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Biomarcadores en Falla Cardíaca
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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
Biomarkers in Heart Failure l June 25, 2011 l 3
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
Biomarkers in Heart Failure l June 25, 2011 l 4
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
Biomarkers in Heart Failure l June 25, 2011 l 5
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
Biomarkers in Heart Failure l June 25, 2011 l 6
Biomarker Discovery
De Couto et al, Nat Rev Cardiol 2010
Biomarkers in Heart Failure l June 25, 2011 l 7
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%
Biomarkers in Heart Failure l June 25, 2011 l 8
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
Biomarkers in Heart Failure l June 25, 2011 l 9
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)
Biomarkers in Heart Failure l June 25, 2011 l 10
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)
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)
Biomarkers in Heart Failure l June 25, 2011 l 11
Risk Stratification: BNP in Acute Heart Failure
Logeart et al, J Am Coll Cardiol 2004Biosite BNP (pg/ml)
Biomarkers in Heart Failure l June 25, 2011 l 12
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
Biomarkers in Heart Failure l June 25, 2011 l 13
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
Biomarkers in Heart Failure l June 25, 2011 l 14
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
Biomarkers in Heart Failure l June 25, 2011 l 15
• 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
Biomarkers in Heart Failure l June 25, 2011 l 16
Risk Stratification: Multimarker Strategy (Serial)
Miller et al, Circulation 2007Shionogi BNP (pg/ml)
Biomarkers in Heart Failure l June 25, 2011 l 17
Natriuretic Peptide-Guided Therapy: BATTLE-SCARRED
Richards et al, JACC 2009
Biomarkers in Heart Failure l June 25, 2011 l 18
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
Minnesota Living With HF Minnesota Living With HF Questionnaire quarterlyQuestionnaire quarterly
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
Visits q3 monthsVisits q3 months
Extra visits as needed for treatment goalsExtra visits as needed for treatment goals
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
Standard of CareStandard of Care
Minnesota Living With HF Minnesota Living With HF Questionnaire quarterlyQuestionnaire quarterly
Standard of Care + NTStandard of Care + NT--proBNPproBNP
Minnesota Living With HF Minnesota Living With HF Questionnaire quarterlyQuestionnaire quarterly
Standard of CareStandard of Care
Minnesota Living With HF Minnesota Living With HF Questionnaire quarterlyQuestionnaire quarterly
Standard of Care + NTStandard of Care + NT--proBNPproBNP
Minnesota Living With HF Minnesota Living With HF Questionnaire quarterlyQuestionnaire quarterly
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 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
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
Visits q3 monthsVisits q3 months
Extra visits as needed for treatment goalsExtra visits as needed for treatment goals
CloseClose--out echocardiogramout echocardiogram
Total cardiovascular events assessedTotal cardiovascular events assessed
CloseClose--out echocardiogramout echocardiogram
Total cardiovascular events assessedTotal cardiovascular events assessed
Januzzi et al, AHA Late-Breaking Clinical Trial (2010)
Biomarkers in Heart Failure l June 25, 2011 l 19
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)
Biomarkers in Heart Failure l June 25, 2011 l 20
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
Biomarkers in Heart Failure l June 25, 2011 l 21
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
Roche NT-proBNP (pg/ml)
Biomarkers in Heart Failure l June 25, 2011 l 22
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
Roche NT-proBNP (pg/ml)
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)
Biomarkers in Heart Failure l June 25, 2011 l 23
McKie et al, Hypertension 2006
Cu
mu
lati
ve s
urv
ival
Cu
mu
lati
ve s
urv
ival
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
Biomarkers in Heart Failure l June 25, 2011 l 24
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
Biomarkers in Heart Failure l June 25, 2011 l 25
Hare et al, J Am Coll Cardiol 2008 Liggett et al, Nature Med 2008
Linking Biomarkers to Therapy
Biomarkers in Heart Failure l June 25, 2011 l 26
“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