Journal Club - Utility of Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of Acute Myocardial Infarction

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Critical Appraisal of:
Reichlin et al. Utility of Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of Acute Myocardial Infarction.Circulation. 2011;124:136-145

Novel High-sensitivity Troponin Assays
EBM topic: ROC curves

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  • Acute MI, one of the most common and most challenging diagnoses in emergency care
  • We don’t want to miss it, because we know the longer it takes to reperfuse ischemic areas, the worse the outcomes
  • Sometimes the diagnosis is easy... we’re not here to talk about that
  • We’re gonna talk about diagnostic uncertainty
  • What do we do when this patient comes with vague epigastric discomfort?
  • Or this patient comes feeling veak and dizzy?
  • We do our clinical exams and our ekg’s which have limited sensitivity and specificity and ultimately we keep themAnd we draw trops 6 – 9 hours after the onset of symptomsWe do this because troponin is highly sensitive for MI, and thus a negative trop at that time means there is no MIWhich raises the question “what exactly do we mean by negative trop?”And what if its not negative?
  • We all know that while Troponin is highly specific for myocardial damage. This does not mean necessarily that there is an acute MI going on, or that there is any coronary disease at all. We’ve all had patients where the history is vague, the ekg is normal and the troponin on arrival is positive (mildly so) but they also have symptoms suggestive of one of the conditions listed here, and it just adds another layer of diagnostic uncertainty.Heart. 2006 July; 92(7): 987–993.Differential diagnosis of elevated troponinsSusanne Korff, Hugo A Katus, and Evangelos Giannitsis
  • So we call our consultants who say:“Meh, we don’t know, Do serial trops and we’ll be in touch”The reason we accept this strategy is because we know that the change in trops level over time is more specific for MIThis raises another question “how much of a change and over how much time?”Current there are no accepted guidelines, research is lacking, but most experts say a change of 30% within 6-9 hours is significantSo we keep the patients even longer, hand them over to our colleagues and..
  • Eventually our departments start to resemble this...
  • But we should have expected this right? I mean this is the sacrifice we must make when we really really don’t want to miss an MIWe understand that with every diagnostic test there is a trade-off between sensitivity and specificity that allows us to differentiate between individuals who have are sick and those are not.The perfect test doesn’t exist...or does it?
  • Enter the next generation of troponin assays, with higher accuracy at lower levels, promising to boldy go where no assay had gone before
  • These 2 articles published in NEJM in 2009 seemed to herald a whole new era in diagnostic accuracy, claiming the ability to diagnose MI sooner, with greater precision. Sensitivities of the new assay measured at 3 hours were comparable to those of conventional assays at 6 hours from onset
  • With names like highly sensitive and ULTRA...
  • And the prospect of being able to discharge patients earlier and improve department flow, it was hard not to get excitedbut wait, didn’t we just say that a higher sensitivity mean a lower specificity? Does this new assay suffer from that same unrelenting truth?The answer is yes. Both articles showed that while sensitivity at 3 hours rose from the realm of 67-75% to about 90-94%, the specificity dropped from 97 to 90%
  • Wont that just lead to more patients hanging around for serial testing??This raises the question “in the era of new assays, how long should we keep them?”“and what exactly makes an assay highly sensitive?”
  • Are we really on the road to a 2-hour rule out protocol for MI? Can we separate the hype from the reality?
  • To do that, we need to understand a bit more about the nature of troponin, its release and how we measure it.As you know there are 3 troponin proteins present in the myofibrils of cardiac mucle tissue that get released into the bloodstream when myocyte necrosis occurs, for whatever reason
  • the process by which they are released is thought to follow first order kineticsWhat this means is that peak levels should occur at roughly the same time following an event (12-24h), but the rate of increase is dependent on the amount of protein released (a large infarct will have a quicker rise than a microinfarctThat means that a large infarct may reach the cutoff value earlier than the small one. As you can see by the difference between b1 and b2The concentration needs to build up enough for it to be detectableFree Troponin molecules actually have a half-life of about 2 hours and those are what we measure. So how are we able to measure trops days after an MI has occurred?The reason that it hangs around for that long due to the fact that it forms protein complexes slowly break down.What we’re not clear on, is whether it is released initially as a free molecule and then complexes, if so how quickly?
  • In fact everything we’ve been able to say can say about what troponin does within the first few hours of its release has depended on our ability to measure it. And as you’ll see in a few minutes, we haven’t really been able to say much due to the limitations of what we’ve had available.The troponin assay is basically an ELISA assay where antibodies specific to troponin bind the protein and another antibody that is linked to an enzyme that causes substrate to fluoresce under specific light.Detection is based on the ability to bind antibodies specific receptor sites on the troponin molecule and not just any other protein. At very low levels this specificity is lost due to low “signal to noise ratio” The assay cannot reliably differentiate troponin from other proteins and thus at the end of the day cannot tell the difference between normal patients and diseased ones
  • The new assays contain a mixture of antibodies with an even higher specificity for troponin. The result of this is a higher signal to noise ratio, which means it is more accurate at detecting low levels. %CV in the y axis of this graph is actually is the standard deviation divided by the mean. Mathematically, this the inverse of the signal to noise ratio. Thus a low coefficient of variation means a high signal to noise ratio. (lowest value detectable used to be 0.02 ug/L now it is 0.006 ug/L) What this means is that now people who were “negative” have actually a value of troponin that is measurable.
  • “To determine the diagnostic accuracy of absolute and relative changes in sensitive cTn rise within 1 and 2 hours of presentation for the diagnosis of AMI as adjudicated on the basis of standard cTn assays”Implied is the fact that clinical judgement can only go so far to pick up MI, and also when you improve sensitivity of atest with lower cut-offs you sacrifice specificity (leading in this case to longer ED LOS for monitoring and serials for patients with positive trops due to other reasons and sometimes unnecessary anticoagulation and/or invasive testing)
  • Prospective CohortMulti-centre, international (2 countries)Subset of larger studyInclusion: Symptoms suggestive of AMI, chest pain. Onset or peak within 12 hoursExclusion:STEMI, dialysis
  • Ask for feedback from audienceBut yes. Yes it does.
  • 1247 enrolled836 had hs, ultra cTnNot clear why others where excluded: Some had STEMI, some must have been Renal Failure patients, but where did the other 411 patients go? Why? What affect does this loss to follow-up have on the data? – Attriton Bias (loss to follow up) Patients lost to follow-up can be influenced by their prognosis. Did these patients do better and not get the tests? Or did they did they die and not get the test? How many of the enrolled patients had full follow up at 60 days – it is implied by the results that all 836 presenting patients did Makes sense that some patients would get not 2 hour high sensitive troponin (first troponin already high, other cause found etc)
  • Statistical difference in age, previous stroke, BNP, and eGFRAge – known risk factor for CAD Previous stroke – indication for athersclerosisBNP – possible relation to myocardial ischemiaeGFR – can be reduced to renal artery athersosclerosis
  • Current guidelines for diagnosing AMI, including 6 and 9 hour cTn.Hx, PEx, labs (except HS + Ultra cTn), radiology, ECG, angio etc. (cardiologists final diagnosis of MI based on composite endpoints)Blinded to sensitive cTN
  • Composite end pointDetection of AMI
  • Yes, Patients presenting with chest pain to ED (all comers, consecutive patients)No independent validation reported yet
  • Yes, all patients recruited who had hs, ultra cTn were compared to the standardWhy is this important – if the test itself influenced the application of reference standard, some patients might get different reference tests etce.g. Verification bias
  • No, reference standard was applied post blood test for cTnManaging physicians blinded to results to sensitive cTnIf the decision to perform the test of interest was influenced by the reference standard, it is possible that there is incorporation bias e.g. that the test and reference standard are not independent
  • Ask audience for feedbackBut yes, it does seem that the results were gathered in a valid way
  • See BMJ article for brief description Useful for comparing tests that are continuous e.g. 2.003 vs “Yes vs No” Calculate sensitivityvs 1-specifity for each “cut-off” of the testPerfect test is vertical and horizontalUseless test is the diagonal The area under the ROC is a estimate of global performance of the test or the “diagnostic accuracy” But also relays the idea that increases in sensitivity come at the cost of increased specificity (more false positives)
  • As your cut-off criteria becomes better at getting “hits” with minimum “false alarms”, the accuracy of your test increasesBut, this comes at the cost of losing specificity
  • Maybe split the audience into groups here, and have each everyone in each group calculate LR’s for the different results and then compare answers to see which tests have the best LR’s? The Likelihood Ratio (LR) is the likelihood that a given test result would be expected in a patient with the target disorder compared to the likelihood that that same result would be expected in a patient without the target disorder.They have advantages over sensitivity and specificity because they are less likely to change with the prevalence of the disorder, they can be calculated for several levels of the symptom/sign or test, they can be used to combine the results of multiple diagnostic test and the can be used to calculate post-test probability for a target disorder.LR+ = sensitivity / (1-specificity) = (a/(a+c)) / (b/(b+d))LR- = (1-sensitivity) / specificity = (c/(a+c)) / (d/(b+d))
  • Look at table 4Stratified by some risk factors It is hypothesized that trop changes (and thus their ability to predict MI) would be affected by these factors. These factors are also known to be related to the outcome of interest (therefore they could be confounders) stratified analysis attempts to elucidate if confounding is present, as we can see it is not, since the accuracy of rise in trops appears to hold true despite
  • Look at table 4 Stratified by some risk factors It is hypothesized that trop changes (and thus their ability to predict MI) would be affected by these factors. These factors are also known to be related to the outcome of interest (therefore they could be confounders) stratified analysis attempts to elucidate if confounding is present, as we can see it is not, since the accuracy of rise in trops appears to hold true despite
  • Ask audience
  • The AUC is is roughly the same for the current assays measured at 6 hours post onset of symptoms, with current recommendations to measure a 20% change 6 hours apart.There are already studies suggesting that measuring change using the current assays with a cut off of 99th percentile as opposed to 95th percentile will already show comparable AUC at 3 hours as 6 hours…
  • The author’s take on this (from an editorial)
  • Again, open for discussion
  • Yes – see Table 1. Chest pain for all comers  No, data collected 2006 – 2009, likely same for us
  • Yes, earlier detection of NSTEMI, earlier treatment, better survival (time = myocardium)
  • Yes, LR + > 10 and LR - < 0.1 (this is the more useful result perhaps, the early rule out of AMI) Likely, a relatively non-invasive test that make an early diagnosis and lead to better outcomes would generally be well accepted by patients
  • Yes it is coming (has been ordered by MUHC)Has other benefits – risk stratification for mortality etc
  • Open for big discussion hereThe technology will be available to us soon, but are we comfortable using it clinically?

Transcript

  • 1. ED Journal Club: T. Reichlin et al. Utility of Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of Acute Myocardial Infarction. Circulation. 2011;124:136-145 Novel high-sensitivity Troponin Assays EBM topic: ROC curves September 19st 2011 Farooq Khan MDCM PGY3 FRCP-EM McGill University Rohit Mohindra MD PGY1 FRCP-EM McGill University
  • 2. Causes of Troponin elevation in the absence of significant CAD • SIRS/Sepsis (supply/demand) • Acute/chronic heart failure • Pulmonary embolism • Peri/myocarditis • ESRD • Cardiotoxic drugs • Infiltrative disorders • Recent defibrillation • Blunt myocardial contusion • Recent cardiac transplant
  • 3. Early Diagnosis of Myocardial Infarction with Sensitive Cardiac Troponin Assays Tobias Reichlin, et al N Engl J Med 2009; 361:858-867August 27, 2009 Sensitive Troponin I Assay in Early Diagnosis of Acute Myocardial Infarction Till Keller, M.D., et al N Engl J Med 2009; 361:868-877August 27, 2009
  • 4. Diagnosing Acute Coronary Syndromes, Biomerieux Diagnostics
  • 5. Troponin I ELISA, Labmaster Ltd. Finland
  • 6. ESC/ACCF/AHA/WHF Universal Definition of MI • Detection of rise and/or fall of cardiac biomarkers (preferably troponin)with at least one value above the 99th percentile of the upperreference limit (URL) together with evidence of myocardial ischaemiawith at least one of the following: • Symptoms of ischaemia; • ECG changes indicative of new ischaemia (new ST-T changes or new left bundle branch block [LBBB]); • Development of pathological Q waves in the ECG; • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
  • 7. Early Detection of disease | Biomarkers, Pictures of the future, Fall 2008
  • 8. Box 1. Babuin L , Jaffe A S CMAJ 2005;173:1191-1202 ©2005 by Canadian Medical Association
  • 9. Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology committee for the redefinition of myocardial infarction The Joint European Society of Cardiology/ American College of Cardiology Committee JACC Volume 36, Issue 3, Sept 2000
  • 10. T. Reichlin et al. Utility of Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of Acute Myocardial Infarction. Circulation. 2011;124:136-145.
  • 11. What is the diagnostic dilemma? • As stated by the authors? • But also implied ... ?
  • 12. How did they decide to study this question? • Type of study? • Inclusion/Exclusion criteria?
  • 13. Does it seem appropriate?
  • 14. Where the results of the study valid? • How many patients enrolled? • Followed?
  • 15. Any differences between AMI and non- AMI patients? • Is this important? • Why?
  • 16. What was the reference standard ? • Was this appropriate? • Was there blinding?
  • 17. Was the end-point reasonable?
  • 18. Was the diagnostic test evaluated in an appropriate spectrum of patients ? • As well, was there an second, independent validation of the results?
  • 19. Was the reference standard applied regardless of the result of the diagnostic test? • Why is this important?
  • 20. Was the decision to perform the diagnostic test influenced by the result of the reference standard? • How could this affect the results?
  • 21. Conclusion: Are the results valid?
  • 22. But now ... are they clinically important? • How will we determine this?
  • 23. First. What is a ROC?
  • 24. MissesHits Hits ySensitivit alarmsFalserejectionsCorrect rejectionsCorrect ySpecificit __ _
  • 25. http://www-psych.stanford.edu/~lera/psych115s/notes/signal/
  • 26. Next: don’t forget the likelihood ratio
  • 27. Was there confounding? • If so, did the authors address this?
  • 28. Was there confounding?
  • 29. What does “tropinin negative” mean, based on the results? • What population might this important in?
  • 30. Case Study • 57 year old male • Brought by EMS from work • CC: severe chest pain since 7am
  • 31. Hx + PEx • Severe retrosternal chest pain since 7am • Radiates to left shoulder and jaw • No change with position • Past Hx of smoking • On Lipitor for past year • Vitals: HR 110, RR 20, BP 110/50, SpO2 97% Gluc 7.2 GCS 15 • Looks pale diaphoretic • Heart sounds normal • Chest clear • Abdomen soft, non- tender
  • 32. Investigations & Management?
  • 33. Results of Investigations • CBC – N • Lytes, Cr – N • Troponin #1 = “negative” < 0.010 μg/L • EKG – Sinus tachycardia • CXR – no significant pathology seen
  • 34. Now what?
  • 35. Sensitive cTn • Baseline sensitive troponin is 0.015 μg/L • Next sensitive troponin is 0.030 μg/L at 2 hours • What is your decision now?
  • 36. How does this compare what is currently available?
  • 37. Swiss Med Wkly. 2011;141:w13202
  • 38. Can we conclude that the results from the study are clinically important?
  • 39. Finally, can we apply these results to our patients? Photo Credit: Pierre Obendrauf , The Gazette
  • 40. Are we able to estimate our pre-test probability for disease? • Are the study patients similar to our own? • Have the disease possibilities or probabilities have changed since the evidence was gathered from the study?
  • 41. Would the consequences of the test help your patient?
  • 42. Will the resulting post-test probabilities affect your management and help your patient? • Could it move you across a test-treatment threshold? • Would your patient be a willing partner in carrying it out?
  • 43. Is the diagnostic test available, affordable, accurate, and precise in our setting? • Is the cost of the new technology worth the benefit of early detection?
  • 44. Is this practice changing for us?