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

The Remarkable Power of Placebo

Have you ever felt pressured to provide a patient with something at the time of discharge?  Something, anything to ease their suffering for an illness of unalterable benign progression?  Never?  You cold-hearted bastard.

This tiny trial, despite its small size, provides yet another beautiful look at the magical healing power of placebo.  Or, more accurately, rather than healing power, at least the satisfying power.  After all – most families in the ED at two in the morning are not there because their child is awake from coughing, but because the parents are.

This trial, in the same vein of several honey trials before it, compared no treatment, a placebo treatment (grape-flavored water), and agave nectar for the treatment of pediatric cough-related illness.  Agave nectar was chosen for its similarity to honey, while not carrying the hypothetical botulism risk.  With ~40 patients in each group, all patients improved during the duration of the study.  However, despite the small sample, both agave nectar and placebo provided durable advantage over no treatment across all surveyed measures of patient and parent comfort.  There was, however, no difference between placebo and agave nectar – or, if there was, it was too small to be detected in this study.

What is most remarkable about this study is the authors discussion – that placebo treatments could be considered ethical, even when no benefit to such treatment is found in controlled studies.  Providing patients – or parents – with, at least, an inexpensive, harmless treatment option takes advantage of the power of belief, to the extent that real patient/parent-oriented benefits may be observed.

Unfortunately, the lead author of this study was a paid consultant to Zarbee’s Inc (a maker of “natural” over-the-counter remedies) at the time the study was initiated, and Zarbee’s provided funding for the study.  But, thanks to their contribution to science, we now know they only work as well as you expect ….

“Placebo Effect in the Treatment of Acute Cough in Infants and Toddlers”
http://www.ncbi.nlm.nih.gov/pubmed/25347696

by Darren Cullen
Copyright Darren Cullen – Spellingmistakescostlives
Homeopathic Accident & Emergency

No Good Ever Comes of Dabigatran

Is anyone actually still using this drug?  If so, why?  There has been nothing but an endless progression of bad news associated with this medication – from Boehringer Ingelheim settling a massive lawsuit, the authors from RE-LY admitting they “missed” additional adverse events for a second time, and, now, further evidence describing flawed real-world effectiveness contrary to its supposed demonstrated efficacy.

The RE-LY trial showed non-inferiority for dabigatran at stroke prevention in non-valvular atrial fibrillation, but appeared to place patients at significantly lower risk of bleeding compared with warfarin.  One of the critiques of RE-LY, however, is the patients were not appropriately representative of the general population at-risk for atrial fibrillation.  By omitting chronic kidney disease and enrolling a generally white population in Europe, the generalizability of their findings is ultimately impaired.

And, thus, we see the fruits of such critiques.  This is a retrospective cohort of Medicare beneficiaries prescribed either dabigatran or warfarin for atrial fibrillation.  Based on propensity matched samples of 1,302 dabigatran users and 8,102 warfarin users, major bleeding of the dabigatran cohort exceeded that of the warfarin cohort – 9.0% (95% CI 7.8 – 10.2) versus 5.9% (95% CI 5.1 – 6.6).  Risks were increased in the elderly, blacks, those with chronic kidney disease, and those on concomitant anti-platelet therapy.

So, we have a lesson – one of effectiveness versus efficacy, or one that’s an indictment of the original RE-LY study protocol.  Medications should not be expected to perform the same in general use as they do in clinical trials – even those with tens of thousands of patients, such as RE-LY.  Independent, confirmatory study ought be mandatory to ensure the safety of the public.

“Risk of Bleeding With Dabigatran in Atrial Fibrillation”

http://archinte.jamanetwork.com/article.aspx?articleid=1921753

Addendum:
Walid Gellad on Twitter points out this study in Circulation, published last week to much lesser fanfare, which uses a larger Medicare sample to come to the opposite conclusion – that dabigatran is better than, and safer than, warfarin.  Which is correct?  A subject for continued debate, to be certain.  The correct answer is probably somewhere in between – dabigatran is safer for some, but more dangerous for others.  However, given the lack of reversal – wouldn’t a Factor Xa inhibitor be a better choice, regardless?

Scientific Writing is a Tragicomedy! Destroy!

Modern scientific writing – both in the exercises of writing and reading – is obtuse and uninviting.  Rather than clearly communicate an unbiased reflection of the conduct and findings of a particular study, the medical literature most commonly succeeds in doing the opposite.  After all, how else would I find enough to complain about on this blog?

This editorial elucidates so many joyfully preposterous notions it cannot help yet be loved.  It is best described as a no holds-barred cagematch versus all the inane pageantry of scientific writing.  Just a few of the gems, paraphrased:

  • Don’t let the authors write the abstract; they’ll just misrepresent the study!
  • Delete the introduction; uninsightful filler.
  • No one cares the brand and manufacturer of the statistical package used.
  • Unequal composite end-points and subgroup analyses should be banished.
  • The discussion section only serves authors’ purposes of dubious claims through selective reporting and biased interpretation of their results.

Some elements of this brief report are, indeed, novel.  Others are simply accepted best practices long since forgotten.  Regardless, it is a refreshing reminder of how brutally poorly the current medical literature serves effective knowledge translation.

“Ill communication: What’s wrong with the medical literature and how to fix it.”
http://www.ncbi.nlm.nih.gov/pubmed/25145940

What Do People Remember From Cardiac Arrest?

The anecdotal experiences and reports from survivors of cardiac arrest are diverse, yet frequently describe common themes.  Detailed memories, “near death experiences” of entering another world, and sights and sounds from the arrest context are frequently reported.  And, what better place to collect cardiac arrest events than in a hospital?

As one might imagine, the population available for such interviews is rather limited – so it requires a massive undertaking, in this case, a four-year prospective evaluation across 15 hospitals in the U.S., UK, and Austria.  Essentially, the local investigator at each institution received notification of every adult, in-hospital cardiac arrest.  Survivors were identified and interviews conducted as soon as feasible, given continued comorbid illness.

Out of 2,060 cardia arrests, only 330 were eligible for study inclusion.  Investigators conducted 140 interviews – and only 55 had any memories.  Of these, 53 had detailed memories, whether unrelated or classic “crossing-over” phenomena – but nothing relating to the circumstances of their arrest event.  Only two patients had detailed memories of the circumstances of their event – one set of memories was not able to be verified, but the authors were able to fully verify the other set of memories by interview of the resuscitation staff.

So, essentially, very rarely do patients have any recollection of their arrest event.

Interestingly, one part of this study attempted to verify the veracity of the “floating above and watching” aspect of some individual’s arrest recollections.  The authors constructed shelves in areas thought most likely to have cardiac arrest, and then placed objects on the shelf that would only be visible from a perspective near the room ceiling.  Unfortunately, 70% of the cardiac arrests in this study occurred in locations where there were no shelves, including both arrests with detailed recollection.

“AWARE—AWAreness during REsuscitation—A prospective study”
http://www.ncbi.nlm.nih.gov/pubmed/25301715

Procalcitonin, Still Auditioning For a Role in Neonatal Sepsis

A single test to rule out bacteria infection would be a lovely invention.  But, in the absence of such, we’ll settle for a test to rule out serious bacterial infection.  But, alas, procalcitonin – despite its sponsored proponents – is not that test.

This is a systematic review and meta-analysis pooling 2,317 patients from seven studies evaluating its use in detection of SBI in a neonatal population of less than 91 days of life.  Most commonly, the discriminatory value reported used was 0.3 ng/mL, with five studies reporting this data and the other two providing this data upon request.  All told, infants with PCT >0.3 ng/mL had a 42.7% prevalence of SBI, while those with PCT below the cut-off had a 12.5% prevalence.

So, this works out to a relative risk of 3.97 (95% CI 3.41 to 4.62) given a PCT greater than the cut-off.  Unfortunately, a prior review of the “Rochester criteria” for infants aged 29 to 90 days noted this cohort of low-risk patients had a prevalence of SBI of only 2.7%, with a RR for SBI of 30.6 (95% CI 7.0-68.13).  Noting 2.7% to be superior to 12.5% as a rule-out mechanism, it would seem prudent to retain the Rochester criteria rather than rely on PCT.

It may be reasonable to incorporate PCT into future decision instruments for risk-stratification, but such validated rules are not yet available.

“Use of Serum Procalcitonin in Evaluation of Febrile Infants: A Meta-Analysis of 2,317 Patients”
http://www.ncbi.nlm.nih.gov/pubmed/25281186

Hoffman v. Albers tPA Debate from Oregon Stroke Network

You know Jerry Hoffman.  Do you know Greg Albers?  Among his many accolades, he was one of the investigators from the failed trial of ATLANTIS – which, not coincidentally, concluded Genentech’s involvement in randomized trials testing tPA in acute stroke.

This past summer, the Oregon Stroke Network hosted Dr. Hoffman debating Dr. Albers, entitled “t-PA: Proof or Peril?”  As one condition of his speaking, he simply asked the debate be recorded and hosted on the internet for all to view.

And so it is:
Debate Part 1 (2 hours)
Debate Part 2 (8 minutes)

In addition, the conference website has the PDFs of their presentations – as well as diverse other presentations, including those of Dr. Tom DeLoughery, covering the new anticoagulation options in atrial fibrillation.

Enjoy:
http://www.oregonstrokenetwork.org/2014conference.html

Should Children Receive Thoracotomy After Blunt Trauma?

Survival rates in the absence of signs of life following blunt trauma, as many have previously noted, are dismal – to be measured in the fractions of a percent.  As such, few advocate the use of the resuscitative thoracotomy, particularly outside centers with such surgical expertise as to definitively manage underlying injury.

But, children tend to exhibit remarkable healing powers compared to adults – are their outcomes any better?

Barely.

This National Trauma Data Bank review identified 3,115,597 individuals less than 18 years of age treated for blunt trauma.  Of these, 7,766 had no signs of life upon initial evaluation.  One quarter of these successfully regained signs of life prior to Emergency Department arrival – and ultimately 13.8% survived to discharge.  The remainder had no signs of life on Emergency Department arrival, and only 1.5% survived.  499 ED thoracotomies were performed – and survival was 1.3% in this cohort.

The authors of this study are very clearly negative in their assessment of the value of ED thoracotomy in this population.  It is a reasonable stance, given the apparent low yield of intervention in such a population.  While it is imprudent to use the word “never” – depending on the resource utilization, costs, and risks associated with an individual resuscitation, unfortunately, it rather seems aggressive measures ought be undertaken only in exceptional circumstances.

“Survival of pediatric blunt trauma patients presenting with no signs of life in the field”
http://www.ncbi.nlm.nih.gov/pubmed/25159245

When Is An Alarm Not An Alarm?

What is the sound of one hand clapping?  If a tree falls in a forest, does it make a sound?  If a healthcare alarm is in no fashion alarming, what judgement ought we make of its existence?

The authors of this study, from UCSF, compose a beautiful, concise introduction to their study, which I will simply reproduce, rather than unimpressively paraphrase:

“Physiologic monitors are plagued with alarms that create a cacophony of sounds and visual alerts causing ‘alarm fatigue’ which creates an unsafe patient environment because a life-threatening event may be missed in this milieu of sensory overload.“

We all, intuitively, know this to be true.  Even the musical mating call of the ventilator, the “life support” of the critically ill, barely raises us from our chairs until such sounds become insistent and sustained.  But, these authors quantified such sounds – and look upon such numbers, ye Mighty, and despair:

2,558,760 alarms on 461 adults over a 31-day study period.

Most alarms – 1,154,201 of them – were due to monitor detection of “arrhythmias”, with the remainder split between vital sign parameters and other technical alarms.  These authors note, in efforts to combat alert fatigue, audible alerts were already restricted to those considered clinically important – which reduced the overall burden to a mere 381,050 audible alarms, or, only 187 audible alarms per bed per day.

Of course, this is the ICU – many of these audible alarms may, in fact, have represented true positives.  And, many did – nearly 60% of the ventricular fibrillation alarms were true positives.  However, next up was asystole at 33% true positives, and it just goes downhill from there – with a mere 3.3% of the 1,299 reviewed ventricular bradycardia alarms classified as true positives.

Dramatic redesign of healthcare alarms is clearly necessary as not to detract from high-quality care.  Physicians are obviously tuning out vast oceans of alerts, alarms, and reminders – and some of them might even be important.

“Insights into the Problem of Alarm Fatigue with Physiologic Monitor Devices: A Comprehensive Observational Study of Consecutive Intensive Care Unit Patients”
http://www.ncbi.nlm.nih.gov/pubmed/25338067

CPR: Crushing It With Machines

In movies and television, CPR is a miraculous, dramatic event.  Pulses return, patients open their eyes and make a witty remark, and everyone celebrates.

The reality: CPR is a brutal, violent intervention.  And, the new mechanical CPR devices are even moreso.

This is a brief autopsy-based survey of 222 patients in whom CPR was unsuccessful, 83 of which were treated with manual CPR only, and 139 patients who received primarily mechanical CPR.  Mean age was ~67 years, about 30% female, and mean CPR time was ~35 minutes.  That is, to say the least, ample time to crush the thorax.

A brief accounting of the injuries from CPR:

  • Multiple rib fractures: 57.3% manual, 65.0% mechanical
  • Sternal fractures: 54.2% manual, 58.3% mechanical
  • Intrathoracic bleeding:  36.1% manual, 48.9% mechanical
  • Cardiac injuries: 7.2% manual, 15.2% mechanical
  • Liver injuries: 3.6% manual, 7.9% mechanical

Pathologists at autopsy, however, did not judge any of the injuries from CPR to have contributed to the cause of death.

Injuries in those for whom CPR is unsuccessful are intuitively more severe than for cases in which patients survive – a result of non-survivors being generally older, more brittle, and longer CPR duration.  However, it’s an interesting window into the destructive nature of vigorous CPR – and the increased injury associated with mechanical devices.

“CPR-related injuries after manual or mechanical chest compressions with the LUCAS device: A multicentre study of victims after unsuccessful resuscitation”
http://www.ncbi.nlm.nih.gov/pubmed/25277343