6/29/2017. Role of Biomarkers in the Management of Heart Failure Patients. What s New in Biomarkers for HF Patients?

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1 What s New in Biomarkers for HF Patients? Role of Biomarkers in the Management of Heart Failure Patients Lori B. Daniels, MD, MAS, FACC Professor of Medicine Director, Cardiovascular Intensive Care Unit Sulpizio Cardiovascular Center UC San Diego Natriuretic Peptides: Guided therapy recommendations Use of NP s in patients on sacubitril/valsartan Procalcitonin to help with HF/PNA Highly sensitive Troponin T approved in the US 3 Assessing Risk for Incident Heart Failure In community-based populations: BNP or NT-proBNP hstnt Adds prognostic information to risk factors alone for predicting new-onset HF Others: sst2, GDF-15, gal-3 May be useful 5 Chow et al. Circulation

2 STOP-HF trial St Vincent s Screening to Prevent Heart Failure Study Ledwidge et al. JAMA 2013 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 STOP-HF trial: results 4.0% Reduction in primary endpoint (p=0.003) 3.5% 3.0% 2.5% Control 2.0% BNP 1.5% 1.0% 0.5% 0.0% LVDD LVSD HF 1 Endpoint: LV systolic or diastolic dysfunction, or heart failure Ledwidge et al. JAMA 2013 STOP HF Also reduced emergency hospitalizations for MACE How? BNP group received reninangiotensin-aldosterone system-based therapy Diagnosis, Prognosis The same players: BNP/NT-proBNP *Predischarge NP level Ledwidge et al. JAMA

3 Guiding Outpatient HF Therapy NP s, ST2 Targeting NT-proNBP <1000 pg/ml (BNP <??? [100 pg/ml?], ST2 < 35 ng/ml) Mixed results in prospective studies New Area of Focus: Use of NP s in patients on sacubitril/valsartan Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696 Sacubitril/valsartan sacubitril valsartan Natriuretic peptides BK, ADM Angiotensin II Subs-P, VIP, CGRP Vasodilation Natriuresis Diuresis Inhibition of pathologic growth/fibrosis Neprilysin AT 1 Receptor Vasoconstriction Sodium/water retention Degradation Fibrosis/hypertrophy products PARADIGM-HF Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial PARADIGM-HF: Primary outcome Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial In brief: Randomized study of NYHA class II-IV HF patients with reduced LVEF 35%, n=8442 Sacubitril/valsartan 200mg bid vs enalapril 10mg bid Median f/u 24 months Primary outcome: CVD death or HF hospitalization Stopped early for benefit Primary Outcome: CVD Death or HF Hospitalization Cumulative Proportion of Patients with Primary End Point (%) HR: 0.80 (0.73, 0.87) p = Enalapril (n=4212) 914 Sacubitril/valsartan (n=4187) McMurray et al. NEJM Days after Randomization At risk Enalapril: LCZ696: McMurray et al. NEJM

4 PARADIGM-HF: NT-proBNP and BNP NT-proBNP pg/ml Data from Packer et al. Circulation NT-proBNP BNP 500 Sacubitril/valsartan Enalapril Months BNP pg/ml BNP versus NT-proBNP in patients taking sacubitril/valsartan BNP, but not NT-proBNP, is degraded by neprilysin Treatment with sacubitril will inhibit the degradation of BNP (but not NT-proBNP) Treatment initiation may result in small increases in BNP (~20%) due to this inhibition The rise is transient Subsequent BNP levels decline, though not typically back to pre-initiation levels Levels of NT-proBNP do not appear to be altered by sacubitril initiation, though levels tend to decline over time, due to: Improved hemodynamics Alternatively, sacubitril may cause glycosylation of NT-proBNP, resulting in underdetection of actual levels Is the Drop in NT probnp Reflecting Improved Prognosis vs. a side effect of the sacubitril/valsartan? More Lessons from PARADIGM: Among pts with NT probnp >1000 pg/ml: A drop to <1000 better outcomes, in both study arms Is the Drop in NT probnp Reflecting Improved Prognosis vs. a side effect of the sacubitril/valsartan? More Lessons from PARADIGM: Among pts with NT probnp >1000 pg/ml: A drop to <1000 better outcomes, in both study arms *2x as likely with sacubitril/valsartan than with enalapril Dropping NT-proBNP better prognosis Early change (rise) in BNP reflects action of the drug Change (drop) in NT-proBNP reflects reduced LV wall stress Zile et al. JACC Zile et al. JACC

5 Recommendations for using NP s in patients on sacubitril/valsartan Is it HF or PNA? Role of Procalcitonin For BNP May need to establish a new baseline/ dry BNP Or account for ~20% rise within ~1 month of initiation For NT-proBNP As far as we know, no adjustment needed We need more real-world and prospective data on NP levels in pts on sacubitril/valsartan Procalcitonin Under Normal Conditions CALC Gene mrna N ProCT Calcitonin Katacalcin The Presence of Bacterial Infection Stimulates Procalcitonin Production ) Thyroid Physiologic PCT Levels: 46.7 pg/ml (97.5 percentile); median = 12.7 pg/ml* (0.05 ug/l and 0.01 ug/l) Morgenthaler N. et al., Clin Lab. 2002, 48: After P. Linscheid, Endocrinology 2003 Bacterial infection and cytokines stimulate production of PCT in parenchymal tissues PCT is rapidly released into bloodstream Cytokines produced by viral infection inhibit this (IFN γ) 5

6 Production is Ubiquitous Calcitonin: Sources of production in healthy people Healthy Sepsis PCT: Sources of Production in Septic Patients Procalcitonin Rises Rapidly Serial procalcitonin concentrations in plasma of normal subjects injected with endotoxin (4 rig/kg BW) at time zero. Ubiquitous fold increase in production More widespread than other common cytokines (TNF α, IL 6) Müller B. et al., J Clin Endocrin Metab. 2001;86: Dandona. J Clin Endocrinol Metab. 1994;79:1605. Predictable Time Dynamics of PCT Procalcitonin: Advantages Brunkhorst FM et al., Intens. Care Med 1998;24: PCT levels rise within 3 6 hours after infectious challenge Peak 6 12 hrs. Half life ~24hrs Specific for bacterial infection Correlates with severity of disease and mortality Rapidly rises declines with control of infection 50% daily decrease associated with control of infection by host immune system/antimicrobials PCT is not impaired by neutropenia or other immunosuppresive states 42 Schuetz P. BMC Medicine. 2011;9:107 Kibe S., et al. J Antimicrob Chemother.2011;66(S2):ii

7 Heart Failure + Infection Procalcitonin: PCT increases with increased likelihood and severity of bacterial infection Heart failure + pneumonia is present ~10-15% of time Heart failure + any infection may occur in up to 20% of hospitalized HF patients. Hospital mortality may be up to 20% (vs 5%) in HF patients with untreated infections Müller B. et al. Crit Care Med 2000 FDA approved for assessing risk of progression to severe sepsis BACH study: Combo of NP + PCT to better diagnose dyspneic patients AHF, no Pneumonia (n=539) BACH Trial 90-d Survival Based on Antibiotic Treatment (yes/no) and PCT Level 1600 Patients presenting to ED with dyspnea PCT levels measured but treating clinicians blinded to results 600 BNP [ng/ml] no AHF, no Pneumonia (n=947) AHF and Pneumonia (n=29) Pneumonia, no AHF (n=126) A. All patients with HF B. Lowest quintile PCT (<0.05 ng/ml) C. PCT between ng/ml D. Highest quintile PCT (>0.21 ng/ml) PCT [ng/ml] Maisel et al. Eur J Heart Fail Maisel et al. Eur J Heart Fail

8 ProHOSP Trial ProHOSP Protocol Multicenter, non inferiority, randomized trial Adults with lower resp tract infxn (LRTI) presenting to ED Randomized to PCT guided vs standard therapy PCT levels at admission If antibiotics started, PCT also on days 3, 5, 7 Recommendation to stop abx based onalgorithm Overruling allowed due to hemodynamic instability, severe disease, + Legionella Ag Schuetz P, et al. JAMA 2009; 302: Schuetz P, et al. JAMA 2009; 302: Antibiotic Use Outcomes ProHOSP: Results Reduction in mean antibiotic exposure (32 65%) Reduction in rate of antibiotic prescriptions (8 27%) Outcome Control (n=688) PCT (n=671) Statistical Analysis [95% CI] Antibiotic 603 (87.7%) 506 (75.4%) 34.8% ( 40.3% to 28.7%) Prescription Rate Mean Antibiotic % ( 16.3% to 8.1%) Exposure (days) Antibiotic Adverse 193 (28.1%) 133 (19.9%) 8.2% ( 12.7% to 3.7%) Event Rate 30 day Adverse 130 (18.9%) 103 (15.4%) 3.5% ( 7.6% to 0.4%) Outcomes Mortality ITT 33 (4.8%) 34 (5.1%) Absolute difference: 0.3% ( 2.1 to 2.5) Mortality PP 31 (4.8%) 29 (4.6%) Absolute difference: 0.2% ( 2.6 to 2) Adverse Outcome = death, ICU admission, recurrence, disease specific complications ITT = intention to treat; PP = per protocol OR of Combined Adverse Outcome = 0.76 (95% CI, ), p=0.64 Schuetz P, et al. JAMA 2009; 302: Schuetz P, et al. JAMA 2009; 302:

9 Pro-HOSP: HF Substudy N=223 with a history of heart failure PCT-guided antibiotic therapy resulted in decreased antibiotic exposure For both low and high initial PCT levels Improved 30-d outcomes in low PCT group randomized to PCT-guided vs standard therapy Consistent with BACH findings Adverse outcomes among pts with low initial PCT (<0.25ug/L) Adverse outcomes: all-cause mortality or ICU admission Interpretation of PCT levels in pts with chronic HF and respiratory symptoms Serial PCT Levels + abx q2 days, same cutpoints or >80% drop No abx repeat after 6-24h Antibiotics may be harmful in HF without bacterial infection Schuetz et al. Int J Cardiol Schuetz, Daniels, et al. Int J Cardiol Keep In Mind the Confounders Physiologic Stress Newborns (<48 72 hours; after 72 interpret levels as usual) Massive stress (severe trauma, surgery, cardiac shock, burns) In absence of infection levels trend down Prolonged, severe cardiogenic shock or organ perfusion abnormalities Non bacterial cytokine activation Some forms of vasculitis and acute graft vs. host disease Malaria and some fungal infections Chronic renal disease (mild increase in baseline) Dysregulated PCT production Treatment with agents which stimulate cytokines (OKT3, anti lymphocyte globulins, alemtuzumab, IL 2, granulocyte transfusion) Paraneoplastic syndromes due to medullary thyroid and small cell lung cancer PCT in Post-Transplant Pts Their conclusions: PCT heavily influenced ( ) by antithymocyte globulin (ATG) administration Need to use higher cut-off values after transplant PCT and CRP in pts without (n=91) and with infxn (n=16) 9

10 Conclusions PCT may help reduce antibiotic usage, improve outcomes in HF patients with suspected LRTI PCT isn t perfect ALL biomarkers in HF!!! Interpret in the clinical context of the patient Serial measurements are preferred and providemore usefulinformation Consider the dynamics of the disease Be aware of conditions which may affect PCT levels Good clinical judgment should always be applied Thank You 61 10