Date:  September 6th, 2013
Title: One is the Loneliest Number
Guest Skeptic: Dr. Andrew Worster, McMaster University

Case Scenario: 43 year old woman comes in with complaining of chest pain for about an hour. The chest pain was at rest with no radiation of the pain. She takes no medications and medical history includes two c-sections. She is Well’s Criteria low and PERC Rule negative. Physical examination and ECG are non-diagnostic.

Question:  Can a single high-sensitivity cardiac troponin (hs-cTn) rule out an acute myocardial infarction?

Background: There have been many markers used over the last 60 years. These have included:

  • Total Creatine Kinase (Total CK)
  • Creatine Kinase Isoenzymes M and B (CK-MB)
  • Lactate Dehydrogenase (LDH)
  • Myoglobin (MB)
  • Troponin (TropT, TropI)
  • Glycogen phosphoylase isoenzyme BB
  • Pro-Brain Natriuretic Peptide (Pro-BNP)
  • Ischemia Modified Albumin (IMA)

The first practical test utilized as a cardiac marker was serum glutamic oxaloacetic transaminase (SGOT) which is now called aspartate amino-transferase (AST). LaDue et al. SGOT activity in human acute transmural myocardial infarction Science 1954;120:497. For a deeper dive on the history of cardiac biomarkers you can read JH Ladenson’s or Rosalski et al review paper.

Since the late 1990‘s the cardiac marker of choice has changed from CK-MB to Troponin. This was in part due to the improved time dependent sensitivity and improved specificity of Troponin compared to CK-MB (Apple et al, Mair et al, Mair et al, and Katus et al)

Screen Shot 2013-09-07 at 2.34.41 PM

Only about 5% of all consecutive patients presenting with acute chest pain will have a ST elevated myocardial infarction (STEMI) (Apple et al). These are the easy ones to diagnose and manage. This leaves the other 95% of chest pain patients. These are the hard ones. We need to figure out who will rule-in vs. rule-out for acute myocardial infarction (AMI).  This is where cardiac biomarkers play a major role.

A limitation of current troponin assays is that they can take 3-4 hours to rise. This means the diagnosis of Non-STEMI can take 6-8 hours of continued monitoring with serial blood sampling. Ruling out AMI takes time, uses resources, contributes to overcrowding, and causes patient anxiety.

In 2000, the European Society of Cardiology and the American College of Cardiology (ESC/ACC) jointly redefined myocardial necrosis making cTn assays the primary tool for AMI diagnosis. They proposed the cTn value at the 99th percentile of a healthy reference population as the single cutoff value with analytical imprecision, measured as the coefficient of variation (CV) at ≤10%.

In 2007, the updated definition of AMI advocated a “rise and/or fall” of cTn again over a 6-9 hour time period using the 99th percentile.

The 3rd Universal Definition of AMI (published August 24,2012) has been reduced to 3-6 hours using a sensitive cTn assay. This means that all patients who undergo cTn testing require at least 2 measurements at least 3 hours apart regardless on the time of symptoms onset.

Because of the lack of evidence, there is no guidance from the 2012 AMI definition on using hs-cTn assays in the emergency department. The general consensus of the definition of a hs-cTn is that levels can be measured in 50% of the normal population. The definition for AMI is still at the 99th percentile. You don’t need to be an epidemiologist to figure out that this changes the prevalence of AMI. The question is whether this increase in prevalence is a numbers game or that we’re detecting people with myocardial injury sooner.

The 3rd Universal Definition of AMI is very explicit. It requires detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following:

  1. Symptoms of ischaemia
  2. New or presumed new significant ST-segment–T wave changes or new left bundle branch block
  3. Development of pathological Q waves in the ECG
  4. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
  5. Identification of an intracoronary thrombus by angiography or autopsy

Reference: Normal presenting levels of high-sensitivity troponin and myocardial infarction. Hoeller et al. Heart 2013 Apr 19

  • Population: Consecutive adult patients presenting to the emergency department with chest pain
  • Intervention: Four different high-sensitivity troponin (hs-cTn)
  • Comparison: Two independent cardiologists
  • Outcome: Death and acute myocardial infarction


Screen Shot 2013-09-07 at 3.33.51 PM

  • Patients were more likely to rule-in if for AMI if older, previous AMI, diabetes, hypercholesterolemia, hypertension, coronary artery disease, peripheral vascular disease, on ASA or ACE-inhibitor at presentation, ECG changes (LBBB, ST elevation or depression and t-wave inversion)
  • Death in the first 30 days more likely if you had positive hs-cTn at presentation
  • AMI was also ore likely in the first 30 days if you had positive hs-cTn at presentation.

Evidence Based Medicine:

  • Sensitivity: Can the test identify positive results or people with the disease accurately. True Positives / True Positive and False Negatives. A highly ‘SeNsitive’ test, when Negative rules OUT disease (SN-N-OUT)
  • Specificity: Can the test identify the negative results or people without the disease accurately. True Negatives / True Negatives and False Positives. A highly SPecific test, when Positive, rules IN disease (SP-P-IN)
  • Negative Predictive Value (NPV): NPV is often used to describe the performance of a diagnostic test. A high NPV for a test means that if the test is negative it is most likely a correct assessment. True Negatives / All Negatives (true and false)

Here is a YouTube video to help with sensitivity and specificity.

Authors Conclusion: Normal hs-cTn levels at presentatio n should not be used as a single parameter to rule out AMI as 6%-23% of adjudicated AMI cases had normal levels of hs-cTn levels at presentation.”

BEEM Comments: This was a prospective, international, multi-centred study with a primary end point was of all cause mortality and AMI during follow-up. Most chest pain patients did not have AMI. The hs-cTn missed up between 6%-23% of AMI.  NPV for the four tests was 94-98% It was no surprise the sensitivity and NPV were better in patients presenting after 6 hours of chest pain. there was variability between four different tests  and lack of standardization.  Because it is observational trial the true clinical benefit can not be determined


There are a couple of other factors to consider when interpreting the results of this study. The authors state that this is part of the APACE study and they limited their population to ED patients with symptoms suggestive of AMI such as acute chest pain, angina pectoris at rest or other thoracic sensations presumably caused by myocardial ischemia.

Interestingly the other published APACE studies describe their population as patients with different symptoms so we really don’t know how all-inclusive the population is. We do know that in North American ED practice we tend to order cTn measurements on a much broader scope of patients.

Second, their follow-up period was 24 months. I think it’s unrealistic for any negative test result to be valid for 24 months.

As an aside, predictive values are dependent upon disease prevalence and their study population has much lower obesity rates than we do in North America which may translate into different coronary artery disease and AMI prevalence.

BEEM Bottom Line: One is a lonely number. A single negative hs-cTn should not be used to rule out acute myocardial infarction.

woman CPCase Resolution: You order a hs-cTn on this 43 year old woman when she arrives to the emergency department which is normal. A repeat hs-cTn and ECG are performed three hours later which are also normal. You discuss the results with her and estimate her chance of AMI in the next 30 days of 1/250 based on the NNT. Shared decision making takes place and you discharge her home with a diagnosis of chest pain NYD and ask her to folow-up with her primary care physician in the next week.

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