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New definition of MI to have broad effect on practice
Part one of round table looks at significant changes outlined in document.
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Cardiology Today convened this round table in November at the American Heart Association Scientific Sessions 2007 in Orlando, Fla. Chief Medical Editor Carl J. Pepine, MD, moderated the discussion. Part one of the round table is presented here. Part two will be published in the March issue of Cardiology Today.
CARL J. PEPINE, MD: Why was it important to have “Myocardial infarction redefined – a consensus document of The Joint European Society of Cardiology/American College of Cardiology?”
JOSEPH S. ALPERT, MD: This arose out of a conversation 10 years ago at the AHA meeting in Atlanta when Kristian Thygesen, MD, and I were discussing an abstract about MI clinical trials presented that day. It was impossible to compare several trials because the populations of patients under study were different even though people were arguing drug A vs. drug B at that time. We asked, “Wouldn’t it be better if everybody had the same definition of MI?”
We convened a task force from the European Society of Cardiology, the AHA, and the ACC, and we wrote a report published in 2000 in the Journal of the American College of Cardiology and the European Heart Journal. This report suggested a standard, global definition of MI for all clinical trials and for all practitioners.
We wanted to update that document to include things that we weren’t even able to comment on because there just wasn’t the scientific data to do it.
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Carl J. Pepine, MD
Bernard R. Chaitman, MD
Allan S. Jaffe, MD
Joseph Alpert, MDPEPINE: One of the things that I believe drove the need for this document has been the tremendous change in technology and advancements in our analytical methods to detect and quantify various products released from the heart.
ALLAN S. JAFFE, MD: As you know, for many years first CK and then CKMB served us quite well as markers of MI. But CKMB lacks specificity for myocardium. It is elevated in skeletal muscle disease, gastrointestinal disease, prostate disease, stroke and a variety of other situations. The troponins were a major advance in the sense that both cardiac troponin I and T, when the assays are configured properly, have tremendous specificity for the heart. They have marked increases in sensitivity as well. Moving to troponins and learning about how to use them really became an important adjunct to more accurate diagnoses. In 2007 we still advocate use of the 99th percentile of a normal reference population.
PEPINE: Another advance that’s helped drive this need for redefinition is the tremendous improvement in revascularization procedures.
BERNARD CHAITMAN, MD: We recognize, of course, that after coronary angioplasty and CABG, a certain percentage of patients will have with elevation of either CKMB or troponin; after CABG as many as 90% of patients; and after angioplasty, between 30% to 45% depending on the biomarker sampled. It has been shown in clinical trials that if a patient has biomarker elevations following revascularization, they’re associated with an adverse prognosis proportional to the magnitude of the biomarker elevation. In the new document, because these revascularization-related biomarker elevations are quite different pathophysiologically than a spontaneous myocardial infarct, they are classified in a different category.
JAFFE: One of the things that helped us was that there are new data in these areas, such as the baseline sample prior to percutaneous coronary intervention and/or CABG. In an analysis first done in 2006 and published in the European Heart Journal, it became clear that patients who have an elevated troponin at baseline, CKMB rises as well.
When that patient then goes for a procedure, the ability to figure out whether or not the subsequent elevations of either biomarker is due to the event that led to the presentation that sent that person to the cath lab or whether it was induced in the cath lab solely, and what proportion of the elevation may be related to one or the other, is probably something we can’t do. This led to redefinition of the PCI guideline predicated on whether one had a normal baseline or an abnormal baseline.
PEPINE: One of the things that impressed me when looking at that data set is that it — an elevated troponin, for example, following a PCI — is associated with impaired long-term outcome. While troponin elevation predicted death, it didn’t necessarily relate to detectable impairment in ventricular function.
ALPERT: It may be that the elevated troponin post-PCI is telling us something entirely different about the atherosclerotic process in that patient than in an individual with a spontaneous MI. For example, it might be telling us that the post-PCI patient with an elevated troponin has a much more friable form of atheroma, and, in fact, there are some observational data that suggest that this is the case. Also, the identification of an elevated troponin in somebody who comes in with an appropriate syndrome suggesting MI helps to dictate therapy.
CHAITMAN: The disconnect also between measuring ventricular function and outcome is partly related to the techniques we use to detect damage. A small MI using imaging techniques may not have sufficient resolution to detect smaller amounts of myocardial damage, particularly in a patient with prior MI and LV dysfunction. Subtle differences, which may relate to prognosis, may not be detectable with 2-D echocardiography for example, whereas if you had MRI techniques or other more sensitive techniques, you might be able to make a better correlation.
JAFFE: In fact, MRI has been used to study both CKMB and troponin elevations post-intervention, and these more sensitive techniques do show additional abnormalities and additional regional abnormalities.
PEPINE: The pathologic definition of MI at the time of autopsy, as I recall from my medical school days, had a fairly finite definition. My suspicion is that may also be something that is subject to change with these newer techniques.
JAFFE: The pathologic definition, which is to see necrotic myocytes with or without contraction band necrosis, what you often see with reperfusion, is still the reference standard pathologic definition. What changed is our ability to detect smaller and smaller increments of that, and that will continue as troponin assays become more sensitive.
CHAITMAN: It might be worth mentioning that in the new document, if a patient has chest pain and ST elevation and dies before biomarkers have been obtained, we now call that a fatal MI.
PEPINE: What are the elements of this new definition, Joe?
ALPERT: The reference standard is the same in 2007 as it was in 2000. The biomarker troponin is the most sensitive and specific one with CKMB far back in second place.
One thing that has changed at this time is that we subcategorize infarctions into five different categories (see chart).
PEPINE: How does this new definition change our practice, Allan?
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JAFFE: There are several ways in which this will change our practice. The first is that for the so-called wild type MI or for MIs that perhaps are related to supply, demand and balance, whether they are due to tachycardia or anemia or hypertension or hypotension, we need to look not only at the presence of an elevated troponin, but also with the fact that troponin is rising.
The ability to classify myocardial infarcts into types will be helpful. The PCI guidelines will be important. Prognosis is not part of the MI definition but this could be important. This finding needs to be confirmed in additional data sets.
Finally, we never defined CABG criteria because we felt that there are elevations in biomarkers after all cardiac surgery. We chose a low biomarker cutoff value and assumed and asked that there be ancillary criteria. There are too many different parameters.
PEPINE: The implications for this definition are fairly broad, but could greatly impact clinical trials. Bernie, let’s say you were designing a trial that might compare CABG with PCI, and with standard medical care. Would it be necessary to have multiple definitions for MI?
CHAITMAN: What you would have is the universal definition of MI applied, and the event committee that is adjudicating these events would have the classifications of the five types of MI. You would have all the MIs captured, and you would be able to look at how many of them were proportionately spontaneous vs. those that were induced, if this were a five-year follow-up study, and how many were stent thrombosis or wild type. We are trying to encourage all investigators to report the data in that way so that we can compare one study with another.
ALPERT: A patient comes in with, let’s say, nonspecific complaints and nothing much on the electrocardiogram. Suddenly, the physicians caring for the patient discover an elevated troponin. As Allan has pointed out, some people, particularly those with renal failure or HF, may have persistently elevated troponins that are probably telling us that there is injury going on in the myocardium, but it is not an ischemic injury that needs a trip to the cath lab.
My answer to that is just like my answer about a patient who has an elevated liver function test: Do you automatically write down hepatitis B in the chart? Of course you don’t. You go through the differential diagnosis. It’s the same thing here. I have seen people who were denied insurance because of a myocardial injury secondary to hypotension from an anesthetic reaction.
CHAITMAN: A table was added to the guidelines to remind physicians of common causes of false positive troponins.
JAFFE: Some of this will be helped if people will look for a rising pattern, but not all of them because a pulmonary embolism and sepsis will still give one an acute pattern.
ALPERT: Trauma, too.
JAFFE: Sure. There are still going to be some distinctions that will need to be made clinically, but some distinctions will be helped by the use of a rising pattern.
Just to get back to the question you asked in regard to clinical trials, Joe, Kristian and Bernie were instrumental in mandating as part of the definition that the five types of MIs be separated. We even have a table in which we advocate that, for clinical trial purposes, the types should be defined. In addition, the elevations of biomarkers used times one, times two, times three or times five, whatever the criteria for each type should be outlined for each trial which would allow clinical trials to set their own endpoints. That also will advocate for consistent reporting of all of the data so that individuals can look across trials and see whether or not there are comparable results.
We’d also like to see and have advocated for and will continue to advocate for individual CPT codes for each one of those MI classifications so that it is clear not only to clinical trials but also to cardiologists and the patients that there are different types of MIs, that they have different prognostic and diagnostic considerations associated with them.
Part two of this round table will be published in Cardiology Today’s March issue.