At some point, it is true – there are no “bad” tests, only “bad” applications and interpretations of those tests. One of those tests, as supported by Abbott Laboratories, is the high-sensitivity troponin. You may also know this test as the “low-specificity” troponin – as, barring small improvements in the assay, a more sensitive test for the same biomarker is bound to result in decreased specificity.
This article describes the populations of ADAPT and APACE for whom high-sensitivity troponins are available. These trials were part of a prospective derivation of an “accelerated diagnostic protocol,” in which low-risk patients (TIMI 0 or 1) with normal ECGs and two negative hsTnI two hours apart were found to be eligible for discharge from the Emergency Department. With an approximately 14% of 30-day MACE (mostly nSTEMI) in each cohort, the authors strategy is reasonable: only ~0.7% of patients meeting these three criteria eventually met a primary endpoint.
Conversation about this article led to this tweet by the primary author:
@EMManchester @240minDoc Precision of hs #troponin assays now shown to have great advantage. ED patients with possible ACS and this assay 1
— Louise Cullen (@louiseacullen) November 7, 2013
… except it isn’t entirely true. The missing key to this statement is precisely what the “great advantage” entails. These authors, sponsored by Abbott Laboratories, do not show this diagnostic strategy utilizing hsTnI is in fact superior to the same strategy using conventional troponins. Quick back-of-napkin math shows the ADAPT conventional troponin cohort using this same strategy gives statistically similar results. This critique led to the final tweet from the primary author:
@emlitofnote @EMManchester @240minDoc OK have to wait til part II where I can show you larger pop and more narrow CIs.
— Louise Cullen (@louiseacullen) November 8, 2013
Yes, with sufficient statistical power, there will likely be a reproducible difference between the different troponin assays. When millions of patients are evaluated for chest pain every year, there may be a few for whom this improved sensitivity is clinically significant. However, it is far more likely this increased sensitivity will end up referring additional patients for testing – resulting in increased costs and harms from overdiagnosis. This is not the fault of the test – but, rather, simply that we don’t yet know the clinical significance of all small troponin elevations, and there is no appropriate algorithm for managing them in current practice.
I actually like what these authors are doing – using a rapid rule-out plus risk-stratification to safely discharge patients from the Emergency Department. However, they’re selling hsTnI without proving it’s superior, in this strategy, to conventional troponin testing. Then, as tests become more sophisticated, our interpretation of them needs to as well – and studies such as these need to do more than simply describe a “minimal-risk” cohort, but also provide useful guidance on the rest of the grey area troponin elevations.
Finally, I’d also like to finally see the TIMI score retired for use in the Emergency Department. Please. Make it die.
“Validation of High-Sensitivity Troponin I in a 2-Hour Diagnostic Strategy to Assess 30-Day Outcomes in Emergency Department Patients With Possible Acute Coronary Syndrome”
It is great to see our work being discussed, and I’m pleased to be able to comment on a few issues about troponin and troponin assays. There is an assumption that the key to high sensitivity/low specificity assays is about lowering the cut-offs and hence finding more patients with elevated troponin values, with the vast majority of these having no evidence of AMI.
We need to stop talking about sensitivity and specificity as most clinicians tag these term to diagnostic categories. We need to start talking about high precision assay – that is assays that give us repeatable, reliable results especially in and around the magical 99th % (the clinical cut point between + and – values..)
What is often confused in this area is that we are not talking about specificity for AMI, but talking about specificity for the detection of the troponin molecule itself. It is simply incorrect to say that a less precise assay which due to analytical reasons give us more FP (and of course also more FNs) performs equally to a more precise assay.
Grouping these assays (whether it is into “conventional”, “sensitive” or “highly sensitive” assays groups) and comparing their performances is too simplistic. And as clinicians we need to be more savvy.
As you well know the journal publications lag at least 12 months behind the data. Many more papers on this topic are in this process of acceptance, and will shed more light on this issue.
And as for risk stratification rules – there are a number of ED-based rules in development and validation around the world. Watch this space – as I know the publications coming in 2014 will create much comment!
It is great to see our work being discussed, and I’m pleased to be able to comment on a few issues about troponin and troponin assays. There is an assumption that the key to high sensitivity/low specificity assays is about lowering the cut-offs and hence finding more patients with elevated troponin values, with the vast majority of these having no evidence of AMI.
We need to stop talking about sensitivity and specificity as most clinicians tag these term to diagnostic categories. We need to start talking about high precision assay – that is assays that give us repeatable, reliable results especially in and around the magical 99th % (the clinical cut point between + and – values..)
What is often confused in this area is that we are not talking about specificity for AMI, but talking about specificity for the detection of the troponin molecule itself. It is simply incorrect to say that a less precise assay which due to analytical reasons give us more FP (and of course also more FNs) performs equally to a more precise assay.
Grouping these assays (whether it is into “conventional”, “sensitive” or “highly sensitive” assays groups) and comparing their performances is too simplistic. And as clinicians we need to be more savvy.
As you well know the journal publications lag at least 12 months behind the data. Many more papers on this topic are in this process of acceptance, and will shed more light on this issue.
And as for risk stratification rules – there are a number of ED-based rules in development and validation around the world. Watch this space – as I know the publications coming in 2014 will create much comment!
Re TIMI scores in the ER. I remind my residents that my TIMI score of 3 (age >65, aspirin daily, BP + cholesterol + family history) is higher than 90% of the people we admit with chest pain
Re TIMI scores in the ER. I remind my residents that my TIMI score of 3 (age >65, aspirin daily, BP + cholesterol + family history) is higher than 90% of the people we admit with chest pain
Thanks for highlighting an important feature – particularly in how Emergency Physicians view troponin (much to the dismay of cardiologists, I'm sure). We frame our question in the Emergency Department in such simplistic, dichotomous terms – STEMI/nSTEMI or null – that, as you say, and I agree, we're asking a question that goes beyond just detecting a troponin molecule. It is mostly in the sense of our unsophisticated interpretation of the test where we end up harming folks with a more sensitive/precise assay.
I am happy to hear there's more in the pipeline regarding overall management strategy for the continuous variable information these next-generation assays provide. That being said – I do like to directly see a comparison to the "old" generation, whenever possible. Perhaps 1st-world countries will have the resources to purchase these new assays, when appropriate, but there will remain a lot of practice settings that will be slower to adopt the new technology, and it's important to have the "conventional" information available to compare.
Thanks for highlighting an important feature – particularly in how Emergency Physicians view troponin (much to the dismay of cardiologists, I'm sure). We frame our question in the Emergency Department in such simplistic, dichotomous terms – STEMI/nSTEMI or null – that, as you say, and I agree, we're asking a question that goes beyond just detecting a troponin molecule. It is mostly in the sense of our unsophisticated interpretation of the test where we end up harming folks with a more sensitive/precise assay.
I am happy to hear there's more in the pipeline regarding overall management strategy for the continuous variable information these next-generation assays provide. That being said – I do like to directly see a comparison to the "old" generation, whenever possible. Perhaps 1st-world countries will have the resources to purchase these new assays, when appropriate, but there will remain a lot of practice settings that will be slower to adopt the new technology, and it's important to have the "conventional" information available to compare.
I couldn't agree more!
One thing that continues to trouble me is that the definition of AMI incorporates a troponin value. Hence in our studies, we are always hampered by measuring the effect of different assays utility for AMI diagnosis, based on different assays!
We have been criticised by reviewers as we have used the sensitive troponin assay results in clinical use at the time of the studies to adjudicate AMI diagnosis. Potentially we have missed some with AMI, but we endeavour to try to measure that effect by looking at 30 day, and now 1 year outcomes. If we are missing some patients with a serious underlying complaint, but with a FN cTn we hope that this will be shown in the long term outcomes.
Fundamentally a biomarker is simply a biomarker. If you decide to use it on its own, with no regard for the clinical context, you will be wrong time and time again not matter which assay you use. Even in the HEART score, you can be deemed ‘low risk’ with a cTn value 2x the normal limit, if no other variables are met. No clinician practices (I hope) this way! Once you use biomarkers within a risk stratification strategy the strategy really is tested. That being said, the biomarkers performance at the cut-off (and don’t get me started on this topic – as you have said it is a continuous variable!) is crucial.
There will never be a time that all clinicians have access to a high precision assay. Even in Australia (a 1st-world country) our rural, regional and remote practitioners need to know how the assays they can access will perform and how this may impact on their clinical care. Even if this simply means that we need to reinforce their need to fall back more heavily on the clinical assessment rather than what many in metropolitan areas are doing and that is rely on the biomarkers…! Hence I look at many assays and how this may fit into things – POC assays, so-called contemporary or sensitive assay and assays with higher precision. It is essential that we all know exactly how our assay performs, and I agree with your comments.
I do hope the work we are doing is clarifying this difficult area. Next to come in print are our ideas about change (delta) values. (another area I cold rant on about – sorry!).
I couldn't agree more!
One thing that continues to trouble me is that the definition of AMI incorporates a troponin value. Hence in our studies, we are always hampered by measuring the effect of different assays utility for AMI diagnosis, based on different assays!
We have been criticised by reviewers as we have used the sensitive troponin assay results in clinical use at the time of the studies to adjudicate AMI diagnosis. Potentially we have missed some with AMI, but we endeavour to try to measure that effect by looking at 30 day, and now 1 year outcomes. If we are missing some patients with a serious underlying complaint, but with a FN cTn we hope that this will be shown in the long term outcomes.
Fundamentally a biomarker is simply a biomarker. If you decide to use it on its own, with no regard for the clinical context, you will be wrong time and time again not matter which assay you use. Even in the HEART score, you can be deemed ‘low risk’ with a cTn value 2x the normal limit, if no other variables are met. No clinician practices (I hope) this way! Once you use biomarkers within a risk stratification strategy the strategy really is tested. That being said, the biomarkers performance at the cut-off (and don’t get me started on this topic – as you have said it is a continuous variable!) is crucial.
There will never be a time that all clinicians have access to a high precision assay. Even in Australia (a 1st-world country) our rural, regional and remote practitioners need to know how the assays they can access will perform and how this may impact on their clinical care. Even if this simply means that we need to reinforce their need to fall back more heavily on the clinical assessment rather than what many in metropolitan areas are doing and that is rely on the biomarkers…! Hence I look at many assays and how this may fit into things – POC assays, so-called contemporary or sensitive assay and assays with higher precision. It is essential that we all know exactly how our assay performs, and I agree with your comments.
I do hope the work we are doing is clarifying this difficult area. Next to come in print are our ideas about change (delta) values. (another area I cold rant on about – sorry!).
And sorry – 140 characters is not enough to have explain on Twitter. Thanks for the opportunity to explain more!
And sorry – 140 characters is not enough to have explain on Twitter. Thanks for the opportunity to explain more!