Pitfalls in the use of biomarkers Alan Maisel MD Professor of Medicine, University of California, San Diego Director Coronary Care Unit And Heart Failure Program San Diego Veterans Hospital
Disclosure information Alan Maisel MD Research support: Alere,Abbott,Brahms- ThermoFisher,Nanosphere Consultant: Alere
The Ideal Biomarker Sensitive and specific Reflects disease severity Correlates with prognosis 2007 2011 Should aid in clinical decision making Either highly sensitive (diagnosis) OR highly specific (treatment effect) Reflects abnormal physiology/biochemistry Prognosis is most meaningful if level is clinically actionable Should be used as a basis for specific biomarker guided-therapy Level should decrease following effective therapy Bio-monitoring during treatment is an effective surrogate of improvement Maisel, JACC 2011
What is the major limitation of using biomarkers in clinical practice?
Excessive Shortness of Breath We Need Rapid and Accurate Diagnosis and treatment THIS COULD BE YOUR MOTHER
Number of Cases How sure are we about the diagnosis of AHF?? 350 300 250 Significant Indecision Exists 43 % 200 150 Pretest Probability of CHF 100 50 0 0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 McCullough, Maisel et al. Circulation. 2002;106:416 422.
Well, Bob, it looks like a paper cut, but just to be sure. Let s get an echo.
mortality (%) What happens if we misdiagnose the acute breathless patient? 14 12 10 8 6 Dyspnea of respiratory origin P<0,05 8 14 4 2 4 0 Wuerz. Ann Emerg Med 1992;21:669-674 bronchodilators No therapy CHF Therapy
Getting it right is important Accuracy counts
Pre-Pro-BNP 1-134 Pro-BNP 1-108 N-terminal Pro-BNP 1-76 BNP 77-108 t 1/2 = 18 min WALL STRESS Pro-BNP 1-108
BNP NT-pro bnp
Breathing Not Properly and Pride STUDY The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency department (PRIDE) study James L. Januzzi Jr, MD, Carlos A. Camargo, MD, PhD, Saif Anwaruddin, MD, Aaron L. Baggish, MD, Annabel A. Chen, MD, Daniel G. Krauser, MD, Roderick Tung, MD, Renee Cameron, MS, J. Tobias Nagurney, MD, Claudia U. Chae, MD, MPH, Donald M. Lloyd-Jones, MD, ScM, David F. Brown, MD, Stacy Foran- Melanson, MD, PhD, Patrick M. Sluss, MD, PhD, Elizabeth Lee- Lewandrowski, PhD, MPH, Kent B. Lewandrowski, MD
Sensitivity Accuracy is 90% Optimal cut-off point determined @ 100 pg/ml 1.0 0.8 0.6 0.4 BNP=50 pg/ml BNP=80 pg/ml BNP=100 pg/ml BNP=125 pg/ml BNP=150 pg/ml Positive predictive value=75% 0.2 0.0 BNP 100 pg/ml Test positive BNP <100 pg/ml Test negative Final Diagnosis Heart Failure Final Diagnosis NOT Heart Failure 673 227 71 Sensitivity =90% 615 Specificity =73% Negative predictive value=90 % 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificity Maisel AS et al. N Engl J Med. 2002;347:161-167.
BNP levels adds to the physician s ability McCullough, Maisel et al., Circulation 2002 106:416-422
Cost-Effectiveness of BNP at ED: The BASEL Study P=0.001 $8000 $6000 $4000 1,545 Savings/Patient Biosite Triage BNP (in pg/ml) $2000 Mueller C, et al. N Engl J Med. 2004;350:647-654. 0
You can t win them all (ask R.Federer) : Caveats to NP testing Dry versus wet BNP Gray Zone Renal dysfunction Obesity Heart Failure with normal levels Gender differences
BNP level (pg/ml) NP level = baseline NP(dry) plus change due to increased volume(wet) Wet (Change due to volume overload) Dry ( NYHA Euvolemic state) NYHA Class - Euvolemic (Dry) BNP
Rule out Rule in Probability (RRT) Grey Zone 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 BM <xx High NPV PROGNOSTIC UNCERTAINTY Grey area Biomarker X BM >XX High PPV
Grey Zone BNP 26.4% of all cases 16.5% CHF 7.9% No CHF McCullough PA, Steg PG, Aumont MC, Duc P, Omland T, Knudsen CW, Nowak RM, McCord J, Hollander JE, Westheim A, Storrow AB, Abraham WT, Lamba S, Wu AHB, Maisel AS, BNP Multinational Study Investigators. What Causes Elevated B-Type Natriuretic Peptide in Patients Without Heart Failure? J Am Coll Cardiol 2003;41:278A.
Maisel, Valle, Aspromente et Al EJHF 2009 Obesity There appears to be a linear inverse relationship between BMI and NP levels Patients who are obese (BMI >35kg/m 2 ) should have their NP doubled to use the standard cutpoints.
McCullough PA,Maisel AS et al. For the BNP Multinational Study Investigators. American Journal of Kidney Disease2008 Mean BNP by egfr- you can still diagnose heart failure cgfr, ml/min/1.73 m 2
The Differential Diagnosis of an Elevated Natriuretic Peptide Unrecognized HF Prior HF LVH Valvular heart disease Atrial fibrillation Advancing age Myocarditis ACS Pulmonary hypertension Congenital heart disease Anemia Pulmonary embolism Cardiac surgery Sleep apnea Critical illness Sepsis Burns Renal failure Toxic-metabolic insults
Normal levels of BNP Heart failure Mistaken for HF Flash pulmonary edema Acute atrial fibrillation Acute papillary muscle rupture Cardiac Tamponade Constrictive pericarditis
Women are more complex than men!
The Female Heart Women have higher basal heart rate than men Women have smaller cardiac vasculature Female hormones effect some cardiac functions Women are more likely than men to have some arrhythmias (Long QT Syndrome, AVNRT, polymorphic VT, et al.)
Age and Sex-Specific Reference Values for BNP 95 th %ile Framingham Study Increase with age Higher in women Olmsted County Median (Shinogi assay) Miller et al. Curr Vasc Pharm 07.
HRT and BNP Levels Increase with age Higher in women on HRT Redfield et al. JACC 2002.
Daniels et al. Eur J Heart Fail 2011. BACH trial: MR-proANP
PRIDE: NT-proBNP Patients WITH Heart Failure: Krauser et al. J Card Fail 2006.
Serial NP for Guiding Treatment During Hospitalization? Courtesy of Damien Logeart.
PAW (mm Hg) Changes in BNP Mirror changes in PAW* During Treatment of Acute Heart Failure 33 31 29 27 25 N = 15 (responders) PAW BNP 1300 1200 1100 1000 BNP (pg/ml) 23 900 21 19 17 800 700 15 baseline 4 8 12 16 20 24 600 *Pulmonary artery wedge. Hours Kazenegra, Maisel, A. et al. J Cardiac Failure, Vol. 7, No. 1, 2001
BNP trends during hospitalization and subsequent prognosis upon hospital discharge Highest baseline, greatest change; highest discharge level= worse prognosis Lowest Predischarge BNP= best prognosis Lowest Baseline BNP Level=second best prognosis
Death or Readmission (%) BNP on Discharge Predictive of Events 100 75 Predischarge BNP >700 ng/l n=41, events=38 p<0.0001 15.2 50 25 0 Predischarge BNP 350-700 ng/l n=50, events=30 Predischarge BNP <350 ng/l n=111, events=18 0 30 60 90 120 150 180 Follow-Up (Days) p<0.0001 1 5.1 Hazard Ratios of 2 nd and 3 rd Versus 1 st BNP Range Logeart D et al. J Am Coll Cardiol 2004;43(4):635-41.
The discharge NP level may be the most important level of all!!!
If your BNP is high at discharge >400 pg what can you do? Are they really euvolemic? Dry BNP Impedance Do they need more diuretics? Consider Aldosterone blockade Home monitoring Return visit within one week
Biomarkers: From Hospital to Home
Bringing NP levels Into the Clinic or Bringing the Clinic to BNP Needs to be interpreted in context Does not take the place of history, physical exam To interpret value must have understanding of NPs and heart failure syndrome Must have previous NP values to which to refer Confidential
Sensitivity Weight Change ROC 1.00 0.75 0.50 0.25 AUC: 0.65/0.63 Source of the Curve Reference Line Percent Absolute 0.00 0.00 0.25 0.50 0.75 1.00 1-Specificity Confidential Lewin J. Eur J Heart Fail. 2005 Oct;7(6):953-7.
BNP Change Correlation Between in BNP and Weight 4000 3000 2000 1000 0 R=0.002 P=0.983 (NS) -1000-2000 -3000-3 -2-1 0 1 2 3 4 5 Weight Change Confidential Lewin J. Eur J Heart Fail. 2005 Oct;7(6):953-7.
Algorithms for BNP Outpatient Management TELEMEDICINE Maisel, Mueller, Yancy, Adams, Nieminen, Zannad, Fonarow, Liu, Peacock, Anker, Cleland, Filippatos, Braunwald, et al BNP consensus. Eur J Heart Fail. 2008 Sep;10(9):824-39 Confidential
The Ideal Biomarker Sensitive and specific Reflects disease severity Correlates with prognosis 2007 2011 Should aid in clinical decision making Either highly sensitive (diagnosis) OR highly specific (treatment effect) Reflects abnormal physiology/biochemistry Prognosis is most meaningful if level is clinically actionable Should be used as a basis for specific biomarker guided-therapy Level should decrease following effective therapy Bio-monitoring during treatment is an effective surrogate of improvement Maisel, JACC 2011
What good is a prognostic marker if you can t act on it?
Typical JACC meeting We have another great prognostic Biomarker paper this week You re fired
Risk Stratification is of Limited Value to Individual Patients #&@(! Great news! I can predict you will live 4.5 months with a p value of 0.04!
Can BNP levels be used to titrate outpatient therapy? The Holy Grail
So everyone is supposed to be on the same dose of heart failure medications. That cannot be personalized medicine
Comparison of Trials BNP-Guided Therapy Trought on STARS- BNP TIME- CHF BATTLE - SCARR ED PRIMA Adapted from Felker et al. Am Heart J 2009; 158: 422 SIGNAL -HF Berger et al. PROTE CT n 69 220 499 364 345 252 278 151 Blinding No No Single Double Single Single? No Marker NT-BNP BNP NT-BNP NT-BNP NT-BNP NT-BNP NT-BNP NT-BNP Aim (ng/l) 1692 100 400/800 1270 discharg e Control HF score Usual care 1 EP Death, CV hosp., HF HF death, HF hosp. class II 2 groups Usual care Death, all-cause hosp. Allcause mortality d alive out hosp. 50% red. 2200 1000 HF spec. 2 groups Usual care d alive out CV hosp. HF hosp., death CV events Age 70 66 77 76 72 77 71 63 NT-BNP 1981 350 4328 2008 2940* ~2500 ~2350 2118
NT-proBNP Concentrations 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
*Adjusted for Primary Endpoint Number of events 120 100 80 60 40 P =.009 100 events 58 events SOC NT-proBNP 20 0 *Logistic Odds NT-proBNP = 0.44 (95% CI=.22-.84; P =.019) Total CV Events
NEW KIDS ON THE BLOCKbiomarkers in acute heart failure Adrenomedulin procalcitonin ST-2 troponin Galactin-3 NGAL Co-peptin-
New biomarkers may give BNP a helping hand! Gal -3 b n p N g a l S T - 2 P C T
MR-ANP adds value where natriuretic peptides are not as strong
Heart Failure + infection Heart failure plus pneumonia is present about 10-15% of time Heart failure plus any infection may occur in up to 20% of hospitalized heart failure patients. Hospital Mortality may be up to 20% (versus 5%) in heart failure patients with untreated infections
BNP [ng/ml] 900 800 AHF, no Pneumonia (n=539) 700 600 500 400 AHF and Pneumonia (n=29) 300 200 100 no AHF, no Pneumonia (n=947) Pneumonia, no AHF (n=126) 0 0 0,05 0,1 0,15 0,2 0,25 PCT [ng/ml] Maisel et al EJHF 2011
Trauma Heart Failure Cardiac surgery Radiocontras t ICU Kidney transpla nt NGAL IgA nephropa thy CKD
1.00 0.95 0.90 0.85 0.80 0.75 0.70 NGAL < 100, BNP < 330 NGAL < 100, BNP > 330 NGAL > 100, BNP < 330 NGAL > 100, BNP > 330 0.65 0 5 10 15 20 25 30 Days
AKINESIS: Acute Kidney Injury N-gal Evaluation of Symptomatic heart failure Study
Find the sweet spot of euvolemia before discharge BNP level Bnp low but is there still wet bnp around? Could you have overdiuresed the patient? Begin diuretics Creatinine Now you ve done- it! 4 more Days in the hospital
Galectin-3 Mediated HF is Inherently Progressive Illustration of two clinically very similar patients with different galectin-3 levels and dramatically different clinical paths 8.5 ng/ml Patient A SEVERITY OF DISEASE CARDIAC FUNCTION 36.4 ng/ml Patient B DEATH TIME 68
Mechanism Galectin-3 and Natriuretic Peptides Who is affected? What happens in decompensation? Response to treatment BNP/NT-proBNP Released by myocytes in response to stretch Maybe elevated in any form of heart failure (100% of HF) Rapid marked rise and fall when cardiac function improves Reduced if treatment is effective Galectin-3 Release by macrophages in response to stimulation by aldosterone and inflammation Only in patients affected by this form of HF (30-50%) Levels unaffected remain constant Most effective treatments work down-stream no effect on galectin-3 levels Role Bystander Mediator or culprit 6 9
1-year Mortality 1-Year Mortality Overview Galectin-3 and Natriuretic Peptides Galectin-3 is Complementary to NT-proBNP Natriuretic peptides (BNP and NT-proBNP) Reflect two important dimensions: Degree of stretch/cardiac overload, and presence/absence of this fibrotic form of heart failure Galectin-3 prognostic information is independent of and complementary to information provided by natriuretic peptides Clinical Use Is it HF? - NP What form? Galectin-3 What to do next? NP & Galectin-3 7 0 60% 50% 40% 30% 20% 10% 0% 40% 35% 30% 25% 20% 15% 10% 5% 0% 13.0% 40.9% 36.9% 51.1% Low NT-proBNP ( 4299 ng/ml) High NT-proBNP (>4299 ng/ml) 6.9% 15.6% 19.3% 36.5% Low BNP ( 447 pg/ml) High BNP (>447 pg/ml) High galectin-3 (>17.8 ng/ml) Low galectin-3 ( 17.8 ng/ml) Galectin-3 is Complementary to BNP High galectin-3 (>17.8 ng/ml) Low galectin-3 ( 17.8 ng/ml) COACH PRIDE-HF
Cumulative hazard Additive value of ST2 to NTproBNP in long term prognosis 0.8 0.6 Both sst2 and NT-proBNP elevated (n=276) Only sst2 elevated (n=95) Only NT-proBNP elevated (n=54) Neither elevated (n=168) 0.4 P <.001 0.2 0.0 0 300 600 900 Days from enrollment 1200 1500
ST2 and BNP Survival Daniels LB, et al. Am Heart J 2010.
BNP on Every Street Corner?
Present and future uptake of NPs Now 5 Years Diagnosis of Acute HF Following Patient in Hospital Utilizing Discharge BNP Monitoring BNP Post-discharge Guiding Outpatient Rx Use as Part of Dx Criteria for HFPEF Screen for LV Dyfx Outpatient Risk Profiling Maisel and Daniels JACC 2012 0 25 50 75 100 Confidence uptake (%)
Biomarkers will Make bad doctors worse and good doctors better!
Thank You