Biomarkers beyond BNP and Troponin

Biomarkers beyond BNP and Troponin Alan Maisel, MD Professor of Medicine, University of California, San Diego Director, Coronary Care Unit and Heart Failure Program San Diego Veterans Hospital

Disclosures Consultant: Alere BG Medicine EFG diagnostics Critical Diagnostics Research: Abbott Alere Nexus Novartis BG medicine Siemens

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

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

NEW KIDS ON THE BLOCKprognostic biomarkers in acute heart failure Adrenomedulin procalcitonin ST-2 troponin Galactin-3 NGAL Co-peptin-

Pressure from Hospital Administration? Novel tools and strategies are available now to assist physicians in reducing readmission and improving patient care

Why aren t we using Are they too expensive? Aren t they available everywhere now? Don t they help us understand pathophysiology? biomarkers?

Surely they can t be as expensive as other tests. Well, Bob, it looks like a paper cut, but just to be sure. Let s get an echo.

A CALL TO ACTION:THE TIME IS NOW GOOD BIOMARKERS ARE AVAILABLE NATRIURETIC PEPTIDES TROPONIN NGAL PCT GALECTIN-3 ST-2

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

PCT Level Increase = Increased Significance of Bacterial Infection In critically ill patients, PCT levels elevate in correlation to the severity of bacterial infection In healthy people, PCT concentration are found below 0.05ng/ml Concentrations exceeding 0.5ng/ml can be interpreted as abnormal

PCT for therapeutic stewardship -> Shortening AB therapy in patients with CAP Prospective interventional trial: 302 patients Tailoring of AB 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. 2006 Apr 7

900 800 700 AHF, no Pneumonia (n=539) BNP [ng/ml] 600 500 400 300 200 100 0 no AHF, no Pneumonia (n=947) AHF and Pneumonia (n=29) Pneumonia, no AHF (n=126) 0 0.05 0.1 0.15 0.2 0.25 PCT [ng/ml]

Kaplan-Meier plot for antibiotic treatment (yes or no) and all cause mortality within 90 days A. all patients with HF B. lowest quintile, patients with PCT levels below 0.051 ng/m C, p=0.356), between 0.051 and 0.205 D. highest quintile, p=0.046), adjusted for covariates Maisel et al in prep

Galectin-3 mediated heart failure Pre-clinical animal model of hypertensive heart failure Increased Gal-3 expression in rats that developed HF Galectin-3 Non-Transgenic Comp. Heart Failure Pericardial infusion of recombinant Gal-3 in healthy rats Increased cardiac fibroblast proliferation Increased collagen production Reduced LVEF Galectin-3 is a mediator of cardiac fibrogenesis resulting in heat failure development and progression Sharma UC, et al. Circulation. 2004; 110: 3121-8 17

Segmenting a Sub-type of Heart Failure Based on the Phenotype of Galectin 3 GALECTIN-3 MEDIATED HF HF GENERAL POPULATION Active scarring (fibrosis) and adverse remodeling Inherently progressive ~30-50% are at greatest risk of adverse outcome NON-GALECTIN-3 MEDIATED HF Heterogeneous etiology Not inherently progressive ~50-70% are at lower risk of adverse outcome

Who has a + Gal-3 phenotype? Maybe 15% of population! Means you could be ticking time bomb if you allow cardiac risk factors to occur (Htn, Diabetes, CAD, MI,HF) The patients need aggressive follow-up

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 20

HEPATITIS Syndromal diagnosis Phenotyping, specific tests specified diagnosis Hepatitis B Hepatitis C Epstein Barr Virus (EBV) Antiviral agents, e.g. lamivudine Interferon Ganclicovir

ACE-inhibitors Beta blockers Mineralocorticoid Receptor Antagonists CRT/ICD HEART FAILURE Syndromal diagnosis Phenotyping, specific tests specified diagnosis CAD Hypertension Cardiomyopathy

HEART FAILURE Syndromal diagnosis Phenotyping, specific tests specified diagnosis Galectin-3 Conduction disturbance Renin Anti Galectin-3 agents CRT Renin inhibitors, e.g. aliskiren

Galectin-3 and Natriuretic Peptides Galectin-3 BNP/NT-proBNP Biology Indicator of cardiac fibrosis Indicator of cardiac stress Short Term Variability - Relatively stable - Not affected by acute decompensation - Marked variability - Elevation with acute decompensation Response to HF Treatments In HF Management Medicare Reimbursement Not immediately affected by acute HF treatment Aid in Rx and risk stratification (mechanism: indication of the pathologic progression of HF) Yes Can be reduced with acute HF treatment in some patients Aid in Dx, Rx and risk stratification (mechanism: indication of cardiac stress in HF) Yes 24

Gal 3 is independent and additive to NPs in risk prediction HF-ACTION; all-cause mortality and allcause hospitalization COACH; 1-year all-cause mortality HF-ACTION: Felker GM, et al. Circ Heart Fail. 2012; 5: 72-8 COACH: de Boer RA, et al. Ann Med. 2011; 43: 60-8 25

Galectin-3 Consistently Predicts Probability of Re-hospitalization in Three Studies COACH PRIDE p=0.017 UMD H23258 P<0.001 de Boer RA, et al. J Cardiac Fail 2011;17:S93 26

Two cut-offs for risk 1 0.9 PROGNOSTIC UNCERTAINTY 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Probability (RRT) Gal-3 <9 ng/ml High NPV Rule out Grey area Galectin 3 Rule in Gal-3 >17.8 ng/ml High PPV

Patients presenting with dyspnea to ED Galectin-3 < 9.5ng/ml Low risk Diagnosis: Acute Heart Failure Galectin-3 9.5 17.8 ng/ml Galectin-3 > 17.8 ng/ml High risk BNP < 400 pg/ml BNP 400 pg/ml BNP < 400 pg/ml BNP 400 pg/ml Diurese and discharge Observation Unit and D/C with f/u if responds well and low risk Admit to hospital

What would you do in the hospital with a high Gal-3 patient? Vigorous treatment and monitoring of fluid, BNP levels Aggressive uptitration of oral medication Early follow-up Home health monitoring Consider CRT/AICD MRA inhibitors?citrus pectin

SERUM LEVELS OF COLLAGEN BIOMARKERS Placebo Eplerenone * Iraqi W et al. Circulation 2009;119:2471-2479 30 *PINP: Pro Collagen type 1 N-terminal propeptide

Cox Regression: Initiation of spironolactone HR=0.362, p=0.027 Cox Regression: Continuation of spironolactone HR=0.294, p=0.02

Cox Regression: Spironolactone therapy HR=0.779, p=0.803 Cox Regression: Spironolactone therapy HR=0.519, p=0.037 Galectin-3 cutoff: 17.8ng/mL

What is ST2? ST2 is a member of the Interleukin-1 receptor family, and is formally known as interleukin 1 receptor like 1 (IL1RL-1) Exists in two main isoforms through alternative splicing and processing ST2L is a membrane-bound isoform with 3 extracellular IgG domains, a single transmembrane domain, and an intracellular domain ST2 is a soluble, circulating isoform, lacks the transmembrane and intracellular domains It was considered an orphan receptor until identification of its ligand, IL-33, in 2005 Was first reported in 1989, but its function was not well elucidated Investigation revealed its participation in inflammatory processes, particularly regarding mast cells, type 2 CD4+ T-helper cells, and the production of Th2-associated cytokines Initially associated with disease entities such as asthma, pulmonary fibrosis, rheumatoid arthritis, collagen vascular diseases, and septic shock In 2002, Richard Lee at Harvard B&W reported ST2 expression in response to myocardial stress and injury ST2 is expressed by cardiac tissue. Subsequently ST2 was shown to be actively involved in the fibrotic response to illness or injury.

Pro-IL-33 Fibroblast Caspase-1 ST2: A DECOY RECEPTOR Myocyte IRAK IL-33 ST2L MyD88 ERK NFκB sst2 CARDIOPROTECTION Adapted from Kakkar et al. Nat Rev Drug Discov 2008

ST2 in Cardiac Medicine Is NOT a stretch marker Is NOT an inflammatory marker Is a marker of fibrosis and cardiac remodeling providing prognostic guidance Clinical use is not effected by typical confounders such as obesity and renal impairment!!!

Reference Analysis and Cutpoint Selection Level Primary Reference Cohort 1 Confirmation Reference Cohort 2 Mean (SD) 20.9 (9.3) 22.4 (8.7) Min 1.8 3.2 25 th percentile 14.5 16.7 50 th percentile (median) 18.8 20.9 75 th percentile 25.2 26.1 90 th percentile 34.2 32.9 95 th percentile* 37.9 37.3 99 th percentile 49.7 51.0 Max 66.3 119.6 N 490 3,450 *cutpoint concentration for assessment of risk in patients with heart failure was selected at the ~95 th precentile of normal 1 Lu et al. 2010, 2 Coglianese et al. 2012

ST2 Concentrations and 1-Yr Mortality in Acute HF: As ST2 levels increase, so does risk One-Year mortality >50% for highest decile Rehman et al. Correlates of ST2 in Acute HF JACC Vol. 52, No. 18, 2008.1458 65

In ADHF Risk is Much Higher if ST2 >35 ng/ml

Additive Value of ST2 to NT-proBNP: Acute HF Cumulative Hazard 0.8 0.6 0.4 0.2 Both sst2 and NT-proBNP elevated (n=276) Only sst2 elevated (n=95) Only NT-proBNP elevated (n=54) Neither elevated (n=168) P < 0.001 Reclassification 0.0 0 300 600 900 1200 1500 Days from Enrollment Patient would have been classified as moderate risk with only NT-proBNP, but is considered high risk with the addition of ST2. Rehman SR, van Kimmenade RR, Januzzi JL. Circulation. 2008;118:S_871.

Additive Value of ST2 to NT-proBNP: Chronic HF Category Death Rate HR (95% CI) p ST2 35 ng/ml NT-proBNP median ST2 35 ng/ml NT-proBNP >median ST2 >35 ng/ml NT-proBNP median ST2 >35 ng/ml NT-proBNP >median 9.0% 1 NA 23.3% 2.87 (1.9 4.32) <0.001 22.2% 2.70 (1.25 5.84) 0.0115 38.9% 5.59 (3.61 8.66) <0.001 Results from HF-ACTION chronic, ambulatory HF study cohort. Median NT-proBNP concentration is 852 pg/ml in this study. Study follow-up period of 4 years. Risk is higher if either marker is elevated and highest if both makers are elevated Felker, et al. 2013, Circ HF

Serial ST2 Measurements for In-Patient Monitoring (SDVA): Mortality N=35 N=115 N= 150 ST2 Values Shown Using 1 st Generation Research Assay. Boisot et al. J Card Failure 2008

Serial ST2 Measurements Categorize Responder Status Low Risk Patients COX Regression Analysis For every 10% ST2 change HR 1.04, p=0.03 High Risk Patients Adjustment for ADHERE Risk Factors and BNP change. Breidthardt, et al. 2013 JCF

ST2 Levels Predict Response to Treatment: BB 1 Cumulative survival 1 2 3 BB treated ST2 responder BB treated ST2 non-responder untreated ST2 responder 2 3 4 p=0.62 p=0.1 Risk is not absolute! It can be attenuated!! 4 untreated ST2 non-responder Days Breidthardt, et al. 2013 JCF

Val-HeFT: Methods and Results The Valsartan Heart Failure Trial (Val- HeFT) randomized 5010 patients with NYHA class II-IV HF to valsartan or placebo. ST2 was measured in 1,650 US patients at baseline, 1,346 at 4 months and in 1,097 at 12 months after randomization. Snider et al. HFA poster #677, 2012

Change in ST2 and Outcomes: Val-HeFT Study Category HR CI p High-High 1.7 Low-High 1.9 High-Low 1.0 5 Low-Low 1.0 1.2-2.3 1.2-2.9 0.7-1.7 0.003 0.03 0.8 Fully adjusted hazard ratios after correction for 22 clinical variables. Conclusion: Change in ST2 over time was independently and significantly related to the subsequent risks of mortality, first morbid event or hospitalization for HF. 72% of patients had persistently low ST2 Another 8% moved from high risk to low risk 20% of patients had persistently high or transition to high ST2

Clinical Characteristics of AHFS Patients Data on approximately 200,000 patients Median age (years) 75 Women >50% Hx of Atrial Fibrillation Preserved Ejection Fraction 30% 50% Hx of CAD 60% SBP >140 mm Hg 50% Hx of Hypertension 70% SBP 90-140 mm Hg 45% Hx of Diabetes 40% SBP <90 mm Hg 5% Adams KF, et al. Am Heart J. 2005;149: 209. Cleland JGF et al. Eur Heart J. 2003; 24: 442; Fonarow GC, et al. J Am Coll Cardiol. 2004; 844 4A. Renal abnormalities 30%

CardioRenal Syndrome Type 1: Creatinine Increase in Acute HF Patients 100 80 Creatinine is a measure of kidney function. An increasing creatinine over time means that the kidney was injured and has lost function. The graph below shows how Cr increases in hospitalized HF patients. 0.1 % Cr 60 40 20 0 X Type 1 CardioRenal Syndrome Also know as: X X X X X X X X X X X X X X Worsening Renal Function (WRF) or Acute Kidney Injury (AKI) 0.2 0.3 0.4 0.5 1 3 5 7 9 11 13 15 Days Cr, serum creatinine. Gottlieb SS et al. J Card Fail. 2002;8:136. Smith G, J Card Fail. 2003 Feb;9(1):13-25

Iatrogenic causes of AKI in HF patients To much Diuretic ACE, ARB, Aldo Blockers Contrast Antibiotics

Outcome Incidence WRF ~ 28%; 90% occurred within 7 days No WRF (n=1212, 72%) WRF (n=469, 28%) Adj Hospital Death (%) 3 7 2.72 30-d Death (%) 6 10 1.87 6-m Death 19 25 1.56 Hospital Stay (d) 6.9 9.1 2.3 Hospital Cost ($) 6,327 8,085 1,758 Krumholz et al Am J Cardiol 2000

Ronco C et al. J Am Coll Cardiol 2008; 52: 1527-39 Cardiorenal Syndrome (CRS) General Definition: A pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ CRS Type I (Acute Cardiorenal Syndrome) Abrupt worsening of cardiac function (e.g. acute cardiogenic shock or decompensated congestive heart failure) leading to acute kidney injury CRS Type II (Chronic Cardiorenal Syndrome) Chronic abnormalities in cardiac function (e.g. chronic congestive heart failure) causing progressive and permanent chronic kidney disease CRS Type III (Acute Renocardiac Syndrome) Abrupt worsening of renal function (e.g. acute kidney ischaemia or glomerulonephritis) causing acute cardiac disorder (e.g. heart failure, arrhythmia, ischemia) CRS Type IV (Chronic Renocardiac Syndrome) Chronic kidney disease (e.g. chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events CRS Type V (Secondary Cardiorenal Syndrome) Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction

Approach in Acute Kidney Injury Identification of Risk patients Primary prevention Early detection of AKI Reduction of Morbidity and Mortality? Secondary prevention

AMI versus AKI Period 1960s 1970s 1980s 1990s 2000s Acute Myocardial Infarction LDH CPK, myoglobin CK-MB Troponin T Troponin I Multiple Therapies 50% Mortality

AMI versus AKI Period Acute Myocardial Infarction Acute Kidney Injury 1960s LDH SCr 1970s CPK, myoglobin SCr 1980s CK-MB SCr 1990s Troponin T SCr 2000s Troponin I SCr Multiple Therapies 50% Mortality Supportive Care High Mortality Need early biomarkers for better treatment of AKI

Up to 50% of kidney function may be lost before serum creatinine even begins to rise

The promise of biomarkers for AKI The nephrologist s troponin Measured in urine or serum Early management (goaldirected therapy) Development of New therapeutic strategies

Protein Biomarkers for the Early Detection of Acute Kidney Injury Biomarker Cystatin C KIM-1 NGAL (lipocalin) NHE3 Cytokines (IL-6, IL-8, IL-18) Actin-actin depolymerizing F α-gst Π-GST L-FABP Netrin-1 Keratin-derived chemokine Associated Injury Proximal tubule injury Ischemia and nephrotoxins Ischemia and nephrotoxins Ischemia, pre-renal, post-renal AKI Toxic, delayed graft function Ischemia and delayed graft function Proximal tubule injury, acute rejection Distal tubule injury, acute rejection Ischemia and nephrotoxins Ischemia and nephrotoxins, sepsis Ischemia and delayed graft function GST = glutathione S-transferase; IL = interleukin; KIM = kidney injury molecule; L-FABP = L-type fatty acid binding protein; NGAL = neutrophil gelatinase-associated lipocalin; NHE = sodium-hydrogen exchanger.

Heart Failure Cardiac surgery Radiocontrast Trauma ICU Kidney transplant NGAL IgA nephropathy CKD

S- and U-NGAL in children after cardiopulmonary bypass (n=71) 28% dev AKI Mishra J et al. Lancet 2005;365.

What can NGAL detect? NGAL Creatinine Marker of Renal Injury High Sensitivity for Injury Moderate Specificity for underlying nephropathy

AKI SPECTRUM Normal markers; no AKI NO STRUCTURAL OR FUNCTIONAL INJURY STRUCTURAL INJURY BUT NORMAL FUNCTION Normal Cr NGAL, Early AKI Normal NGAL, Cr Pre-renal AKI FUNCTIONAL LOSS BUT NORMAL STRUCTURE BOTH STRUCTURAL AND FUNCTIONAL LOSS Cr NGAL, Establishe d AKI

Grey Zone Probability (RRT) 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 BM <xx High NPV Rule out PROGNOSTIC UNCERTAINTY Rule in Grey area Biomarker X BM >XX High PPV

Clinical Scenario: Year 2014 NGAL level Diagnosis Intervention <100 ng/ml No AKI Routine care

NGAL level Diagnosis Intervention <100 ng/ml No renal injury Routine care 150-300 ng/ml High risk for AKI Hold ACE Hold ARB Hold Aldo blockers No contrast No renal toxic antibiotics No NSAIDS Judicious diuretics

Discharge levels of markers Maisal et al Eur J Heart Fail 2011

Group HR p NGAL <100 BNP <330 NGAL <100 BNP >330 NGAL >100 BNP <330 NGAL >100 BNP >330 1.00-3.23 0.3 9.95 0.04 16.85 <0.001 Maisal et al Eur J Heart Fail 2011