Category: Troponin

Highly Sensitive Troponins – False Positive Bonanza

The “highly sensitive” troponin has received a great deal of publicity, hyped ad nauseum, see: “Simple test could help rule out heart attacks in the ER.”

But, as sensitivity increases – invariably, specificity decreases.  However, that is not the fault of the test – it is a failure of clinicians to ask the correct question of the test.  When asking “does this patient have an acute myocardial infarction?”(most commonly Type 1 MI in the ED), our training and education has been outpaced by assay technology – the test no longer provides a dichotomous “yes” or “no”.

This publication provides a lovely window into precisely the added value of the hsTnI compared with conventional TnI, both assays by Abbott Laboratories.  In this study, the authors simultaneously drew research samples of blood any time a cTnI was ordered.  The sample was frozen, and then analyzed at least 1 month following presentation.  Authors performed hospital records review, telephone follow-up, and vital records search to evaluate adverse events in patients with hsTnI or cTnI elevation.

Overall, they enrolled 808 patients, 40 of which received an adjucated diagnosis of “acute coronary syndrome” – 26 with AMI and 14 with unstable angina.  61 patients had acute heart failure, 7 had volume overload, 7 had pulmonary emboli, and 41 had other non-ACS cardiac diagnoses.

All told, there were 105 elevated cTnI samples – and 164 elevated hsTnI samples.  This means, essentially – in the acute setting, asking our question of interest – there were 50% greater false positives associated with hsTnI.  No patients would have been reclassified as nSTEMI based on the hsTnI result.  The authors sum this up nicely in their discussion:

“The preponderance of novel elevations (roughly 10% in this study) will be observed mainly in subjects with non-ACS conditions.”

The authors go on to note the value in detecting these novel or detectable troponin levels – essentially, non-ACS, subclinical disease – with a much poorer long-term prognosis.  This is almost certainly the case, although it will require further investigation to reliably demonstrate cost-effective management strategies based on these results.

“Troponin Elevations Only Detected With a High-sensitivity Assay: Clinical Correlations and Prognostic Significance”
http://www.ncbi.nlm.nih.gov/pubmed/25112512

Addendum:  As Stephen Smith points out, it may be possible to use the greater precision of hsTnI at the low end of the assay to more accurately adjudicate some MI.  Great insight!

Highly-Sensitive, But Not Highly Valuable

There is a great deal of continuing debate raging over the use of “high sensitivity” troponins in the Emergency Department.  But, it’s not the test alone at fault – the responsibility for interpreting and acting upon the results lay with clinicians.  In the era of conventional troponins, the test was a powerful tool to rule-in myocardial infarction.  With high sensitivity troponins, the greater value in the tool is in ruling-out.

However, while much is made of the theoretical beneficial test characteristics of high sensitivity troponins, few have measured actual patient-oriented outcomes.  This group from Valencia, Spain, prospectively evaluated consecutive patients at a single institution as their laboratory switched from a conventional TnI assay to a highly sensitive one.  Comparing 699 consecutive patients from the pre-hsTnI period to 673 consecutive patients in the post-hsTnI … there were too many baseline differences to draw any useful conclusions.

But, in an effort to salvage the paper, the authors perform a propensity-score matching algorithm to balance to cohorts.  Based on these matched cohorts, for which they do not offer much in the way of detail, there were no differences in major adverse cardiac events or death at 6-month follow-up.  Regarding management decisions after the change, they note patients were less likely to undergo non-invasive testing in a chest pain observation unit, but substantially more likely to undergo invasive procedures.

This is just a single-center experience, and their observations are incontrovertibly corrupted by the unfortunate change in patients characteristics across their study periods.  It does, at least, provide some small window into how hsTnI might impact the management pathway for patients presenting with chest pain.

“High-sensitivity versus conventional troponin for management and prognosis assessment of patients with acute chest pain”
http://heart.bmj.com/content/early/2014/06/19/heartjnl-2013-305440.abstract

The Troponin to End All Troponins

Yet again, the internet has exploded with magical thinking: “Simple test could help rule out heart attacks in the ER: study”

What is this one “weird” trick that builds muscle, saves electricity, gives you a flat belly, and detects heart attacks in the Emergency Department?

It’s just another high-sensitivity troponin publication.

This is a two-year retrospective evaluation of patients presenting to two Emergency Departments in Sweden, culling the electronic health record for patients aged greater than 25 who were evaluated for chest pain and had at least one hs-cTnT level measured.  These patients were then followed through the central Swedish Health Registry for subsequent hospital admissions or death for 30, 180, and 365 days following their Emergency Department Visit.

Of this cohort, 8,883 had an initial hs-TnT <5 ng/L; within 30 days, 15 of these patients received the diagnosis of MI and two patients died.  Thus, a negative initial hs-TnT was associated with a 0.17% absolute risk for MI and a 0.023% risk of death from cardiovascular causes within 30 days.  Therefore, this test is magic.

Except, it isn’t.  We’ve known for almost two decades that negative biomarkers confer an excellent 30-day prognosis.  This is simply a more sensitive version of those prior assays, with the potential to pick up troponin elevations earlier in the time course of cardiac ischemia.  Earlier detection of cardiac ischemia then potentially enables a one-set rule-out, rather than a two-set or three-set traditional evaluation.

However, as is the natural order of things, when the balance of a test shifts to assign greater significance to a negative test result, the significance of a positive test results declines.  Patients admitted to the hospital with hs-TnT levels >14 ng/L received a diagnosis of MI only 30% of the time.  Their data tables are insufficient to estimate the specificity of the test at the cut-offs provided in the paper, but, clearly it is poor.

The authors promote this test as a tool to discharge greater numbers of patients from the Emergency Department.  However, any potential performance improvement will depend on the baseline admit rate at your institution.  Then, ultimately, we’ll need a more sophisticated approach to interpreting this test – moving beyond the dichotomous interpretation of “positive” and “negative” biomarkers, and describe the detectable levels on a continuum in the context of the concomitant disease processes – including, but not limited to, acute coronary syndrome.

“Undetectable High Sensitivity Cardiac Troponin T Level in the Emergency Department and Risk of Myocardial Infarction”
https://content.onlinejacc.org/article.aspx?articleID=1854323

A Snapshot of Chest Pain Waste

The Lown Institute continues their conference today on avoidable care in the U.S., so this study is a lovely glimpse into one of the worst offenders in Emergency Medicine – chest pain.

Coming from the University of Pennsylvania, this is a retrospective review of patients 805 patients for whom an ED observation protocol of rapid rule-out and stress testing was performed.  The supposed point of this article is to demonstrate the potential safety of stress testing after two sets of cardiac troponin 2-hours apart, and, in theory, they do demonstrate this.  Of these 805 patients, 16 patients were diagnosed with acute myocardial infarction on index visit through this protocol – and within 30 days, 1 patient had AMI and 2 received revascularization.

The authors conclusion: “…serial troponins 2 hours apart followed by stress testing is safe and … rapid stress testing represents another option to expedite care of patients with potential ACS”.

789 of 805 patients received serial troponins and a negative stress test to identify a handful of higher than minimal risk folks.  The 16 AMI diagnoses were based on 12 patients with negative troponins and positive stress tests, 1 patient with troponins that rose from <0.02 to 0.16 ng/mL and a negative stress test, and 3 patients with troponins rising from <0.02 to 0.06-0.09 ng/mL and positive stress tests.  But, in order to dredge up these soft diagnoses of ACS, hundreds of thousands of dollars in financial damage were inflicted on the remaining cohort.

These authors feel rapid stress testing is an alternative to CTCA for preventing avoidable admissions.  In the spirit of the Lown Institute, and of Rita Redberg’s NEJM editorial regarding CTCA, the true strategy for preventing an avoidable admission is simply to discharge the majority of these patients.  A less than 2% yield for an expensive observational diagnostic strategy is far more grossly negligent a failure of medicine than an occasional missed minor MI.  We can do nearly as well, for much less cost – but if only we continue to address our “zero-miss” cultural expectations surrounding diagnosis and treatment.

“Safety of a rapid diagnostic protocol with accelerated stress testing”
http://www.ncbi.nlm.nih.gov/pubmed/24211281

hsTnI – All Promise, No Proof

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”

Copeptin & Publication Bias

There is a phenomenon in the medical literature called publication bias.  It results from two phenomena – authors are more likely to submit the results of trials with positive results, and editors tend to publish articles with positive results.  This results in all sorts of flaws with regard to the composition of the scientific literature, and exerts a particularly troubling hidden effect in meta-analyses and systematic reviews.

I comment upon this in the context of yet another cardiovascular assay article that has – essentially – negative results that are spun to be positive.  Copeptin, as I’ve discussed before, is another acute phase indicator of myocardial demise – but sacrificing specificity for sensitivity.  These authors combine copeptin with hs-TnT for evaluation of chest pain in the Emergency Department, and report several favorable findings in their abstract and the text of their discussion.

In reality only one of the findings they focus on is truly positive – an increase in sensitivity from 76% to 96%.  The NPV increases from 95% (90.4-98.3) to 98.9% (94.2-100) and is not truly a positive result.  More importantly, the authors report copeptin “adds incremental value” – when the area under the receiver operating curve is statistically identical at 0.886 (0.85-0.922) vs. 0.928 (0.89-0.967).

Perhaps copeptin will someday be proven to add true clinical value in an algorithm for the rapid assessment of chest pain in the Emergency Department.  This paper, however, seems to have exaggerated the positivity of its results.  Considering the spate of other recent “positive” copeptin articles – I foresee systematic reviews and meta-analyses of the test characteristics further perpetuating any unremarkable reported advantage in test characteristics.

“Early rule out of acute myocardial infarction in ED patients: value of combined high-sensitivity cardiac troponin T and ultrasensitive copeptin assays at admission”
http://www.ncbi.nlm.nih.gov/pubmed/23816196

A Lovely Overview of Highly-Sensitive Troponin

Although ranting is fun, I much prefer pointing readers in the direction of useful, educational articles – and dispensing with the lighthearted vitriol.

Today, I don’t have to gripe about JAMA – because they’ve published a succinct and fair assessment of the new highly-sensitive troponins by Dr. Lemos from UT Southwestern.  Written for a general audience, he begins with, essentially, a case example of mismanaged Type II MI resulting from non-specific troponin rise, and then progresses through the various confounding causes of elevated troponins and the definition of myocardial infarction.  He then proceeds to frame these problems in the context of ruling out ACS and balancing sensitivity and specificity, as I’ve previously covered here, here, and here.  He makes a fine point that expanding use of these assays will mean approaching the troponin measurement as a continuous value, rather than dichotomous, and a more nuanced diagnostic process.  He also cautions against over-testing and over-diagnosis in the low-risk population.

He also half-proposes the use of troponin testing in the outpatient setting, as elevated baseline troponin levels are associated with poor prognosis.  However, he notes it remains uncertain the effect routine measurement might actually have on cost-effective care and outcomes.

The author discloses conflict-of-interest with several firms, including manufacturers of the highly-sensitive assays – but his conclusion is quite restrained, and acknowledges the very real practice limitations.

“Increasingly Sensitive Assays for Cardiac Troponins” 
jama.jamanetwork.com/article.aspx?articleid=1693870‎

All Elevated Troponins Are Not MI

Have you ever received sign-out on a patient, heparinized, awaiting cardiology consultation – and later, at your leisure, realized the troponin level just barely tips into positive territory and probably has nothing to do with acute coronary syndrome?

I know you have.

This is the cardiology “expert consensus” on interpretation of troponin elevations – 25 pages of clinical summary and 360 references worth of dissecting what an elevated troponin really means.  There’s an hour-long lecture worth giving based on this publication.

The key portions include:
 – Figure 1, which is a nice conceptual overview in which elevated troponins are separated into their “ACS” and “non-ACS” categories.
 – Section 6, which discusses the possible role (if any) for troponins in non-ischemic conditions.
 – Appendix 4, the clinical conditions in which positive troponins are non-cardiac and confounding in origin.

Positive troponins need to be evaluated properly in their clinical context, and this is a lovely (if very, very long) reference document for describing it.

“ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations”
www.ncbi.nlm.nih.gov/pubmed/23154053

How Fast Can We Rule-Out AMI?

Six hours?  Two hours?  One hour?  McDonalds’ drive-thru?

This is the paper from Archives of Internal Medicine that’s been making the rounds in the lay press regarding how quickly the ER should be able to detect your AMI with the new highly-sensitive troponins.  This is the APACE, prospective, international, multi-center study evaluating patients with “symptoms suggestive of acute myocardial infarction” and onset within the last 12 hours.

In this cohort, 1247 patients were recruited – and >300 were excluded for either going straight to the cath lab or having “another procedure performed” at the 1-hour time mark – and received hs-cTnT at index, 1, 2, 3, and 6 hours after presentation.  Myocardial necrosis was defined as a hs-cTnT >99th percentile, which for this assay is 14 ng/L, and a diagnosis of acute MI was made by two independent cardiologists upon review of records and lab results.

The authors split their cohort into two groups, a derivation cohort and a validation cohort, and did some statistical wrangling to come up with two cut-off strategies – one for rule-in and one for rule-out.  They were able to make diagnostic decisions on ~76% of their cohort at the one-hour time point, and 52 ng/L at presentation or an increase within an hour of 5 ng/L or more was ~94% specific for AMI.  Likewise, 12 ng/L and an increase less than 3 ng/L at 1 hour was ~100% sensitive for AMI.  The remaining 25% of their cohort was in a non-diagnostic zone.  At 30 days, there was one death in their rule-out cohort, for a 99.8% survival rate.

So, can you use this strategy?  If you feel as though this study is externally valid to your populations and you’re using the same Roche Diagnostics test, you certainly may.  Every piece of data is something you can incorporate to your discussions with a patient regarding diagnostic certainty and risk.  Even an extra hour occupying an ED bed rather than moving out to a chest pain observation facility can significantly impede ED flow, while observation admissions are costly and inconvenient to patients.  The ideal strategy will depend on the capabilities of individual departments.

This study, along with the primary author, are sponsored in part by Abbott, Roche, and Siemens.
www.ncbi.nlm.nih.gov/pubmed/22892889

Yet Another Highly Sensitive Troponin – In JAMA

…peddling the same tired phenomenon of magical thinking regarding the diagnostic miracle of highly sensitive troponins.  However, this one is different because it’s been picked up by the AP, CBS News, Forbes, etc. saying: “Doctors are buzzing over a new blood test that might rule out a heart attack earlier than ever before” and other such insanity.  Yes, our hearts are in atrial flutter around the water cooler about a new assay that changes sensitivity from 79.4% to 82.3% at hour 0 and 94.0% to 98.2% at hour 3.


Unless you actually read the article.

Somehow, contrary to every other high-sensitivity troponin study, this particular highly-sensitive troponin had increased specificity as well – which simply doesn’t make sense.  If you’re testing for the presence of the exact same myocardial strain/necrosis byproduct as a conventional assay, it is absolutely inevitable that you will detect a greater number of >99th percentile values in situations not reflective of acute coronary syndrome.  The only way to increase both sensitivity and specificity is to measure something entirely different.


Or, if it suits your study aims, you can manipulate the outcomes on the back end.  In this study, the final diagnosis of ACS “was adjudicated by 2 independent cardiologists” whose diagnostic acumen is enhanced by financial support including Brahms AG, Abbott Diagnostics, St Jude Medical, Actavis, Terumo, AstraZeneca, Novartis, Sanofi-Aventis, Roche Diagnostics, and Siemens.

I am additionally not impressed by their results reporting – sensitivity and specificity, followed by the irrelevant positive predictive and negative predictive values.  Since the PPV and NPV are determined by the incidence of disease in their cohort, they’re giving us numbers that are potentially not externally valid.  Rather, they should be reporting positive and negative likelihood or odds ratios – which are relatively cognitively unwieldy, but at least not misleading, but conceptually facile, like PPV and NPV.

And this is from JAMA.  Oi.

“Serial Changes in Highly Sensitive Troponin I Assay and Early Diagnosis of Myocardial Infarction”