Stretch That Thrombectomy Window

It’s the thing to do in stroke – wedge new treatments into practice with a narrow time window and strict eligibility requirements, then expand, expand, expand.

This latest publication/advertising supplement in the Journal of the American Medical Association pools together the endovascular trials MR CLEAN, ESCAPE, EXTEND-IA, REVASCAT, and SWIFT-PRIME for an individual-patient meta-analysis to explore the various nuances of the treatment effect. After much cleaning and tweaking, the authors come around and say “Whoa! We found a benefit out to 7.3 hours from symptom onset, not just the 6 hour limit recommended by the American Heart Association!”

These were all positive trials, so it’s no surprise the overall outcome is positive – nor is these authors ability to drag out favorable outcomes beyond the 6-hour cut-off, considering some of these trials enrolled patients out to twelve hours. However, in their clumsy calisthenics to marry these data to the time-based hypothesis of acute stroke practice, these authors are clearly dancing around the most important bit of evidence emerging from these trials: imaging selection. They spend a handful of sentences discussing the imaging selection eligibility criteria of the included trials, but one benefit of meta-analyses is its use as a tool to obfuscate such inconvenient aspects in favor of words, words, words relating to the methods of their statistical analysis.

As I described in my #smaccDUB talk, you need two things for stroke therapy to be effective: viable tissue and effective reperfusion. These trials – ESCAPE, EXTEND-IA, and SWIFT-PRIME – finally hit that sweet spot with small infarct cores and safe, effective recanalization. Some of that viable tissue absolutely decays over time, so the time-based hypothesis is not entirely untrue, but it’s a low-value oversimplification. As many of use in Comprehensive Stroke Centers have seen, perfusion imaging can direct therapy for patients far outside the general AHA recommendations. The obvious corollary to this, however, is that perfusion imaging similarly identifies patients for whom intervention is futile, regardless of time window. This second point runs contrary, however, to the financial interests at stake here.

The authors do mention imaging-based criteria is being investigated in multiple clinical trials, e.g.: NCT02142283, NCT02586415.  However, these trials are carefully designed not to enroach upon established time-based criteria, and to use imaging only to further extend the treatment windows.

Other fun tidbits:

  • A few patients randomized to endovascular intervention did not receive one. After all, most received pre-intervention tPA – some would be expected to recanalize with medical therapy alone. However, this publication gives another lovely window into our clot-buster that doesn’t bust clots: only 6.8% could be reasonably concluded to have had clot thrombolysis after medical therapy alone. We probably should not be giving tPA to patients for whom endovascular intervention is planned.
  • All five studies cited here were published in the New England Journal of Medicine.  This meta-analysis is in JAMA. Presented without comment.

“Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis”


Coda – there were just a couple relevant conflict of interest disclosures:

Dr Saver reports being an employee of the University of California; serving as an unpaid site investigator in multicenter trials run by Medtronic and Stryker for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled; receiving stock options for services as a scientific consultant regarding trial design and conduct to Cognition Medical; receiving funding for services as a scientific consultant regarding trial design and conduct to Covidien/Medtronic, Stryker, Neuravi, BrainsGate, Pfizer, Bristol Myers-Squibb, Boehringer Ingelheim (prevention only), ZZ Biotech, and St Jude Medical; serving as an unpaid consultant to Genentech advising on the design and conduct of the PRISMS trial; neither the University of California nor Dr Saver received any payments for this voluntary service. The University of California has patent rights in retrieval devices for stroke. Dr Goyal reports receiving grants from Covidien/Medtronic, consulting payments from Covidien/Medtronic, and having patent rights in systems and methods for diagnosing strokes (PCT/ CA2013/000761) licensed to GE Healthcare. Dr van der Lugt reports grant funding from the Dutch Heart Foundation, AgioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/LAMEPRO/Penumbra, Stryker, and Top Medical/Concentric. Dr Menon reports serving as an unpaid member of in the ESCAPE trial, which received support from Covidien/Medtronic, receiving grant support from AstraZeneca, honoraria from Penumbra, a submitted patent for triaging systems in ischemic stroke, and serving on the board of QuikFlo Health. Dr Majoie reports that his institution has received honoraria for his service on a Speaker’s Bureau from Stryker. Dr Dippel reports that his institution has received honoraria for his speaking from Stryker and grant funding from the Dutch Heart Foundation, AgioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/ LAMEPRO, Penumbra, Stryker, and Top Medical/ Concentric. Dr Campbell reports that his institution received a grant to support the EXTEND-IA trial from Covidien/Medtronic. Dr Campbell reports grant funding from the National Health and Medical Research Council of Australia and Medtronic and fellowships from the National Heart Foundation of Australia, National Stroke Foundation of Australia, and Royal Australasian College of Physicians. Dr Nogueira reports receiving fees for service on steering and data safety monitoring committees to Medtronic, Stryker, Penumbra, and Rapid Medical. Dr Demchuk reports receiving grant support and personal fees from Covidien/Medtronic and personal fees from Pulse Therapeutics. Dr Devlin reports that his institutions received clinical trial payments for patients enrolled in clinical trials from Medtronic, clinical trial support from Brainsgate and Genervon, and holding a patent. Dr Frei reports personal fees from Penumbra, Stryker, Codman, MicroVention, and Siemens. Dr Jovin reports receiving fees for service on steering committees from Silk Road Medical, Covidien, Stryker Neurovascular, Air Liquide; personal fees from Neuravi and Johnson & Johnson; nonfinancial support from Fundacio Ictus; and serving on the advisory board for Anaconda. Dr Siddiqui reports personal fees from StimSox, Valor Medical, Neuro Technology Investors, Cardinal Health, Medina Medical Systems, Buffalo Technology Partners, International Medical Distribution Partners, Codman & Shurtleff, Medtronic, GuidePoint Global Consulting, Penumbra, Stryker, MicroVention, W. L. Gore & Associates, Three Rivers Medical, Corindus, Amnis Therapeutics, CereVasc, Pulsar Vascular, the Stroke Project, Cerebrotech Medical Systems, Rapid Medical, Lazarus, Medina Medical, Reverse Medical, Covidien, Neuravi, Silk Road Medical, Rebound Medical, Intersocietal Accreditation Committee; other fees from Penumbra, 3D Separator Trial, Covidien, SWIFT PRIME and SWIFT DIRECT trials, MicroVention, FRED trial, CONFIDENCE study, LARGE trial, POSITIVE trial, COMPASS trial, INVEST trial. Dr van Zwam reports that his institution has received honoraria for his speaking from Stryker and Codman. Dr Davis reports lecture fees and research support from Covidien/Medtronic; travel support from Bristol Myers-Squibb and Pfizer; and advisory board fees from Boehringer Ingelheim and Medtronic. Dr Silver reports personal fees from Boehringer Ingelheim. Dr Donnan reports nonfinancial support from Boehringer Ingelheim; grants from the Australian National Health and Medical Research Council; and fees for service on advisory boards for Boehringer Ingelheim, AstraZeneca, Bristol Myers-Squibb, Pfizer and Merck Sharp & Dohme. Dr Brown reports receiving consulting fees from Medtronic/Covidien and personal fees from the University of Calgary. Dr Mitchell reports that his institution received a grant to support the EXTEND-IA trial from Covidien/Medtronic; his institution has received unrestricted research funding and grants from Codman Johnson and Johnson, Medtronic, and Stryker; and serving as an unpaid consultant to Codman Johnson and Johnson. Dr Davalos reports receiving payments for serving on a multicenter study steering committee and grant funding from Medtronic. Dr Roos reports grant funding from Medtronic. Dr Hill reports unrestricted grant funding for the ESCAPE trial to University of Calgary from Covidien/Medtronic, and active/in-kind support consortium of public/charitable sources (Heart and Stroke Foundation, Alberta Innovates Health Solutions, Alberta Health Services) and the University of Calgary (Hotchkiss Brain Institute, Departments of Clinical Neurosciences and Radiology, and Calgary Stroke Program); personal fees from Merck, nonfinancial support from Hoffmann-La Roche Canada. In addition, Dr Hill has a submitted patent for triaging systems in ischemic stroke, and owns stock in Calgary Scientific, a company that focuses on medical imaging software. No other disclosures were reported.
Funding/Support: The HERMES pooled analysis project is supported by a grant from Medtronic to the University of Calgary.

Magic Stone Mountain

Roller coasters are fun – and have many health benefits. They’re good for asthma. Now, apparently, they’ll help you pass kidney stones.

See the headlines:
Here’s Why Kidney Stone Sufferers Should Ride Big Thunder Mountain Railroad

Thrilling Cure: A Roller Coaster Ride Can Help Get Rid Of Kidney Stones

Got kidney stones? Ride a roller coaster! Study shows it is the most pain-free cost-efficient way to pass them

Kidney Stones? Science Suggests Heading To Disney World

And so on.

It’s just clickbait, as usual.

Now, I’m not saying the citation here isn’t on to something – but in this study, zero people pass kidney stones. Rather, a rubber ureteroscopic simulator was loaded with calcium oxalate calculi of various sizes and taken on Thunder Mountain. A few stones were shaken loose – particularly at the rear of the coaster train – and, presto! Roller coasters cure kidney stones!

Now, this may yet have some element of truth supporting anecdotal tales of stone passage while on coasters – but it’s clearly a surrogate far removed from reliable in vivo evidence.

“Validation of a Functional Pyelocalyceal Renal Model for the Evaluation of Renal Calculi Passage While Riding a Roller Coaster”

When Is An Extremity CTA Necessary?

Here’s another piece regarding low-value testing in trauma, focusing on another topic: the use of CT angiograms for evaluation of extremity vascular injury.

This single-center, retrospective series looks at use of the extremity computed tomography angiogram in the setting of orthopedic and multi-system trauma. For what it’s worth, at least, there were only 275 scans identified during their 10-year study period. However, the bad news, of course: only 16 (6%) of those scans identified an injury requiring treatment.

Of greatest interest to those trying to eradicate low-value care comes the entirely unsurprising observation that 109 (40%) of patients received CTAs despite the absence of hard or soft signs of vascular injury – and all were normal. Additionally, all 16 cases requiring treatment had diminished or absent distal pulses on presentation.

I do anedcotally see the clinical examination being devalued, especially in trauma – it shouldn’t be!

“When are CT angiograms indicated for patients with lower extremity fractures? A review of 275 extremities”

From Way Too Many CTs to Many CTs

I am always keen to hear reports of successful imaging reduction interventions – and, even moreso, in trauma. The typical, modern, approach to trauma involves liberal use of advanced imaging – almost to the point of it being a punch line.

This single-center before-and-after report details their experiences between 2006 and 2013. Before 2010, there was no specific protocol regarding CT in trauma – leading to institutional self-examination in the setting of rampant overuse. After 2010, the following protocol was in effect:

trauma algorithm

There isn’t much besides good news presented here. Their primary imaging use outcome, abdominopelvic CT, decreased from 76.7% to 44.6% of all presentations. This was related to an increase in mean ISS for those undergoing CT. When free fluid from non-traumatic causes was individually accounted for, the rate of positivity of these CT rose from 12.3% to 17.5%. Finally, mortality was unchanged – 3.1% vs. 2.7%.

No doubt, any reduction in imaging will miss some important findings. The net counterbalancing effect, however, is likely a massive reduction in costs and harms from further evaluation of false-positives, renal contrast injury, and radiation. And, after all, they’re still performing CTs on nearly half their patients!

“Effect of an Institutional Triaging Algorithm on the Use of Multidetector CT for Patients with Blunt Abdominopelvic Trauma over an 8-year Period”

The 5-Second Rule, Meet Science!

Again with the headlines: “The ‘5-second rule’ is disproved in new study”.

And, again, checking the veracity of their knowledge translation distillation: not exactly.

These authors placed four different foods (watermelon, bread, buttered bread, and gummy candy[Haribo, Strawberries]) on four different surfaces (steel, tile, wood and carpet). They let the food stay in contact with the surface for <1 second, 5 seconds, 30 seconds, or 300 seconds. However, where this study falls off the generalizability wagon: each surface was pre-coated with bacteria-rich broth.

So, yes, in their study, even instant contact was adequate to transfer some bacteria from surface to food. Five seconds quite obviously transferred plenty of bacteria. Otherwise, the amount of bacteria transferred was roughly related to moisture in the food item and surface area in direct contact.

But, is the “5-second rule” obsolete? Hardly. Consider the context of history – where humans have been eating in less sanitary situations for hundreds of thousands of years. Then, chances are your hands are more likely to contaminate your food than the floor in your house. So, food that has been dropped on most clean floors may pick up some bacteria – but these authors’ results are only a surrogate for multifactorial confounded potential downstream harms.

However, if your floor is coated with a thriving culture of pathogenic bacteria – all bets are off.

“Longer Contact Times Increase Cross-Contamination of Enterobacter aerogenes from Surfaces to Food”

Imprecise Dosing of Liquid Medications

Many parents are overdosing their kids, study says”. Is this true? Are parents poisoning their own children, as the headline implies?

Of course not; this is not in fact a study regarding overdose incidence at all. It is, quite simply, a measurement precision study.

This study involves 2,110 parents randomly assigned to measure doses of liquid medication in various quantities using either a cup, a 0.2mL syringe, or a 0.5mL syringe. Approximately a quarter of parents were >20% off with their measurement, and 2.9% doubled the instructed dose. Taking these results as a surrogate for overdose depends on the therapeutic range for a medication – so, while the headline is not technically incorrect, the implication is an exaggeration.

With regard to measurement and dosing errors, there were a few important trends to note. Health literacy had a large influence on dosing errors – regardless of whether teaspoons or mL were used in the instructions. Then, the cup: avoid the cup when possible. Almost three-quarters of parents committed measurement or dosing errors when asked to provide a 2.5mL dose in the cup. Stick to the syringe and target round numbers (5mL) to minimize errors.

With regard to the premise of overdose – for medications with a wide therapeutic range, these data are not quite as clinically relevant. However, for high-risk medications, more time and effort should be taken to demonstrate proper dosing with parents.

“Liquid Medication Errors and Dosing Tools: A Randomized Controlled Experiment”

Stumbling Around Risks and Benefits

Practicing clinicians contain multitudes: the vastness of critical medical knowledge applicable to the nearly infinite permutaions of individual patients.  However, lost in the shuffle is apparently a grasp of the basic fundamentals necessary for shared decision-making: the risks, benefits, and harms of many common treatments.

This simple research letter describes a survey distributed to a convenience sample of residents and attending physicians at two academic medical centers. Physicians were asked to estimate the incidence of a variety of effects from common treatments, both positive and negative. A sample question and result:

treatment effect estimates
The green responses are those which fell into the correct range for the question. As you can see, in these two questions, hardly any physician surveyed guessed correctly.  This same pattern is repeated for the remaining questions – involving peptic ulcer prevention, cancer screening, and bleeding complications on aspirin and anticoagulants.

Obviously, only a quarter of participants were attending physicians – though no gross differences in performance were observed between various levels of experience. Then, some of the ranges are narrow with small magnitudes of effect between the “correct” and “incorrect” answers. Regardless, however, the general conclusion of this survey – that we’re not well-equipped to communicate many of the most common treatment effects – is probably valid.

“Physician Understanding and Ability to Communicate Harms and Benefits of Common Medical Treatments”

All Glory to the Triple-Rule-Out

The conclusions of this study are either ludicrous, or rather significant; the authors are either daft, or prescient. It depends fundamentally on your position regarding the utility of CT coronary angiograms.

This article describes a retrospective review of all the “Triple-Rule-Out” angiograms performed at a single center, Thomas Jefferson University Hospital, between 2006 and 2015. There were no specific circumstances under which the TRO were performed, but, grossly, the intended population were those who were otherwise being evaluated for an acute coronary syndrome but “was suspected of having additional noncoronary causes of chest pain”.

This “ACS-but-maybe-not” cohort totaled 1,192 patients over their 10 year study period. There were 970 (81.4%) with normal coronary arteries and no significant alternative diagnosis identified. The remaining, apparently to these authors, had “either a coronary or noncoronary diagnosis that could explain their presentation”, including 139 (11.7%) with moderate or severe coronary artery disease. In a mostly low-risk, troponin-negative population, it may be a stretch to attribute their symptoms to the coronary artery disease – but I digress.

The non-coronary diagnoses, the 106 (8.6%) with other findings, range from “important” to “not at all”. There were, at least, a handful of aortic dissections and pulmonary emboli picked up – though we can debate the likelihood of true positives based on pretest odds. However, these authors also credit the TRO with a range of sporadic findings as diverse as endocarditis, to diastasis of the sternum, and 24 cases of “aortic aneurysm” which were deemed important mostly because there were no priors for comparison.

The authors finally then promote TRO scans based on these noncoronary findings – stating that, if a traditional CTCA were performed, many of these diagnosis would likely be missed. Thus, the paradox. If you are already descending the circles of hell, and are using CTCA in the Emergency Department – then, yes, it is reasonable to suggest the TRO is a valid extension of the CTCA. Then again, if CTCA in the acute setting is already outside the scope of practice, and TRO is an abomination – carry on as if this study never existed.

“Diagnostic Yield of Triple-Rule-Out CT in an Emergency Setting”