Category: Cardiology

Should Men and Women Use Different Troponin Cut-Offs?

Much ado is made regarding potential differences in symptoms between men and women presenting with acute coronary symptoms.  Little is mentioned, however, about potential differences in laboratory thresholds between the sexes.  Considering women, on average, have decreased myocardial mass than men, any ischemic insult simply damages a smaller absolute quantity of myocardium.  Less damaged tissue, then, ought to lead to lower circulating biomarkers.

Why haven’t we tried this before?  Because the limit of detection of conventional troponin assays are above the clinically important thresholds for delineating such small quantities of circulating molecules.  However, with the advent of highly-sensitive troponins with reasonable precision below  the conventional troponin cut-off of 50 ng/L, it’s now a reasonable concept for investigation.

These authors conducted a yearlong prospective evaluation of all patients with suspected acute coronary syndrome, collecting conventional and highly-sensitive troponins on each.  Treating clinicians and initial adjudication of myocardial infarction were blinded to the results of the hsTnI.  Following conclusion of the study, records and unmasked hsTnI values were provided for independent adjudication and diagnosis changes accordingly.

Initially, 19% of men were diagnosed with Type 1 MI based on conventional troponin testing.  After using a gender-specific cut-off for men of 34 ng/L, only a handful of additional cases were re-classified – rising to 21%.  For women, 11% were initially diagnosed with Type 1 MI.  Using a gender-specific cut-off for hsTnI of 16 ng/L, however, doubled the diagnosis cohort to 22%.

Of course, simply lowering the threshold for any assay increases the rate of diagnosis.  In order to answer the question of whether the re-classified cases were clinically appropriate, all patients were also followed for survival free from death or MI.  While women not diagnosed with MI at initial presentation did well throughout the follow-up period, the women reclassified as MI using the hsTnI threshold suffered the same dismal outcomes as those initially diagnosed with MI.

I like this concept, and this is promising preliminary data.  It remains to be seen whether treatment, including increased treatment intensity for women, based on the gender-specific cut-offs changes clinical outcomes – or whether splitting these little nanograms worth of hairs is just overdiagnosis.  The good news: a clinical trial is ongoing.  I look forward to their results.

“High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study”
http://www.bmj.com/content/350/bmj.g7873 (free fulltext)

One Troponin is All You Need

The newer, highly-sensitive troponin assays have their pitfalls.  Specifically, specificity.  However, most of the issues associated with diminished specificity are iatrogenic – transitioning from use of troponin as a dichotomous test that used to tell us “yes” to one that does a better job of telling us “no”.

This is a pre-planned substudy as part of a prospective evaluation of patients with chest pain and non-diagnostic ECG, prospectively evaluated for acute coronary syndrome.  These authors looked at hsTnI, but, rather than using the 99th percentile as their cut-off for “negative”, they evaluate the utility of an undetectable hsTnI – which, for this Siemens assay, was <0.006 µg/L.  Based on 1,076 patients evaluated, 647 had an undetectable troponin at initial presentation.  Of these, 4 patients had a subsequently detectable troponin and were adjudicated as acute MI, 3 of which had coronary artery disease and received revascularization.

What was special about those four patients?  Each of them presented within 2 hours of symptom onset.  All told, 399 patients presented more than 2 hours after the onset of symptoms, had an undetectable troponin, and were free of MACE at 7 and 30 days.  These results are generally consistent with other work looking at the sensitivity of the (duh) highly-sensitive troponin assays – capable of conferring an excellent instant rule-out.

So, if you’re asking the question – does this patient have an acute MI? – you’re in good shape.  However, if you’re using highly-sensitive troponin assays, you’ll also need to be smart about appropriately interpreting the indeterminate range – or your patients will ultimately suffer as a result of decreased specificity and downstream over-testing.  Lastly, this is only valid as a diagnostic tool for acute MI – the extent to which it provides prognostic or diagnostic information regarding acute coronary syndromes, coronary artery disease, or ischemic heart disease is still being refined.

“Does undetectable troponin I at presentation using a contemporary sensitive assay rule out myocardial infarction? A cohort study”
http://www.ncbi.nlm.nih.gov/pubmed/25552547

FFR(CT) Is Back! And Better Than Ever!

Invasive coronary angiography is problematic – specifically, it’s invasive.  Radial artery approaches have reduced the incidence of bleeding complications, but it remains a costly and non-risk-free procedure.  In lieu of ICA, CT coronary angiography has become increasingly popular.  However, CCTA is problematic – specifically, it’s inaccurate.

A few years ago, DeFACTO was published in JAMA and covered on this blog, a study evaluating a non-invasive model of fractional flow reserve added on to CCTA in an attempt to improve accuracy at identifying true culprit lesions.  DeFACTO was negative – specifically, the per-vessel performance at predicting flow-limiting lesions compared to the traditional 50% stenosis cut-off of CCTA was nearly identical.

Two years have passed, however, and we have a new study – NXT – using the next iteration of the HeartFlow software, and, of course, performed by authors with robust conflicts-of-interest.  Now, improvements in image quality and luminal modeling – as well as refined exclusion criteria to prevent troublesome images confounding their software – have improved performance to the point where, yes, it now seems to out-perform baseline CCTA.

The catch, of course, is the CCTA criterion standard is abysmal.  Compared with the ACRIN-PA or ROMICAT studies with their pro-CCTA COI, in which CCTA is the best thing since sliced bread, these folks are unconcerned with the collateral damage of degrading CCTA.  In this study, as performed on patients with suspected CAD, of 237 vessels read as “positive” by CCTA (>50% stenosis), only 83 (35.0%) were actually judged to be flow-limiting lesions on ICA – which is to say, false positives doubled the true positives.  Likewise – in contrast to the ROMICAT and ACRIN studies purveying CCTA as a bulletproof mechanism for discharge – 17 of 247 (6.8%) patients read as negative by CCTA (<50% stenosis) actually had flow-limiting disease.

False positives more two-thirds of the time?  And then a 7% miss rate of clinically important stenosis?  Basic, anatomic CCTA as previously described – not as fantastic as you’ve been led to believe.

The HeartFlow software?  Perhaps.  Effectiveness evaluations absent pervasive COI will be necessary to truly describe its value.

“Diagnostic Performance of Noninvasive Fractional Flow Reserve Derived From Coronary Computed Tomography Angiography in Suspected Coronary Artery Disease”
http://www.ncbi.nlm.nih.gov/pubmed/24486266

A Thicket of Coronary Disease Prognostications

This recent article out of JAMA garnered headlines primarily for the insight into the risk of non-obstructive coronary artery disease – headlines such as: “Risk of Heart Attack Jumps with Non-Obstructive Heart Disease” or “Increased Risk Found For People With Even ‘Minor’ Narrowing of Heart Arteries”.

Somehow, this is profound – that individuals with measurable atherosclerotic plaque are at greater danger of suffering an acute coronary syndrome than those without.  And, frankly, despite this “significantly increased risk”, the most interesting insights – from an Emergency Medicine standpoint – are tied to how low the risks of MI were, overall.

This is a Veterans Affairs database of coronary angiography findings observed on “elective” cardiac catheterization – meaning the indication for coronary angiography in all cases was not associated with an acute coronary syndrome.  Most cases were referred primarily for chest pain, with a minority for a positive functional study.  Catheterization findings were classified as non-obstructive, 20-70% stenoses, or >70%/>50% left main stenoses, subdivided into single, double, or triple vessel disease.  Center for Medicare Services data was queried to determine 1-year outcomes, specifically myocardial infarction or death from any cause.

As expected from a VA study, the cohort is mostly male and aged between 50 and 70 years.  Nearly all had a history of hypertension and hyperlipidemia, while smoking, diabetes, and obesity were well-represented.  In short, exactly the folks you’d expect to refer for catheterization in the setting of chest pain – the sort of individual every Emergency Physician would consider “high risk”.

But the catheterization only revealed obstructive coronary artery disease in about half of these patients.  And, among those, only a little more than half received an intervention associated with angiography – either PCI or CABG.  The remainder were amenable only to medical intervention.  But, even in this cohort with pervasive vascular disease, the 1-year rate of MI was only between 1.18% and 2.47%, depending on the number of vessels involved.  Then, if non-obstructive disease was found, the 1-year rate of MI falls to 0.24% to 0.59%.  And, those without CAD had a 0.11% incidence of MI within a year.

My takeaway from all this?  As a whole, even this highest-risk cohort has a combined ~1% risk of MI within a year – meaning one could theoretically discharge nearly every chest pain patient from the Emergency Department if proper short-term follow-up were in place, and the number of adverse outcomes would be a tiny fraction of a percent.  [Add:  Stephen Smith takes issue with the generalizability of this elective catheterization cohort to our Emergency Department population, and suspects we have a much higher prevalence of unstable plaques – and potential for a greater number of adverse events.]

What’s unfortunate in the data presented, however, are few obvious differences between those who had severe – even 3-vessel disease – and those who had no disease whatsoever.  In aggregate, even though the differences met statistical significance, the absolute differences were small.  Indications were similar between groups, comorbid disease was similar between groups, and, perhaps, those with more advanced disease were slightly older.  Perhaps some type of matching algorithm could be used to generate more precise, individualized estimates for individual patients, but such is just speculation.

“Nonobstructive Coronary Artery Disease and Risk of Myocardial Infarction”
http://jama.jamanetwork.com/article.aspx?articleid=1920971

More CT Coronary Angiography Dreaming

CT coronary angiography has been touted as a lovely test for the acute setting – a relatively fast, non-invasive method of obtaining information on the coronary vasculature with reasonable-sounding diagnostic characteristics.  However – despite what these authors seem to be trying to convey – it’s simply a test, not a protective intervention.

This is a prospective longitudinal cohort study of 585 individuals at a single institution undergoing CT coronary angiography for suspected ischemic chest pain.  Patients with negative troponins were enrolled during weekday, daytime hours, had TIMI 0-4 (mostly 0-2), and absent the usual contraindications to CTCA.  Patients were followed for nearly two years – and, of 506 patients with zero or insubstantial plaque seen on CTCA, all were still alive, and none had suffered an acute coronary syndrome.  Thus, the fantastic protective effect of a negative CTCA.

The only issue – all those patients would have achieved such event-free survival whether they underwent CTCA or not.

Of the 79 admitted for invasive angiography with severe stenosis, only 34 received PCI or CABG, and 10 were found to have less than 40% stenosis.  So – ultimately – 585 CTCAs to identify the 6% of patients who may potentially have benefited, harming just as many with invasive procedures and the remainder with radiation.  There is a reasonable, ultimate question regarding whether those with negative evaluations are obviated from additional chest pain work-up over the long run – but that has yet to be demonstrated in practice, and the costs associated with the initial false positives subtract from those future potential savings.

Rather than demonstrate the utility of CTCA in the Emergency Department, these authors better demonstrate the unfortunate characteristics of its overuse.

“Long-term Outcome after CT angiography in Patients with Possible acute coronary syndrome”
http://www.ncbi.nlm.nih.gov/pubmed/24738614

Does Cardiac Catheterization Help After OHCA?

Yes!

Probably.

It sure seems like it.

But, we still don’t really know for whom.

We’ve reviewed several of the prospective and retrospective studies regarding post-arrest cardiac catheterization on this blog over the years.  The general conclusion – the authors are very enthusiastic about their outcomes, but their comparison groups are invalidated by selection bias.  So, unsurprisingly, when a systematic review and meta-analysis of these studies is performed – the same critiques hold.

This review identifies 50 studies with sufficient reporting and design for analysis.  27 of these studies describe use in STEMI complicated by OHCA – and outcomes are largely excellent, compared to typical OHCA survival.  Good neurologic survival, in the 18 studies reporting such, averaged 68.4%.  There’s not much debate regarding STEMI complicated by OHCA – cardiac catheterization, when available.

The problem, however, arises when evaluating patients with OHCA and no clear cause for arrest.  There were 15 studies comparing outcomes with and without cardiac catheterization – and, overall, good neurologic outcome was present in 58% versus 35.8%, with and without cardiac catheterization, respectively.  However, 11 of these 15 studies were retrospective, and patients undergoing conservative management tended to have poorer prognosis at baseline and those who underwent cardiac catheterization tended to have more prominent ischemic changes on post-arrest ECG.

So, it’s another garbage-in, garbage-out sort of meta-analysis and review.  It cannot be used to support universal expansion of the target population for cardiac catheterization after OHCA, and tells us, essentially, what we already knew.  Clearly, some patients – particularly those for whom a culprit lesion is identified – benefit.  For the remainder, the treatment population remains unclear, particularly in the face of the extraordinary resource utilization.

“Cardiac catheterization is associated with superior outcomes for survivors of out of hospital cardiac arrest: Review and meta-analysis”

EM Physicians Can Accurately Measure Systolic Function… Well Not Really

A guest post by Dr. Andrew Kirkpatrick (@AskEMdoc), an Emergency Medicine resident at the University of Texas Medical School at Houston.

With all of the recent advancement in the field of Emergency Department (ED) ultrasound, you may be tempted to think Emergency Physicians are masters of the bedside cardiac ultrasound and the assessment of systolic heart failure.  Despite the misleading title, the results of this article would suggest that is not the case.   
This is a prospective observational study to determine if E-point Septal Separation (EPSS) measurements made by emergency physicians correlated with calculated Left Ventricular Ejection Fraction (LVEF) measured by cardiologist using comprehensive Trans-Thoracic Echocardiography (TTE). Cardiac ultrasound and TTE were performed on 80 patients between the ages of 22 and 100 years old, of which 71 were included in the final analysis.  The study took place in the academic setting of Denver Health, conducted by 3 ultrasound fellows who had done at least 100 ultrasound scans.  They were given a 10 minute didactic presentation and supervised doing 3 EPSS measurements before they were set loose in the hospital to find patients who had undergone TTE in the last 24 hours. 
Based on their results, the authors conclude that  an EPSS of greater than 7mm is ideal for diagnosing severely reduced LVEF (<30%), with a sensitivity of 100% and a specificity of 51%.  This suggests EPSS is only useful in ruling out severe systolic heart failure – as values over 7mm were poor predictors of actual LVEF.  This inability to provide predictive information is well demonstrated by Figure 2, in which there are 3 patients with EPSS clearly in the range associated with severe systolic dysfunction- 20-22mm – and 2 of these 3 had normal ejection fraction on formal echocardiography.  Put another way, only 31 of the 63 patents with EPSS >7mm had moderate heart failure, calling into question the author’s suggestion the EPSS is a tool to accurately assess for LVEF.  In addition to the previous findings, the authors find that an EPSS of >8mm is a poor predictor of any systolic dysfunction with a sensitivity and specificity of 83.3% and 50.0%, respectively.  The authors also assessed the ability of emergency physicians to visually estimate ejection fraction, and found generally poor correlation with echocardiography and only fair interobserver reliability. 
There are several problems with this paper.  The sample size was small, and generalizability to Emergency Department patients may be limited because a majority of the population studied was inpatient.  More importantly, three ED ultrasound fellows performed all of the EPSS measurements.  These physicians having a special interest in ultrasound are likely more adept at wielding an ultrasound than the average emergency physician.  At best, this article makes a weak case for the clinical relevance of EPSS.  And, ultimately, subtle systolic dysfunction that may or may not be picked up by using a cutoff EPSS of >8 may not be as important as the ejection fraction that is so low it can be seen on the ultrasound screen from across the room. 
“E-point septal separation: a bedside tool for emergency physician assessment of left ventricular ejection fraction”

The 2014 AHA NSTE-ACS Guidelines

One of the best things about Emergency Medicine is the preponderance of guidelines imposed upon our management of patients by non-Emergency Medicine clinicians.  One of the most glorious offenders is the American Heart Association, dictating our care of Stroke and Acute Coronary Syndrome.

But, actually, this most recent update – despite the continued absence of Emergency Medicine from the Writing Committee – contains some interesting subtle shifts.  Out of its 150-odd pages of content and evidence, most of the Emergency Medicine-relevant content is in Section 3: Initial Evaluation and Management.  Many of the guidelines are not controversial – send patients with suspected ACS to the Emergency Department, give aspirin, obtain an ECG, etc.

But, as a Class I recommendation, they note patients with suspected ACS can be risk-stratified based on likelihood of ACS to decide on the need for hospitalization.  They also now include an expanded discussion of tools beyond the old stalwarts TIMI and GRACE, incorporating ED-centric tools such as the Vancouver Rule, the HEART score, and the HEARTS3 score.  This greatly expands guideline-based backing of these rules for shared decision-making with patients, and, frankly, makes the previously “mandatory” observation of patients with chest pain less so.

The next interesting bit relevant to the ED lay in subsection 3.4.1 – the use of biomarkers.  I’ll just reproduce my favorite bit here:

Class III: No Benefit
1. With contemporary troponin assays, creatine kinase myocardial isoenzyme (CK-MB) and myoglobin are not useful for diagnosis of ACS (158-164). (Level of Evidence: A)

The guidelines also imply, if symptom onset can be reliably determined, a single troponin measurement is reasonable 6+ hours after onset, or, for shorter onset timeframes, a troponin on arrival and a second as few as 3 hours after onset is reasonable to detect rising or falling levels.  And, beautifully, in subsection 3.5.1, all recommendations regarding discharge from the ED are Class IIa, only make weak recommendations for the reasonableness of observation, and acknowledge most patients with chest pain do not have ACS, and most are not at risk of ACS.

There is ample further fodder for the interested reader to pick apart recommendations and conflicts of interest – particularly with regards to the incorporation of newer antiplatelet agents – but, I’m generally pleased with the general direction of this guideline, as it applies to our practice.  However, this does not preclude the need for ACEP to develop its own Clinical Policy, to further guide and protect both patients and Emergency Physicians.

“2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines”
http://circ.ahajournals.org/content/early/2014/09/22/CIR.0000000000000134.full.pdf+html

Emergency PCI for STEMI is Dead?

This somewhat befuddling study tries desperately to create a problem where there probably truly wasn’t – but as soon as the conflict-of-interest disclosures come up, it’s clear why.

This is the 1-year outcomes from STREAM, a prospective, open-label, parallel-group trial enrolling participants with acute STEMI, but unlikely to undergo primary PCI within 1 hour of diagnosis.  Participants were then randomized to either still undergo emergency PCI, or to fibrinolysis followed by urgent or emergency rescue PCI.  The initial 1-month composite outcome, despite an excess of deaths secondary to intracranial hemorrhage in the fibrinolysis group, did not demonstrate any disadvantage to fibrinolysis with delayed PCI.  There was actually a 2% absolute decrease in the composite outcome favoring fibrinolysis – and thus the 1-year follow-up, hoping this small advantage in morbidity would translate into a measurable mortality advantage.

This was, however, not the case – as cardiac mortality was 4.0% with fibrinolysis vs. 4.1% with PCI.  Adding in the ICH and other non-cardiac deaths, the all-cause mortality rose to 6.7% with fibrinolysis vs. 5.9% with PCI.  Baseline characteristics probably favored the fibrinolysis group, so there’s actually a reasonable chance the mortality disadvantage owed to the fibrinolysis strategy might indeed be durable if properly powered and balanced.

Ostensibly, the authors claim to be addressing a problem of resource scarcity.  Using their fibrinolysis strategy, they seem to suggest, allows elimination of the expensive healthcare delivery models predicated on timely PCI.  However, a full 36% of patients failed to re-establish flow and still required emergency rescue angiography.  Then, all remaining patients still underwent urgent angiography, with greater than 95% receiving a stent.  So, in essence, the trade-off for increased flexibility in the timing of angiography is the added expenditure of tenecteplase – and possibly an increase in long-term mortality.

Certainly, there are many remote or resource austere settings where revascularization by thrombolysis is appropriate.  However, Boehringer Ingelheim and their sponsored collaborators have produced this scientific work simply in a transparent attempt at promoting an expansion of the pharamacoinvasive group (read: sell more tenecteplase) – and, frankly, failing.

“STEMI Patients Randomized to a Pharmaco-Invasive Strategy or Primary PCI: The STREAM 1-Year Mortality Follow-Up”
http://www.ncbi.nlm.nih.gov/pubmed/25161043

Early P2Y12 Antagonists Just Don’t Seem Useful

When undergoing an early invasive strategy for myocardial infarction, the guidelines and trials typically support dual platelet inhibition.  Most commonly, this regimen consists of aspirin and clopidogrel.  However, the P2Y12 receptor antagonists ticagrelor and prasugrel have been promoted as options due to incremental increased platelet inhibition over clopidogrel.  The theoretical benefits of early dual platelet inhibition include spontaneous lysis and prevention of re-thrombosis, as well as decreased early in-stent thrombosis.  Unfortunately, the ACCOAST trial demonstrated early prasugrel was associated only with increased bleeding and no associated cardiovascular endpoint benefits.

Now we have ATLANTIC, with a similar treatment strategy, utilizing ticagrelor.

Which is also negative.

Negative for the “co-primary” endpoints of ST-segment resolution or pre-PCI TIMI flow grade, at least.  The authors, however, focus on two other endpoints: bleeding, and in-stent thrombosis.  These authors note, contrary to ACCOAST, there was no detectable difference in bleeding between the pre-hospital and in-hospital groups.  They also note, as expected but not witnessed in ACCOAST, there was a reduction in short-term “definite” in-stent thrombosis.  Therefore, the authors – by which I mean AstraZeneca and their ghostwriters – clearly present this secondary outcome (Figure 2) and conclude pre-hospital ticagrelor is safe.

Interestingly, there was a 1% absolute difference favoring pre-hospital ticagrelor in “definite” in-stent thrombosis at 30 days – but a 0.2% absolute difference favoring in-hospital ticagrelor in “definite or probable” in-stent thrombosis.  For their definition, “probable” in-stent thrombosis included any death at 30 days for a patient receiving a stent.  I’m not sure the expanded definition accurately reflects underlying stent thrombosis, but it is a fair combined endpoint to report for completeness.

There are a few differences between this trial and ACCOAST, however.  In ACCOAST, patients were diagnosed with NSTEMI based on elevated troponin levels, and all were scheduled for coronary angiography 2 to 48 hours later.  In ATLANTIC, patients were diagnosed prehospital with STEMI – and required to undergo PCI within 120 minutes.  This reduced time of exposure to multiple anticoagulants may explain discrepancy in bleeding events between the trials.  The in-stent thrombosis rate was also much higher in the peri-PCI antiplatelet group in ATLANTIC compared with ACCOAST, leading to the possibility of detecting a difference in in-stent thrombosis.

Details aside, however – it’s simply not clear there’s any advantage to utilizing these agents outside the peri-PCI environment.  Regardless, I expect we will see more resources devoted to similar trials in slightly different populations, attempting to ferret out some subgroup and primary outcome definition capable of demonstrating a statistically significant benefit.

“Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction”
http://www.nejm.org/doi/full/10.1056/NEJMoa1407024