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”

Zeno’s Zero-Hour Rule-Outs

This is TRAPID-AMI, a prospective Roche hs-TnT (99th percentile 14ng/L) study for patients presenting within 6 hours of peak chest pain symptoms.  Samples were drawn on arrival, then serially over the next two hours, and a final sample drawn 4-14h after presentation.  The primary outcome was acute MI, as adjudicated by a panel of cardiologists blinded to the hs-TnT result but aware of a Siemens conventional troponin I (99th percentile 40ng/L) result.  Interestingly, they powered their study specifically for a negative predictive value, rather than a specific sensitivity result – certainly an easier enrollment target, but also potentially more difficult to generalize.

All told, they included 1,282 patients in the study and there were 213 patients ultimately diagnosed with AMI on their initial presentation.  In 30-day follow-up, 11 patients could not be contacted, and an additional 18 patients not originally diagnosed with AMI met their combined MACE endpoint, 15 of which were revascularlization.  Of these 213 patients with initial diagnosis of AMI, there were four false-negatives with respect to the troponin assays being below the limit of detection.  For their primary outcome, then, sensitivity was 98.1% (95.3-99.5) with specificity 52.0% (49.0-55.0).  The authors go on to present several different strategies based on various cut-offs and various EKG findings, the effect of which are various trade-offs between number of patients eligible for a zero-hour rule-out, the sensitivity, and the specificity.  Negative predictive values, of course, generally ran >99%, owing the the relative infrequency of AMI diagnoses.

This study, like most before it, provides little additional insight.  Sensitive troponin assays are, indeed, more sensitive.  The sensitivity comes at a cost of specificity.  We are also encountering a sort of Zeno’s Paradox with regard to our evaluation of these strategies.  We employ more sensitive assays both to detect AMI up-front, but also as our gold-standard for adjudicated final outcome.  The increased sensitivity, then, cuts both ways – as we detect tinier and tinier nSTEMI as a sort of ceiling for our sensitivity of any rapid rule-out strategy.  Is it reasonable to suggest the occasional 1-in-200 tiny myocardial injury missed is unlikely to have serious clinical consequences?  If so, the best question to address is how to continue the care of these patients after they leave the Emergency Department such that those who would benefit from additional medical and endovascular intervention are not lost.

“The use of very low concentrations of high sensitivity troponin T to rule out acute myocardial infarction using a single blood test”
http://www.ncbi.nlm.nih.gov/pubmed/27178492

Still Making Sense of High-Sensitivity Troponin

Figuring out the value of a troponin measurement is both simple, and complicated.  Big numbers are still straightforward and trouble.  Small numbers – and even smaller still – are increasingly difficult to parse.

What does seem to be true, at least: the closer to zero, the better.

This is a multi-center evaluation of a 0- and -1hour troponin delta strategy, based on a hs-cTnT from Roche.  These authors prospectively enrolled 1,458 patients with chest pain of peak intensity within 6 hours.  Samples were then taken at 0, 1, 2, and then at least 4 hours after presentation.  The outcome of interest was an independently adjudicated final diagnosis of acute myocardial infarction.  And, this study probably shows just about what every similar study has shown: initial sensitivity is ~90%, with marginal increases as additional time points are added, while specificity suffers predictably due to the nature of the assay.

However, there are a couple concerning potential sources of bias.  The authors enrolled 1,458 patients – but exclude 176 of them from analysis for a variety of reasons.  In a study trying to catch rare events to demonstrate near-100% sensitivity, over 10% of patients dropping out is an important consideration.  There were also issues with slow enrollment, compared to previous studies, and the patient flow diagram is extremely sparse.  Over two years, the centers involved likely had many thousands of chest pain presentations.  No information regarding the missed enrollments is presented.

There are also issues with the adjudication downstream, which was based on the results of various follow-up examinations as well as, oddly enough, a different troponin assay: s-cTnI-ultra.  213 (17%) patients received a final diagnosis of AMI, while 167 (13%) received a diagnosis of unstable angina.  The clinical significance of their definition of unstable angina remains unclear to me – myocardial ischemia without cellular injury associated with chest pain at rest.  The authors reference these UA patients as being at low risk for poor long term outcomes, which seems clinically discontinuous with the sort of “critical near-occlusion” working definition I’m familiar with for true UA.  Regardless, the safety of their strategy is only reasonable if UA is a relatively benign catch-all diagnosis for troponin-negative chest pain, so I will accept their categorization.

There were also diverse and perverse conflicts-of-interest described with the manufacturer of the assay involved.

Regardless, as previously stated, these data are consistent with prior demonstrations – so, yes, using these assays at presentation, or as 1- or 2-hour deltas in the Emergency Department, will result in a very low miss rate when paired with low pretest likelihoods of disease.  Furthermore, anything missed by these assays will be such a minute injury pattern as to be extremely low-risk for short term cardiac mortality.

Yes, Virginia, you can discharge chest pain.

“Multicenter Evaluation of a 0-Hour/1-Hour Algorithm in the Diagnosis of Myocardial Infarction With High-Sensitivity Cardiac Troponin T”
http://www.annemergmed.com/article/S0196-0644(15)01501-2/abstract

Again, One Troponin is Enough

As we’ve seen suggested in prior work, an undetectable high-sensitivity, high-precision troponin at presentation is a powerful predictor of minimal risk in the short-term.

In this prospective study based at four hospitals in Scotland, 6,304 eligible patients with suspected acute coronary syndrome were captured for analysis across three prospectively gathered cohorts.  These patients were split across a derivation cohort to establish a threshold with an appropriate negative predictive value, an internal validation cohort, and an external validation cohort.  Their target for a 30-day MACE of MI or cardiac death was a negative predictive value of 99.5%.

Making essentially a long story short, they found a threshold of 5 ng/L established this minimal-risk population, with only 9 patients meeting the primary outcome out of of 2,302 patients with an initial troponin less than the threshold.  And, if you want to be even more airtight, 6 of these presented within 2 hours of the onset of chest pain, and 3 had apparent ischemic changes on their initial EKG – which may have been picked up by a rapid repeat testing protocol in the ED for some patients.

There are a few holes in this paper, of course.  Not all patients were hospitalized and had such repeat testing, so some small nSTEMI or vasospasm events could have been missed.  Patients in this study required a median of 54 minutes for blood sampling after presentation to the ED, so some caution should be exercised regarding repeat troponin testing if your department is efficient regarding phlebotomy at presentation and onset of symptoms was just prior to arrival.  But, on the whole, this greatly adds to the body of evidence we’ve been building – that cutting edge troponin assays alone can provide powerful prognostic information.

Now, what to do with all the “intermediate” cases ….

“High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00391-8/abstract

Risk Stratification Cage Match & The Return of TIMI

Sending home chest pain has completely jumped the shark from frankly illegal to fashionably vogue.  Every day, another stick is shaken, and a mess of monkeys and new studies evaluating discharge strategies fall from the trees.

Today in the Octagon, five “established” risk scores for patients with acute coronary syndrome are pitted against each other in a prospective, observational study in Britain:  TIMI, GRACE, HEART, the Vancouver Chest Pain Rule (sure, OK), and the modified Goldman (???).  Each of these risk scores were paired with non-ischemic EKGs, and single initial blood samples for high-sensitivity troponin T (14 ng/L) and high-sensitivity troponin I (26.2 ng/L).  The authors’ stated goal: a negative predictive value of 99.5% for myocardial infarction within 30 days, and a capability of discharging at least 30% of patients at the initial presentation.

Oddly, it’s unexpectedly difficult to pick a winner.  The decision instrument with the greatest ability to discharge patients was TIMI ≤1, over 50% home from the ED, but it just barely missed the NPV threshold.  The modified Goldman ≤1, when paired with the troponin T, was capable of discharging 39.8% of patients with a sensitivity of 98.7%.  Then, the HEART score ≤3 was the most clinically acceptable when used with the troponin I assay, as it was the only decision-instrument taking into account small variations in serum troponin.  However, it just failed to meet the authors’ NPV threshold, as well.

So, what has changed since we last crowned HEART the new gnat’s pajamas?  Mostly the troponin assays, although this study also focuses more on NPV than sensitivity.  Indeed, a single hs-cTnT <14 ng/L had an NPV of 98.3% in this study, regardless of all other clinical features.  The implication, potentially, may be that the ideal risk-stratification decision-instrument can be designed for greater specificity, rather than sensitivity.  Other methods to increase sensitivity, such as paired troponins in certain situations, may allow for even further decision-instrument specificity, depending, of course, on the acceptable miss rate.

Despite its performance here, I’m not advocating for a return to TIMI – or to the modified Goldman – because I’m not quite so keen on their sensibility in the ED.  However, the interaction of HEART with different assays is intriguing, and perhaps a venue for further investigation and refinement.  It’s probably also worth mentioning an additional overlooked aspect – it is still OK to discharge a patient with a higher risk of AMI or death within 30 days if there is no additive survival benefit associated with acute hospitalization.

“Identifying Patients Suitable for Discharge After a Single-Presentation High-Sensitivity Troponin Result: A Comparison of Five Established Risk Scores and Two High-Sensitivity Assays”
http://www.ncbi.nlm.nih.gov/pubmed/26260100

Why Do We Still Admit Chest Pain?

If you worked a shift today, you had a patient with chest pain.  As these authors cite in their introduction, visits for chest pain comprise 1 in 20 presentations to Emergency Departments – and the evaluation of such patients costs more than the annual GDP of Malta.  As our hospitalist colleagues lament, a massive subset of inpatient evaluations for chest pain are invariably negative – or, even worse, generate false positives and other iatrogenic harms.

This study is an retrospective evaluation of an observational registry of chest pain presentations to three Ohio Emergency Departments.  The authors perform a search of five years worth of data, and generate a cohort consisting of patients who received at least two consecutive negative troponins initiated in the Emergency Department.  The primary outcome was in-hospital life-threatening arrhythmia, STEMI, cardiac arrest, or death.

In this database of 45,416 patients, 11,230 met their inclusion criteria.  Independent, hypothesis-blinded abstractors reviewed a subset of “possible” primary outcomes based on electronic data, and manually abstracted those identified.  From this manual review, there were 20 (0.18%) patients for whom a critical outcome was identified.  The authors reviewed each specific case and tried to identify specific risks for adverse outcome – and, if patients with abnormal vital signs, left bundle branch block, pacemaker rhythm, or signs of EKG ischemia were further excluded, the incidence of critical outcomes drops to 4 out of 7,266 (0.06%).

The supposed takeaway from this article is that patients who have been ruled out by serial troponin testing have uneventful hospital courses.  Extending this to practice, the theory is we could perhaps generalize this evidence to our 1- or 2-hour rapid-biomarker rule-outs.  These patients would then supposedly have such an acceptable safety profile as could be discharged from the ED with outpatient follow-up to assess the need, or appropriateness, for further provocative or anatomic testing.

These data are not quite strong enough to claim such a strategy as bulletproof.  The risk, I agree, is certainly small – with thousands requiring hospitalization in order to obtain benefit for one patient.  The benefit, however, for the patients in this study is not the soft MACE outcome described in other studies – these are hard endpoints of folks who would likely be dead if not observed in the hospital.

While I expect outpatient evaluation of substantial numbers of chest pain patients to be the new culture in Emergency Medicine in the future – and as much as I would like to purchase Malta for ACEP next year – this isn’t zero-miss.  These data support development of appropriate outpatient strategies – but not wholesale practice revision based solely on this data set.

Addendum: Louise Cullen makes a few excellent points on social media peer review I’ll paraphrase here: 1) The endpoints measured here are not the only important patient-oriented outcomes.  There are a small number of initially troponin-negative acute coronary syndromes that may be missed here. 2) There are patients for whom hospitalization and urgent evaluation has value due to medical interventions initiated in the hospital.  An aggressive discharge strategy cannot be based on a catch-and-release foundation without tightly integrated follow-up.

“Risk for Clinically Relevant Adverse Cardiac Events in Patients With Chest Pain at Hospital Admission”
http://archinte.jamanetwork.com/article.aspx?articleid=2294235

Will You Be My SWEDEHEART?

I may be reviewing this article just because of its acronym – a recognition of the serious efforts expended to derive SWEDEHEART and its full name: “Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies”.

Briefly, this is a prospective registry of patients admitted to coronary care units in Sweden with symptoms suggestive of acute coronary syndrome.  These authors’ goal was to describe the implications and prognostic value of the new, 5th-generation highly-sensitive troponins, specifically the Elecsys hsTnT.  This particular assay has a limit of detection of 5 ng/L, a 99th percentile in healthy controls of 14 ng/L, and less than 10% coefficient of variation at 13 ng/L.  This compares to the prior generation of assays in which positive results were roughly ~50 ng/L.  Overall, the authors reviewed the inpatient stays for 48,594 patients.

There are probably two useful takeaways from this article:

  • Only 18% of patients with “positive” hsTnT between 14-49 ng/L were ultimately diagnosed with MI.  This compares with 81.2% of those with hsTnT >50 ng/L.
  • The one-year mortality of patients with hsTnT between 14-49 ng/L on admission was 10.3%.  This compares to 2.0% for those less than 14 ng/L and 17.1% for those >50 ng/L.

The acute implication for Emergency Medicine is mostly a recognition of the prevalence of elevations >99th percentile outside the context of an acute coronary syndrome.  The less acute, but equally important implication, is recognizing the need for aggressive referral and follow-up for those with small elevations in the absence of ACS.  While no “emergency” intervention is necessary, detection of even low levels of cardiac suffering is a strong predictor of future risk, and should be recognized accordingly.

“Implications of Introducing High-Sensitivity Cardiac Troponin T Into Clinical Practice”
http://www.ncbi.nlm.nih.gov/pubmed/25908071

The 1-Hour Rule-Out

All of a sudden, it’s become vogue to send home chest pain.  After a decade of horror stories regarding the diagnostic errors and medicolegal consequences of discharging chest pain, there is no shortage now of strategies for rapid disposition.  Do you like HEART?  Go ahead and use it.  Do you like CCTA?  Please, no – but, OK.  Do you like high-sensitivity troponin?  Then this is for you.

From Switzerland, Spain and Italy, these authors prospectively evaluated the sensitivity and area under the receiving operator curve for a 1-hour rule-out.  Analyzing 1,320 patients with acute chest pain of onset within 12 hours, after excluding STEMI and those with missing data.  Final adjudication of MI was performed by two independent cardiologists and based additionally on 3- and 6-hour conventional troponins for each patient.  3, 12, and 24-month follow-up was attempted on each patient.  As with each of these new studies, the devil is in the assay – in this case, the Roche Elecsys 2010 hsTnT with a 99th percentile healthy reference cut-off of 14ng/L.

The algorithm for rule-in and rule-out entailed the following:

  • Out: hsTnT less than 12 ng/L and a less than 3 ng/L 1-hour delta.
  • In:  hsTnT greater than 52 ng/L or a greater than 5 ng/L 1-hour delta.
  • Who knows (the “observation zone”):  Everyone else!

This resulted in 786 (59.5%) patients classified as “rule out”, with 1 patient ultimately falling out with a diagnosis of acute MI.  “Rule in” occurred in 216 (16.4%) of cases, with 169 (78.2%) true positives.  318 (24.1%) remained in the Danger Zone, where 59 (18.6%) ultimately ruled-in.  The AUC of the algorithm – based on the rule in/rule out – was 0.96 for the 1-hour strategy, as compared to 0.93 for just an initial measurement, or 0.96 for a 2-hour delta.  30-day follow-up showed zero mortality for the “rule out” patients, and even 24-month follow-up with less than 1% all-cause mortality.

These results are fairly consistent with prior strategies incorporating the use of high-sensitivity troponins, which inevitably produce a “gray area” of sorts between the rule-in and rule-out requiring further observation.  An area of continued concern, as well, remains the false-positives – nearly a quarter of the “rule in” cohort.  The authors provide a small breakdown of these patients, and most were suffering from some acute cardiopulmonary condition – heart failure, myocarditis, acute pulmonary embolism, etc.

However, not mentioned in the paper, but noted on the last page of the appendix, is the full accounting of final adjudicated diagnoses.  In addition to the 229 with a final diagnosis of acute MI, another 109 received a diagnosis of unstable angina and 194 “cardiac but non-coronary disease”.  Unstable angina, per the authors definition, was a bit of a catch-all category, including those with positive functional testing, cardiac catheterization, and acute MI within 60 days.  More detailed information on this heterogeneous endpoint, and their distribution within the “rule out”/“observation zone”/“rule in” cohorts would be helpful.

From a pragmatic standpoint, I think most groups will have success with these accelerated rule-out strategies.  The key, as always, is intelligent disposition and management of those in the ambiguous range – in which additional resource utilization associated with troponin measurements above the 99th percentile can torpedo any advantages to this strategy.  Regardless, these assays are certainly proliferating, and clinicians need be familiar with their advantages and disadvantages.

Naturally, there were diverse conflicts-of-interest with the makers of the assay involved.

“Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay”
http://www.cmaj.ca/content/early/2015/04/13/cmaj.141349.full.pdf+html