Category: Cardiology

ADAPTing & Improving

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

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

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

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

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

All NSAIDs are Created Equally . . . Right?

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

It’s been more than 10 years since Merck made headlines regarding the increased risk of atherothrombotic events with it’s drug rofecoxib (Vioxx) and 3 years since the almost $1 billion settlement regarding the drug. Over this time period, physicians have questioned the use of all non-steroidal anti-inflammatory drugs (NSAIDs) in patients with increased risk of coronary artery disease. Rofecoxib and its brethren were developed in the 1990’s as alternatives to the traditional NSAIDs (tNSAIDs). These newer drugs only inhibited COX-2 and theoretically would lead to less gastrointestinal bleeding since inhibition of COX-1 is believed to lead to this side effect. Based on this pathophysiologic theory and strong marketing, the drugs became widely prescribed. Unfortunately for our patients, saving the gut may compromise the heart. Or is it actually that all NSAIDs, regardless of which COX they inhibit, raises the risk?

This research group performed a meta-analysis of a large number of trials looking at both NSAIDs vs. placebo (280 trials) and one NSAID vs. another NSAID (474 trials). All of the studies look at length of use of at least four weeks but many had longer treatment durations. So, what did they find? When compared to placebo, coxibs (COX-2 inhibitors), diclofenac and ibuprofen all increased the risk of major coronary events but naproxen did not:
Coxibs RR (CI)
Diclofenac RR (CI)
Ibuprofen RR (CI)
Naproxen RR (CI)
Major Vascular Events
1.37 (1.14 – 1.66)
1.41 (1.12 – 1.78)
1.44 (0.89 – 2.33)
0.93 (0.69-1.27)
Major Coronary Events
1.76 (1.31-2.37)
1.70 1.19-2.41)
2.22 (1.10 – 4.48)
0.84 (0.52 – 1.35)
Gastrointestinal Complications
1.81 (1.17-2.81)
1.89 (1.16-3.09)
3.97 (2.22-7.10)
4.22 (2.71-6.56)

Additionally, it didn’t matter which coxib they looked at: all of them increased major coronary events. The coxibs did, however, do what they were supposed to do; the risk of gastrointestinal bleeding was lower in comparison to tNSAIDs like ibuprofen and naproxen.

Does this change what we should do? Can we give NSAIDs to older patients without fearing a major coronary event or death from an MI? The numbers here are small but important. For every 1000 patients allocated to a coxib, three more had major vascular events and one of these events would be fatal. That’s an absolute increase of 0.1% in comparison to placebo. Small increased risk but avoidable. Why not give naproxen instead? In fact, NSAIDs like ibuprofen interfere with the binding of aspirin negating its cardioprotective effects if the two are taken together. Naproxen doesn’t have this issue.
The relative safety in terms of major vascular events associated with naproxen versus ibuprofen was recently written about by the FDA and reported by the Associated Press here –

http://hosted.ap.org/dynamic/stories/U/US_PAIN_RELIEVERS_SAFETY?SITE=AP&SECTION=HOME&TEMPLATE=DEFAULT

I think the bottom line here isn’t much of a surprise. If you can, avoid NSAIDs in patients with cardiac risk factors. Ibuprofen isn’t a safe alternative. If you need to give an NSAID for whatever reason, use naproxen and use short courses of therapy.
“Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials”

More Bleeding Nightmares

Do you like managing bleeding on aspirin?  How about aspirin plus clopidogrel?  What would you say to aspirin + clopidogrel + vorapaxar?

Vorapaxar, a selective antagonist for protease-activated receptor 1, is the next proposed layer of anti-thrombotic prevention for high-risk cardiovascular patients.  Just this week, back from the dead, it received a favorable review from an FDA panel tasked with examining its application for approval.

The subject of both TRACER and TRA 2°P-TIMI 50, vorapaxar may soon bless your Emergency Department with a roughly 60% increase (2% vs. 3.5%) the risk of GUSTO moderate or severe bleeding.  What’s most fascinating about this drug is, technically, both trials were negative for the primary endpoint, and TRACER was stopped early after interim safety review.  However, a pre-specified and pre-allocated subgroup from TRA 2°P-TIMI 50 for patients with recent MI – and no history of stroke – showed benefit.

Of course, as is standard for these sorts of cardiovascular trials, it showed benefit primarily in the questionable combined endpoints – and, likewise, was only safe in the narrowest slicing and dicing of favorable endpoints and bleeding outcomes.

It should be of no surprise to anyone most authors are being substantially enriched by multiple drug companies.  I’m certain whatever foot-in-the-door Merck receives will be enough to extract the necessary healthcare dollars from the system for minimal benefit – a net NNT for mortality of ~450.

Oh, and as the great Tom Deloughery (@bloodman) writes:

“Hmmm – a competitive platelet inhibitor with a T1/2 of ~300hrs!  So, sounds like it will inhibit any platelets you give for the next 12 days … I guess Dr. Radecki will be holding direct pressure for a long time!”

“Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial”
http://www.ncbi.nlm.nih.gov/pubmed/22932716

Time to Move to the HEART Score

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

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

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

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

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

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

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

Gender-Specific Symptom Nonsense

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

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

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

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

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

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

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

Unlocking the Secrets of Atherosclerotic Plaques

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

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

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

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

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

Glucose and Insulin, Less is More

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

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

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

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

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

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

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

Glucose and Insulin, Less is More

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

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

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

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

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

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

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

hsTnI – All Promise, No Proof

At some point, it is true – there are no “bad” tests, only “bad” applications and interpretations of those tests.  One of those tests, as supported by Abbott Laboratories, is the high-sensitivity troponin.  You may also know this test as the “low-specificity” troponin – as, barring small improvements in the assay, a more sensitive test for the same biomarker is bound to result in decreased specificity.

This article describes the populations of ADAPT and APACE for whom high-sensitivity troponins are available.  These trials were part of a prospective derivation of an “accelerated diagnostic protocol,” in which low-risk patients (TIMI 0 or 1) with normal ECGs and two negative hsTnI two hours apart were found to be eligible for discharge from the Emergency Department.  With an approximately 14% of 30-day MACE (mostly nSTEMI) in each cohort, the authors strategy is reasonable:  only ~0.7% of patients meeting these three criteria eventually met a primary endpoint.

Conversation about this article led to this tweet by the primary author:

@EMManchester @240minDoc Precision of hs #troponin assays now shown to have great advantage. ED patients with possible ACS and this assay 1
— Louise Cullen (@louiseacullen) November 7, 2013

… except it isn’t entirely true.  The missing key to this statement is precisely what the “great advantage” entails.  These authors, sponsored by Abbott Laboratories, do not show this diagnostic strategy utilizing hsTnI is in fact superior to the same strategy using conventional troponins.  Quick back-of-napkin math shows the ADAPT conventional troponin cohort using this same strategy gives statistically similar results.  This critique led to the final tweet from the primary author:

@emlitofnote @EMManchester @240minDoc OK have to wait til part II where I can show you larger pop and more narrow CIs.
— Louise Cullen (@louiseacullen) November 8, 2013

Yes, with sufficient statistical power, there will likely be a reproducible difference between the different troponin assays.  When millions of patients are evaluated for chest pain every year, there may be a few for whom this improved sensitivity is clinically significant.  However, it is far more likely this increased sensitivity will end up referring additional patients for testing – resulting in increased costs and harms from overdiagnosis.  This is not the fault of the test – but, rather, simply that we don’t yet know the clinical significance of all small troponin elevations, and there is no appropriate algorithm for managing them in current practice.

I actually like what these authors are doing – using a rapid rule-out plus risk-stratification to safely discharge patients from the Emergency Department.  However, they’re selling hsTnI without proving it’s superior, in this strategy, to conventional troponin testing.  Then, as tests become more sophisticated, our interpretation of them needs to as well – and studies such as these need to do more than simply describe a “minimal-risk” cohort, but also provide useful guidance on the rest of the grey area troponin elevations.

Finally, I’d also like to finally see the TIMI score retired for use in the Emergency Department.  Please. Make it die.

“Validation of High-Sensitivity Troponin I in a 2-Hour Diagnostic Strategy to Assess 30-Day Outcomes in Emergency Department Patients With Possible Acute Coronary Syndrome”

Bivalrudin Trumps Heparin (Or Not)(Who Knows?)

10 out of 10 physicians employed by the Medicines Company approved this message.

Straight out of Jeff Drazen’s unbiased news pipeline, a treatment you might now start seeing more of in the Emergency Department: bivalrudin (Angiomax) for anticoagulation prior to PCI in the setting of STEMI.  In this trial, 2,231 patients across Europe were randomized pre-hospital (or at non-PCI hospitals) to either bivalrudin or heparin plus optional glycoprotein IIb/IIIa inhibitor.  The primary outcome, as typical of these sorts of trials, is another muddled composite: death from any cause, re-infarction (MI), or major bleeding not related to CABG.

Oh, wait, that was the original primary outcome.  In December of 2012, over three-quarters of the way through the enrollment period, the Medicines Company dropped re-infarction (MI) from the primary outcome.  It may or may not be a coincidence re-infarction due to stent thrombosis favored the control intervention, but I will leave that speculation up to the astute reader.  Regardless, the new final composite endpoint favored bivalrudin: 5.1% to 8.5%.  However, this outcome also depends on their own unique definition of “major bleeding”, which is different from TIMI and GUSTO.  If the TIMI and GUSTO definitions are used, the trend towards reduced bleeding with bivalrudin is still there, but the absolute differences become trivial and the overall primary outcome (original or eventual) is a wash.  Finally, this may all simply be a straw-man comparison for the safety outcome, as it’s reasonable to ask whether 69% of cases ought to be receiving prehospital glycoprotein IIb/IIIa inhibitor (an AHA Class IIb recommendation).

However, better questions may be – as are a recurring theme for the NEJM – do you trust the results of an open-label trial sponsored by the manufacturer, designed by the manufacturer, with data stored and dispensed to the academic oversight group by the manufacturer?  Are you less or more convinced when four authors are employed by the manufacturer, and the manufacturer employed a scientific communications firm for “editorial support”?  Why is NEJM publishing a trial that changed its primary outcome in clinicaltrials.gov – even, as the authors claim, to “reduce the necessary sample size”?

Physicians ought to be outraged at this transparent and unbalanced pharma shill – but, such occurrences have become so commonplace, it’s hard to not just surrender to lassitude.  Bivalrudin doubtless has an advantage in some specific subgroup, but with this sort of offal clogging the evidence, we’ll never really know.

“Bivalirudin Started during Emergency Transport for Primary PCI”
www.ncbi.nlm.nih.gov/pubmed/24171490