The Beginning of the End of Heparin for ACS?

We’ve been routinely starting anticoagulation therapy on patients diagnosed with an acute coronary syndrome for a couple decades. The evidence from the preceding era is clear – patients treated with anticoagulation plus aspirin are at much lower risk for subsequent ischemic events than those treated with aspirin alone.

However, these trials are not generalizable to most modern care for ACS. For example, the FRISC and ATACS trial discharged patients with nSTEMI or unstable angina with continued anticoagulation for weeks to months. Revascularization procedures were performed only as rescue therapy, rather than the routine early invasive strategies in use today. Dual anti-platelet and other adjunctive therapies were unavailable. So – do we actually still need the heparin?

These authors retrospectively evaluated the association between parenteral anticoagulation therapy and in-hospital death and in-hospital major bleeding. There were 6,804 patients included in their 4-year, multi-center data set, about two-thirds of whom did not receive parenteral anticoagulation prior to PCI. There were small, probably unimportant differences reported between groups, excepting one feature: time to intervention. Time to intervention was a median of 1 day in those managed without anticoagulation versus a median of 3 days in those managed with. Overall, there was no difference in in-hospital death, nor 30-day, 1-year, or 3-year death for those included in long-term follow-up. A handful of cases suffered bleeding complications, with a small absolute excess in those managed with anticoagulation.

This is neither prospective nor a randomized trial, and there could certainly be unexamined confounding baseline characteristics favoring one treatment group over the other. The authors also note bleeding complications could be ameliorated by use of fondaparinux rather than heparinoids, but this would still be moot if there is still no benefit to anticoagulation. Finally, in-hospital mortality is a fabulous patient-oriented endpoint, but it does not tell the entire story with regard to any additional morbidity potentially resulting from anticoagulation being withheld. We should not change practice based on this level of evidence, but these data should prompt further examination and potentially prospective evaluation.

“Association of Parenteral Anticoagulation Therapy With Outcomes in Chinese Patients Undergoing Percutaneous Coronary Intervention for Non–ST-Segment Elevation Acute Coronary Syndrome”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2719425

Don’t Bother With the Parachute!

Most folks erroneously believe a parachute is necessary when jumping from an aircraft. There’s never been evidence to support such a belief in the form of a true randomized-controlled trial. That said, it would be hard to achieve the ethics board approval to perform such a study – and this concept of treatments and medical devices as “parachutes” persists, supposedly obviated from prospective evaluation. The lesson here is a cautionary one, actually, that too many medical practices are inappropriately characterized as parachutes, not so much that parachutes require an RCT.

However, this is precisely what we’ve received for Christmas – an RCT of parachute use for preventing death and major trauma. In this trial, 92 aircraft passengers were screened, and ultimately 23 were randomized to jump from an aircraft wearing either a parachute or an empty backpack. This was an unblinded trial, as well, in which all participants knew whether they were wearing a parachute or an empty backpack at the time of jump. With regard to their primary outcome of death from impact with the ground, there was 0% mortality in the parachute cohort and – wait for it – 0% mortality in the empty backpack cohort.

There were some important differences noted – not between those randomized, but between those screened and those randomized. The altitude of those screened but not randomized was 9,146m, at a velocity of 800 km/h. The altitude of those randomized is best described by the following representative photo:

It should probably be noted zero parachutes were actually deployed by jumpers randomized to that arm.

The lesson here is another fabulous one. The results from clinical trials cannot necessarily be applied to all those included in the eligibility criteria, but can rather be best generalized from those actually receiving the intervention. Insidiously controlling the population undergoing an intervention, among many others, is one of the various tricks those who design clinical trials can use to bias their results, and ultimately mislead.

“Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial”
https://www.bmj.com/content/363/bmj.k5094

Rochester v. Philadelphia, Pediatric Edition

It’s a little tough for Rochester to go head-to-head against Philadelphia – with apologies to the Americans, Red Wings, Rhinos, Knighthawks, and Razorsharks. The playing field of … the playing field … is just on another level in Philadelphia. The playing field of febrile infants, however, is another matter.

This small study re-analyzed prospective data from 135 febrile children ≤60 days of age with documented invasive bacterial illness, and applied the Rochester and modified Philadelphia criteria for risk-stratification. IBI was defined as having a positive blood or CSF culture, if obtained. In this small sample, both Rochester and Philadelphia were 100% sensitive for all cases of meningitis in infants greater than 28 days of age, but each missed similar numbers of those with bacteremia. A comparison for those below 28 days is frankly irrelevant, as the modified Philadelphia criteria specifically applies only to those >28 days of life – so, yes, it is comically 100% sensitive and 0% specific in neonates. The Rochester criteria, which does not mandate CSF, if applied to those ≤28 days, would have missed two cases of meningitis, and is therefore not suitable for use.

The takeaway here is not so much which criteria is superior to the other – the elements of each are virtually identical. Moreso, it is the recognition that each is about 83% sensitive, and all children in this age range evaluated in the ED and discharged will require close follow-up for re-evaluation of clinical status.

“Risk Stratification of Febrile Infants ≤60 Days Old Without Routine Lumbar Puncture”
https://www.ncbi.nlm.nih.gov/pubmed/30425130

Did You Miss … CATCH2?

We’ve talked about the PECARN vs. CATCH vs. CHALICE cage-match before. PECARN has been the subject of multiple sub-investigations, but CHALICE has been neglected and gone to seed. CATCH, on the other hand, has a sequel.

What’s new in CATCH2? Vomiting!

Adding to the original 4 + 3 item list, these authors conducted a new multi-center study comprised of 4,060 children with minor head injury. The stated purpose was to prospectively evaluate CATCH, with a secondary plan to improve performance if found to be deficient – and, although it is not explicitly stated, it appears these authors anticipated the missing link to be inclusion of vomiting.

Only 23 children in their cohort required neurosurgical intervention, while 197 had any brain injury on CT. The original CATCH had sensitivity of 97.5% and specificity of 59.6% for any brain injury, while adding “≥4 episodes of vomiting” increased sensitivity to 99.5% and decreased specificity to 47.8%. Sensitivity of CATCH2 was 100% for any cases requiring neurosurgical intervention, although confidence intervals are obviously wide, given the paucity of events.

So, another entrant arrives to the pediatric head injury decision-instrument sweepstakes. Interestingly enough, these instruments were created because of concerns of CT overuse – up to 53% in 2005! – as cited by these authors. With CATCH2, the CT ordering rate would be 55%. This is both greater than the 34% rate witnessed in this study, and vastly greater than the 8% seen in Australian and New Zealand, although with different entry criteria. It would seem to me these instruments are rather making the problem worse, rather than better ….

“Validation and refinement of a clinical decision rule for the use of computed tomography in children with minor head injury in the emergency department”
http://www.cmaj.ca/content/190/27/E816

Dentist, Dealer?

In the Emergency Department, we appreciate all the various sources of opiates in our healthcare system. We are, after all, effectively the last-resort after-hours refill destination – and patients with dental complaints are not uncommon.

These authors performed a retrospective, claims-based analysis of adolescents and young adults with exposures to opiates via a dental provider. In this database, there were 754,002 patients with continuous enrollment during the study period, 97,462 of whom received at least one prescription for an opiate. Of these, 29,791 (30.6%) received a prescription from a dental clinician. As compared with a randomly-selected opiate non-exposed cohort, the difference between subsequent healthcare encounters with an opioid abuse-related diagnosis was profound: 5.6% of the exposed cohort, compared with 0.4% of those unexposed.

It’s the same sort of high-level analysis with vast gulfs of inference as the “Emergency Physicians Are The Problem” article in the NEJM a few months back. It has obvious face validity, however, that an exposure to a potentially dependence-forming medication can result in downstream harms. Dental providers are not obviously any greater problem than other surgical specialties, but, yes, we are all similarly responsible for appropriate prescribing practices.

I also incidentally applaud these authors for their use of absolute risk differences – it would have been all too easy to breathlessly report relative risks, considering the low prevalence of opioid-abuse among “controls”.

“Association of Opioid Prescriptions From Dental Clinicians for US Adolescents and Young Adults With Subsequent Opioid Use and Abuse”
https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2717503

Precog for Medical Errors

Medical errors are grossly under-reported, with only an estimated 10% safety events ever identified via voluntary reporting systems. There’s an entire line of academic inquiry simply targeted at increasing the proportion of safety events detected, with the overall goal of informing subsequent practice change. This study – mentioned in the daily ACEP News briefing – takes it one step further, attempting to predict future safety events in real-time.

These authors used a continuous stream of data from the electronic health record to create a “patient safety active management” system. They created an initial model based on four years worth of data from 2009-13, and subsequently validated it by pilot implementation at two hospitals between 2014-17. During these pilot phases, each nursing unit was provided with a dashboard for every patient indicating whether a trigger event had occurred, along with a twice-daily updated score of their overall risk for an event. A nurse reviewer followed all the automated positive triggers and evaluated their downstream harms, as well as the harm severity.

We’re a long way from prime time. There were 775,415 trigger events in 147,503 inpatient admissions, resulting in 3,896 clinically validated safety events. The vast majority of events were “temporary harm” or “increased length-of-stay”, although there were a few serious safety events as well. Worse still, these authors don’t specifically delve into “preventable” harms, as their list of most common adverse events do not clearly offer clues as to whether the harms could specifically be mitigated or avoided. For example, many of their harms were medication-related bleeding or medication-related Clostridium difficile infection – unintended harms, to be sure, but frankly known risks of the likely medically-appropriate treatment pathways.

Every project has to start somewhere, of course, and these early steps will hopefully further inform more specific tools. Hopefully – though I’m unfortunately skeptical – I primarily expect more low-value, alert fatigue-inducing hiccups along the way.

“An Electronic Health Record–Based Real-Time Analytics Program For Patient Safety Surveillance And Improvement”
https://www.healthaffairs.org/doi/abs/10.1377/hlthaff.2018.0728

The Probiotic Hoax?

The concept of probiotic therapy is a compelling one: under duress from illness or adverse effects from medications, the gastrointestinal biome becomes altered. Orally repleting this biome to restore “normal balance” ought to improve morbidity. Sounds good, right?  Unfortunately, plausibility is not the same as practical efficacy.

Other indications or specific contexts notwithstanding, this multi-center trial shows probiotics confer no advantage for progression of gastroenteritis in children. These authors conducted a randomized, double-blinded trial in six pediatric Emergency Departments in Canada, including 886 children presenting with fewer than 72 hours of infectious diarrheal symptoms. They each received a 5-day course of either Lactobacillus rhamnosus R0011 and L. helveticus R0052 or placebo. Short answer: about 25% of each cohort progressed to moderate-to-severe gastroenteritis, and the duration of diarrhea was a little over two days, regardless.

The authors note “5 out of 12 leading guidelines endorse the use of probiotics”, although it does not appear they have a citation regarding how many dentists would recommend.  While these data do not generalize to all indications, nor potentially all possible probiotic formulations, these data certainly tilt the board away from “potentially useful” towards “probably not useful”.  Adverse events were common and similar between groups, so probiotics are unlikely to be harmful in a population with normal baseline health status – but you might as well just visualize your money concurrently swirling along down the toilet.

“Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis”

https://www.nejm.org/doi/full/10.1056/NEJMoa1802597

That Lego is Gone

Lego, a portmanteau of Danish words meaning “play well”, are ubiquitous toys around the world. This means the bite-sized bits are equally prevalent in the hands of infants and toddlers around the world – and in their mouths. What goes in a toddler’s mouth goes into their stomach.

This brief study evaluates six toddlers – ahem, pediatricians – who each swallowed a Lego head:

These adult children subsequently searched stools for signs of the swallowed item, as well as performed an assessment of stool consistency. Most importantly, they were able to derive infantile acronyms for their assessments – the SHAT and FART scores.

One of the six participants was never able to locate the ingested Lego part, despite two weeks of stool searching. The other five found them in their second or third bowel movement, which, on average, was 1.71 days later.  Stool consistency was unrelated to passage of the head.

Obviously, the generalizability and reliability of such a study is quite low, being adults and only six of them. Then, although these authors report “no complications”, they have not yet located one of the six heads – perhaps a future case report: “Acute appendicitis involving an unusual appendicolith”?  At the least, a potential future IgNobel prize awardee.

“Everything is awesome: Don’t forget the Lego”
https://onlinelibrary.wiley.com/doi/full/10.1111/jpc.14309

The Fourth Universal Definition of Myocardial Infarction

You’ve seen Sepsis-3 – but did you miss MI-4?  Not, unfortunately, a James Bond reference – but the “long-awaited” 2018 Fourth Universal Definition of Myocardial Infarction.

Effectively, the crux of this document is to help specifically describe cardiac injury and differentiate the MI and non-MI causes of troponin elevation. This ties to tweezing out the difference between “myocardial injury” and “myocardial infarction”. “Myocardial injury” simply describes circulating cardiac troponin levels ≥99th percentile, and can be acute or chronic. “Myocardial infarction”, on the other hand, is effectively myocardial injury plus supporting evidence for acute myocardial ischemia.

Exciting, I know!

Finally, to recap, the five (six?) types of myocardial infarction:

  • Type 1 – Myocardial ischemia and troponin levels ≥99th percentile resulting from atherosclerosis and thrombosis, encompassing STEMI and NSTEMI.
  • Type 2 – Myocardial ischemia and troponin levels ≥99th percentile resulting from thophysiologic mechanisms leading to a mismatch of oxygen supply and demand.
  • Type 3 – Sudden death suspected to be from new cardiac ischemia, specifically when cardiac biomarkers are not available.
  • Type 4a – Coronary intervention-related MI with troponin levels more than 5 times the 99th percentile, or rising troponin levels, and other supporting evidence for new ischemia within 48 hours of PCI and relating to a specific procedural complication.
  • Type 4b – Same criteria as Type 1 MI, but related to stent/scaffold thrombosis, absent a specific procedural complication.
  • Type 5 – Effectively Type 4a, but with troponin levels 10 times the 99th percentile, and associated with complications from CABG.

Just keeping up, keeping up.

“Fourth Universal Definition of Myocardial Infarction (2018)”
http://www.onlinejacc.org/content/early/2018/08/22/j.jacc.2018.08.1038

Computer Says: Discharge that Pulmonary Embolism!

We’ve learned a couple important things about pulmonary emboli for the past five or so years. First, we diagnose too many of them. Second, all pulmonary emboli do not need to be hospitalized. Knowing, as they say, is half the battle. That’s a start – but it’s not enough.

This study involves important thing number two above, the hospitalization of PE. Kaiser Permanente, in its endless quest for value, has already published several studies demonstrating the safety of discharging patients with PE. However, hidden in the descriptive statistics from those studies are the unfortunate still-low percentages of patients discharged.

In this prospective, multi-center, “convenience-assigned” trial, a computerized decision-support tool was rolled out to support risk-stratification for patients diagnosed with PE. Based on the pulmonary embolism severity index (PESI), patients scoring in class I or II were encouraged to be discharged, while those with higher scores were nudged towards hospitalization. In their pre-post design, little change occurred at the control hospitals, while the percentage of patients with PE discharged from the intervention hospitals jumped from 17.4% to 28.0%. No issues regarding untoward 5-day recidivism or 30-day adverse events were detected.

This is a great step forwards, and, frankly, one of the most prominent examples of decision-support being actually useful to implement practice change.   That said, in the intervention hospitals, there were “physician champions” associated with the roll-out of the CDS intervention, which almost certainly increased update.  Then, 41.2% of patients were PESI class I or II, so there’s even further room for improvement above these topline results – but this is an at least solid effort.

“Increasing Safe Outpatient Management of Emergency Department Patients With Pulmonary Embolism”

http://annals.org/aim/article-abstract/2714293/increasing-safe-outpatient-management-emergency-department-patients-pulmonary-embolism-controlled