Chest Pain – Page 6 – Emergency Medicine Literature of Note

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

There’s No Telling What Patients Want

“Shared decision-making” has become a frequent watchword of sorts, encompassing participatory concepts in which patients are better involved in their own care. I, and many others, have espoused this sort of paradigm in medicine.

Unfortunately, there’s a bit of a problem. On the physician side, we probably don’t have good mechanisms through which to translate evidence to individual patients. Most information derived from clinical studies describes outcomes from aggregated cohorts – so, usually, the best we can do is inform our patients how the “average” person performed with a specific treatment.

Then, on the patient side – as this study demonstrates – their risk-taking behavior is heterogenous, irrational, and extreme. These authors report on 234 surveys of patients presenting with low-acuity chest pain in a Veterans Affairs cohort, trying to get a handle on hospitalization preferences given a certain pretest likelihood of disease. Their basic model: hospitalization reduces the risk of bad outcome by 10%. Then, they asked if the patient would like to be hospitalized for base likelihood of poor outcomes ranging from 1 in 2 to 1 in 10,000.

Half the patients wanted to be hospitalized, even when the benefit to hospitalization reduced the event rate from 1 in 10,000 to 1 in 11,000 (an NNT of 110,000). Then, another 10% of patients wanted to be discharged in all circumstances, even when the risk of poor outcome was improved from 1 in 2 to 5 in 11 (an NNT of 22). And, depending on how the risks were communicated, and whether visual or numeric scales were used, also affected how the patients chose.

So, ultimately – yes, we’d like to involve patients in their decisions. But, unfortunately, it looks as though it’s going to be quite the challenging proposition – and we might not like (or have the capacity to abide by) their preferences.

“Measuring Patient Tolerance for Future Adverse Events in Low-Risk Emergency Department Chest Pain Patients”
http://www.ncbi.nlm.nih.gov/pubmed/24530111

ADAPTing & Improving

By far, the most promising of the publications to yet emerge from the ADAPT cohort – 1,974 patients evaluated for acute chest pain in the Emergency Department – is this re-analysis and decision instrument.

The original ADAPT publication, despite over 80% of the patients having no major cardiac event at 30 days, was only able to identify 20% of patients as “low-risk”. The HEART Score and the Vancouver Chest Pain Rule improve on this, but only incrementally. This publication, however, improves the identification of a low-risk cohort to nearly 50%. By incorporating and weighting 37 different predictor variables, then adding a layer of expert review and acceptability evaluation, these authors ultimately arrive at the “Emergency Department Assessment of Chest Pain Score (EDACS)”. Using age, gender, history, and symptoms, when combined with negative ECG and 0 and 2 hour troponins, a score of 16 constitutes a breakpoint for a decision instrument with ~99% sensitivity and ~55% specificity for MACE at 30 days.

As far as decision instruments go, it’s relatively reasonable – although, certainly, nothing you’d be able to keep in your head. Scores for age range from +2 to +20, while four different symptoms and signs have varying positive and negative values. However, in the age of computerized decision-support, at least, mildly complex rules are not as burdensome as they once were.

I would like to see, at least, prospective validation in a North American population – but this appears to be a lovely step forward.

“Development and validation of the Emergency Department Assessment of Chest pain Score and 2 h accelerated diagnostic protocol“
http://onlinelibrary.wiley.com/doi/10.1111/1742-6723.12164/abstract

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

Time to Move to the HEART Score

A couple posts ago I mentioned it was time for the TIMI Risk Score for UA/nSTEMI to go the way of the dodo for evaluation of chest pain in the Emergency Department. It wasn’t derived from an Emergency Department population, doesn’t have great predictive skill in identifying very-low-risk patients, and includes nonsensical elements (did you take an aspirin within the last 7 days?).

Alternatively, we have the HEART score: History, ECG, Age, Risk factors, Troponin. This was derived – like the Wells score – from the elements of clinical gestalt, and ought to at least make better intuitive sense than the occasionally frizzy outputs from multivariate logistic regression. It was initially derived and refined retrospectively, and this represents the prospective validation study. These authors prospectively enrolled 2,440 patients from 10 centers in the Netherlands and followed them for a primary endpoint of a major adverse cardiac event (AMI, PCI, CABG, death) for six weeks. They also collected the variables of interest necessary to calculate TIMI and GRACE risk scores for comparison of c-statistic.

Obviously, I’m recommending the HEART score because it outperformed the others – the c-statistic for HEART was 0.83, 0.75 for TIMI, and 0.70 for GRACE. Most importantly, for the Emergency Department, it was superior at the low-end of the spectrum. For the 34% of the population that was TIMI 0-1, 23/811 (2.8%) had 6-week MACE. 14.0% had GRACE 0-60, and 10/335 (2.9%) had MACE. For HEART, 36.4% were 0-3 and ultimately 15/870 (1.7%) had MACE.

Even though there are 2,400 patients in this study, there are few enough in each individual category that confidence intervals for each predictive bucket are still relatively wide. Then, you can still have a HEART score in the “very low risk” 0-3 range with a troponin >3x the normal limit and an abnormal EKG – which is seemingly counterintuitive. They also don’t compare their rule to clinical judgment, so we can’t measure the performance of the rule in actual decision-making.

A couple other studies have either prospectively or retrospectively validated these findings with reasonable consistency. It isn’t perfect – but it’s better than TIMI or GRACE – and it’s what I currently use to support my shared decision-making discussions at disposition of the appropriate chest pain cohort.

http://www.heartscore.nl/en/

“A prospective validation of the HEART score for chest pain patients at the emergency department”
http://www.ncbi.nlm.nih.gov/pubmed/23465250

Gender-Specific Symptom Nonsense

This comical, fundamentally flawed publication has already been skewered online in just the handful of days since it hit publication. But, any press is good press, right?

We’ve been practicing under the prevailing notion women more frequently manifest atypical constellations of symptoms when presenting with acute myocardial infarction. We’ve inferred this from observational cohort data, and from studies indicating we miss more diagnoses of AMI in women. So, these authors set to prospectively validate this notion.

It’s rather sad, unfortunately, how much effort and time was spent prospectively enrolling the 2,475 patients recruited for this study. Each patient underwent a structured clinical interview to determine the presence or absence of specific chest pain features, and these were correlated with final adjucated diagnosis of AMI. And, in the end, the positive and negative likelihood ratios for AMI for nearly every recorded feature were identical for men and women.

But, when you exclusively enroll patients with “symptoms suggestive of AMI”, you’ve designed precisely the type of study that will never detect atypical presentations of AMI. If clinicians didn’t suspect acute coronary syndrome associated with an episode of chest pain, these patients are discarded from follow-up. Unfortunately, then, this work is unable to conclusively answer any question regarding gender-specific symptoms.

To truly evaluate this question, the inclusion criteria would have be far more expansive. Essentially, nearly all atraumatic patients with a somatic complaint above the pelvis should be screened and followed for a definitive diagnosis of AMI. Perhaps that study would be too large and unwieldy to successfully execute, but that would be the scope required to answer this question once and for all (within the bounds of external validity).

Finally, I just want to point back to Seth Trueger’s write-up of a lovely ED chest pain study, where expert rheumatologists made gold standard diagnoses of costochondritis in the Emergency Department. Incidence of AMI in “costochondritis” patients? 6%.

“Sex-Specific Chest Pain Characteristics in the Early Diagnosis of Acute Myocardial Infarction”
http://archinte.jamanetwork.com/article.aspx?articleid=1783306

Unlocking the Secrets of Atherosclerotic Plaques

In general, the best way to determine the cause of death is autopsy. Most of our patients, however, aren’t willing to undergo this procedure in order to guide preventative care. Thus, we are left using imprecise predictive instruments to prognosticate and prevent untimely demise.

In the cardiovascular sciences, a large part of what we do is salvage – catheterization, stenting, and cardiovascular care units to minimize myocardial injury after infarction. These authors, however, believe they’ve identified a new paradigm in cardiovascular imaging: identification of individual high-risk atherosclerotic plaques.

In this observational cross-sectional study, the authors enrolled 40 patients immediately following myocardial infarction and 40 patients with known stable angina. All patients underwent combined PET and CT with radioactive tracers. In 37/40 post-MI patients, the culprit lesion had significantly higher radioactive uptake compared with all non-culprit lesions. Extending this observation to the 40 patients with stable angina, 18/40 had lesions associated with similar radioactive tracer uptake compared to background. Patients with these lesions underwent intravascular ultrasound, which confirmed high-risk features such as remodeling, microcalcifications, and necrotic cores.

This is light-years away from being validated, and then being further translated into routine care – but it is quite fascinating work. We’ve bemoaned the limitations of our non-invasive imaging, based on our inability to characterize lesion histology or adequacy of tissue perfusion from varying levels of stenosis, and this is a promising step for guiding management of a subset of high-risk patients.

“18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61754-7/abstract

Glucose and Insulin, Less is More

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

With the recent publication of the AHA updated guidelines on the management of cholesterol and their bafflingly continual support of cholesterol management despite the mounting evidence to the contrary, it is only fitting that we turn our attention to the other surrogate endpoint that has for so long supported the fallacy of cardiovascular health: sugar.

In an article by Mulder et al published in the November 2013 JAMA Internal Medicine, the authors attempt to show the benefit of intensive glucose control following an acute myocardial infarction. This hypothesis has been tested several times and other than its initial go around in DIGAMI-1 has not manifested in any positive outcomes. Despite its disappointing history the authors felt that in this trial, in their hospital, with their protocol they would find success. After all, nowadays, clinical trial success is all in how you define it.

These authors defined success in a variety of surrogate endpoints meant to encapsulate infarct size. Both TnT and CKMB measurements were taken serially throughout the first 72 hours. In addition all patients received rest-gated myocardial perfusion scintigraphy (MPS-SPECT) after 6-weeks to grade the extent of their infarct.

Using their intensive glucose control protocol the authors were successfully able to control blood glucose levels far better than those in the standard therapy group. Though this procedural success did not translate into a difference in infarct size, they did manage to find a clinical and statistical difference in the occurrence of in-hospital death and recurrent MI. Specifically there was a 5% absolute increase in death and MI in those patients receiving intensive insulin therapy. This increase in clinical events cannot be accounted for by episodes of hypoglycemia as in this cohort they were very rare (0.4%).

This trial is in no way definitive, but it is becoming increasingly clear that both in the acute setting and long-term, intensive glucose control does more harm than good. Though elevated glucose levels may be a harbinger of future disease, silencing this messenger does not prevent these foretold events from transpiring.

“Intensive Glucose Regulation in Hyperglycemic Acute Coronary Syndrome: Results of the Randomized BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome-2 (BIOMArCS-2) Glucose Trial”
http://www.ncbi.nlm.nih.gov/pubmed/24018647

Glucose and Insulin, Less is More

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”