Biomarkers In Heart Failure Heart Failure Teleconference  ●  June 25, 2011
Biomarker:  Definition <ul><li>A characteristic that is objectively measured and evaluated as an indicator of normal biolo...
Monitoring Heart Failure:  Necessary Pre-requisites <ul><li>Broadly available </li></ul><ul><li>Accurate and precise </li>...
Objectives of Biomarker Testing in Heart Failure <ul><li>Diagnosis: </li></ul><ul><li>To establish or refute a diagnosis  ...
Non-Specific Blood Biomarkers in Heart Failure  <ul><li>BUN, creatinine, microalbuminuria </li></ul><ul><li>Bilirubin, INR...
Biomarker Discovery De Couto et al,  Nat Rev Cardiol  2010
Natriuretic Peptide Testing in Acute Heart Failure Januzzi et al,  AJC  2006 Maisel et al  N Engl J Med  2002 Biosite BNP ...
Confounders of Plasma BNP Levels <ul><li>Increase BNP </li></ul><ul><li>Increasing age </li></ul><ul><li>Female gender </l...
Incremental Benefit with Natriuretic Peptide Testing in Acute Heart Failure Muller et al,  N Engl J Med  2003  Moe et al, ...
Incremental Benefit with Natriuretic Peptide Testing in Acute Heart Failure Muller et al,  N Engl J Med  2003  Moe et al, ...
Risk Stratification:  BNP in Acute Heart Failure Logeart et al,  J Am Coll Cardiol  2004 Biosite BNP (pg/ml)
Risk Stratification:  Concordance with Clinical Status Morrow et al,  JAMA  2005 Bayer ADVIA BNP (in pg/ml) High BNP at Mo...
Current FDA-Cleared Indications for NPs <ul><li>Aid in the  diagnosis  of individuals suspected of having congestive heart...
Refinement:  Criteria for a Clinically Useful Biomarker <ul><li>Can the clinician measure it? </li></ul><ul><ul><li>Accura...
Biomarker-Guided Strategies in Heart Failure <ul><li>Risk-Driven Management:  “looking back” </li></ul><ul><ul><li>“ Spot ...
Risk Stratification:  Multimarker Strategy (Serial) Miller et al,  Circulation  2007 Shionogi BNP (pg/ml)
Natriuretic Peptide-Guided Therapy:  BATTLE-SCARRED Richards et al,  JACC  2009
Natriuretic Peptide-Guided Therapy:  PROTECT Januzzi et al , AHA Late-Breaking Clinical Trial (2010)
Natriuretic Peptide-Guided Therapy:  PROTECT Januzzi et al , AHA Late-Breaking Clinical Trial (2010) <ul><li>Changes in th...
Monitoring Progression Towards Heart Failure Adapted from Jessup et al,  Circulation  2009; and Aamer et al,  Circulation ...
Screening:  Echocardiographic Abnormalities (Olmsted County) McKie et al,  Hypertension  2006 Roche NT-proBNP (pg/ml)
Screening:  Echocardiographic Abnormalities (Olmsted County) McKie et al,  Hypertension  2006 Roche NT-proBNP (pg/ml) HFSA...
Prognostic Value of “Screening” Natriuretic Peptides McKie et al,  Hypertension  2006 Lowest third <13.4 pg/mL Middle thir...
Subclinical Myocardial Damage and CV Risk Tang et al,  Art Thromb Vasc Biol  2010 Cardinale et al,  Circulation  2006 <ul>...
Linking Biomarkers to Therapy Hare et al,  J Am Coll Cardiol  2008 Liggett et al,  Nature Med  2008
<ul><li>“ Clinicians caring for patients with heart failure are no strangers to ambiguity of clinical presentation and imp...
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Biomarkers in Heart Failure

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Biomarkers in Heart Failure

  1. 1. Biomarkers In Heart Failure Heart Failure Teleconference ● June 25, 2011
  2. 2. Biomarker: Definition <ul><li>A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. </li></ul>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
  3. 3. Monitoring Heart Failure: Necessary Pre-requisites <ul><li>Broadly available </li></ul><ul><li>Accurate and precise </li></ul><ul><li>Consist results </li></ul><ul><li>Responsive to interventions </li></ul><ul><ul><li>Non-pharmacologic </li></ul></ul><ul><ul><li>Pharmacologic </li></ul></ul><ul><li>Reimbursed </li></ul>Whellan et al, Am Heart J Suppl 2007
  4. 4. Objectives of Biomarker Testing in Heart Failure <ul><li>Diagnosis: </li></ul><ul><li>To establish or refute a diagnosis </li></ul><ul><li>To understand the underlying pathophysiologic processes </li></ul><ul><li>Risk Stratification / Screening: </li></ul><ul><li>To determine the presence or level of severity of disease </li></ul><ul><li>To detect adverse consequences </li></ul><ul><li>Monitoring / Therapeutic Guidance: </li></ul><ul><li>To guide or monitor responses to treatment. </li></ul>Condition X Outcome A Outcome B Biomarker Intervention
  5. 5. Non-Specific Blood Biomarkers in Heart Failure <ul><li>BUN, creatinine, microalbuminuria </li></ul><ul><li>Bilirubin, INR, albumin, AST/ALT </li></ul><ul><li>Fasting cholesterol panel </li></ul><ul><li>Sodium, potassium </li></ul><ul><li>Hemoglobin </li></ul><ul><li>Iron deficiency panel </li></ul><ul><li>Thyroid panel </li></ul><ul><li>Uric acid </li></ul><ul><li>Leukocyte count </li></ul><ul><li>C-reactive protein </li></ul>Tang W, Biomarkers Med 2009; Braunwald, HF Clin NA 2009
  6. 6. Biomarker Discovery De Couto et al, Nat Rev Cardiol 2010
  7. 7. Natriuretic Peptide Testing in Acute Heart Failure Januzzi et al, AJC 2006 Maisel et al N Engl J Med 2002 Biosite BNP (pg/ml) Roche NT-proBNP Negative Predictive Value >90%
  8. 8. Confounders of Plasma BNP Levels <ul><li>Increase BNP </li></ul><ul><li>Increasing age </li></ul><ul><li>Female gender </li></ul><ul><li>Renal insufficiency </li></ul><ul><li>Thyroid disorders </li></ul><ul><li>Atrial fibrillation </li></ul><ul><li>Cardiac surgery </li></ul><ul><li>Anemia </li></ul><ul><li>Pulmonary hypertension </li></ul><ul><li>Pulmonary embolism </li></ul><ul><li>Mitral regurgitation </li></ul><ul><li>Right ventricular failure </li></ul><ul><li>Genetic predisposition </li></ul><ul><li>Beta-blocker therapy (transient) </li></ul><ul><li>Anti-androgen therapy </li></ul><ul><li>Decrease BNP </li></ul><ul><li>Stunning </li></ul><ul><li>Obesity </li></ul><ul><li>Diuretics </li></ul><ul><li>RAAS drugs </li></ul>Troughton et al, J Am Coll Cardiol 2004
  9. 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)
  10. 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)
  11. 11. Risk Stratification: BNP in Acute Heart Failure Logeart et al, J Am Coll Cardiol 2004 Biosite BNP (pg/ml)
  12. 12. Risk Stratification: Concordance with Clinical Status Morrow et al, JAMA 2005 Bayer ADVIA BNP (in pg/ml) High BNP at Month 4 Low BNP at Month 4
  13. 13. Current FDA-Cleared Indications for NPs <ul><li>Aid in the diagnosis of individuals suspected of having congestive heart failure (all assays): </li></ul><ul><ul><li>BNP: ≥ 100 pg/mL </li></ul></ul><ul><ul><li>NT-proBNP: ≥ 125 pg/mL </li></ul></ul><ul><li>Aid in risk stratification : (Biosite, Siemens, Roche) </li></ul><ul><ul><li>Acute coronary syndromes: </li></ul></ul><ul><ul><ul><li>BNP ≥ 80 pg/mL; NT-proBNP ≥ 240 pg/mL </li></ul></ul></ul><ul><ul><li>Heart failure: </li></ul></ul><ul><ul><ul><li>BNP ≥ 100 pg/mL; NT-proBNP ≥ 1,000 pg/mL </li></ul></ul></ul><ul><li>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) </li></ul><ul><ul><li>NT-proBNP ≥ 125 pg/mL </li></ul></ul>
  14. 14. Refinement: Criteria for a Clinically Useful Biomarker <ul><li>Can the clinician measure it? </li></ul><ul><ul><li>Accurate and reproducible methods </li></ul></ul><ul><ul><li>Rapid turn around </li></ul></ul><ul><ul><li>Reasonable costs </li></ul></ul><ul><li>Does it add new information? </li></ul><ul><ul><li>Strong and consistent association between marker and outcome or disease of interest in multiple studies </li></ul></ul><ul><ul><li>Decision limits are validated in generalizable populations </li></ul></ul><ul><li>Will it help with management? </li></ul><ul><ul><li>Superior performance to existing tests </li></ul></ul><ul><ul><li>Evidence that it enhances outcomes or process of care </li></ul></ul><ul><li>Can it be incorporated into workflow? </li></ul>Morrow & Braunwald, Circulation 2007
  15. 15. Biomarker-Guided Strategies in Heart Failure <ul><li>Risk-Driven Management: “looking back” </li></ul><ul><ul><li>“ Spot check” </li></ul></ul><ul><ul><li>Identify vulnerability </li></ul></ul><ul><ul><li>Variety of tools (external / implanted) </li></ul></ul><ul><li>Event-Directed Management: “looking now” </li></ul><ul><ul><li>Interval assessments </li></ul></ul><ul><ul><li>Alert vulnerability </li></ul></ul><ul><ul><li>Infrastructure and response solutions needed </li></ul></ul><ul><li>Goal-Directed Management: “looking forward” </li></ul><ul><ul><li>Disease- and therapy-specific </li></ul></ul><ul><ul><li>Reduce vulnerability </li></ul></ul><ul><ul><li>Infrastructure and response solutions needed </li></ul></ul><ul><ul><li>Potential for closed-loop system </li></ul></ul>Samara & Tang, Heart Fail Rev 2011
  16. 16. Risk Stratification: Multimarker Strategy (Serial) Miller et al, Circulation 2007 Shionogi BNP (pg/ml)
  17. 17. Natriuretic Peptide-Guided Therapy: BATTLE-SCARRED Richards et al, JACC 2009
  18. 18. Natriuretic Peptide-Guided Therapy: PROTECT Januzzi et al , AHA Late-Breaking Clinical Trial (2010)
  19. 19. Natriuretic Peptide-Guided Therapy: PROTECT Januzzi et al , AHA Late-Breaking Clinical Trial (2010) <ul><li>Changes in therapy at follow-up </li></ul><ul><li>(NT-proBNP vs SOC): </li></ul><ul><li> Aldo antagonists (63% vs 45%, p=0.001) </li></ul><ul><li> Loop diuretics (85% vs 96%, p=0.05) </li></ul>
  20. 20. Monitoring Progression Towards Heart Failure Adapted from Jessup et al, Circulation 2009; and Aamer et al, Circulation 2007
  21. 21. Screening: Echocardiographic Abnormalities (Olmsted County) McKie et al, Hypertension 2006 Roche NT-proBNP (pg/ml)
  22. 22. Screening: Echocardiographic Abnormalities (Olmsted County) McKie et al, Hypertension 2006 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)
  23. 23. Prognostic Value of “Screening” Natriuretic Peptides McKie et al, Hypertension 2006 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
  24. 24. Subclinical Myocardial Damage and CV Risk Tang et al, Art Thromb Vasc Biol 2010 Cardinale et al, Circulation 2006 <ul><li>cTnI >0.07 ng/mL </li></ul><ul><li>114 out of 473 (24%) recipients of high-dose chemotherapy </li></ul>No ACE-I ACE-I LVEF (%)
  25. 25. Linking Biomarkers to Therapy Hare et al, J Am Coll Cardiol 2008 Liggett et al, Nature Med 2008
  26. 26. <ul><li>“ 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 &quot;evidence&quot; 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.” </li></ul><ul><ul><li>Tang WH, Circulation Heart Failure 2009 </li></ul></ul>

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