Biomarkers & Treatment Guidance

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1 Biomarkers & Treatment Guidance Alan S. Maisel MD FACC Professor of Medicine, University of California, San Diego, Director, CCU and Heart Failure Program San Diego VA Medical Center

4 Easy to measure Inexpensive Can be point-of- care Results back in less than one hour Reliable surrogates

Biomarkers Clinical Relevance in Heart Disease Over the last decade, measurement of biomarkers is being considered as an add-on to routine laboratory investigations in the management of HF 1,2 Levels

5 Biomarkers Clinical Relevance in Heart Disease Over the last decade, measurement of biomarkers is being considered as an add-on to routine laboratory investigations in the management of HF 1,2 Levels of the different biomarkers may indicate a spectrum of underlying pathophysiological aspects of HF 1 Currently, biomarkers are considered to be potential supplementary aids for the diagnosis, prognostication, and management of patients Neurohormones Norepinephrine Renin, Angiotensin II Copeptin, Endothelin Vascular system Homocysteine Adhesion molecules (ICAM, P-selectin) Endothelin Adiponectin C-type natriuretic peptide Inflammation C-reactive protein sst2, TNF, APO-1, GDF-15 Pentraxin 3, Adipokines Cytokines, Procalcitonin Osteoprotegerin Biomarkers in HF Myocardial stress Natriuretic peptides Mid-regional Pro-adrenomedullin Neuregulin, sst2 Cardio-renal syndrome Creatinine Cystatin C, NGAL Β-Trace protein Myocardial Injury Cardiac troponins High sensitivity cardiac troponins Myosin light-chain kinase 1 Heart-type fatty acid binding protein Pentraxin 3 Oxidative stress Oxidized LDL Myeloperoxidase Urinary biopyrins Urinary and plasma isoprostanes Plasma malondialadehyde Matrix and cellular remodeling Galectin-3 sst2, GDF-15 MMPs, TIMPs Collagen propeptides Osteopontin Adapted from Ahmad, T. et al. Nat. Rev. Cardiol doi: /nrcardio CHF, chronic heart failure; GDF-15, growth differentiation factor 15; HF, heart failure; NGAL, neutrophil gelatinase-associated lipocalin; sst2, soluble suppression of tumorigenicity 2; TNF, tissue necrosing factor; APO-1 apolipoprotein 1; GDF growth differentiating factor 1. Yancy CW. et al. J Am Coll Cardiol. 2013;62(16):e147-e Maisel AS. et al. Nat Rev Cardiol. 2012;9(8):

6 Objectives of Biomarker Testing in Heart Disease Diagnosis 1 Condition X To establish or refute a diagnosis To understand the underlying pathophysiologic processes Biomarker Risk Stratification/Screening 1 To determine the presence or severity of disease To detect adverse consequences Monitoring/Therapeutic Guidance 1 Outcome A To facilitate selection of an appropriate therapeutic intervention Many To guide biomarkers or monitor responses may be to risk factors themselves; treatment therefore, may be potential targets of therapy 2 HF, heart failure. Intervention Outcome B 1. Morrow DA, et al. Circulation. 2007;115: Kalogeropoulos AP, et al. Prog Cardiovasc Dis. 2012;55(1):

7 The Epidemic of Heart Failure Prevalence Incidence Mortality Hospital Discharges Outpatient Visits Cost 5,100, ,000 50% at five years 1,023, million $39.8 billion Heart failure is common, costly, and deadly Prevention, diagnosis, risk stratification, monitoring, and managing heart failure is challenging There has been great interest in the clinical role of biomarkers in heart failure American Heart Association Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 2013.

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

9 Indecision Clarification of Diagnosis & BNP 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 43% Clinical Evaluation BNP reduces clinical indecision by 74% * P < % Clinical Evaluation and BNP

10 PAW (mm Hg) Changes in BNP Mirror changes in PAW* During Treatment of Acute Heart Failure N = 15 (responders) PAW BNP BNP (pg/ml) baseline *Pulmonary artery wedge. Hours Kazenegra, Maisel, A. et al. J Cardiac Failure, Vol. 7, No. 1, 2001

11 In volume overloaded patients: NP level = baseline NP (dry) + change due to increased volume (wet) BNP level (pg/ml) 2500 Wet (change due to volume overload) 2000 Dry ( NYHA Euvolemic state) I II III IV NYHA Class - Euvolemic (Dry) BNP

13 NP Guided Therapy GUIDE-IT Trial Hospitalization for HF LVEF 40 within 12 months NT-proBNP >2000 pg/ml or BNP >400 pg/ml during index hospitalization Screening Randomized within 2 weeks of hospital discharge Usual Care N = 550 Biomarker Guided NTproBNP <1000 pg/ml N = 550 Randomization Follow-up: 2 weeks, 6 weeks, 3 months, then Q3 month for months Additional 2 week follow-up after changes in therapy Follow-up The GUIDE-IT study is designed to provide the definitive answer about the safety, efficacy, and cost-effectiveness of NP-guided therapy for chronic systolic HF HF, heart failure; LVEF, left ventricular ejection fraction; NP, natriuretic peptide; NT-proBNP, N-terminal pro B-type natriuretic peptide; Q3, every 3 months. Felker GM. et al. JACC Heart Fail. 2014;2(5):

Routine PCP care Cardiology care PRN Vs.

14 Ledwidge et al. JAMA 2013 STOP-HF trial St Vincent s Screening to Prevent Heart Failure Study Routine care (n=677) Routine PCP care Cardiology care PRN Vs. BNP-directed care (n=697) Annual BNP check If BNP >50 pg/ml at any time: cardiology consult, echo, nurse-coaching 1 Endpoint: LV systolic or diastolic dysfunction, or heart failure 2 Endpoints: Emergency hospitalization for arrhythmia, TIA, stroke, MI, PE/DVT, HF

15 Ledwidge et al. JAMA 2013 STOP-HF trial: results Reduction in primary endpoint (p=0.003)

16 Ledwidge et al. JAMA 2013 STOP-HF Also reduced emergency hospitalizations for MACE BNP group received renin-angiotensinaldosterone system-based therapy

Prognosis at hospital d/c ADD-00056844 Emerging Indications Guide

17 NP in management of Heart Failure Accepted Indications New Diagnosis of HF in Community Differentiating dyspnoea in ER Prognosis at hospital d/c ADD Emerging Indications Guide to therapy Predicting outpatient deterioration Driver of prevention strategies

18 NT-proBNP pg/ml BNP pg/ml PARADIGM-HF: NT-proBNP and BNP NT-proBNP BNP Months LCZ696 Enalapril

19 Confounders of NP interpretation * Delineates likely elevation from Ventricular stretch Higher NP levels than expected Lower NP levels than expected Increasing age* ACS* Renal insufficiency RV dysfunction* Atrial fibrillation Obesity Flash pulmonary edema Pericarditis/Tamponade Genetic polymorphisms Burned-out Cardiomyopathy Pulmonary hypertension* Pulmonary embolism* Anemia/high output states* Sepsis Mitral Regurgiation*

20 Heart Failure + Infection 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

21 Müller B. et al., Crit.Care Med The likelihood and severity of bacterial infection increase with increasing PCT levels

PCT in "Antibiotic Stewardship": -> Reducing Duration of Antibiotic Therapy in patients with CAP Prospective interventional trial: 302 patients Tailoring of antibiotics

22 PCT in "Antibiotic Stewardship": -> Reducing Duration of Antibiotic Therapy in patients with CAP Prospective interventional trial: 302 patients Tailoring of antibiotics treatment to the individual patient needs Reduction of average treatment duration from 12 to 5 days. Same outcome! (Safety) Christ-Crain M et al. Am J Respir Crit Care Med Apr 7

25 A combination of Natriuretic Peptide and PCT can be used to better diagnose dyspneic patients Maisel Eur J HF 2012

26 Improved Management of heart failure with ProcAlCiTonin

clinical assessment chief complaint SOB Informed

Randomization PCT guided group N= 900 PCT blind

blood sampling PCT > 0.2 PCT =< + Abx 0.

27 8-24 h Max. 8 h IMPACT-EU Presentation in the ED Routine clinical assessment chief complaint SOB Informed Consent, Evaluation of In/Exclusion Criteria Randomization PCT guided group N= 900 PCT blind group N= 900 blood sampling, PCT measurement blood sampling PCT > 0.2 PCT =< + Abx 0.2 -ABx Standard diagnostics + ABx - ABx Follow-up PCT day 1 Follow-up PCT day 1 Follow up blood sample day 1

28 Positive Troponin in Acute Heart Failure: What Does it Mean? What Should I Do?

29 Choose: 1 or 2? When faced with an AHF patient with a positive troponin, the ER will.

30 Choose: 1 or 2? When faced with an AHF patient with a positive troponin, the ER will. 1. Carefully consider the clinical context, review all past records, discuss with the cardiologist or primary care physician of record and in consideration of the patients other co-morbid conditions, determine whether admission or discharge with early follow up is best.

31 Choose: 1 or 2? When faced with an AHF patient with a positive troponin, the ER will. 1. Carefully consider the clinical context, review all past records, discuss with the cardiologist or primary care physician of record and in consideration of the patients other co-morbid conditions, determine whether admission or discharge with early follow up is best. 2. Admit the patient

32 Cardiac Troponins Overview and Mechanism of Troponin Release Increased Wall Stress Epicardial CAD Oxidative Stress Reversible Injury Cardiac Troponin Release Myocyte Apoptosis Myocyte Necrosis Troponin Degradation Products Neurohormo nal Activation Altered Calcium Handling Inflammato ry Cytokines 32

33 In-Hospital Mortality According to Conventional ctni or ctnt Quartile Patients with Acute Decompensated Heart Failure Data from the ADHERE Registry Ischemic heart disease was not a useful discriminator of troponin status or mortality with a positive troponin result Peacock WF IV et al. N Engl J Med 2008;358:

34 Event Free (Death or Readmission) Cardiac Troponins Role in Prognosis 90-day Mortality and HF-related Readmissions by Discharge Troponin I Levels Troponin <23.25 ng/l (59 subjects) Troponin >23.25 ng/l (85 subjects) Time (Days) Patients with a discharge TnI >23.25 ng/l had significantly higher 90-day mortality and HF-related readmissions than patients with a discharge TnI <23.25 ng/l (P=0.003, HR, 3.547) 2 ACS, acute coronary syndrome; AHF, acute heart failure; CHF, chronic heart failure; HR, hazard ratio; hs-ctnt, high-sensitive cardiac troponin T; TnI, troponin I. 1. Maisel. et al. Circulation. 2007;116(5):e

35 Cardiac Function AHF Contributes to the Progression of HF Goal: prevent myocardial and renal damage and implement life-saving therapies Hospitalization Hypothesis: with each hospitalization there is myocardial and/or renal damage Hospitalization Hospitalization Time Gheorghiade et al. Am J Cardiol 2005;96(6A):11G 17G

36 Prognostic Value of a >20% hs-ctnt Increase From Baseline and Effects of Serelaxin Percent of patients with hs-ctnt increase Troponin T p = Metra et al. JACC Placebo Serelaxin

37 PARADIGM-HF: median hs-tnt (µg/l) concentration by visit Randomization Prior to Run-in Randomization 4 weeks 8 months

38 Recommendations for using troponin in Acute Heart Failure Exclude type I MI (ACS) Rising/falling pattern Signs/symptoms of ischemia Imaging evidence May rise and fall even without MI ADHF rise; treatment of HF fall Tn >99 th percentile worse outcome Regardless of type I MI/ACS

39 Proportion of Adults with Detectable ctnt (>3ng/L) Dallas Heart Study Cardiovascular Health Study ARIC

40 Proportion of subjects with elevated contemporary ctnt levels in the general population Total population ctnt 0.01 ng/ml = 0.7% Risk factor determinants: (DM, HF factor, LVH, or CKD) Wallace TW. Circulation 2006;113:

41 Left Ventricular Hypertrophy Heterogeneous Progression to Heart Failure

42 The malignant phenotype of LVH ctnt+ defined as > 3 ng/l Neeland I. J Am Coll Cardiol 2013;61:187 95

43 Risk of New Onset Heart Failure Ambulatory Older Adults Stratified by ctnt level defilippi JAMA 2010;304:

44 ng/ml Cardiac Troponin T levels Pre and post marathon in 25 adults > 50 years Karlstedt et al. Journal of Cardiovascular Magnetic Resonance 2012, 14:58

45 Association of Physical Activity, NT-proBNP and hs ctnt level in older adults The ActiFE Study Duration of walking measured by accelerometer over 1 week Klenk J. J Epidemiol Community Health 2013;67:

activities A higher score is a faster pace and longer duration of activity.

46 Association of moderate physical activity, rise in hs ctnt level and risk of new onset heart failure Composite score is a sum of walking pace and duration of moderate to intense leisure activities A higher score is a faster pace and longer duration of activity. Significant increase in hs ctnt defined as > 50% rise from the baseline level. defilippi C. J Am Coll Cardiol 2012;60:2539-4

47 sst2- has evolved to be a useful marker

Soluble ST 2 ST-2: Suppressor of tumorigenicity 2 (IL-1 receptor-like-1) Member of Interleukin-1 receptor family ST2 gene encodes isoforms by alternative promotor splicing membrane bound receptor:

48 Soluble ST 2 ST-2: Suppressor of tumorigenicity 2 (IL-1 receptor-like-1) Member of Interleukin-1 receptor family ST2 gene encodes isoforms by alternative promotor splicing membrane bound receptor: ST-2L (Profibrotic signaling) soluble truncated form: sst-2 (Decoy receptor) IL-33: Interleukin 33, Binds to ST-2L & Inhibits Profibrotic signaling ST2L Interleukin-33 (IL-33) X Pro-fibrotic Signaling

49 sst-2 binds IL-33 & inhibition of ST-2L profibrotic signaling Fibrosis sst2l ecoy Receptor ST2L Interleukin-33 (IL-33) X Pro-fibrotic Signaling

50 Single ST2 Cut-point: > ng/ml = RISK

Measured levels of ST2 and BNP on consecutive admissions for AHF Looked at admissions in previous 3 months Looked at admissions in the 3 months following discharge

51 Measured levels of ST2 and BNP on consecutive admissions for AHF Looked at admissions in previous 3 months Looked at admissions in the 3 months following discharge Related ST2 and BNP levels to total number of admissions ROC curve analysis to predict probability of other admissions when they come to hospital ( ie readmission risk)

52 Admissions Admissions ST2 and Admissions Over 6 Months BNP and Admissions Over 6 Months 10 8 R² = ST2 (ng/ml) Wetterson, Maisel AJM R² = BNP (pg/ml) 52

53 Maisel s Frequent-Flyer Index

54 Changes one might consider on the basis of a biomarker prior to discharge Extra hospital time One week follow up Home nursing Telemonitoring More aggressive titration of medications

55 ST2 in Ambulatory Heart Failure

Number of Eligible Patients 2,459,644 2,512,560

56 A Large Number of Eligible Patients are Untreated U.S. Data ACEI/ARB BB MRA Hydral/Nitr ate CRT ICD Number of Eligible Patients 2,459,644 2,512, , , ,151 1,725,732 Fonarow et al. Am Heart J 2011

57 Serial ST2 Measurements Categorize Responder Status ST2 Responders ST2 Non-Responders Decrease 50% Decrease 25 49% Adjusted for ADHERE Risk Factors and BNP change. Increase or decrease <25% Basel ADHF cohort 57

ST2 Predicts Response to Treatment: Aldosterone Blockade in STEMI Eplerenone prevents adverse ventricular remodeling ST2 predicts which pts are most at risk AND which pts will benefit most

58 ST2 Predicts Response to Treatment: Aldosterone Blockade in STEMI Eplerenone prevents adverse ventricular remodeling ST2 predicts which pts are most at risk AND which pts will benefit most from aldosterone blockade Weir AP, et al. J. Am. Coll. Cardiol. 2010;55; High and low ST2 separated at median. Eplerenone attenuates remodeling more in pts with higher baseline ST2.

59 Old biomarkers become new guided treatment biomarkers Sodium Potassium Pulmonary pressure Heart rate Tolvaptan New K drugs CardioMems Ivabridine

60 The Future is closer than we think Screening for risk of disease: Purpose is to Prevent the Disease 1. LV dysfunction 2. Fibrosis 3. CAD NP, hstroponin, ST2 Condition X Biomarker Intervention And a new one: Proneurotensin Outcome A Outcome B. 60

61 What if? There was a protein biomarker associated with insulin and fasting blood glucose Higher in women predicts incident diabetes mellitus in females independent from glucose and insulin And also predicts incident CVD Death Breast cancer Slide 61

62 Fat abnormalitydiet,lipids, etc DIABETES CARDIOVASCULAR DISEASE BREAST CANCER 62

Proneurotensin (1-117) = pro-nt Stable fragment of the

63 Proneurotensin (pro-nt) Neurotensin is not stable in-vivo and in-vitro Not applicable for laboratory routine use Proneurotensin (1-117) = pro-nt Stable fragment of the precursor molecule pro-nt: stable surrogate marker for Neurotensin Slide 63

Proneurotensin (pro-nt) released Neuronal

dopaminergic transmission Signals satiety

gastric and small bowel motility Neurotensin

in breast cancer tissue Missing link between

Increased risk of stroke, coronary heart

64 Proneurotensin (pro-nt) released Neuronal Functions Neurotransmitter Influences dopaminergic transmission Signals satiety Pancreatic Functions Insulin resistance Elevated pro-nt levels Gastrointestinal Functions The insulin of fat Inhibition of gastric and small bowel motility Neurotensin and the Neurotensin 1 receptor are expressed in breast cancer tissue Missing link between diet and breast cancer? Increased risk of stroke, coronary heart disease and diabetes Daniels, L.B. and Maisel, A.S., Cardiovascular biomarkers and sex: the case for women. Nat Rev Cardiol Jul 7. doi: /nrcardio [Epub ahead of print] Slide 64

65 Malmö Diet And Cancer Study pro-nt associated with cardiovascular mortality and CVD in females Slide 65

66 Malmö Diet And Cancer Study pro-nt predicts risk of inc. diabetes 1484 men and 2220 women 142 (68 men and 74 women) events event rate of 30.2 per person-years pro-nt only significant for women (P=.003) but not in men (P=.10) Relatively high pro-nt predicts risk of incident diabetes in women subjects with prevalent diabetes at baseline were excluded adjusted for age, sex, use of antihypertensive medication, systolic, blood pressure, BMI, waist circumference, prevalent cardiovascular disease, current smoking, and fasting concentrations of glucose, highdensity lipoprotein cholesterol (HDLC), LDL-C, triglycerides, and insulin (diabetes risk factors) Melander O et al., JAMA Oct 10;308(14): Slide 66

67 Breast Cancer Slide 67

68 OR Malmö Prevention Project confirms Proneurotensin is an independent predictor for incident breast cancer Relatively high pro-nt predicts risk of incident breast cancer 10 p for trend < Q1 Q2 Q3 Q4 pro-nt In MPP adjusted for age, antihypertensive medication, HRT, systolic blood pressure, BMI, current smoking, prevalent diabetes mellitus and cardiovascular disease and fasting concentrations of HDL-C, LDL-C MDC: Melander O et al., JAMA Oct 10;308(14): MPP: Melander O et al, 2014, Cancer Epidemiol Biomarkers Prev; 23(8); Slide 68

69 pro-nt [pmol/l] Influencing pro-nt levels by diet 350 For all with baseline pro-nt >200 pmol/l Subjects with baseline pro-nt above 200 pmol/l were on a lowfat diet for 8 weeks 300 P value < pro-nt was measured again after 8 weeks mean value of % change per subject: 25.2% (332 subjects) Upon a low-fat diet pro-nt decreased significantly Low-fat diet: A pro-nt-modulating intervention to decrease risk? 0 baseline 8 weeks low-fat diet Rudovich N.N., Pfeiffer A.F.H., unpublished Slide 69

70 The Promise of Personalized Medicine Genomic Profile Biomarker Profile Imaging Integrated Data Insight into Pathophysiology Clinical Data Individual Risk Assessment Predict response to a therapy Morrow DA ESC 2007; Adapted from West et al. Genome Research 2006; 16:

Biomarkers in the Age of Sacubitril/Valsa rten: Has the PARADIGM Changed

Biomarkers in the Age of Sacubitril/Valsa rten: Has the PARADIGM Changed Alan S. Maisel MD FACC Professor of Medicine, University of California, San Diego, Director, CCU and Heart Failure Program San Diego