2017 ACC/AHA/HFSA HF guidelines. Advances in the Use of Biomarkers in Heart Failure Patients. Outline

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1 Advances in the Use of Biomarkers in Heart Failure Patients Lori B. Daniels, MD, MAS, FACC, FAHA Professor of Medicine Director, Cardiovascular Intensive Care Unit Sulpizio Cardiovascular Center UC San Diego Outline HF Guidelines 2. Sacubitril/valsartan and NP s 3. ST ACC/AHA/HFSA HF guidelines 1. Prevention of HF 2. Diagnosis 3. Prognosis Natriuretic peptides Markers of injury or fibrosis hstn ST2 Galectin Heart failure clinical practice guidelines Indication Class LOE NPs for diagnosis I A NPs for prognosis I A NPs for pre-discharge risk assessment IIa B-NR NPs to prevent HF onset IIa B-R NPs to guide HF therapy IIb B-NR Fibrosis/injury markers for risk assessment IIb B-NR 1

2 Prevention of Heart Failure STOP HF trial St Vincent s Screening to Prevent HF Study Randomized, Controlled Trial Routine care (n=677) Routine PCP care vs. BNP-directed care (n=697) Annual BNP check STOP-HF PONTIAC Cardiology care PRN 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 Ledwidge et al. JAMA 2013 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 STOP HF Also reduced emergency hospitalizations for MACE How? BNP group received reninangiotensin-aldosterone system-based therapy 1 Endpoint: LV systolic or diastolic dysfunction, or heart failure Ledwidge et al. JAMA 2013 Ledwidge et al. JAMA

3 PONTIAC Single center RCT N=300 subjects with type 2 diabetes and NT-proBNP >125 pg/ml Control group care at diabetes unit Intensified group additional treatment at cardiology clinic for uptitration of RAS and BB Outcome hospitalization/cardiac death at 2 years (Aside: based on post-hoc analysis of HOPE study, showing the benefit was primarily in pts with NTproBNP > median) Huelsmann et al. JACC 2013; Gaede et al. Diabetol PONTIAC: results Significant reduction in the 1⁰ endpoint Hospitalization or Cardiac Death Intensified group Control group p=0.035 Huelsmann et al. JACC 2013 PONTIAC: how was 1⁰ endpoint achieved? Why did STOP HF and PONTIAC work? What early signal are the biomarkers picking up on? Similar BP, but Higher use and doses of RAS and BB Huelsmann et al. JACC

4 Biomarkers as a surrogate for early fibrosis Frequency of LV scar on LGE cardiac MRI by hs ctnt category in clinically CVD free adults LGE was identified in 113 (6.3%) LGE pattern distribution were classified as ischemic in 38 (33.6%) N=1753 Malignant Left Ventricular Hypertrophy Minor elevations in hstnt associated with fibrosis and progressive p<.001 for trendchanges in LV structure precedes HF sx s by years Seliger, Hong, Christensen, Kronmal, Daniels et al. Circulation th %ile: 19 ng/l Peters, Seliger, Daniels, et al. JAHA Cumulative risk of HFrEF and HFpEF by LVH biomarker group Incident HFrEF Incident HFpEF Malignant LVH defined by LVH + biomarkers risk of progression to LV dysfn, HF (HFrEF) * Elevated hs ctnt or NT probnp defined as upper tertile per decade of age No LVH, no biomarker elevated N=2206 No LVH, 1 biomarker elevated N=2275 LVH, no biomarker elevated N=153 LVH, 1 biomarker elevated N=351 Peters, Seliger, Daniels, et al. JAHA Cumulative risk of HFrEF and HFpEF by LVH biomarker group Cumulative CV mortality Incident CV Mortality Malignant LVH defined by LVH + biomarkers risk of progression to CV death Elevated hs ctnt or NT probnp defined as upper tertile per decade of age No LVH, no biomarker elevated N=2206 No LVH, 1 biomarker elevated N=2275 LVH, no biomarker elevated N=153 LVH, 1 biomarker elevated N= Follow-up (years) No LVH, neither biomarker elevated LVH, neither elevated No LVH, >=1 biomarkers elevated LVH, >=1 elevated Peters, Seliger, Daniels, et al. JAHA

5 Diagnosis of Heart Failure Prognosis in Heart Failure: NP s Prognosis in HF: Other Markers Guidelines Summary: Indications for use of Biomarkers in HF hstn, ST2, Galectin-3 5

6 From the 2017 ACC/AHA/HFSA HF Guidelines: Outline HF Guidelines 2. Sacubitril/valsartan and NP s 3. ST2 Note that the type of natriuretic peptide assay that has been performed must be considered during interpretation of natriuretic peptide biomarker levels in patients on ARNI. Pre-Pro-BNP aa signal sequence Angiotensin Receptor Neprilysin Inhibition (ARNI) Sacubitril/Valsartan Pro-BNP sacubitril valsartan Natriuretic peptides BK, ADM Subs-P, VIP, CGRP Angiotensin II WALL STRESS N-terminal BNP Pro-BNP 1-76 t 1/2 = ~18 min Natriuresis lusitropy Vasodilatation RAAS Vasodilation Natriuresis Diuresis Inhibition of pathologic growth/fibrosis Neprilysin Degradation products AT 1 Receptor Vasoconstriction Sodium/water retention Fibrosis/hypertrophy 6

7 PARADIGM HF Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial McMurray et al. NEJM 2014 PARADIGM-HF: Primary outcome Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial Age 18 years. NYHA class II-IV. LVEF 40% (amended to 35%). BNP 150 pg/ml (NTpro-BNP 600 pg/ml) or if HF hosp. within12 mo. BNP 100 pg/ml (NTpro-BNP 400 pg/ml) Background RAS blocker therapy equivalent to enalapril 10 mg/d Beta-blocker and MRA as recommended by guidelines SBP 100 mmhg run-in/ 95 mmhg at randomization egfr 30 / no decrease >25% (amended to 35%) Potassium 5.2 run-in/ 5.2 at randomization Single-blind period Double-blind period LCZ mg BID (n=4187) CVD Death or HF Hospitalization Cumulative Proportion of Patients with Primary End Point (%) HR: 0.80 (0.73, 0.87) p = Enalapril (n=4212) LCZ696 (n=4187) 914 Enalapril 5-10 mg bid LCZ 100 mg bid LCZ 200 mg bid 1-2 weeks 1-2 weeks 2 weeks Prior ACEi/ARB use discontinued N = 8442 (1:1 randomization) Enalapril 10 mg BID (n=4212) Outcome driven (CV death): Stopped early for benefit Median follow-up = 27 months Days after Randomization At risk Enalapril: LCZ696: McMurray et al. NEJM PARADIGM HF: NT probnp and BNP NT-proBNP pg/ml Data from Packer et al. Circulation NT-proBNP BNP 500 LCZ696 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 Early changes in BNP reflect action of the drug levels Changes in NT-proBNP reflect reduced LV wall stress Alternatively, sacubitril may cause glycosylation of NT-proBNP, resulting in underdetection of actual 7

8 Monitoring with NP s: Lessons from PARADIGM NP Levels in PARADIGM-HF and Outcomes Among pts with NT probnp >1000: A drop to <1000 better outcomes, in both study arms 2x as likely with sacubitril/valsartan than with enalapril Dropping NP better prognosis Figure 1. Effects on Risk of Primary Endpoint if NT-proBNP Achieved or Did Not Achieve a Value of <1,000 pg/ml 1 Month After Randomization Risk of primary endpoint after 1 month of randomization in patients with a baseline N-terminal pro B-type natriuretic peptide. Zile et al. JACC Michael R. Zile, Brian L. Claggett, Margaret F. Prescott, John J.V. McMurray, Milton Packer, Jean L. Rouleau, Karl Swedberg, Akshay S. Desai, Jianjian Gong, Victor C. Shi, Scott D. Solomon Journal of the American College of Cardiology, Volume 68, Issue 22, 2016, Levels of other biomarkers may be arbitrators of improvement PARADIGM HF: median hs TnT concentration by visit Randomization Data from Packer et al. Circulation Prior to Run-in Randomization 4 weeks 8 months 8

9 PARAMOUNT Study: HFpEF Solomon et al. Lancet 2012 PARAMOUNT Primary Endpoint PARAMOUNT an NT-proNBP endpoint study (Phase II) LCZ mg bid vs valsartan 160mg bid Primary Endpoint: change in NT-proBNP at 12 weeks N=149, EF 45% (mean 58%), class II-IV HF, NTproBNP>400 Results: LCZ696 reduced NT-proBNP 12 wks (1ᵒ outcome) Not powered for events numerically less in LCZ696 group Similar safety profile What can NP s tell us about sacubitril/valsartan in HFpEF? NT-proBNP (pg/ml) Solomon et al. Lancet 2012 Weeks A new class of agents for HFpEF? ARNI s in HFpEF PARAGON: Phase III study of sacubitril/valsartan in HFpEF Not yet out STAY TUNED! Recommendations for using NP s in patients on sacubitril/valsartan 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 data on NP levels in pts on sacubitril/valsartan 43 9

10 ST2 Outline HF Guidelines 2. Sacubitril/valsartan and NP s 3. ST2 Also called sst2 Less subject to confounding factors like age, sex, BMI, renal disease etc Marker of prognosis (not diagnosis) Acute and chronic HF MI ST2 and IL-33: Cardioprotective Competitive Model of ST2/IL-33 Signaling ST2: member of the Interleukin-1 receptor family Exists in two main isoforms ST2L Circulating sst2 IL-33 binding to ST2L triggers cardioprotective effects. ** Cardioprotection ** sst2 acts as decoy receptor IL-33 can bind to sst2, reducing [IL-33] available to ST2L Kakkar et al. Nat Rev Drug Discov 2008 Kakkar et al. Nat Rev Drug Discov

11 ST2 in Acute Decompensated HF Cohorts HR for risk of death at 1 year, with ST2 >35 ng/ml Univariable Risk Adjusted ST2 in Chronic, Ambulatory HF Cohorts HR for risk of death at 1 year, with ST2 >35 ng/ml Univariable Risk Adjusted Daniels LB, Future Cardiol 2014 Adjusted for age, sex, NYHA class, EF, GFR, diabetes, HTN, and smoking Daniels LB, Future Cardiol 2014 Adjusted for age, sex, NYHA class, EF, GFR, diabetes, HTN, and smoking Acute HF pooled studies Predicting Short-Term Adverse Events: ST2 vs Natriuretic Peptides When to order ST2 in ADHF? Admission? Discharge? Post-discharge? ST2 gives an earlier and stronger signal for short-term adverse events than NPs. 11

12 Admission vs Discharge ST2 in Acute HF N=182 pts admitted with AHF; real life population Admission and d/c ST2 and NT probnp Admission vs Discharge ST2 Admission ST2 Level Discharge ST2 Level Llibre et al, Biomarker Discharge ST2 more predictive of outcomes Llibre et al, Biomarker Discharge ST2 more predictive of outcomes Short-Term Changes in ST2 are Associated With Long-Term Events in HF Serial ST2 Levels: U Shaped versus J Shaped Curves TRIUMPH study 496 pts with acute HF ST2 measured 7x over 1 yr f/u ST2 Ratio: Week 2/Baseline Lower is better, <0.75 2x as many pts with U-shape pattern reached the 1⁰ endpoint ST2 levels begin to elevate several weeks before the 1⁰ endpoint 1-year CV death, hospital admission for HF, or urgent cardiac transplant Bayes-Genis A, et al., Rev Esp Cardiol van Vark et al, JACC

13 ST2 Predicts Response to Treatment: Aldosterone Blockade in STEMI Prediction of Exercise Response in Chronic HF HF-ACTION Eplerenone prevents adverse ventricular remodeling ST2 predicts which pts are most at risk AND which pts will benefit most from aldosterone blockade High and low ST2 separated at median. Eplerenone attenuates remodeling more in pts with higher baseline ST2. Line 1 is low ST2-exercise Line 2 is low ST2-usual care Line 3 is Line high ST2-usual 1: Low ST2 care and exercise Line 4 is Line high ST2-exercise 2: Low ST2 and usual care Line 3: High ST2 and usual care Line 4: High ST2 and exercise Pts with lower ST2 levels more likely to benefit from exercise 1 P= Weir AP, et al. J. Am. Coll. Cardiol. 2010;55; Felker, et al Circ HF How to Use ST2: Chronic Heart Failure or Post MI Baseline ST2 level after acute decompensation +/- 2 week level ST2 ratio : 2 weeks/baseline Ratio 0.75 or higher increased risk ST2 >35 ng/ml, or rising U-shape Optimize/uptitrate medications (BB, ACEi/ARB) Aldosterone blockade if appropriate (K<5.0, Cr<2.5) Closer follow-up: Phone calls? Home monitoring? Summary ST2 is a powerful predictor of short-term mortality in acute & chronic HF and MI HFpEF, HFrEF (data not shown) ST2 and NPs are synergistic Admission and D/C levels give different info D/C level more predictive of outcomes Changes in ST2 levels have important clinical implications Non-responders are at higher risk, and optimizing therapy can attenuate this 13

14 Thank You 14