Category: Cardiology

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

Nitrate Use in Aortic Stenosis Nonsense

This is another instance in which the “Editor’s Capsule Summary” and my interpretation diverge significantly:

“This study provides some support that nitrates do not cause relevant hypotension and may be judiciously used in patients with aortic stenosis and pulmonary edema.”

Rather, as was the consensus last night at OHSU’s journal club, these data provide essentially no support.

These authors provide a retrospective regarding the incidence of “clinically relevant hypotension”, identifying three groups of patients presenting with acute pulmonary edema – severe, moderate, and no aortic stenosis.  There were 65 patients in each cohort, and all patients received nitrates in either sublingual or intravenous form.  Regarding their primary composite outcome, there was no difference between arms.  Thus, the dogmantic avoidance of nitrates in aortic stenosis is challenged.

I am quite enthusiastic, as is Newman’s editorial, regarding the refutation of dogmatic (and erroneous) medical practice – he cites the example of the “dangers” of ketamine following head injury.  However, these retrospective data are not of appropriately high quality to inform practice in the absence of stronger prospective or randomized, controlled trial data.

The retrospective selection of patients only with prior discharges from the enrolling hospitals, as well as the inclusion of multiple presentations of some patients, likely amplifies selection bias with the effect of overstating the apparent safety of the intervention.  The study is powered to 80% to detect a 20% absolute difference between arms, which certainly exceeds the clinically relevant safety margin when comparing outcomes between cohorts.  The primary composite outcome for “clinically relevant hypotension” was mostly comprised of outcomes for which nitroglycerin needed to be terminated.  Termination of potentially helpful therapy is not a patient-oriented outcome or even a physiologic surrogate for one.  Sustained hypotension for >30 minutes is a better physiologic outcome for judging potential adverse effects of nitrate use, and, finally, intubation or mortality are better clinical outcomes.  The severe AS cohort had much higher incidence of these more serious outcomes, as opposed to the primary outcome in this study.  Finally, as a catastrophic oversight, these authors fail to provide any sort of control group – there’s no way to compare these patients’ outcomes to any similar cohorts managed without nitrates.

If you place this study in context with Ioannidis’ “Why Most Published Research Findings Are False” it is easy to see, rigorously, why these data should have little impact.  This study is underpowered, replete with bias, and the pre-study odds – for what “tradition” is worth – speak against the safety of nitrates in aortic stenosis.  Now, importantly, I am not saying you should not use nitrates in aortic stenosis – only, rather, doing so requires acknowledging the profoundly limited clinical evidence guiding such a strategy.

“Complications Associated With Nitrate Use in Patients Presenting With Acute Pulmonary Edema and Concomitant Moderate or Severe Aortic Stenosis”
http://www.ncbi.nlm.nih.gov/pubmed/26002298

Thanks to Ran Ran, Ben Sun, Kavita Gandhi and the other OHSU residents for their excellent contributions to the discussion!

The Unintended Harms of “Quality”

Harder!  Better!  Faster!  Stronger!  There is a proliferation of time-based measures in the Emergency Department – the glut of which funds a horde of administrative overhead, and for which the Center for Medicare and Medicaid Services will audit.  These measures must frequently seem relatively benign and commonsense when conceived – but their implementation is anything but.

This is a retrospective quality evaluation from the Christiana Health System, looking at their door-to-balloon time metric for STEMI.  Faster is better – of course – so, in 2009, an aggressive quality improvement intervention was performed to decrease delays and obstacles to cardiac catheterization.  As described in the article, this mostly seemed to consist of exhorting each step the process to be performed more rapidly, and providing additional feedback during the QI initiative.

And, it worked!  Median door-to-ballon time sank from 76 minutes to 61 minutes by 2010.

Unfortunately, this came at a cost: false-positive activations more than doubled.  Furthermore, the mortality rate of false-positive activations jumped from 5.6% to 21.6%.  The fatal alternative diagnoses included massive PE, intracranial hemorrhage, severe sepsis, and aortic dissection.

The authors go on further to describe a follow-up QI intervention of education and feedback regarding the missed diagnoses, and, over time, the mortality rate has improved.  However, false positives persist around 20% of activations – triple the original rate.

So, they’ve saved 15 minutes of door-to-balloon time – a probably clinically insignificant amount – at the cost of scads new false-positives and at least one substantial bump in mortality.  And, you know this is but _one_ of many time-based metrics invading – and harming patients in – the Emergency Department.

Will the madness ever stop?

“Aggressive Measures to Decrease “Door to Balloon” Time and Incidence of Unnecessary Cardiac Catheterization: Potential Risks and Role of Quality Improvement”
http://www.ncbi.nlm.nih.gov/pubmed/26549506

The Macrolide Scourge, Updated

We’ve had a couple prior alerts regarding the potential cardiovascular risks of macrolides.  These have been taken with quite the grain of salt, particularly considering macrolides were, at one point, prescribed in a trial thought to be cardioprotective.

This meta-analysis is probably the most reasonable data to date on the subject.  These authors (of which there are 17) gather 33 studies comprising 20,779,963 participants.  These studies show, reasonably consistently, small increases in ventricular arrhythmias and sudden cardiac death.  The relative risks reported are 2.52 for VT and 1.31 for SCD, and there was not much reliable variation between different macrolide antibiotics.
However, these relative risks translate into just a handful of additional cases per million prescriptions.  The number needed to harm with cardiovascular death is about 25,000.  On the flip side, across the included studies, the all-cause mortality was unchanged.  So, yes, perhaps macrolides are not entirely benign – but neither is the underlying condition for which they are prescribed.
Overall, this study doesn’t add much to our insight into appropriate macrolide usage.  There may be particular subgroups for whom they may be best avoided, but, the alternative agent must be equally effective against the existing pathology – and not have its own particular undesired interaction.

Of course, if macrolides are used in context where their benefit is minimal or zero – then there is only harm.

“The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk”

What Did We Find On Stress Testing?

The so-called “provocative” testing advocated by the American Heart Association for every patient with chest pain of possible ischemic origin has been the thistle in our salad for many years.  They are the nidus for the crystallization of countless chest-pain observation units in our Emergency Departments.

And, they are one of lowest-yield venues in medicine.

Last year, I reported on a set of 1,754 biomarker-negative patients undergoing stress testing in Rhode Island, only 20 of which were true positives.  This latest report follows-up the stress testing outcomes from the ASPECT and ADAPT cohorts in New Zealand.  Of the 1,483 patients enrolled with negative biomarkers, 749 ultimately underwent exercise tolerance testing – 32 of which were positive, 22 of such had stenosis of greater than 70%.  Including index admission and 1-year follow-up of the study cohort, 20 of these received some form of revascularization (PCI or CABG).  In addition, there were 66 equivocal and 103 submaximal stress tests contributing to a total of 70 episodes of invasive coronary angiography, 32 of which identified stenosis >70%.

This is slightly higher yield, overall, than the previously reported U.S. cohort.  Most likely, this is due to patients in this study being almost a decade older – almost 60 years on average – and having median TIMI score of 2, compared with the U.S. stress test population having a TIMI of 0.  But, clearly, a cohort referred for stress testing resulting in only a 4.8% initial revascularization, including just 36 of 93 referred for coronary angiography, is not an effective use of healthcare resources.  And, this presumes the interventions performed as a result of stress testing provide some incremental morbidity or mortality benefit.

There are certainly patients for whom the various types of stress testing, non-invasive coronary angiography, and invasive angiography are each appropriate – but clearly we need to dramatically improve the specificity of our selection criteria.

“The incremental value of stress testing in patients with acute chest pain beyond serial cardiac troponin testing”

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

Valsalva 2.0

The Valsalva maneuver’s effectiveness for supraventricular tachycardia is, essentially, the reason adenosine exists.  With rates of non-pharmacologic cardioversion merely 5-20%, it’s not absent of value, but hardly reliable.

So, I appreciate these authors innovation in trialling a new, improved Valsalva maneuver.  The comparator in this study was the “traditional” maneuver, as applied via a forced exhalation of 40 mmHg for 15 seconds.  The “modified” maneuver was the same exhalation, but followed by immediately laying the patient supine and having a passive leg raise performed.

With 214 patients analyzed in the intention-to-treat population in a multi-center randomized trial, the success rate was, essentially: 43% vs. 17% in sinus rhythm one minute after Valsalva.  This boiled down to only 57% of patients in the modified Valsalva group ultimately requiring any pharmacologic therapy, compared with 80% of the traditional method.

I don’t see any particular reason to suspect the modified version would be more harmful than the otherwise safe traditional method, so there shouldn’t be any reason to avoid teaching and using this new alternative.  This may also be of more use to patients at home in preventing an Emergency Department visit in the first instance.

“Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61485-4/abstract (oa)

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