Heart Failure Biomarkers: Advances in Diagnostics and Therapeutics

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1 Heart Failure Biomarkers: Advances in Diagnostics and Therapeutics Michael Felker, MD, MHS, FACC, FAHA Associate Professor of Medicine Director, Heart Failure Section

2 Disclosures Consulting and/or Grant funding from: NHLBI Novartis Amgen Otsuka Trevena Merck Roche Diagnostics Critical Diagnostics BG Medicine Singulex

3 What Is a Biomarker? If it costs less than 20 bucks, it s a lab test. If it costs more than 20 bucks, it s a biomarker.

4 Potential Clinical Uses of Biomarkers in HF Diagnosis: Does this patient have heart failure or something else? Risk Stratification/Triage: Should this patient go to the CCU? Telemetry unit? Home? Selection of Therapy: What should I do to make this patient better? Titration of Therapy: Should I keep doing what I am doing or should I do something else?

Biomarkers as Windows into Pathophysiology LV

Marrow Hb, RDW Inflammation CRP, IL-6, TNF ST2, Fas, FasL

injury ctnt and ctni Genetics Renal BUN, cystatin C,

5 Biomarkers as Windows into Pathophysiology LV Remodeling/Fibrosis Collagen peptides Galectin-3 Bone Marrow Hb, RDW Inflammation CRP, IL-6, TNF ST2, Fas, FasL ICAM, VCAM, MPO Neurohormones NE, PRA, ET-1 Myocyte injury ctnt and ctni Genetics Renal BUN, cystatin C, NGAL, KIM1 Thrombosis TF, vwf fibrinogen Hemodynamic Stress Mid- proanp BNP, NTproBNP

6 Biomarkers in Heart Failure From Very Long List Established for HF Natriuretic Peptides (NTproBNP, BNP) Established for other conditions High sensitivity troponins FDA approved but optimal use uncertain ST2 Galectin-3

7 Pharmacologic Actions of hbnp D R I S S S M S K G R L G G F C S S C K V L R R H G S P K M V Q G S Cardiac lusitropic antifibrotic anti-remodeling Hemodynamic (balanced vasodilation) veins arteries coronary arteries Neurohumoral aldosterone endothelin norepinephrine Renal diuresis natriuresis GFR

8 Which BNP are you Talking About? Corin

9 Correlation of NTproBNP and BNP Levels NT-proBNP~5-10 times higher than BNP for given patient Lainchbury JACC, 2003

10 BNP in the Diagnosis of Heart Failure There is no gold standard for the diagnosis of heart failure! History and Physical Echocardiography BNP

11 BNP Correlates with LV Filling Pressures PAW (mm Hg) baseline *Pulmonary artery wedge. Hours PAW BNP BNP (pg/ml) Kazanegra J, Cardiac Failure 2001

12 BNP for Diagnosis in Patients with Acute Dyspnea Optimal cut-off point 100 pg/ml BNP=50 pg/ml BNP=80 pg/ml BNP=100 pg/ml BNP=125 pg/ml Sensitivity BNP=150 pg/ml Final Diagnosis Heart Failure Final Diagnosis NOT Heart Failure Positive predictive value=75% BNP 100 pg/ml Test positive BNP <100 pg/ml Test negative Sensitivity =90% 615 Specificity =73% Negative predictive value=90% Specificity Maisel AS et al. N Engl J Med. 2002;347:

13 Use of BNP Values in Triage in the ED: A Practical Approach If BNP < 100 pg/ml, heart failure highly unlikely Negative predictive value ~ 90% If BNP > 500 pg/ml, heart failure highly likely Positive predictive value ~ 90% BNP between pg/ml = grey zone Consider other diagnoses (PE, cor pulmonale) Baseline BNP very helpful if available

14 BNP and Prognosis in Heart Faliure

BNP and Prognosis in Chronic HF: VAL-HeFT 1.0 0.95 Survival Probability 0.90 0.85 0.80 0.75 0.

15 BNP and Prognosis in Chronic HF: VAL-HeFT Survival Probability Q1 Q2 Q3 Q Months Anand Circulation 2003

16 Natriuretic Peptides and Risk of Death at 1 yr in Patients With Dyspnea NT-proBNP measured on presentation with dyspnea Patients with acute HF (n=209) Patients without acute HF (n=390) 1 1 Age-adjusted Survival NT-proBNP 986 pg/ml NT-proBNP > 986 pg/ml P=0.001 Age-adjusted Survival NT-proBNP 986 pg/ml NT-proBNP > 986 pg/ml P< Days after Presentation Days after Presentation Januzzi, Arch Int Med, 2006

17 BNP at Discharge: Failure to decrease BNP Predicts Readmission or Death 100 Death or readmission (%) Pre-discharge BNP >350 pg/ml Pre-discharge BNP <350 pg/ml Follow up (days) Logeart JACC 2004

18 Take Home Message BNP or NTproBNP are among the strongest predictors of long term outcome in any HF patient population ADHF Acute dyspnea but without heart failure Chronic HF Diastolic HF normals

19 Significance of Estimating Prognosis for the Individual Patient is Limited Great news! I can predict you will live 4.5 months with a p value of 0.03

20 Troponinology for the Non-Geek Upper Reference Limit (URL): 99 th percentile value in normal population Lower limit of detection (LLOD): Value that can be reliably distinguished from 0 Progressively more sensitive assays allow for greater proportion of patients to have measureable values below LLOD of less sensitive assays Discussion of troponin values as positive or negative increasingly irrelevant

21 Stages of Heart Failure D ctn 6.2% hstni ~ 100% C Symptoms ctnt 10% hstnt 92% B Structural Abnormalities A Risk Factors ctn 0.7-8% hstnt 25-66%

Causes of Troponin Release in HF 0.05 0.04 0.03 0.02 ctni by Etiology P = 0.

22 Causes of Troponin Release in HF ctni by Etiology P = 0.77 Ischemic Non-Ischemic Januzzi et al. EHJ 2012 Felker, GM et al. EJHF 2012

23 Troponin I and In-hospital Mortality in ADHF Peacock, NEJM 2008

24 ctni in AHF: Data from ASCEND-HF Worsening HF/Death to D7 Felker, GM et al. EJHF 2012

25 hs-ctnt & risk of death: GISSI HF 50 Hazard ratio (95% CI) Masson, Circ 2012

26 Changes in HS-Trop T and Outcomes: GISSI-HF and VAL-HeFT Masson, Circ 2012

27 Hs-Troponin T in Older Adults: Cardiovascular Health Study DeFilippi, C. JAMA 2010

28 Troponin in Heart Failure Greater sensitivity leading to many/most HF patients having elevated levels Know your assay Very sensitive assays may be most helpful in at risk individuals (stage A and B) as compared to those w advanced disease (stage C and D)

29 ST2 Background ST2 is a member of the interleukin-1 receptor family ST2 protein is found both as a trans-membrane form as well as a soluble form in serum The ligand for ST2 was recently identified to be IL-33 Links inflammation, myocardial stretch, and remodeling

30 ST2/IL-33: Receptor-Ligand Complex ST2L: membrane-anchored receptor Intracellular Toll-interleukin receptor (TIR) domain ST2: secreted receptor IL-1RAcP IL-33 Extracellular IgG domains In serum/plasma 57 kda protein detected

31 ST2 plays a role in reducing cardiomyocyte hypertrophy and fibrosis Abnormalities in ST2 experimentally result in severe cardiac fibrosis and hypertrophy (in red) Intact ST2 ST2 knock out

32 ST2 Trends as a Function of Mortality sst2 (ng/ml) Death 0.1 Survival First Day 2 Day 3 Day 4 Day 5 Last Time Boisot, J Card Failure, 2008

33 ST2 and Prognosis in Acute HF ST ng/ml ST2 <0.20 ng/ml 0.4 Log rank P< Log rank P< Mortality at One Year Days from enrollment Days from enrollment Acute Heart Failure (n=208) Not Acute Heart Failure (n=385) Januzzi et al, JACC, 2007

34 ST2 Predicts Response to Aldosterone Blockade in STEMI ST2 predicts which patients will benefit most from aldosterone blockade. Eplerenone attenuates remodeling more in patients with a higher baseline ST2 ST2 not only predicts outcomes but also predict which patients will benefit most from intervention. High and low ST2 separated at median. Weir AP, et al. J. Am. Coll. Cardiol. 2010;55;

35 Galectin-3 Biology Beta-galactoside binding lectin Secreted by macrophages Mechanistic role in fibrosis Anti-apoptotic The switch that turns quiescent fibroblasts into activated, matrixsecreting myofibroblasts

36 Galectin-3 Animal Model of Compensated HF Galectin-3 emerged as the most overexpressed gene in failing versus functionally compensated hearts in HF animal model (TGRmRen2-27 rats)* Normal Myocardial Inflammation Galectin-3 Control Comp. Heart Failure Sharma UC, Circulation. 2004

Galectin-3 Administration Promotes Remodelling Collagen I Content of LV 140 120 100 80 60 40 20 2.4 fold increase P<0.01 * LV Ejection Fraction 70% 60% 50% 40% 30% -22% * P<0.

37 Galectin-3 Administration Promotes Remodelling Collagen I Content of LV fold increase P<0.01 * LV Ejection Fraction 70% 60% 50% 40% 30% -22% * P<0.05 W4 Placebo Group W4 Galectin-3 Baseline Placebo W4 Group Baseline Galectin-3 W4 Intrapericardial administration of galectin-3 markedly increases LV collagen content and reduces LV EF Sharma, et al. Circulation 2004.

38 Galectin-3 and NT-proBNP in AHF 1.0 P= Death/recurrent heart failure Neither elevated (n=94) NT-proBNP only elevated (n=36) Galectin only elevated (n=41) Both elevated (n=53) Days from Enrollment van Kimmenade RR et al. JACC 2006

39 Galectin-3 and Incident HF: Framingham Ho, J. JACC 2012

40 Does Galectin-3 identify a specific HF Phenotype? Low Galectin 3 = Non-remodeling HF Relatively good prognosis Likely to be responsive to traditional treatments High Galectin 3 = Remodeling HF Relatively poor prognosis May need earlier referral for advanced HF therapies Lambert JM, et al. Int J Cardiol 2008

41 What are the Unmet Needs in Heart Failure? Diagnostic markers? Natriuretic peptides are already extremely good for diagnosis of ADHF Prognostic markers? > 150 prognostic markers have already been identified in heart failure, very few of which are employed by clinicians Markers that tell us what we should do (ie, what is likely to work) or what we shouldn t do (ie, what is unlikely to work) for an individual patient Markers that may lead to new therapeutic targets

42 Biomarker Targeted Therapy Marker not elevated Marker elevated McLeod, H. Ann Rev of Pharmacol and Toxicol 2001.

43 ST2 Predicts Response to Therapy in STEMI ST2 predicts which patients will benefit most from aldosterone blockade. Eplerenone attenuates remodeling more in patients with a higher baseline ST2 ST2 not only predicts outcomes but also predict which patients will benefit most from intervention. Weir AP, et al. JACC 2010

44 Change in BNP Over Time and Mortality Mortality 25% 23% 13% 8% N=3740 Latini, R. Am J Med 2006

45 How Should we Apply our Current Therapies in Chronic HF? Current guidelines: Therapy should be up-titrated to targets from clinical trials or the maximally tolerated dose An alternate hypothesis: Therapy should be up-titrated based upon the personalized physiologic response of each individual patient

46 Examples from other Areas of Medicine HIV/Hepatitis Diabetes mellitus Hypertension Hyperlipidemia Anticoagulation Viral load HbA1C Blood pressure LDL INR Heart failure?

47 Chronic HF Therapy Guided by BNP Event free (%) Cardiovascular events NT-proBNP Clinical 100 Heart failure or death NT-proBNP Clinical N = P = P = Time after randomisation (days) Time after randomisation (days) Troughton, R. Lancet 2000

48 BNP guided HF therapy: STARS-BNP Event free survival % Clinical group BNP group P < T (days) Jourdain, JACC 2007

49 NT-proBNP and HF Outcomes: TIME-CHF 499 subjects with systolic HF, recent event, randomized to NT-proBNP versus Standard HF management 18 month follow up: Endpoint Overall <75 years 75 years Hosp-free survival 0.92 ( ) 0.76 ( ) 1.06 ( ) Survival 0.68 ( ) 0.38 ( ) ( ) HF hosp-free survival 0.66 ( ) ( ) ( ) 1 P =.008; 2 P =.01; 3 P =.002 Pfisterer, JAMA 2009

50 Biomarker Guided Therapy and All-Cause Mortality: Meta-Analysis Adjusted HR = 0.69 ( ) N = 1627 Felker GM. Am Heart J 2009

52 Equipoise? BGT might work TIME-CHF BATTLESCARRED BGT works PROTECT STARS-BNP Troughton pilot Berger BGT doesn t work PRIMA Northstar STARBRITE

53 GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment GUIDE-IT

Hospitalization for heart failure LVEF 40 within 12 months NTproBNP > 2000 pg/ml during index hospitalization Randomized within 2 weeks of hospital discharge

Additional 2 week follow up after changes in therapy Primary endpoint: Time to CV death or first HF hospitalization Endpoints Secondary Endpoints: All-cause

54 Hospitalization for heart failure LVEF 40 within 12 months NTproBNP > 2000 pg/ml during index hospitalization Randomized within 2 weeks of hospital discharge Screening Randomization Usual Care N= 550 Biomarker Guided NTproBNP < 1000 pg/ml N=550 Follow up: 2 wks, 6 wks, 3 months, then Q3 month for mos Follow-up Additional 2 week follow up after changes in therapy Primary endpoint: Time to CV death or first HF hospitalization Endpoints Secondary Endpoints: All-cause mortality Total days alive and out of hospital during follow-up CV mortality or CV hospitalization Safety Health related quality of life Resource utilization, costs, cost-effectiveness

55 Biomarkers Always Augment Clinical Judgment

Natriuretic Peptide Guided Therapy for Heart Failure

Natriuretic Peptide Guided Therapy for Heart Failure Michael Felker, MD, MHS Associate Professor of Medicine Director of Heart Failure Research Duke Clinical Research Institute Disclosures Research Grants