemoglobin

• Iron deficiency panel

• Thyroid panel

• Uric acid

• Leukocyte count

• C-reactive protein


Biomarker Discovery

De Couto et al, Nat Rev Cardiol 2010


Natriuretic Peptide Testing in Acute Heart Failure

Januzzi et al, AJC 2006Maisel et al N Engl J Med 2002Biosite BNP (pg/ml) Roche NT-proBNP

Negative Predictive Value >90%


Increase BNP• Increasing age

• Female gender

• Renal insufficiency

• Thyroid disorders

• Atrial fibrillation

• Cardiac surgery

• Anemia

• Pulmonary hypertension

• Pulmonary embolism

• Mitral regurgitation

• Right ventricular failure

• Genetic predisposition

• Beta-blocker therapy (transient)

• Anti-androgen therapy

Decrease BNP• Stunning

• Obesity

• Diuretics

• RAAS drugs

Confounders of Plasma BNP Levels

Troughton et al, J Am Coll Cardiol 2004


Incremental Benefit with Natriuretic Peptide Testing in Acute Heart Failure

Muller et al, N Engl J Med 2003

Moe et al, Circulation 2007

IMPROVE-CHF

BASEL

Biosite BNP (pg/ml)

Roche NT-proBNP (pg/ml)


Incremental Benefit with Natriuretic Peptide Testing in Acute Heart Failure

Muller et al, N Engl J Med 2003

Moe et al, Circulation 2007

IMPROVE-CHF

BASEL

Biosite BNP (pg/ml)


HFSA 2010 Guideline Recommendation 4.6: It is recommended that BNP or NT-proBNP levels be assessed in all patients suspected of having HF, especially when the diagnosis is not certain.

(Strength of Evidence = A)


Risk Stratification: BNP in Acute Heart Failure

Logeart et al, J Am Coll Cardiol 2004Biosite BNP (pg/ml)


Risk Stratification: Concordance with Clinical Status

Morrow et al, JAMA 2005Bayer ADVIA BNP (in pg/ml)

High BNP at Month 4

Low BNP at Month 4


Current FDA-Cleared Indications for NPs

• Aid in the diagnosis of individuals suspected of having congestive heart failure (all assays):– BNP: ≥100 pg/mL

– NT-proBNP: ≥125 pg/mL

• Aid in risk stratification: (Biosite, Siemens, Roche)– Acute coronary syndromes:

–BNP ≥80 pg/mL; NT-proBNP ≥240 pg/mL

– Heart failure:

–BNP ≥100 pg/mL; NT-proBNP ≥1,000 pg/mL

• Aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease: (Roche)– NT-proBNP ≥ 125 pg/mL


Refinement: Criteria for a Clinically Useful Biomarker

• Can the clinician measure it?– Accurate and reproducible methods

– Rapid turn around

– Reasonable costs

• Does it add new information?– Strong and consistent association between marker and outcome or

disease of interest in multiple studies

– Decision limits are validated in generalizable populations

• Will it help with management?– Superior performance to existing tests

– Evidence that it enhances outcomes or process of care

• Can it be incorporated into workflow?

Morrow & Braunwald, Circulation 2007


• Risk-Driven Management: “looking back”– “Spot check”

– Identify vulnerability

– Variety of tools (external / implanted)

• Event-Directed Management: “looking now”– Interval assessments

– Alert vulnerability

– Infrastructure and response solutions needed

• Goal-Directed Management: “looking forward”– Disease- and therapy-specific

– Reduce vulnerability

– Infrastructure and response solutions needed

– Potential for closed-loop system

Biomarker-Guided Strategies in Heart Failure

Samara & Tang, Heart Fail Rev 2011


Risk Stratification: Multimarker Strategy (Serial)

Miller et al, Circulation 2007Shionogi BNP (pg/ml)


Natriuretic Peptide-Guided Therapy: BATTLE-SCARRED

Richards et al, JACC 2009


Natriuretic Peptide-Guided Therapy: PROTECT

Patient with Class IIPatient with Class II--IV symptoms, EF IV symptoms, EF 40%, recent HF event40%, recent HF event

Randomization echocardiogramRandomization echocardiogram

Standard of CareStandard of Care

Minnesota Living With HF Minnesota Living With HF Questionnaire quarterlyQuestionnaire quarterly

Standard of Care + NTStandard of Care + NT--proBNPproBNP


Therapy adjusted to achieve Therapy adjusted to achieve optimal drug targetsoptimal drug targets

Visits q3 monthsVisits q3 months

Extra visits as needed for treatment goalsExtra visits as needed for treatment goals

Therapy adjusted to achieve optimal drug Therapy adjusted to achieve optimal drug targets targets PLUSPLUS NTNT--proBNP proBNP 1000 pg/1000 pg/mLmL



CloseClose--out echocardiogramout echocardiogram

Total cardiovascular events assessedTotal cardiovascular events assessed

Patient with Class IIPatient with Class II--IV symptoms, EF IV symptoms, EF 40%, recent HF event40%, recent HF event

Randomization echocardiogramRandomization echocardiogramRandomization echocardiogramRandomization echocardiogram

























Januzzi et al, AHA Late-Breaking Clinical Trial (2010)


Natriuretic Peptide-Guided Therapy: PROTECT

Januzzi et al, AHA Late-Breaking Clinical Trial (2010)

Treatment arm

80.0%69.9%<3000 pg/mL68.6%57.5%<2000 pg/mL44.3%35.6%<1000 pg/mL

NT-proBNPSOCAchieved valueTreatment arm

80.0%69.9%<3000 pg/mL68.6%57.5%<2000 pg/mL44.3%35.6%<1000 pg/mL

NT-proBNPSOCAchieved value

Days from enrollment0 73 146 219 292 365

0

0.2

0.4

0.6

0.8

1.0

Eve

nt f

ree

surv

iva

l

Log rank Log rank PP =.03=.03

StandardStandard--ofof--care (N=76)care (N=76)

NTNT--proBNP (N=75)proBNP (N=75)

StandardStandard--ofof--care (N=76)care (N=76)

NTNT--proBNP (N=75)proBNP (N=75)

0

20

40

60

80

100

120

Total CV Events

Nu

mb

er o

f ev

ents

100 events100 events

58 events58 events

PP =.009=.009PP =.009=.009 SOCNT-proBNPSOCNT-proBNP

*Logistic OddsNT-proBNP= 0.44 (95% CI= .22-.84; P =.019)

*Logistic *Logistic OddsOddsNTNT--proBNPproBNP= 0.44 = 0.44 (95% CI= .22(95% CI= .22--.84; .84; PP =.019)=.019)

*Adjusted for age, LVEF, NYHA Class, and age, LVEF, NYHA Class, and eGFReGFR

*Logistic OddsNT-proBNP= 0.44 (95% CI= .22-.84; P =.019)

*Logistic *Logistic OddsOddsNTNT--proBNPproBNP= 0.44 = 0.44 (95% CI= .22(95% CI= .22--.84; .84; PP =.019)=.019)

*Adjusted for age, LVEF, NYHA Class, and age, LVEF, NYHA Class, and eGFReGFR

Changes in therapy at follow-up (NT-proBNP vs SOC):

Aldo antagonists (63% vs 45%, p=0.001) Loop diuretics (85% vs 96%, p=0.05)


Monitoring Progression Towards Heart Failure

Adapted from Jessup et al, Circulation 2009; and Aamer et al, Circulation 2007

50-60 million

8-10 million

High Risk for Developing HFHypertension

CADDiabetes mellitus

Family history of cardiomyopathy

Asymptomatic HFPrevious MI

LV systolic dysfunctionAsymptomatic valvular disease

Symptomatic HFKnown structural heart diseaseShortness of breath and fatigue

Reduced exercise tolerance

Refractory End-Stage HF

Marked symptoms at restdespite maximal medical therapy

A

B

C

D5 million

0.2 million

New York Heart Association Classification

IV

III

II

I

Established HF Diagnosis

ACC/AHA Staging Olmsted (45+ yrs)

0.2%

12%

34%

22%

32%Normals


Screening: Echocardiographic Abnormalities (Olmsted County)

McKie et al, Hypertension 2006

Prevalence(%)

Prevalence(%)

0

10

20

30

40

EF <50EF <50 ValvulardiseaseValvulardisease

RWMARWMA Diastolicdysfunction

Diastolicdysfunction

LVHLVHLAELAE

Lowest third

Middle third

Highest third

Lowest third

Middle third

Highest third



Screening: Echocardiographic Abnormalities (Olmsted County)


Prevalence(%)

Prevalence(%)

0

10

20

30

40

EF <50EF <50 ValvulardiseaseValvulardisease

RWMARWMA Diastolicdysfunction

Diastolicdysfunction

LVHLVHLAELAE

Lowest third

Middle third

Highest third

Lowest third

Middle third

Highest third


HFSA 2010 Guideline Recommendation 4.3: Routine determination of plasma B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) concentration as part of a screening evaluation for structural heart disease in asymptomatic patients is not recommended.

(Strength of Evidence = B)



Cu

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ival

Cu

mu

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urv

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YearsYears0 1 2 3 4 5 6 7

0.0

0.2

0.4

0.6

0.8

1.0

NT-proBNPNT-proBNPAAAA

647 646 644 643 640 479 212 29646 646 645 642 639 450 193 34646 641 635 619 604 413 201 33

647 646 644 643 640 479 212 29646 646 645 642 639 450 193 34646 641 635 619 604 413 201 33

No. at RiskLowest thirdMiddle thirdHighest third

No. at RiskLowest thirdMiddle thirdHighest third

YearsYears

BiositeBiositeCCCC

0 1 2 3 4 5 6 7

624 624 622 621 618 464 219 28624 623 621 617 614 433 205 31624 621 617 603 589 401 207 36

624 624 622 621 618 464 219 28624 623 621 617 614 433 205 31624 621 617 603 589 401 207 36

Lowest thirdLowest third

Middle thirdMiddle third

Highest thirdHighest third

Lowest third <13.4 pg/mL

Middle third 13.4–39.7 pg/mL

Highest third >39.7 pg/mL

Lowest third <36.7 pg/mL

Middle third 36.7-109.0 pg/mL

Highest third >109.0 pg/mL

Prognostic Value of “Screening” Natriuretic Peptides


Subclinical Myocardial Damage and CV Risk

Tang et al, Art Thromb Vasc Biol 2010

Cardinale et al, Circulation 2006

No ACE-I ACE-I

LV

EF

(%

)

cTnI >0.07 ng/mL

• 114 out of 473 (24%) recipients of high-dose chemotherapy


Hare et al, J Am Coll Cardiol 2008 Liggett et al, Nature Med 2008

Linking Biomarkers to Therapy


“Clinicians caring for patients with heart failure are no strangers to ambiguity of clinical presentation and imprecision of diagnostic and monitoring tools…. Anyone who demands the ultimate proof or "evidence" for the clinical utility of natriuretic peptide testing should reflect on what evidence should be demanded for a diagnostic test and whether such standards have been imposed on other clinical tests.”

Tang WH, Circulation Heart Failure 2009

Biomarkers in Heart Failure

Health & Medicine

pgml heart failure

acute heart failure

acute heart failure

acute heart failure

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monitoring heart failure

pgml high bnp

pgml ntprobnp