Category: Troponin

New Troponin, Same as Old Troponin?

It doesn’t take more than a quick search through the archives to notice a great deal of gnashing of teeth over the introduction of high-sensitivity troponin. The perpetual concern: trade-offs with sensitivity and specificity, leading to downstream increased resource utilization.

This brief research letter is basically good news: the Mayo Clinic hospital system rolled out high-sensitivity troponin assays and very little changed. Looking at about 54,000 patients divided equally into pre- and post- periods, the diagnosis of myocardial infarction increased significantly. However, most of the change was coded as Type 2 MI, rather than an acute coronary syndrome, leading to little change in resource use – no difference in admissions, echocardiography, stress testing, or angiography.

There’s brief allusion in the article to the underlying protocols in place – in which patients are typically assessed using HEART, along with a system of champions and education supporting the change. Assuming these retrospective coded data accurately reflect practice, it is likely these concerted efforts prevented misinterpretation of detectable troponin levels – hence the increase in Type 2 MI. Implementation of these assays in other health systems may not reflect these same successes, but it is reasonable to expect the on-ramp for high-sensitivity troponin has likely now been long enough most are now familiar with their interpretation.

Finally, the ultimate better question might be – if high-sensitivity assays didn’t clearly impact care, what value do they confer? If there are no measurable improvements in diagnosis of acute MI, is there much utility? However, these data do not provide insight into whether there are downstream changes in medication management potentially reducing long-term cardiovascular adverse outcomes – nor, likewise, any medication changes resulting in increased costs and adverse outcomes without an improvement in cardiovascular health. And, asking these questions is likely moot, regardless – these assays are here and here to stay.

“Implementing High-Sensitivity Cardiac Troponin T in a US Regional Healthcare System”
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.045480

Women are Just as Typical as Men?

It’s somewhat dogmatic in medicine to teach men and women present with differing symptoms during myocardial infarction. Women are, as they say, more likely to have “atypical” symptoms.

This study differs slightly from previous accounting of the presenting symptoms of men and women with potential cardiac ischemia. This is a pre-planned, prospective analysis accompanying the High-STEACS trial, featuring in part an evaluation of gender-specific cut-offs for high-sensitivity troponin. As part of this trial, rather than using a typical “conventional” troponin cut-off for the 99th percentile of 50 ng/L, they used 16 ng/L for women and 34 ng/L for men. These cut-offs were correlated with clinical information to determine the diagnosis of type I myocardial infarction, generating a prevalence of 16% for men and 12% for women among the 1,941 included in the analysis.

Among these, authors found similar prevalence of “typical” symptoms – dull, tight, pressure, aching, crushing, in the chest, arm or jaw – in women as men considered for potential acute coronary syndrome. Among those ultimately diagnosed with type I MI, women were actually slightly more likely to manifest “typical” symptoms – 77% versus 59%. The authors did not find the presence of multiple “typical” symptoms to have a terribly useful positive likelihood ratio for MI in either women or men.

Unfortunately, these data run into unavoidable selection bias: “All patients over 18 years of age in whom the attending clinician requested cardiac troponin for suspected acute coronary syndrome were eligible for inclusion.” Therefore, the so-called “atypical” presentation in which ACS was not suspected – i.e., the women with “atypical” presentations – would be, by definition, missed. It may be the difference between men and women is not as great as originally thought – but these data cannot definitively answer the question.

“Presenting Symptoms in Men and Women Diagnosed With Myocardial Infarction Using Sex-Specific Criteria”
https://www.ahajournals.org/doi/10.1161/JAHA.119.012307

If You Guessed “Definitely Not ACS” …

This little observational study, part of a larger troponin-centric evaluation, looked at the predictive value of clinician gestalt for acute coronary syndrome. This has been evaluated before – including by this same group – but this cohort is three times the size of their prior effort.

Of the 1,391 patient encounters included, 207 had an acute MI, and another 33 died or underwent coronary revascularization within 30 days. Only 60 patients actually fell into the category of “definitely not ACS”, and 3 of those turned out to actually have an AMI. However, adding an ECG and a troponin to the initial gestalt was ultimately 100% sensitive for acute MI said “definitely not” cohort.

The other end of the spectrum – the “definitely ACS” side – was similar, with gestalt requiring supplementation by troponin and ECG testing to confirm.

One of the authors’ takeaways: a label of “definitely not” isn’t safe enough to forgo troponin testing. However, this comes with a big caveat: the enrolled patient cohort was specifically chosen for the main study because the treating clinician judged they required evaluation for ACS. Thus, effectively by definition, “definitely not” is incompatible with the study population.

You should not use this study to justify evaluation with additional or definitive testing in those who are truly “definitely not” ACS – the cohort here was enriched by 60 year old patients with hypertension, hyperlipidemia, prior MIs, smokers, and diabetes, and it would truly be the exception for one of these patients to “definitely not” have ACS. The 28 year-old for whom you think “definitely not” can still be evaluated as you feel appropriate.

“Can emergency physician gestalt “rule in” or “rule out” acute coronary syndrome: validation in a multi-center prospective diagnostic cohort study”
https://www.ncbi.nlm.nih.gov/pubmed/31338902

Ye Big High-Sensitivity Troponin Evaluation

After many years of various studies of moderate size looking at the diagnostic performance of high-sensitivity troponin assays, now we have a new entry: the Calculation of Myocardial Infarction Risk Probabilities to Manage Patients with Suspicion of Myocardial Infarction (COMPASS-MI) project.

This is not new data, but rather the power team of Roche and Abbott pooling the results of 15 prior studies to describe the diagnostic performance of their Elecsys and Architect high-sensitivity platforms. Then, there are really two parts of this article. There is an initial analysis looking at the performance characteristics of differing combinations of initial and serial sampling of each. After that, these authors pull in several age- and comorbidity-matched comparison populations and describe the long-term 1- and 2- year outcomes of patients with differing levels of troponin concentrations.

The main product of their work, however, boils down to a set of mildly confusing wheels of data regarding the negative predictive value of various combinations of initial troponin level and serial troponin change, divided up based on whether repeat sampling was performed early or late. These cut-offs are further divided on the wheel regarding the proportion of the population with a certain risk level for 30-ay MI or death.

The end result, combined with the various massive supplementary appendicies, are massive amounts of data to help systems using these assays tailor their practice patterns to their desired level of sensitivity and specificity. The authors are not specifically prescriptive in any one cut-off, but rather try to provide as much data as possible. Prevalence of nSTEMI in their population was about 14%, meaning the negative predictive values are only generalizable to to similar patient demographics.

If you’re using these assays, this is quite important work to help assist in interpretation. If not, considering there’s no comparative data to conventional assays, it seems to have limited utility.

It should finally be noted virtually all the listed authors of this work receive some financial support from the manufacturers of these assays.

“Application of High-Sensitivity Troponin in Suspected Myocardial Infarction”
https://www.nejm.org/doi/full/10.1056/NEJMoa1803377

Any Troponin is Bad Troponin – Gender-Specific Edition

High-sensitivity troponins mean a lower limit of detection. Picking up these lower quantitative values for circulating troponin – and new reference limits for the 99th percentile of normal – has required an adjustment in perspective with respect towards making the diagnosis of acute coronary syndrome. Now, the question with these more sensitive assays becomes: should we adjust our clinical considerations to incorporate sex-specific reference intervals?

This brief analysis from the UTROPIA study looks specifically at the downstream MACE in patients whose serial troponin measurements fall between the limit of detection and the sex-specific 99th percentile intervals. For this Abbott assay, that means 34 ng/L for men and 16 ng/L for women. In their 180-day follow-up period, they found the incidence of major adverse cardiac events was vanishingly small for those with undetectable levels of circulating troponin. However, those with any circulating troponin – even below the 99th percentile reference interval – were vastly more likely to experience an event within the next 180 days, reaching about 10% incidence of MACE. Importantly, however, the distributions of probability for downstream MACE were similar with regard to the measured value with respect to the sex-specific 99th percentile.

This confirms some of what we already knew: any troponin is bad troponin, even if it’s lower than the 99th percentile. Then, this also validates sex-specific 99th percentiles, as percentile levels conveyed similar risk between men and women.

Just another insight into the next level of sophistication for use of these assays in assessing patients with potential ACS, and for downstream anatomic assessment and preventive interventions.

“Clinical Features and Outcomes of Emergency Department Patients With High- Sensitivity Cardiac Troponin I Concentrations Within Sex-Specific Reference Intervals”

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.038284

Clinical Policy: Sanity Returns to ACS

This may be the most important recent sentence in modern emergency medicine:

“… based on limitations in diagnostic technology and the need to avoid the harms associated with false-positive test results, the committee based its recommendations on the assumption that the majority of patients and providers would agree that a missed diagnosis rate of 1% to 2% for 30-day MACE in NSTE ACS is acceptable.”

It’s no longer the domain of rogue podcasters and throwaway magazine editorialists to declare our zero-miss culture destructive and self-defeating – it’s finally spelled out in black & white by our speciality society. This is not a license to kill, of course, but it is now utterly reasonable to feel as though the wind is at your back when sending an appropriately-evaluated patient home.

This clinical policy statement does not address terribly many questions, but it does jam a lot of evidence into one document in their review. Specifically, these authors ask:

1. In adult patients without evidence of ST-elevation ACS, can initial risk stratification be used to predict a low rate of 30-day MACE?

In short, yes. These authors recommend HEART as their decision instrument du jour, but also acknowledge other scores that simply do not yet have enough diverse evidence to support their use. Interestingly, they also note clinical gestalt may be just as good as any decision instrument, at least when the ECG and troponin are negative for new ischemia. Again, more prospective evidence would be required to formally enshrine such a recommendation into a clinical policy statement.

2. In adult patients with suspected acute NSTE ACS, can troponin testing within 3 hours of ED presentation be used to predict a low rate of 30-day MACE?

Here the authors have only Level C recommendations, which means their recommendations are based on low levels of evidence. Overall, they are weakly in favor of using of high-sensitivity troponins alone, or repeat conventional troponin testing as part of a risk-stratification or accelerated diagnostic pathway.

3. In adult patients with suspected NSTE ACS in whom acute MI has been excluded, does further diagnostic testing (eg, provocative, stress test, computed tomography [CT] angiography) for ACS prior to discharge reduce 30-day MACE?

Please no: “Do not routinely use further diagnostic testing (coronary CT angiography, stress testing, myocardial perfusion imaging) prior to discharge in low-risk patients in whom acute MI has been ruled out to reduce 30-day MACE.”  Take that, CCTA proponents.  They give an expert consensus recommendation of 1 to 2 week primary care follow-up when feasible, or consideration of observation when no follow-up is possible.

The fourth question posed deals with use of P2Y12 and
glycoprotein IIb/IIIa inhibitors in the ED, and is met basically with a shrug.

So!  Go forth and provide good medical care – specifically, high-value medical care, further freed from the mental oubliette of zero-miss.

“Clinical Policy: Critical Issues in the Evaluation and Management of Emergency Department Patients With Suspected Non–ST-Elevation Acute Coronary Syndromes”
https://www.ncbi.nlm.nih.gov/pubmed/30342745

You’ve Got (Troponin) Mail

It’s tragic, of course, no one in this generation will understand the epiphany of logging on to America Online and being greeted by its almost synonymous greeting “You’ve got mail!” But, we and future generations may bear witness to the advent of something almost as profoundly uplifting: text-message troponin results.

These authors conceived and describe a fairly simple intervention in which test results – in this case, troponin – were pushed to clinicians’ phones as text messages. In a pilot and cluster-randomized trial with 1,105 patients for final analysis, these authors find the median interval from troponin result to disposition decision was 94 minutes in a control group, as compared with 68 minutes in the intervention cohort. However, a smaller difference in median overall length of stay did not reach statistical significance.

Now, I like this idea – even though this is clearly not the study showing generalizable definitive benefit. For many patient encounters, there is some readily identifiable bottleneck result of greatest importance for disposition. If a reasonable, curated list of these results are pushed to a mobile device, there is an obvious time savings with regard to manually pulling these results from the electronic health record.

In this study, however, the median LOS for these patients was over five hours – and their median LOS for all patients receiving at least one troponin was nearly 7.5 hours. The relative effect size, then, is really quite small. Next, there are always concerns relating to interruptions and unintended consequences on cognitive burden. Finally, it logically follows if this text message derives some of its beneficial effect by altering task priorities, then some other process in the Emergency Department is having its completion time increased.

I expect, if implemented in a typically efficient ED, the net result of any improvement might only be a few minutes saved across all encounter types – but multiplied across thousands of patient visits for chest pain, it’s still worth considering.

“Push-Alert Notification of Troponin Results to Physician Smartphones Reduces the Time to Discharge Emergency Department Patients: A Randomized Controlled Trial”
http://www.annemergmed.com/article/S0196-0644(17)30317-7/abstract

Troponin Sensitivity Training

High-sensitivity troponins are finally here! The FDA has approved the first one for use in the United States. Now, articles like this are not for purely academic interest – except, well, for the likely very slow percolation of these assays into standard practice.

This is a sort of update from the Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) consortium. This consortium is intended to “advance the early diagnosis of [acute myocardial infarction]” – via use of these high-sensitivity assays for the benefit of their study sponsors, Abbott Laboratories et al. Regardless, this is one of those typical early rule-out studies evaluating the patients with possible acute coronary syndrome and symptoms onset within 12 hours. The assay performance was evaluated and compared in four different strategies: 0-hour limit of detection, 0-hour 99th percentile cut-off, and two 0/1-hour presentation and delta strategies.

And, of course, their rule-out strategies work great – they miss a handful of AMI, and even those (as documented by their accompanying table of missed AMI) are mostly tiny, did not undergo any revascularization procedure, and frequently did not receive clinical discharge diagnoses consistent with acute coronary syndrome. There was also a clear time-based element to their rule-out sensitivity, where patients with chest pain onset within two hours of presentation being more likely missed. But – and this is the same “but” you’ve heard so many times before – their sensitivity comes at the expense of specificity, and use of any of these assay strategies was effective at ruling out only half of all ED presentations. Interestingly, at least, their rule-out was durable – 30-day MACE was 0.1% or less, and the sole event was a non-cardiac death.

Is there truly any rush to adopt these assays? I would reasonably argue there must be value in the additive information provided regarding myocardial injury. This study and its algorithms, however, demonstrates there remains progress to be made in terms of clinical effectiveness – as obviously far greater than just 50% of ED presentations for chest pain ought be eligible for discharge.

“Direct Comparison of Four Very Early Rule-Out Strategies for Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin I”
http://circ.ahajournals.org/content/early/2017/03/10/CIRCULATIONAHA.116.025661

The High-Sensitivity Troponin Ennui

They’re coming. It’s inevitable. They have yet to be approved in the the United States, but every year the news is the same: they’re coming.

High-sensitivity troponins have been both lauded and mocked from various perspectives. The literature is replete with examples of expedited rule-outs in the Emergency Department owing to their improved lower limit of detection for myocardial injury. However, every study touting the benefits of improved sensitivity has begrudgingly or worse acknowledged the correspondingly diminished specificity.

This, then, is a randomized trial of reporting either a conventional troponin assay result or a high-sensitivity troponin assay result, with a multitude of patient-oriented short- and long-term outcomes measured. The specific assays used here were either a c-TnT with a threshold of detection of 30 ng/L, or a hs-TnT with a threshold of detection of 3 ng/L. Clinicians caring for patients were randomized to making care decisions based on one, without knowledge of the other.

For all the various propaganda for and against high-sensitivity troponins, this trial is highly anticlimactic. There were, essentially, no changes in physician behavior resulting from the additional information provided by the more sensitive assay. No fewer patients were admitted, similar numbers of ultimate downstream tests occurred, and there were no reliable differences in long-term cardiac or combined endpoint outcomes.

The only outcome of note is probably consistent with what we already knew: any circulating troponin portends worse outcomes. This may be most helpful in directing the long-term medical management of those whose troponin levels were previously undetectable with a conventional assay; these patients clearly do not have the same virtually-zero risk as a patient with undetectable troponin levels. Indeed, troponin levels alone were a better predictor of long terms outcomes than the Heart Foundation Risk Stratification, as well.

I’ll let Judd Hollander sum it up in his most concise – with a link to much more verbose – terms:

“Randomized Comparison of High-Sensitivity Troponin Reporting in Undifferentiated Chest Pain Assessment”
http://circoutcomes.ahajournals.org/content/early/2016/08/09/CIRCOUTCOMES.115.002488.abstract

Perpetuating the Flawed Approach to Chest Pain

Everyone has their favored chest pain accelerated diagnostic risk-stratification algorithm or pathway these days.  TIMI, HEART, ADAPT, MACS, Vancouver, EDACS – the list goes on and on.  What has become painfully clear from this latest article, however, is this approach is fundamentally flawed.

This is a prospective effectiveness trial comparing ADAPT to EDACS in the New Zealand population.  Each “chest pain rule-out” was randomized to either the ADAPT pathway – using modified TIMI, ECG, and 0- and 2-hour troponins – or the EDACS pathway – which is its own unique scoring system, ECG, and 0- and 2-hour troponins.  The ADAPT pathway classified 30.8% of these patients as “low risk”, while the EDACS classified 41.6% as such.  Despite this, their primary outcome – patients discharged from the ED within 6 hours – non-significantly favored the ADAPT group, 34.4% vs 32.3%.

To me, this represents a few things.

We are still have an irrational, cultural fear of chest pain.  Only 11.6% of their total cohort had STEMI or NSTEMI, and another 5.7% received a diagnosis of “unstable angina”.  Thus, potentially greater than 50% of patients were still hospitalized unnecessarily.  Furthermore, this cultural fear of chest pain was strong enough to prevent acceptance of the more-aggressive EDACS decision instrument being tested in this study.  A full 15% of low-risk patients by the EDACS instrument failed to be discharged within 6 hours, despite their evaluation being complete following 2-hour troponin testing.

But, even these observations are a digression from the core hypothesis: ADPs are a flawed approach.  Poor outcomes are such the rarity, and so difficult to predict, that our thought process ought be predicated on a foundation that most patients will do well, regardless, and only the highest-risk should stay in the hospital.  Our decision-making should probably be broken down into three steps:

  • Does this patient have STEMI/NSTEMI/true UA?  This is the domain of inquiry into high-sensitivity troponin assays.
  • Does the patient need any provocative testing at all?  I.e., the “No Objective Testing Rule”.
  • Finally, are there “red flag” clinical features that preclude outpatient provocative testing?  The handful of patients with concerning EKG changes, crescendo symptoms, or other high-risk factors fall into this category.

If we are doing chest pain close to correctly, the numbers from this article would be flipped – rather than ~30% being discharged, we ought to be ~70%.

“Effectiveness of EDACS Versus ADAPT Accelerated Diagnostic Pathways for Chest Pain: A Pragmatic Randomized Controlled Trial Embedded Within Practice”