Cardiology – Page 11 – Emergency Medicine Literature of Note

A Lovely Overview of Highly-Sensitive Troponin

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

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

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

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

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

Misleading Claims for Coronary CTA

The authors of this article make several discrete claims regarding the utility of coronary CT angiography – simply stated right in the title of the article: “Routine coronary computed tomographic angiography reduces unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the Emergency Department triage of chest pain”. And, essentially all the assertions made in this observational, retrospective review are suspect.

Reduces unnecessary hospital admissions:
The article in no fashion addresses “unnecessary” hospital admissions. After all, of their selected cohort of patients, a tiny fraction – 9 of 1,788 – ruled-in for acute MI. A total of 42 underwent revascularization, but this is a measure reflecting only the aggressiveness of their local cardiology groups. It would seem the real problem regarding “unnecessary” admissions is an inability to select patients with appropriate clinical probability for further evaluation.

Reduces length of stay:
There is a less than 1 hour reduction in length of stay only for discharged ED patients. A true accounting of the LOS and congestion of chest pain patients ought to include admitted patients who depart the ED for their hospital observation bed soon after their initial biomarker result – but that would probably make their overall result contrary to their chosen narrative. The reduction in length of stay is also influenced by the authors exclusion of patients who had ED LOS less than 3 hours – as the authors simply decide no adequate evaluation of low-risk chest pain patients could be performed in that timeframe.

Reduces recidivism rates:
The reduction in recidivism rates may have reached statistical significance, but the absolute difference was only 20 patients, most of whom were discharged from the Emergency Department.

Reduces invasive coronary angiography:
There is a reduction in coronary angiography – mostly, from what I can tell, in that the handful of patients with multi-vessel disease detected on CCTA were referred to CABG, and the use of invasive coronary angiography was obviated. The absolute difference was only 19 angiography episodes – an avoidance of a handful of $2000-$3000 procedures at the cost of nearly a thousand $700-$1200 CCTAs.

Finally, their abstract conclusion claims it reduces healthcare resource utilization:
The authors never explicitly define this endpoint – which is probably for the best, as I count 960 non-invasive and 8 invasive tests in their CCTA cohort versus 368 non-invasive and 27 invasive tests in their “standard evaluation” cohort. The admission rate, however, is more than halved from 40% to 14%. A reduction in resource utilization would be contrary to general consensus from trials of CCTA versus standard care.

Most disturbingly, this article reports “Disclosures: none”. However, a simple internet search reveals multiple authors having prior relationships with Siemens and GE Healthcare. Perhaps by some narrowest definition this isn’t untruthful, but it is certainly misleading.

“Routine coronary computed tomographic angiography reduces unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the Emergency Department triage of chest pain”
http://www.ncbi.nlm.nih.gov/pubmed/23684682

Here Comes Copeptin

Are you interested in making your AMI diagnostic evaluation even less specific? Good! Because Brahms Thermo Fisher et al want to sell you a rapid copeptin assay to help with that.

Copeptin is a stable, terminal portion of the arginine vasopressin peptide. This peptide is released from the pituitary in response to cardiovascular hemodynamic stress and has a theoretical role in the diagnosis of acute myocardial infarction. The advantage copeptin may have over conventional troponin assays is detectable release in circulation preceding troponin.

In 1971 patients collected through their multi-center trial, 156 were diagnosed with AMI (7.9%). Upon presentation to the Emergency Department, 40 were STEMI. 281 patients had cTnI greater than 40ng/L, 97 of whom were subsequently diagnosed with nSTEMI. 1646 had cTnI less than 40ng/L, 19 of whom eventually were diagnosed with nSTEMI – a miss rate of 1.1%. Pretty good – but, obviously, we practice in a zero-miss world. Adding copeptin to this troponin-negative population with a cut-off of 14pmol/L decreased the miss rate to 0.5%. The specificity, of course, was useless – only 10 of 493 patients with positive initial copeptin and negative inital troponin went on to receive a diagnosis of nSTEMI.

So, the question is – would a negative copeptin change your practice? Is there a clinically important difference between a 1 in 100 miss rate vs. a 1 in 200 miss rate? These authors think adding copeptin to troponin will allow you to discharge a patient after the inital biomarker result – but I think this minimal incremental improvement in diagnostic performance doesn’t change whatever pathway the patient was already on, nor add much to a discussion of shared decision-making with the patient. They also don’t address a performance advantage compared to high-sensitivity troponin assays (which have, of course, their own issues).

These authors are pretty high on copeptin – but, then again, many of them are employed by or sponsored by the manufacturers of the copeptin assay.

“Copeptin Helps in the Early Detection Of Patients with Acute Myocardial Infarction: the primary results of the CHOPIN Trial”
http://www.ncbi.nlm.nih.gov/pubmed/23643595

Questioning “Atypical Angina”

The prevailing notion has been that women present with symptoms of angina that are “atypical” from men – headaches, jaw pain, generalized malaise – rather than definitive anginal-type chest pain or pressure. These authors would like to suggest this global characterization is incorrect.

These authors enrolled a sample of 128 men and 109 women who underwent coronary angiogram following an abnormal stress test. Patients with obstructive coronary artery disease on their angiogram were surveyed regarding the symptoms that prompted them to seek care. Of this cohort, 89 men had obstructive disease compared with 50 women.

Overall, there was no significant statistical difference in the rate of most descriptors used by men or women. Surprisingly, women were statistically more likely to use “typical” terms such as “discomfort”, “crushing”, “pressing” and “aching” to describe their chest pain. Therefore, these authors conclude the clinical construct of “atypical angina” in women is incorrect.

I would tend to agree – excepting their study suffers from selection bias. If patients are only referred for testing due to suspected coronary artery disease, then the population with “atypical” symptoms might not be fully captured. That being said, it does look as though the female population in their study encompassed a number of patients who potentially were referred for atypical symptoms, considering the yield of their coronary angiography was much lower in women. It would have been interesting to compare the referral symptoms to the subset with demonstrated obstructive CAD.

“Reconstructing Angina: Cardiac Symptoms Are the Same in Women and Men”
www.ncbi.nlm.nih.gov/pubmed/23567974‎

Azithromycin & Cardiovascular Risk, Belabored

Last year, I noted a study concerning a report of excess deaths associated with azithromycin use. This study, a retrospective, observational cohort from Tennessee Medicaid data suggested a death rate double that of other antibiotics. This led to the FDA issuing a warning regarding azithromycin use.

I thought all this fuss was absurd – the data quality was one step above junk and the absolute magnitude of the proposed harms was trivial.

Now, we have the counterpoint – a retrospective, observational cohort from Denmark, using their national health system database to compare prescriptions for azithromycin to penicillin V over the last 13 years. In their cohort, there’s an obvious increase in risk of death from cardiovascular causes simply from being prescribed any antibiotics – but no difference between azithromycin and penicillin V. This seems to indicate either the systemic infectious process contributes to excess cardiovascular risk, or that respiratory symptoms are being misdiagnosed as infectious rather than cardiovascular. The absolute effect in their propensity matched cohorts is also tiny – a handful of patients or fewer spread across a million prescription events.

The accompanying opinion seems to attempt to justify the FDA review based on the wide confidence intervals in the Danish study – the OR for death from cardiovascular causes vs. penicillin V is 1.06 (0.54 – 2.10) and doesn’t statistically contradict the Tennessee study. However, yet again, I would point to the reason behind the wide confidence intervals – the nearly trivial absolute magnitude of the harms, which amount to fractions of a patient per 1000 patient-years.

Again, plenty of reasons to responsibly reduce azithromycin prescriptions – but this cardiovascular hullabaloo probably isn’t one of them.

“Use of Azithromycin and Death from Cardiovascular Causes”
http://www.nejm.org/doi/full/10.1056/NEJMoa1300799

Back For More With Cangrelor

Two negative studies weren’t enough to stop the Medicines Company from CHAMPION PHOENIX, the third attempt at demonstrating cangrelor is useful during PCI.

Cangrelor is a direct-acting platelet adenosine diphosphate inhibitor – same as prasugrel and clopidogrel – that differs in its half-life and route of administration. Rather than clopidogrel, which is a long-acting oral loading dose during STEMI, cangrelor is a continuous intravenous inhibitor that wears off after minutes. This has some theoretical advantages, such as when multiple lesions are found on invasive angiography and coronary bypass need not be delayed for the antiplatelet effects of clopidogrel to wear off.

So, PHOENIX follows up CHAMPION PCI and CHAMPION PLATFORM, each of which were negative for their primary combined endpoint of death, myocardial infarction, or ischemia-driven revascularization. In fact, these studies were stopped at their interim analysis for futility, as they were unlikely to show superiority given the planned enrollment.

So, why does PHOENIX succeed where others have failed? Well, they changed the primary endpoint to a new composite – death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis. And, PHOENIX shows a 0.8% vs 1.4% advantage to cangrelor for stent thrombosis – which accounts for most of the new advantage in primary outcome. In previous CHAMPION studies, stent thrombosis was 0.2% vs. 0.3% and 0.2% vs. 0.6%. So, truly, cangrelor succeeds here mostly because the clopidogrel group fares so much more poorly, rather than on its own merits. Considering 25.7% of the clopidogrel group received only 300mg rather than 600mg, and 36.6% received their clopidogrel during or after PCI, it’s no wonder they had greater stent thrombosis in this study.

It’s pretty clear the Medicines Company learned from its two negative studies and rigged the third one to succeed – and kept it just underpowered enough that severe or moderate bleeding with cangrelor didn’t reach statistical significance (0.6% vs. 0.3% p = 0.09). This reinforces a bias frequently seen in sponsored trials – failure at first begets further trials, while initial success doesn’t lead to confirmatory RCTs that might cast doubts upon the authenticity of the golden goose.

“Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events”
www.ncbi.nlm.nih.gov/pubmed/23473369

The Sad Reality of Chest Pain Observations

Chest pain observation units run by the Emergency Department are fairly popular – and it’s easy to see why. It eliminates the need to fight a hospitalist for admission, allows for complete coverage of medicolegal liability, captures another set of billing codes for ED revenue, and keeps the cardiologists happy with a steady stream of interpretation and consultation revenue.

Duke University has one of these such chest pain observation units, and this study is a retrospective evaluation of the subgroup of patients aged less than 40 years. Of the 2,231 patients observed for suspected acute coronary syndrome, 362 met eligibility based on age. Of these 362 patients, median age 36, 238 underwent stress testing and the remainder underwent serial enzymes.

From this cohort, there was a single true positive – defined as a patient who underwent a coronary angiogram with an intervention performed.

There were, however, 14 false positives – indeterminate or positive stress tests and one set of positive biomarkers, leading to five negative invasive coronary angiograms.

The authors sum it up quite nicely: “The extremely risk- adverse physician cannot totally exclude the possibility of ACS based on age, but it seems that routine observation for such patients may cause the potential for as much harm as good.”

“Utility of Observation Units For Young Emergency Department Chest Pain Patients”
www.ncbi.nlm.nih.gov/pubmed/22975283

You Can Trust a Cardiologist

Or, at least, their integrity in conduct of research is unimpeachable.

Adding to the conflict of interest debate, this study from the American College of Cardiology evaluated all studies regarding “cardiovascular disease” published in the New England Journal of Medicine, Lancet, and JAMA over an eight year period. Studies were discarded if no conflict of interest information was explicitly provided, and, eventually, 550 articles were selected for analysis.

The bad news: conflict of interest was “ubiquitous”, in the authors’ own words. The good news: it didn’t seem to affect positivity/negativity of the results. In fact, the authors couldn’t identify any specific funding or COI factor associated with a preponderance of positive published trial results.

It’s a little odd these authors evaluated solely cardiovascular trials. And, yes, these journals have the greatest impact factor – but there are plenty of trials published in a variety of other relatively prominent cardiovascular journals that might have been interesting to include. The external validity of their study is limited by their methodology.

But, at least, for this narrowest of narrow slices, positive and negative trials abounded. Quite unexpected, to say the least.

“Authors’ Self-Declared Financial Conflicts of Interest Do Not Impact the Results of Major Cardiovascular Trials”
www.ncbi.nlm.nih.gov/pubmed/23395075

Pooled CCTA Outcomes

The state of the art for coronary CT angiograms progressed a great deal in the past year. Four recent studies, CT-STAT, ACRIN-PA, ROMICAT II, and a fourth by Goldstein et al., have added to our knowledge base regarding the performance characteristics of this test.

Overall, by pooling 3,266 patients from these four trials, a couple new features shake out as statistically significant. Specifically, patients undergoing CCTA were significantly more likely (6.3% vs 8.4%) to undergo ICA, and then more likely to receive revascularization (2.6% vs. 4.6%). This adds to what we already knew – CCTA shortens ED length of stay and reduces overall ED costs compared with “usual care”.

But, we still don’t really know if this test is improving important patient-oriented outcomes. These intervention numbers are quite low – meaning a great number of patients simply received expensive diagnostic testing, without any sort of treatment. Then, we don’t even know if these revascularizations are improving (or worsening!) outcomes. Technology keeps blundering forward with its flawed disconnect from rationality – the costs go up and up, but we don’t hardly stop to measure whether we’re actually doing any good….

“Outcomes After Coronary Computed Tomography Angiography in the Emergency Department”
content.onlinejacc.org/article.aspx?articleID=1569168

The Future of Heart Failure Admissions

At least, this is how Cardiologists think the Emergency Department should be handling heart failure in The Future.

Specifically, Cardiologists would like us to stop admitting patients with acute exacerbations of established heart failure – and, interestingly, they’re a bit apprehensive about discharging them. Their earth-shaking, practice-modifying innovation is this: observation unit management.

This strategy is founded partly out of interest of the patient’s well-being, but mostly out of interest for the hospital’s financial well-being. In general, heart failure remains one of the most difficult hospital readmissions to prevent. This is important because, suddenly, readmissions within 30 days are no longer reimbursed by CMS. Now, rather than, re-admit patients for free, they’ve decided the New Fabulous Idea is to place them in outpatient observation status – which is a lower level of reimbursement, but still better than nothing. In addition to the other obviously indicated admissions, they also feel some of the gray area discharges would probably benefit from observation, appropriately noting heart failure patients discharged from the ED are at high risk of having subsequent worsening due to a variety of contributing factors.

Overall, as far as actual patient care, there’s probably little difference – somewhat cynically, the entire strategy seems mostly to be an advisory on how to minimize the impact of reimbursement losses from readmissions.

“Is Hospital Admission for Heart Failure Really Necessary? The Role of the Emergency Department and Observation Unit in Preventing Hospitalization and Rehospitalization”
www.ncbi.nlm.nih.gov/pubmed/23273288

And, just as a rather inspirational aside, this is one of the longest disclosures list I have ever seen for an author:
“Dr. Gheorgiade has received support from Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd., CorThera, Cytokinetics, CytoPherx, Inc., DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Inc, John- son & Johnson, Medtronic, Merck & Co., Inc., Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, sanofi-aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics; and has received significant (>$10,000) support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, and Takeda Pharmaceuticals North America, Inc.”