Category: Chest Pain

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

The “No Objective Testing” Rule for Chest Pain

As “zero-miss” philosophies for chest pain proliferated, so did the “early objective testing” phenomenon.  Chest pain presentations of all colors and ages, following an initial evaluation in the Emergency Department, have been invariably referred for inpatient observation and stress testing.  The problem?  Most of these tests are performed in patients for whom the pretest likelihood of coronary artery disease is low, and the incidence of false-positives outweighs that of true-positives.

This rehash of prior observational data aims to address this issues – specifically deriving a prediction rule for those who are so low risk any follow-up testing ought be obviated.  Based on cohorts enrolled for two previous studies of potential acute coronary syndrome presentations in New Zealand and Australia, these authors track 2,396 patients for 30 days.  Following an initial negative ED evaluation, 5.6% were diagnosed with acute coronary syndrome within 30 days – mostly “unstable angina”, and mostly based on follow-up objective testing.  Using standard statistical bootstrapping techniques, the authors partition out 31.1% of this cohort as having a <1% risk of ACS within 30-days: age <50, <3 risk factors, and no prior CAD or MI.  The authors suggest patients meeting these criteria, following a negative ED evaluation, need not be referred for any objective testing.

The puzzle here is in the outcomes measured: 30-day AMI, cardiovascular death, unstable angina, or revascularization.  The leap, then, involves associating a lack of these outcomes with the disutility of provocative or anatomic testing.  It is probably true there is colinearity between clinically important coronary artery disease and incidence of major adverse cardiac outcomes, but this is a bit tenuous of a foundation for their conclusions.  A lack of 30-day adverse event does not exclude benefit from cardiac imaging, and, vice versa, the presence of a 30-day adverse event does not imply a benefit from cardiac imaging.  However, given the lack of other useful evidence, this is as valid a proxy as we have to inform practice.

Finally, what tends to disappoint me most in these sorts of articles is something of a disconnect between the study design and the clinical questions relevant in practice.  Chest pain presentations lay somewhere on a bell curve.  At the low end, a subset of young and healthy folks are mostly harmed by overdiagnosis and additional resource utilization.  Then, at the high end, patients with multiple risk factors and known disease can no longer be substantially helped by additional invasive interventions.  Each of these cohorts is appropriate for early discharge from the Emergency Department without additional cardiac imaging, yet the focus is persistently on only the very low-risk end of the spectrum.  I hope future study is able to provide a more sophisticated analysis of the features of moderate- and high-risk patients to identify the individuals within these cohorts who do benefit from cardiac imaging, and which specific testing best informs downstream care.

“A Clinical Decision Rule to Identify Emergency Department Patients at Low Risk for Acute Coronary Syndrome Who Do Not Need Objective Coronary Artery Disease Testing: The No Objective Testing Rule”
http://www.ncbi.nlm.nih.gov/pubmed/26363570

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

The NNT of a Chest Pain Admission

To prevent death: 333.

In a bitterly complex analysis of Center for Medicare and Medicaid Services data, these authors describe a relationship between admission rate and subsequent cardiac adverse events.  Based on a statistical sample of Medicare patients visiting acute care hospitals, these authors calculate an admission rate for chest pain for each, and divide the sample into quintiles.  Then, the authors follow index visits for chest pain to those hospitals, and measure 30-day acute myocardial infarction or death.  Thus, a relationship between admission rate and poor outcomes.

The mean adjusted admission rate for chest pain ranged from 37.5% in the lowest quintile to 81.0% in the highest quintile.  Owing to the large sample size, many of the differences between hospitals in each quintile meet statistical significance.  However, the difference that leaps out at me the most, for-profit hospitals represented 24% of the highest quintile for admissions, while for-profit hospitals were only 7.8% of the lowest.

And, what was that massive variation and expenditure associated with, in terms of beneficial outcomes?  An inconsistent reduction in subsequent AMI and death which, through multivariate logistic regression, was equal to about 3.6 fewer AMIs and 2.8 fewer deaths per 1,000 patients – with very wide 95% CIs.

And, thus, to oversimplify and overstate the soundness of the analysis, the NNT of 333.

It seems very reasonable to suggest a relationship between intensity of care and 30-day cardiac outcomes.  Such intensity of care, however, is quite expensive – on the order of probably $1.5-$2M per life shortened and captured in this 30-day window.  As our population ages, we are simply going to have to do better – in order to maximize the value of the limited healthcare dollars.

“Variation in Chest Pain Emergency Department Admission Rates and Acute Myocardial Infarction and Death Within 30 Days in the Medicare Population”
http://www.ncbi.nlm.nih.gov/pubmed/26205260

Expunging “Zero-Miss” from Chest Pain Evaluation

The admit rate for chest pain from the Emergency Department varies widely.  In some instances, the rule “chest pain = admit” is the norm – or, at the least, observation and provocative or anatomic radiology from the Emergency Department.  Indeed, such studies exhorting the advantages of CCTA in the ED included those aged as low as 30 years – patients in whom the false positives from testing far outweigh the true.

The typical motivating factor for such aggressive admission rates has been a culture of “zero miss”, motivated by huge settlements for missed MI.  Accordingly, this brief study followed Emergency Physicians and asked – what if there were no legal liability?  What if there was an acceptable miss rate of 1 or 2% in chest pain?  How many of these people would be discharged instead of admitted?

Based on 259 surveys completed regarding a convenience sample of admitted chest pain patients, the answer from this single-center study is: 30%.

With over 5 million ED visits for chest pain annually, cutting the current 35% admission rate by 30% turns into a massive reduction in resource utilization.  And, frankly, it’s not as daunting to implement such thresholds as one might imagine: ED physicians set the standard of care, not lawyers.  As Jeff Kline has alluded to the possibility, it’s time for domain experts to set reasonable practice variation and resource utilization, rather than leave it up to lawyers and their hired guns:

Some argue that “standard of care” is only determined by a jury. I disagree. Physician topic experts should write the standard of care.

— jeffrey kline (@klinelab) July 12, 2015

This definitely should be done.

“The Association Between Medicolegal and Professional Concerns and Chest Pain Admission Rates”
http://www.ncbi.nlm.nih.gov/pubmed/26118834

Oxygen: Friend or Foe?

I’m a huge fan of oxygen.  I breathe oxygen nearly every day, and without it, I would literally, moreso than figuratively, die.

But, oxygen is a highly reactive molecule with many adverse effects in the human body.  Recognition of such seems to be in direct contrast to the otherwise reasonable hypothesis of increased oxygenation providing benefit in ischemic disease states.  The most recognizable of these is acute myocardial infarction, where oxygen is enshrined in the classical (and outdated) MONA mnemonic.

This is the AVOID trial, randomizing patients in the field with prehospital diagnosis of STEMI to either 8L/min inhaled oxygen, or oxygen only as needed to maintain saturations >94%.  All patients received aspirin from paramedics en route to the receiving facility, with further care as per local standards and protocols.  The primary outcome was infarct size, as measured by peak troponin and creatine kinase levels.

Paramedics screened 836, randomized 638, an additional 50 were protocol non-compliant, and then 118 were declared not to be STEMI upon arrival at the receiving facility.  The remaining 470 underwent angiography, and the final cohort for analysis was the 441 for whom STEMI was ultimately confirmed.  Groups were generally similar between interventions, although there was an excess of 8 patients with LAD lesions in the oxygen arm and of 10 patients with circumflex lesions in the no-oxygen arm.  There were 11 excess single-vessel patients in the oxygen arm and 17 excess multi-vessel disease patients in the no-oxygen arm.

The answer?  Oxygen is probably bad.  There was no statistically significant difference in mean peak troponin values, favoring the no-oxygen having a p-value of 0.18.  The mean peak CK difference did, however, reach significance, with a p-value of 0.01.  In the 127 patients for whom follow-up MRI imaging was available, measures of infarct size all favored the no-oxygen group, with p-values ranging between 0.04 and 0.08.  However, clinical outcomes were all over the map.  The no-oxygen arm had higher in-hospital mortality, but the oxygen arm had higher rates of recurrent myocardial infarction.  Long-term, six-month outcomes were likewise similar, with trivial clinical differences.

So, oxygen application during routine pre-hospital transport for chest pain is certainly useless and wasteful – and most likely at least a little bit harmful.

“Air Versus Oxygen in ST-Segment Elevation Myocardial Infarction”
http://circ.ahajournals.org/content/early/2015/05/22/CIRCULATIONAHA.114.014494.abstract

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

More Discharges With HEART

Although, the observed improvements are probably more a result of their preposterously high initial admit rate.

The HEART score, already evangelized in multiple venues, is a tool for risk-stratifying chest pain patients in the Emergency Department.  Its advantage over other, competing scores such as GRACE and TIMI, is its specific derivation intended for use in the Emergency Department.  This trial, of note, is one of the first to do more than just observationally report on its effectiveness.  These authors randomized patients to the “HEART Pathway” or “usual care”.  The HEART Pathway was a local decision aid, combining the HEART score and 0- and 3-hour troponin measurements.  Patients with low-risk HEART scores (0 to 3) were further recommended to treating clinicians for discharge from the Emergency Department without additional testing.  The primary outcome was rate of objective cardiac testing, along with other secondary outcomes related to resource utilization.  Patients were also followed for 30-day MACE, with typical endpoints for cardiovascular follow-up.

With 141 patients each arm, the cohorts were generally well-balanced – specifically with regard to TIMI score >1 and accepted cardiovascular comorbidities.  Stunningly, 78% of the usual care cohort was hospitalized at the index visit.  Thus, the mere 60% hospitalized in the HEART pathway represented a massive improvement – and, such difference likely played a role in the 57% vs. 68% reduction in objective cardiac testing within 30 days.  17 patients suffered MACE, all at the index visit – and, even though the trial was not powered for safety outcomes, none occurred in the “low risk” patients of the HEART cohort.

The authors go on to state strict adherence to the HEART pathway could have eked out an additional 6% reduction in hospitalization.  Certainly, in a nearly 80% admit rate environment, scaling back to a 54% rate is an important reduction.  But, considering only 6% suffered an adjudicated MACE, there remains a vast gulf between the number hospitalized and the number helped.  Some non-MACE patients probably derived some benefit from their extended healthcare encounter as a result of better-tailored medical management, or detection of alternate diagnoses, but clearly, we can do better.

“The HEART Pathway Randomized Trial – Identifying Emergency Department Patients With Acute Chest Pain for Early Discharge”