Current Utilities of Cardiac Biomarker Testing at POC. June 24, 2010 Joe Pezzuto, MT (ASCP) Carolyn Kite, RN

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1 Current Utilities of Cardiac Biomarker Testing at POC June 24, 2010 Joe Pezzuto, MT (ASCP) Carolyn Kite, RN

2 1. Discuss challenges associated with diagnosing Acute Coronary Syndromes (ACS) and Heart Failure (HF). Objectives 2. Examine the utilization of a rapid algorithm to aid in the recognition of ACS. 3. Describe pathophysiology and clinical presentation of patients with HF and the role of the natriuretic peptide system in HF 4. Review the use of B-type Natriuretic Peptide (BNP) as an aid in the diagnosis and assessment of disease severity in patients with HF and the role of cardiac markers and BNP for risk stratification in ACS. 5. Discuss evidence based indications of use for cardiac markers and BNP at Point-of-Care through review of current literature.

3 Leading Causes Of Unexpected Death DEATHS PER ANNUM (000) Heart-related conditions comprise the #1 cause of unexpected death in the US (1999). Only 12% of US hospitals (2004) utilize POC Cardiac instruments. Diabetes is the 7 th leading cause of unexpected death in the US. 100% of US hospitals utilize POC glucose instruments HEART ALL CANCERS PE STROKE LUNG CANCER COPD DIABETES BREAST CANCER EAC 2004 US Hospital POC Survey, Sept. 2004

4 Nearly 2400 Americans die of CVD each day, an average of 1 death every 36 seconds. AHA Heart Disease and Stroke Statistics Update

Over 600 EDs have closed in the same 10-year period.

Physicians continue to demand faster turnaround times.

The number of uninsured patients has risen dramatically and will continue

5 POC Market Conditions U.S. ED visits have increased by 26% over the past 10 years. Over 600 EDs have closed in the same 10-year period. EDs are often understaffed and most EDs are experiencing labor shortages. Physicians continue to demand faster turnaround times. ED diversion and overcrowding is a significant & growing problem. The number of uninsured patients has risen dramatically and will continue to increase. People live longer and older people have more health problems. Advance Data, No 372, June 23, 2006 National Hospital Ambulatory Medical Care Survey: 2004 Emergency Department Summary

6 Acute Coronary Syndromes ST- Segment Myocardial Infarction (STEMI) Unstable Angina (UA) Non ST- Segment Myocardial Infarction (NSTEMI)

7 Acute Coronary Syndrome Physiology: Plaque Rupture Reduced Blood Flow Myocardial Necrosis Unstable Plaque Clinical Presentation: Intracoronary Thrombus Myocardial Ischemia Asymptomatic Unstable Angina Acute MI (NSTEMI and STEMI)

8 The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return. Heart Failure Defined E. Braunwald

9 Heart Failure Statistics ~5 million people currently have HF 550,000 new cases diagnosed every year 300,000 HF deaths per year Most common cause of hospitalization in patients >65 ACC/AHA practice guidelines, J American College of Cardiology, Vol. 38, no. 7, 2001

10 Patient presentation to the ED for suspected ACS or HF may include: Chest pain Arrhythmia Decrease mental status Shortness of breath Hypotension Hypertension Cardiopulmonary arrest

11 Determining a Differential Diagnosis Requires Costly Testing Differential diagnosis Myocardial Infarction Congestive Heart Failure Pneumonia COPD Cardiac Tamponade Anxiety Diagnostic testing Cardiac markers CBC, chemistry, lipid panel EKG CXR Cultures Echocardiogram Stress test Left/Right Heart Catheterization Pulmonary Function Test

12 Initial Testing Misses 28% of AMI Patients ECG can miss up to 60% of AMI patients Cardiac marker tests miss over 50% of AMI patients at presentation Patient history is subjective Non Diagnostic for MI 28% 72% Positive ECG and/or Enzyme Tests Source: Young, G.P. and Owen, T.R., AJEM Volume 11, Number 5, September 1993

13 Attributes of Ideal Marker Found in high concentration in the heart Not found in other tissues, even in trace amounts or under pathological conditions Low molecular weight and thus released early in the course of AMI Remains elevated for several days

14 Advanced Cardiac Markers of Choice Currently, no single marker meets these ideal requirements Current studies support a panel approach Myoglobin CK-MB Cardiac Troponin I

15 Biomarker Release Kinetics Demonstrate real time Value Maximal Benefit Definite Benefit No Clear Benefit 100% Multiple of Upper Reference Range Myoglobin CKMB TnI % 50% 25% 0% Hours After Onset of MI

16 Professional Guidelines* Have Been Established for AMI Management Diagnosis of AMI based on at least 2 of 3 criteria Clinical history ECG Temporal changes in cardiac markers Initial patient evaluation within 20 minutes of ED arrival Door to needle time < 30 minutes Turn around Time (TAT) for cardiac markers should be 30 minutes PTCA (PCI) minutes * WHO, AHA, ACC

17 New ACC/AHA Guidelines state (Regarding Bedside Cardiac Marker Testing): When the central lab is used, results should be available within 60 minutes, preferably within 30 minutes... POC Systems have the advantage of reducing delays in transportation and processing and can reduce delays at all hours The evolution of technology that will provide quantitative assays of multiple markers that are simple to use will improve the diagnosis and management of patients with suspected ACS in the E.D.. Braunwald et al. ACC/AHA Guidelines for Unstable Angina, JACC vol. 36, No. 3 Sept. 2000

18 ACEP Guidelines for Evaluation of Non-STEMI ACS Patients Cardiac Biomarkers to exclude NSTE AMI (WHO) Level B Recommendations: 1. A single negative CK-MB mass, Troponin I or Troponin T measured 8-12 hours after symptom onset 2. A negative myoglobin in conjunction with a negative CK-MB mass, or negative Troponin when measured at baseline and 90 minutes in patients presenting less than 8 hours after symptom onset 3. A negative 2-hour delta CK-MB mass in conjunction with a negative 2-hour delta Troponin in patients presenting less than 8 hours after symptom onset Fesmire FM et al. Ann Emerg Med 2006;48:

19 ACEP Guidelines for Evaluation of Non-STEMI ACS Patients Cardiac Biomarkers: No single serum marker used alone has sufficient sensitivity or specificity to reliably identify or exclude AMI within 6 hours after symptom onset. Neither CK-MB nor the troponins have a clear sensitivity advantage for the diagnosis of AMI in the initial 12 hours after symptom onset. Measurements of myoglobin in the first few hours after onset appear to have better sensitivity with lower specificity when compared with CK-MB and the troponins. Fesmire FM et al. Ann Emerg Med 2006;48: From the NACB Guidelines: For patients who present within 6 H of the onset of symptoms, an early marker of myocardial necrosis may be onsidered.myoglobin is the most extensively studied marker for this purpose (Level B)

20 ACEP Guidelines for Evaluation of Non-STEMI ACS Patients Conclusions: Unless the patient presents >8 hours after symptom onset, a multimarker approach is recommended by ACEP Myoglobin and Troponin or CK-MB and Troponin are recommended within the first 8 hours following symptom onset Fesmire FM et al. Ann Emerg Med 2006;48:

21 Comparison of Point of Care (POC) Testing Strategies for Rapid ED Diagnosis of AMI Straface AL, Myers JH, and Kirchick HJ Purpose: Evaluate the performance of a pathway utilizing three cardiac markers and a rapid testing algorithm American Journal of Clinical Pathology, 2008

22 Background and History Biosite Triage systems were approved by HCA for point of care diagnostics. Three HCA facilities in the North Texas division were selected to perform a pilot study utilizing the Triage Cardiac Panel to validate the Triage system and the CCMN position statement. Medical City Dallas (Dallas, TX) Medical Center of Arlington (Arlington, TX) Plaza Medical Center (Ft. Worth, TX)

23 Multimarker Algorithm The algorithm consisted of the following: The average time between draws was two hours. A patient with a TnI concentration 0.4 ng/ml on any draw was considered positive for acute myocardial infarction (AMI). A patient with a doubling of myoglobin between two draws and a detectable TnI at least by the second draw was considered positive for AMI. A patient with a doubling of myoglobin between two draws but without a detectable TnI on either of the two draws was considered positive for AMI if the CK-MB went up by 50% between the two draws.

24 Results Serial draw multi-marker algorithm 99.9% negative predictive value 99.7% accuracy Algorithm Results + - Total Diagnosis + - Total % CI Sensitivity 98.0% 95.7% % Specificity 99.8% 99.6% % Accuracy 99.7% 99.6% % PPV 92.4% 88.2% % NPV 99.9% 99.9% %

25 Results Serial draw Troponin only algorithm Poor Sensitivity Too Many False Negatives Poor Specificity Too Many False Positives 0.40 ng/ml (WHO ROC) 0.05 ng/ml (~99 th %tile) Diagnosis Diagnosis + - Total + - Total TnI Results Total TnI Results Total % CI Sensitivity 68.2% 60.7% % Specificity 99.8% 99.6% % Accuracy 98.9% 98.6% % PPV 89.4% 83.7% % NPV 99.1% 98.8% % 95% CI Sensitivity 97.3% 94.7% % Specificity 95.0% 94.4% % Accuracy 95.1% 94.5% % PPV 36.4% 31.6% % NPV 99.9% 99.8% %

26 Summary A multi-marker rapid serial draw protocol: Is extremely accurate in the diagnosis of AMI (99.7%); Has a near perfect NPV (99.9%) that allows for rapid rule out Allows the physician to benefit from the high sensitivity afforded by using a 99 th percentile TnI; Retains specificity by requiring a doubling of myoglobin for those patients whose TnI is 0.05 ng/ml but < 0.4 ng/ml; Has the potential to decrease ED LOS; and Has the potential to increase the number of stays less than 24 h (decreases unnecessary admissions).

27 BNP Function Found primarily in the cardiac ventricles Primary regulators of BNP include left ventricular stretch/wall tension Antagonist of RAAS & SNS Promote natriuresis and diuresis Act as Vasodilator Inhibit secretion of renin and aldosterone

28 BNP Utilization.Evidence Based Aid to Diagnosis of CHF in the ED Assessment of CHF Disease Severity Risk Stratification of Patients with Acute Coronary Syndromes

29 Release of BNP Pro-BNP NT Pro-BNP BNP WALL STRESS Natriuresis Vasodilatation RAAS

30 Heart Failure Pathophysiology Myocardial injury Fall in LV performance Activation of RAAS, SNS, ET, AVP, and others Myocardial toxicity Peripheral vasoconstriction Hemodynamic alterations Morbidity and mortality Remodeling and progressive worsening of LV function Heart failure symptoms

31 Staging of Heart Failure New York Heart Association Classification Class I-No limitations of physical activity Class II-Slight limitations Class III-Marked limitations of physical activity Class III 1,200,000 (25%) Class IV 240,000 (5%) Class II 1,680,000 (35%) Class IV-Inability to carry out physical activities without discomfort Class I 1,680,000 (35%) American Heart Association

32 BNP Relationship to NYHA Objective Vs. Subjective Evaluation 1200 Median [BNP] (pg/ml) NYHA I NYHAII NYHA III NYHA IV Triage BNP package insert. Data on File at Biosite Diagnostics Inc.

33 Tool for ACS risk stratification? BNP

34 The Prognostic Value of B-Type Natriuretic Peptide in Patients with Acute Coronary Syndromes Purpose: To evaluate the utility of BNP in ACS De Lemos, J.S. et al New England Journal of Medicine October, 2001

35 Study Design/Methods 2525 patients from the TIMI (Thrombolysis in Myocardial Infarction) 16 trial included Specimens obtained at 40 + /-20 hours after onset of ischemic symptoms End points of death or nonfatal MI were evaluated at 30 days and 10 months

36 Endpoints via BNP Cut-off of 80 pg/ml P<0.005 for each comparison 10 BNP <= 80 pg/ml (n=1251) BNP > 80 pg/ml (n=1274) Percent of Patients Death CHF MI Death CHF MI 30 days 10 months De Lemos, et al. N England J Med, Vol 345, No. 14, 2001

37 Conclusions BNP provides powerful risk stratification information across a spectrum of Acute Coronary Syndromes (ACS) BNP of 80 pg/ml is an appropriate risk threshold among patients with ACS Prognosis via neurohormonal activation (BNP) are distinct from those of myocyte necrosis (TnI) BNP measurement should be considered after an ACS in order to identify patients at high and low risk for adverse outcomes. Treatments including increased surveillance, pharmacologic and interventional therapy should be adjusted accordingly

38 Summary of Advantages of POC Cardiac Marker & BNP Testing Lower Risk of indecision Early risk stratification of acute coronary syndrome patients Initiate clinical protocols and effective treatment earlier Potential Cost benefit with earlier and appropriate intervention

39 CARDIAC POC IS A TRICKY BALANCING ACT

40 Thank you Questions?

Measuring Natriuretic Peptides in Acute Coronary Syndromes

Measuring Natriuretic Peptides in Acute Coronary Syndromes Peter A. McCullough, MD, MPH, FACC, FACP, FAHA, FCCP Consultant Cardiologist Chief Academic and Scientific Officer St. John Providence Health