Biomarkers I: Defining the value of measuring

Transcription

1 Biomarkers I: Defining the value of measuring Alan S. Maisel MD FACC Professor of Medicine, University of California, San Diego, Director, CCU and Heart Failure Program San Diego VA Medical Center

2 The Epidemic of Heart Failure Prevalence Incidence Mortality 5,100, ,000 50% at five years Hospital Discharges Outpatient Visits 1,023, million Cost $39.8 billion Heart failure is common, costly, and deadly Preven5on, diagnosis, risk stra5fica5on, 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.

3 Objec5ves of Biomarker Tes5ng in Heart Failure Diagnosis 1 To establish or refute a diagnosis To understand the underlying pathophysiologic processes Risk Stra/fica/on/Screening 1 To determine the presence or severity of disease To detect adverse consequences Monitoring/Therapeu/c Guidance 1 To facilitate selec5on of an appropriate therapeu5c interven5on To guide or monitor responses to treatment Condition X Outcome A Biomarker Intervention Outcome B Many biomarkers may be risk factors themselves; therefore, may be potential targets of therapy 2 HF, heart failure. 1. Morrow DA, et al. Circulation. 2007;115: Kalogeropoulos AP, et al. Prog Cardiovasc Dis. 2012;55(1):

4 WeDerson, Maisel AJM in press

5 Biomarkers Indications for Use *Other biomarkers of injury or fibrosis include soluble ST2 receptor, galectin-3, and highsensitivity troponin. ACC indicates American College of Cardiology; AHA, American Heart Association; ADHF, acute decompensated heart failure; BNP, B-type natriuretic peptide; COR, Class of Recommendation; ED, emergency department; HF, heart failure; NT-proBNP, N-terminal pro-b-type natriuretic peptide; NYHA, New York Heart Association; and pts, patients.

6 Raising the bar Natriuretic peptides are and will remain the standard diagnostic biomarker for acute heart failure

7 Congestion Often Does not Translate in Signs/Symptoms Among pts. with severe heart failure 1 PCWP 33 ± 6 mmhg, CI 1.8 ± 0.5, LVEF 0.18 ± 0.06 CXR: 27% no congestion, 41% minimal congestion Among pts. with moderate to severe heart failure 2 PCWP 30 ± 9 mmhg, CI 2.1 ± 0.8, LVEF 0.18 ± 0.06 No rales: 84%, No edema: 80%, No JVP 50%, No orthopnea: 22% 1 Mahdyoon H et al. Am J Card. 2003; 63: Stevenson LW et al. JAMA. 1989; 261: 884

8 JVP- misconcep5ons When its very high it is oken mistaken for caro5d Docs tend to think if jvp is not elevated, it cant be heart failure Eleva5ons only mean right sided- and might not explain sob

9 You can buy 7 dollar disposable stethoscopes

10 A chest x-ray can NEVER rule out acute heart failure! Misses 20% of Echocardiogram proven cardiomegaly Even worse if done portable Diagraghm not well distended

11 Well, Bob, it looks like a paper cut, but just to be sure. Let s get an echo.

12 How sure are we about the diagnosis of AHF?? Number of Cases Significant Indecision Exists 43 % Pretest Probability of CHF McCullough, Maisel et al. Circula(on. 2002;106:

13 What happens if we misdiagnose the acute breathless pa5ent? 14 Dyspnea of respiratory origin 12 mortality (%) P<0, Wuerz. Ann Emerg Med 1992;21: bronchodilators No therapy CHF Therapy

14 Breathing Not Properly STUDY

15 Accuracy is 90% Op/mal cut-off point 100 pg/ml 1.0 Sensitivity BNP 100 pg/ml Test posi5ve BNP=50 pg/ml BNP=80 pg/ml BNP=100 pg/ml BNP=125 pg/ml BNP=150 pg/ml Final Diagnosis Heart Failure Final Diagnosis NOT Heart Failure Posi5ve predic5ve value=75% Nega/ve predic/ve value=90% BNP <100 pg/ml Test nega5ve 71 Sensi5vity =90% 615 Specificity =73% Maisel AS et al. N Engl J Med. 2002;347: Specificity

16 BNP levels adds to the physician s ability McCullough, Maisel et al., Circulation :

17 Clarifica5on of Diagnosis & BNP BNP reduces clinical indecision by 74% 45% Indecision 40% 35% 30% 25% 20% 43% * P < % 10% 5% 11% 0% Clinical Evalua/on Clinical Evalua/on and BNP

18 NtproBNP cut-offs < 75 y.o. and 450 > 75 yo , 900, 1800 based on age to rule out.

19 Biomarkers Biomarkers for Diagnosis COR LOE Recommenda/on I A In pa5ents presen5ng with dyspnea, measurement of natriure5c pep5de biomarkers is useful to support a diagnosis or exclusion of HF. Comment/ Ra/onale MODIFIED: 2013 acute and chronic recommenda5on s have been combined into a diagnosis sec5on.

20 BNP Levels in Patients Presenting With Either Systolic or Diastolic Dysfunction BNP (pg/ml) Median= 413 pg/ml Median= 34 pg/ml Median= 821 pg/ml 5 Non CHF Diastolic Systolic n=844 n=165 n=287 Maisel et alj Am Coll Cardiol 2003;410(11):

21 Confounders of NP interpreta5on * 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*

22 Grey Zone 1 Probability (RRT) BM <xx High NPV Rule out PROGNOSTIC UNCERTAINTY Rule in BM >XX High PPV 0 Grey area Biomarker X

23 Sacubitril / Valsartan Mechanism of Ac5on

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

25

26 Heart Failure- Cause for Hospital Admission Other Non compliance Ischemia Arrhythmia Volume overload % of Pa/ents

27 Diure5c Based Clinical Strategies Are Not Always EFFECTIVE in Reducing Weight (n=25,799) Enrolled Discharges (%) % 6% 13% 24% 30% 16% 21% discharged without weight loss or weight gain 3% 2% 0 (<-20) (-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10) Change in Weight (lbs) Note: For the chart, n represents the number of patients who have both baseline and discharge weight, and the percentage is calculated based on the total patients in the corresponding population. Patients without baseline or discharge weight are omitted from the histogram calculations. All Enrolled Discharges in the Last 12 Months ( ) Discharged Home (including home with addi5onal and/or outpa5ent care) Who Were ADHERE Database

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

29 Biomarkers Biomarkers for Prognosis or Added Risk Stratification COR LOE Recommenda/ons I I A A Measurement of BNP or NTproBNP is useful for establishing prognosis or disease severity in chronic HF. Measurement of baseline levels of natriure5c pep5de biomarkers and/or cardiac troponin on admission to the hospital is useful to establish a prognosis in acutely decompensated HF. Comment/ Ra/onale 2013 recommenda5on remains current. MODIFIED: Current recommenda5on emphasizes that it is admission levels of natriure5c pep5de biomarkers that are useful.

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

31 BNP Measurement- Discharge (2) Relative concentrations also prognostic BNP reduction by >30% is an independent predictor of reduced mortality (HR = 0.57, 95% CI ) Lourenço, et al. Am J Cardiol. 2015;116: Di Somma et al. Crit Care. 2010;14:R116. S L I D E 99

32 Biomarkers Biomarkers for Prognosis or Added Risk Stratification COR LOE Recommenda/ons IIa B-NR During a hospitaliza5on for HF, a predischarge natriure5c pep5de level can be useful to establish a postdischarge prognosis. Comment/ Ra/onale NEW: Current recommenda5on reflects new observa5onal studies. IIb B-NR In pa5ents with chronic HF, measurement of other clinically available tests, such as biomarkers of myocardial injury or fibrosis, may be considered for addi5ve risk stra5fica5on. MODIFIED: 2013 recommenda5ons have been combined into prognosis sec5on, resul5ng in LOE change from A to B- NR.

33 In my shop, most of the the ADHF pa/ents are being treated the same way Tune up with diuretics-iv for 2-3 days, then a new oral dose - A bit of education - Push patient out the door & wave good-bye

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

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

36 Changes one might consider on the basis of a BNP prior to discharge Extra hospital 5me One week follow up Home nursing Telemonitoring More aggressive 5tra5on of medica5ons

37 The use of NPs for rule-out heart failure in symptomatic patients in primary care Identifying the right patients for echocardiography Presenting at the GP with symptoms suggestive of heart failure < cut-off value Rule out Search for other explanation? > cut-off value Referral to specialist

38

39 Current NT-proBNP cut-offs for outpa5ent use NPV op5mized 125 pg/ml <75 years of age 450 pg/ml 75 years of age

40 150 The problem : NT-proBNP and age The median value for an 80-year old is 150 pg/ml

41 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

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

43 Biomarkers Biomarkers Indications for Use COR LOE Recommendation IIa B-R For patients at risk of developing HF, natriuretic peptide biomarker based screening followed by teambased care, including a cardiovascular specialist optimizing GDMT, can be useful to prevent the development of left ventricular dysfunction (systolic or diastolic) or new-onset HF. Comment/ Rationale NEW: New data suggest that natriuretic peptide biomarker screening and early intervention may prevent HF.

44

45 Research JAMA Original Investigation Effect of Natriuretic Peptide Guided Therapy on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction A Randomized Clinical Trial G. Michael Felker, MD, MHS; Kevin J. Anstrom, PhD; Kirkwood F. Adams, MD; Justin A. Ezekowitz, MBBCh, MSc; Mona Fiuzat, PhD; Nancy Houston-Miller, RN, BSN; James L. Januzzi Jr, MD; Daniel B. Mark, MD, MPH; Ileana L. Piña, MD, MPH; Gayle Passmore, PMP; David J. Whellan, MD, MHS; Hongqiu Yang, PhD; Lawton S. Cooper, MD, MPH; Eric S. Leifer, PhD; Patrice Desvigne-Nickens, MD; Christopher M. O Connor, MD IMPORTANCE The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ( guided therapy ) with inconsistent results. OBJECTIVE To determine whether an amino-terminal pro B-type natriuretic peptide (NT-proBNP) guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF). Editorial page 707 Supplemental content CME Quiz at jamanetwork.com/learning and CME Questions page 747 DESIGN, SETTINGS, AND PARTICIPANTS The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction 40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP guided strategy or usual care. INTERVENTIONS Patients were randomized to either an NT-proBNP guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/ml. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group. MAIN OUTCOMES AND MEASURES The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events. RESULTS The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, ; P =.88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; (95% CI, ; P =.75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups. CONCLUSIONSANDRELEVANCE In high-risk patients with HFrEF, a strategy of NT-proBNP guided therapy was not more effective than a usual care strategy in improving outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT JAMA. 2017;318(8): doi: /jama Author Affiliations: Duke Clinical Research Institute, Durham, North Carolina (Felker, Anstrom, Fiuzat, Mark, Passmore, Yang, O Connor); University of North Carolina, Chapel Hill (Adams); Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada (Ezekowitz); The LifeCare Company, Menlo Park, California (Houston-Miller); Cardiology Division, Massachusetts General Hospital, Boston (Januzzi); Albert Einstein College of Medicine, Bronx, New York (Piña); Thomas Jefferson University, Philadelphia, Pennsylvania (Whellan); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland (Cooper, Leifer, Desvigne-Nickens); Inova Heart and Vascular Center, Fairfax, Virginia (O Connor). Corresponding Author: G. Michael Felker, MD, MHS, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC American Medical Association. All rights reserved. (Reprinted) 713

46