Tuesday, February 21, 2012

Is Midazolam Really Superior to Lorazepam?

Or, more accurately, is it reasonable to perform an intramuscular injection of midazolam rather than an intravenous injection of lorazepam for seizure-like activity in the prehospital setting?

Almost certainly.

In fact, some folks are taking this article and claiming that intramuscular midazolam is superior to intravenous lorazepam, that it's a "game changer."

Well, let's not go crazy here.

As with any piece of literature, the more vocal the giddiness I see perpetuated about the internet, the more cautious I am with rushing to judgement.  It is, of course, a very well-designed, prospective, double-dummy, randomized, non-inferiority comparison between midazolam and lorazepam.  The aim of the study is, essentially, to show that, even though midazolam is not typically as rapidly effective at terminating seizures, the time difference is made up by intramuscular route versus the time required for an IV start.

What's kind of odd that I see in this article is that nearly a third of the lorazepam group did not receive the benzodiazepine portion of the intervention - and they compare it to the midazolam group in which all but 5 patients received the intervention.  When their primary outcome is the number of folks who arrived seizure-free in the Emergency Department - it seems as though the 7% absolute difference between the two groups could be easily explained by the fact that a third of the lorazepam group didn't receive an intervention.  Most of the lorazepam group had the intervention withheld because they stopped seizing of their own accord at the time of enrollment, with a minority having the intervention withheld because IV access could not be obtained.

And, the differences favoring midazolam are hard to pin down whether it's actually medication superiority, or something different about the seizures.  42 patients in the lorazepam group failed to stop seizing after additional therapy, compared with only 22 in the midazolam group - is this a difference in efficacy, or a difference in the underlying disease process - which appears to be more resistant to any therapy, including rescue, in the lorazepam group?

But, in any event, this just nitpicking against the superiority argument, and not the non-inferiority argument.  From a clinical standpoint, it is clearly safe and effective to use intramuscular midazolam for seizures in the prehospital setting.  However, what I'd prefer to see is a similarly powered trial of intranasal midazolam, which takes all the injection risks for patient and provider out of the equation during the seizure.  This is a good first step, but I think we can make effective treatment even safer if intranasal can be shown non-inferior as well.

"Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus"

Sunday, February 19, 2012

No One Knows How To Diagnose CAD

And, once they diagnose it - it doesn't seem like anyone knows what to do with it, considering all the brouhaha these days about potentially unnecessary PCI and stenting.

But, this is a prospective coronary CT angiography registry that was reviewed to determine whether any value was added with the CCTA over conventional stress testing in patients without known CAD.  They reviewed 22,551 patient records, excluded patients with known CAD, incomplete data, and patients who hadn't undergone a recent (<3 months) cardiac stress test, and ended up with 6,198 patients.

The point the authors seem to be trying to make is that CCTA is a better test than stress testing, but that's only part of the story.  What they note that is interesting along the way is that there is absolutely no correlation between stress testing results and CCTA results.  Patients with normal, equivocal, and abnormal stress results had, essentially, the same incidence of normal, <50%, and >50% coronary stenosis.  And, the hidden story about how CCTA is being used in their patient cohort is fascinating - a younger group with typical chest pain and normal stress tests referred to CCTA vs. an older group with less typical symptoms and abnormal stress tests referred to CCTA.

But, then, finally they compare both of their disparate tests to the "gold standard" of invasive angiography, and they find that both tests are awful at predicting >50% coronary stenosis.  Stress testing was 60.4% sensitive and 34% specific, while CCTA was 94% sensitive and 37% specific.  So, we have two tests that are wrong about the presence of disease twice as often as they're right - and these authors are using a clinically irrelevant 50% stenosis as their "gold standard".

Rather entertaining to observe the difficulty the cardiology literature is having reconciling all their different imaging options with clinically relevant stenoses, much less outcomes.  Good thing all these inadequate tests are cheap and harmless....

"Coronary Computed Tomography Angiography After Stress Testing"

Friday, February 17, 2012

The Tiniest Three Year Sinusitis Trial

Yet again, another article that saturated the lay press due to its publication in JAMA - this time regarding amoxicillin for acute sinusitis.

The problem is, I agree with the fundamental point the authors are making - according to the introduction, antibiotics for sinusitis account for 1 in 5 antibiotic prescriptions in the United States and they're typically unnecessary, especially in an era where better antibiotic stewardship is needed.  However, I cannot imagine how a multicenter study of ten community clinics in St. Louis over three years only managed to enroll 166 adults into this study over the course of three years.  Their recruitment diagram states only 244 patients were assessed for eligibility - which seems like it ought to be a a couple months worth of URI presentations in an outpatient setting.

If you read the newspaper, you already know the main results - "no difference between 10 days of amoxicillin and placebo."  But 11 of 85 intervention group patients discontinued treatment, as well of 12 of 81 placebo patients.  Due to lost data, 4 of 85 intervention patients were excluded from analysis, as well as 7 of 81 placebo patients.  Then, 32% of patients in the intervention group were non-compliant with the intervention - so, while this is valid in a real-world effectiveness sense, they're increasingly no longer relevant to the actual efficacy of the intervention.  These are big holes in a small study.

And, bizarrely, the baseline characteristics they use to describe the two groups include more social characteristics than clinical characteristics - healthcare insurance, family income, etc.  Children living in the home, children in day care, etc., is an interesting demographic criteria, suggesting unique infectious exposure - 9% more intervention group patients had children at home, but this isn't statistically significant because the sample sizes are so tiny.  Then, the clinical characteristics they chose only seem to partially reflect issues relevant to antibiotic efficacy - "usual health excellent or good" isn't a very useful descriptor of whether they have impaired baseline immune function that places them at increased risk of significant bacterial superinfection.  For what it's worth, the control group was significantly "healthier", but also had significantly more smoking history.

Getting back to the main results - yes, the average SNOT-16 scores were equal at day 0, 3 and 10, but favored the intervention at day 7 - leading to their final conclusion that amoxicillin was of no benefit.  But, at the individual patient level, the control group patients were impaired from their usual activities almost 50% longer - 1.67 days vs. 1.15 days, and there was a 12% absolute difference in satisfaction with treatment favoring the intervention - 53% vs. 41 %.  But, due to the tiny sample size, none of these differences reached statistical significance.

In the end, it's a fair real-world trial and addition to the literature, but it's far too small and flawed a trial to stand on to as evidence.

Oddly, one of the authors receives royalties for the SNOT-16 scale.

"Amoxicillin for Acute Rhinosinusitis: A Randomized Controlled Trial"

Thursday, February 16, 2012

Bunnahabhain, Highland Park, Ardbeg

I had a request for a Scotch posting again - and, it has been about six months since I made a Scotch post - so, here's what's left on my shelf at the moment.

 - Bunnahabhain 28-year Signatory Collection.  This was a gift Scotch that is, essentially, my major celebration Scotch.  Cardinals won the World Series, bought a house, got a grant, etc.  Smooth and tastes like caramel.
 - Highland Park 18.  Has won several sort of "Scotch of the Year" type awards.  It's not as complex as other Scotches I've had, but it's sort of a sweet, smooth Scotch that will likely appeal to a wide variety of drinkers.
 - Ardbeg Alligator.  In contrast, this will not appeal to a wide variety of drinkers.  It is a peaty, burning, smoky/charcoal Scotch that has a very distinct taste acquired from being aged in charred barrels.  It's not for everyone, and it takes a little bit of water to soften up, but the uniqueness outweighs the harshness.

I'm lucky enough to live, literally, within walking distance of the world's largest liquor store, so typically when I'm shopping for Scotch, I have plenty to choose from.  I've also given the Octomore 3.1/152 as a gift, which was the fourth edition in their super-phenolic distillations, and it makes for a very uniquely peaty, nose-filling sensation that lasts forever.  Hard to find, but absolutely well worth it.  Comes in a kind of silly black matte bottle, however:

Patients: More Satisfied, More Dead?

Another article pulled out of the mainstream media - and one that highlights an issue many are familiar with: patient satisfaction.  There isn't an ED out there whose medical director doesn't know their patient satisfaction scores, whether Press-Ganey or their own evaluations, and many EPs compensation (or employment) is tied to their patient satisfaction.  And, we've argued time and time again that patient satisfaction has nothing to do with high-quality care, and that it's insulting to degrade medical practice to customer service.

Now, this prospective cohort study of 36,428 patients from Archives demonstrates an association between patient satisfaction with their primary care physician and worse health outcomes.  They used the "Consumer Assessment of Health Plans Survey", which included four items of interest to the authors: whether the physician listened carefully, explained things well, showed respect, and spent enough time with the patient.  There was also a fifth overall item of general health care rating for all their physician visits from the past year.

For a huge data set with a lot of granularity, the authors, unfortunately, don't report the unadjusted mortality - which seems like it would be appropriate, when the major selling point is that mortality difference.  But, in any event, a few of the interesting adjusted associations:
 - Black race was more likely to be satisfied with their physicians. (1.17)
 - College graduates were less likely to be satisfied with their physicians. (0.78)
 - Public insurance was more likely to be satisfied with their physicians. (1.14)
 - Those in poor health were more likely to be satisfied with their physicians. (1.33)

That last item - the poor health - could potentially explain all the mortality difference.  They report unadjusted percentages for the rest of their measures, in addition to the adjusted OR, and then their main results come out: more satisfied patients are less likely to show up in the ED, more likely to be admitted, consumed slightly more healthcare dollars, and had slightly more prescription drug expenditures.  And, then, finally, the 1.26 increased hazard ratio for mortality.  Interestingly enough, when patients who have self-reported poor health and more than three chronic diseases are removed, the hazard ratio increases to 1.44.

So, satisfied patients in fairly good health, on whom more healthcare dollars are being expended, have significantly worse outcomes?  There must be more to this story than just patient satisfaction - which, unfortunately, seems to be all the lay press focuses on.

"The Cost of Satisfaction"

Tuesday, February 14, 2012

Automagical Problem Lists

This is a nice informatics paper that deals mostly with problem lists.  These are meticulously maintained (in theory) by inpatient and ambulatory physicians to accurately reflect a patient's current medical issues.  Then, when they arrive in the ED, you do your quick chart biopsy from the EMR, and you can rapidly learn about your patient.  However, these lists are invariably inaccurate - studies show they'll appropriately be updated with breast cancer 78% of the time, but as low as 4% of the time for renal insufficiency.  This is bad because, supposedly, accurate problem lists lead to higher-quality care - more CHF patients receiving ACE or ARBs if it was on their diagnosis list, etc.

These authors created a natural language processing engine, as well as a set of inference rules based on medications, lab results, and billing codes for 17 diagnoses, and implemented an alert prompt to encourage clinicians to update the problem list as necessary.  Overall, 17,043 alerts were fired during the study period, and clinicians accepted the recommendations of 41% - which could be better, but it's really quite good for an alert.  As you might expect, the study group with the alerts generated 3 times greater additions to the patient problem lists.  These authors think this is a good thing - although, I have seen some incredible problem list bloat.

What's interesting is that a follow-up audit of alerts to evaluate their accuracy based on clinical reading of the patient's chart estimated the alerts were 91% accurate - which means all those ignored alerts were actually mostly correct.  So, there's clearly still a lot of important work that needs to go into finding better ways to integrate this sort of clinical feedback into the workflow.

So, in theory, better problem lists, better outcomes.  However, updating your wife's problem list can probably wait until after Valentine's Day.

"Improving completeness of electronic problem lists through clinical decision support: a randomized, controlled trial."

Sunday, February 12, 2012

Eat Your Vegetables!

This may be a candidate for an IgNobel Prize, published as a research letter in JAMA: how to get schoolchildren to eat their vegetables!

Control group: normal lunch trays.  Intervention group: lunch trays with compartments specifically labeled with photographs of green beans and carrots.  Results: success!  Green bean choice went from 6.3% of children to 14.8% of children, and carrot choice went from 11.6% to 36.8%.  Amount of green bean and carrot consumption was stable on an individual basis, resulting in an overal net consumption of both green beans and carrots by their cohort.

Of course, this was only a single day intervention - my guess is the effect would fatigue - but, at least, for one day, children ate more vegetables.

This has far-reaching implications for Emergency Medicine.

"Photographs in Lunch Tray Compartments and Vegetable Consumption Among Children in Elementary School Cafeterias"

Friday, February 10, 2012

Ketamine For Acute Pain Control

So, there's effective.  And then there's effective, but insane.  I am aware that low-dose continuous infusions of ketamine are excellent adjunctive therapies to decrease narcotic use in trauma and orthopedic patients, but I have never seen ketamine used in bolus form to treat acute pain in the out-of-hospital setting.

But, that's what we have.  After an initial 5mg IV bolus of morphine, patients were randomized to receive either additional morphine or ketamine boluses - 1 to 5mg of morphine every five minutes, or 10 to 20mg of ketamine every three minutes.  Pain medication was given per protocol until relief or adverse events.  And, the ketamine group was superior - pain scores dropped 5.6 points on the numerical verbal scale with ketamine and 3.2 with morphine.

However, the ketamine group also had a 39% incidence of adverse effects, compared with 14% of the morphine group.  The morphine group had mostly nausea, with one patient exhibiting a change in level of consciousness.  However, the ketamine group had multiple patients with decreased consciousness, disorientation, and emergence phenomena.  So, while the editor capsule summary states "Supplementing out-of-hospital opiods with low-dose ketamine is an effective strategy to mitigate trauma pain" he is technically correct, but the insanity of this strategy is trying to make an evidence-based decision about intracranial imaging after iatrogenically altering your patients prehospital.

What I appreciate best about this paper is how aggressive the paramedics were with treating pain - the patients receiving morphine averaged 14.4mg, with a standard deviation of 9.4mg!  I see my residents ordering 2mg at a time and it drives me nuts.

"Morphine and Ketamine Is Superior to Morphine Alone for Out-of-Hospital Trauma Analgesia: A Randomized Controlled Trial"

Wednesday, February 8, 2012

Finally, A Useful TPA Concept

Frequent readers of this site will be familiar with my distaste for TPA in stroke - not because I think it's a therapeutically invalid option, but mostly because its use is being promoted beyond its original scope, too many stroke mimics are receiving TPA, and the published literature supporting new "innovations" in TPA have a skewed interpretation of "safe".

This paper from Stroke is the first I've seen that finally tries to determine whether a patient will actually benefit from TPA in acute ischemic stroke, rather than chaining together studies in a logical fallacy to extend treatment to a larger population.  These authors have developed the "iScore" (no affiliation with Apple Computer), which was developed by logistic regression to predict outcomes in patients with ischemic stroke not treated with TPA.  The components include age, stroke severity, stroke subtype, and medical comorbidities in a scoring system that defines low (>50% good outcome), moderate (10-50%), and high-risk (<10%) groups.

These authors then apply the iScore in a retrospective fashion to their stroke database, looking both at their TPA recipients as well as propensity-matched patients in their non-TPA group.  Now, it's not exactly prospective, randomized, controlled, but it's an interesting trick that provides a limited comparison.  The stroke patients in the low-risk group had ~12% absolute outcomes benefit from TPA, the, the moderate group ~10% benefit, and the high-risk group ~2.6%.  There were no statistically significant benefits (or harms) from TPA in the high-risk group, but those patients were >90% disabled or dead at 30 days, regardless of therapy.

One weakness the authors point out in their study - it is sometimes clinically difficult to determine stroke subtype in the acute setting based solely off clinical presentation, particularly when baseline functional status is not perfect.  Regardless, it's nice to see a paper that looks at better individualizing the risk/benefit equation for TPA - seems as though the 400 patients in the high-risk group did not benefit from spending $2000 on alteplase or the associated increased DRG billing associated with it.  Money isn't free, after all....

"The iScore Predicts Effectiveness of Thrombolytic Therapy for Acute Ischemic Stroke"

Monday, February 6, 2012

Would Free Medications Help?

It's too bad this study doesn't actually look at what I would have hoped it would - but it's interesting, nonetheless.  One of my hospitals is a true safety-net hospital and we see, repeatedly, repeatedly, repeatedly, the complications of neglected chronic disease.  One of our frequent laments is whether the costs of recurrent acute hospitalization wouldn't be prevented a hundred times over if we'd simply sink some costs into preventative maintenance care, free medications, etc.

This study almost looks at that.  This is from the NEJM which compared the outcomes of patients following myocardial infarction, and they follow a group which receives completely free medication and a group that does not.  Unfortunately, the group that does not receive free medications is still receiving heavily subsidized medication support, and is only responsible for a co-pay.

Despite only needing to come up with a co-pay, there's a significant difference in medication compliance, with an average absolute difference in full adherence with medications of ~5-6%.  With this minimal absolute difference in adherence, the full adherence group had significantly fewer future vascular events - mostly from stroke and myocardial infarction - approximately a 1% absolute decrease.  There was a non-significant decrease in total costs associated with the patients who were on the full-coverage medication plan.

Now, they don't follow-up any medication-related adverse events, so this is the most optimistic interpretation of benefits of full-coverage, but it would seem that it is overall cheaper and more beneficial to supply medications for free.  And, it makes me wonder what the results of a similar cost/health-benefit study would show in our safety-net population.

"Full Coverage for Preventive Medications after Myocardial Infarction"

Saturday, February 4, 2012

Safety-Nets & ED Length of Stay

This is a relatively intriguing public policy article in JAMA following up in a timely fashion regarding the new CMS Emergency Department quality measures.  These new measures include various time-to-X measures, including length of stay, length of time to admission from bed request, etc.  There is some concern that these quality measures may be tied to federal funding, unfairly targeting "safety-net" hospitals that are not at baseline provided with the resources to address patient flow issues.

This article is a review of the NHAMCS database, a national probability sample survey of patient visits, looking at independent predictors of increased length of stay in patients admitted and discharged from the Emergency Department.  Based on the review of this sample, they do not see a significant difference in ED length of stay - and conclude that these quality measures should not be of concern to "safety net" EDs.  However, these general time-based measures mask most of the problems encountered in "safety net" institutions.

There are some baseline differences in patient characteristics between the safety-net and non-safety-net hospitals in their sample, and they tend to work in favor of safety-net hospitals.  The safety net hospitals in this sample tended to have younger patients with lower triage acuities, which should work in favor of reduced ED overall average length of stay.  My anecdotal experience suggests that, once the quality measures track more detailed ED transit times, I believe we will see more significant deficiencies drop out in the safety-net group.

"Association of Emergency Department Length of Stay With Safety-Net Status"

Thursday, February 2, 2012

Half of Fractures Received No Analgesia

One of the new CMS quality measures involves measuring time to receipt of pain medication for patients diagnosed with long bone fractures.  While this isn't the most exciting quality measure in terms of outcomes, it is probably a reasonable expectation that fractures receive pain control, and it might be a plausible surrogate marker for overall Emergency Department operations - at least, until the powers that be focus solely on these few measures at the expense of other clinical operations.

This article is a retrospective review of all pediatric long bone fractures evaluated at their facility.  They used the electronic medical record to track the timing of any "adequate" pain medication.  They have a specific weight-based definition of "adequate" for IV narcotics, PO narcotics, and non-narcotic analgesics, and they specifically break down pain medication received within 1 hour of arrival.

They identified 773 cases in their records, and by their definitions, 75 patients received an "adequate" dose of pain medication within 1 hour.  One can quibble with their definition of "adequate" because there is a range of pain needs that don't necessarily require maximal dosing.  But, you cannot quibble with the fact that 353 children received no pain medication at all within an hour of ED arrival (or prior to ED arrival).  Certainly, some individual factors at play would result in reasonable delays to pain medication, but definitely not nearly half.

"Analgesic Administration in the Emergency Department for Children Requiring Hospitalization for Long-Bone Fracture"

Tuesday, January 31, 2012

Congratulations Michelle Lin!

One of the prominent medical education bloggers - who is really much more than just a great blogger - has been awarded an endowed chair by the University of San Francisco School of Medicine to support her medical education efforts.  This is notable to me because, in the press release, they specifically mention part of the mission of the award specifically notes "keep up her active 'Academic Life in Emergency Medicine' blog".  

It's fascinating to see how alternative publication sources and online media are influencing the perception of "academic achievement".  For instance, my JAMA commentary - a journal with Impact Factor of 30 - has been viewed as full text or downloaded as PDF ~2000 times in the last six months.  This blog, on the other hand, exceeds 400 views per day.  There's no question which has been more rewarding to my brief career so far.

Again, congratulations to Michelle!  Now she has to do, not just great things, but insanely great things!  (also, go Stanford!)

"Inaugural Academy Chair in Emergency Medicine"

Dosing Errors With IV Acetaminophen

As a follow-up to the recent posting regarding IV acetaminophen, this recent article in Pediatrics highlights a few case reports regarding overdose.

According to the authors, the most frequent error in administration when the order is written in milligrams, but the medication order is administered in milliliters - a 10-fold overdose.  All of the patients in this series received n-acetylcysteine infusion, and none appeared to suffer significant liver injury specifically attributed to the overdose.

Another lovely demonstration of the potential for iatrogenic injury in healthcare.  Even the most apparently benign orders can have unanticipated harmful consequences, and a demonstration how intravenous administration is at higher risk.

"Intravenous Acetaminophen in the United States: Iatrogenic Dosing Errors"

Monday, January 30, 2012

Scattering Tacks In The Road

I might be the only one who finds the irony in this, but, at long last, we have a rapid assay to estimate the activity of the new oral direct thrombin inhibitor, dabigatran.

Just to recap, with coumadin, we can measure PT/INR; for heparin, PTT; and for enoxaparin and its brood, (less rapidly) Factor Xa levels.

Now, we have the HEMOCLOT test.

Created and marketed by Boehringer Ingelheim, the manufacturers of dabigatran. (Edit: sorry!  This is not manufactured by Boehringer - they only published this study.  Boehringer is, however, working on a FAB antibody to dabigitran to use as an antidote, however.)

It's a beautiful piece of business to put a dangerous medication on the market, and then sell the only practical means of monitoring levels.

"Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran."

Sunday, January 29, 2012

Further Harms of IV Contrast

Radiation: cancer.  Iodinated contrast: renal injury.  Now, iodinated contrast: thyroid dysfunction.

This is a retrospective, matched, case-control study performed in Boston to evaluate any association between CT administration of IV contrast and hyper- and hypothyroidism.  They gathered 178 new-onset hyperthyroid and 213 new-onset hypothyroid cases and statistically matched them in their patient database to euthyroid "controls".  There were no significant differences between the groups at baseline - although, they don't match between terribly many clinical variables.

In the end, they find the patients who developed thyroid dysfunction had higher rates of iodinated contrast exposure - primarily from cardiac catheterization, but also from CT scans.  For hyperthyroidism, 6.1% of controls had contrast exposure, whereas 10.7% of their hyperthyroid patients had received contrast.  For hypothyroidism, the numbers are 8.5% controls vs. 12.2% hypothyroid.

It's a bit of a backwards way to approach it - ideally they'd compare a group receiving iodinated contrast against a group that did not, and observe the incidence of thyroid dysfunction - but it seems that's not the format of data to which they have access.  In any event, the physiologic basis is reasonable for the association - more data needed to confirm these findings.

Just in case you needed another reason to not order a contrasted CT.

"Association Between Iodinated Contrast Media Exposure and Incident Hyperthyroidism and Hypothyroidism"

Friday, January 27, 2012

The Harmful Rush To Hypothermia

Mild hypothermia seems to be a clinically useful therapeutic modality for improving neurologic outcomes following return of spontaneous circulation in cardiac arrest.

However, like any emerging therapy, the precise details regarding which patients are most likely to benefit and how to best apply it are still in flux.  This is an Italian registry study that gathered prospective data on all individuals at 17 hospitals who underwent therapeutic hypothermia following cardiac arrest.  The specific question asked by these authors is regarding the optimal time for initiation of hypothermia - using 2 hours after ROSC as their cut-off.

Turns out, they found an association between "early" (< 2 hours to initiation) therapeutic hypothermia and worsened mortality - 47% mortality vs. 23% mortality in the ICU.  This ~20% absolute difference in outcomes holds up over the 6 month follow-up period.  No difference in cerebral performance category is observed between the two groups, although there is a nonsignificant trend towards better CPC in the "early" group.

Hard to know what to actually do with data.  Is early hypothermia truly harmful?  Because of the observational design, it's hard to say whether there aren't confounding baseline differences in the "late" population that produces selection bias for higher survival rates.  Or, are the mortality rates higher in the early group because patients are incompletely resuscitated before initiating hypothermia?

More questions, no answers.

"Early- versus late-initiation of therapeutic hypothermia after cardiac arrest: Preliminary observations from the experience of 17 Italian intensive care units"

Wednesday, January 25, 2012

Helping TPA Help Patients Bleed

TPA for stroke, the miracle therapy that has your Emergency Department shoving people out of the way to drag someone to the CT scanner within 10 minutes of ED arrival, isn't good enough.  After all, TPA, a "clot-busting" drug that saves dying brain cells by restoring flow, only completely opens up the occluded target vessel within 2 hours in 20 to 30% of the cases, with partial recanalization occurring in up to 60%.  So, the "Texas Biotechnology Corporation" and their equity stakeholders at The University of Texas Health Science Center at Houston have undertaken a project to add additional anticoagulation - argatroban - to TPA in the interests of actually delivering on the "clot-busting" part of the promise.

This is an open-label, pilot safety study enrolling 65 patients.  It was stopped after the first 15 patients for safety review after two experienced intracranial hemorrhage.  After review, it was restarted with additional restrictions on only giving it to milder stroke patients with NIHSS score < 15 (right hemisphere) and < 20 (left hemisphere).  All patients subsequently underwent vascular imaging to assess for recanalization, and the authors reported safety outcomes for events within seven days.

The good news: sorry, no good news.  14 had sustained complete recanalization at 2 hours - 30%.  An additional 12 patients had sustained partial recanalization at 2 hours - 25%.  Of course, this isn't a controlled trial, so comparison to the recanalization rates demonstrated in existing literature is flawed - but it's certainly not an order of magnitude better.

But, this wasn't an efficacy trial, this was a safety trial.  And seven patients met the ultimate safety endpoint of death - 10%.  For intracranial hemorrhage, 19 (29%) patients had ICH, 3 of which were symptomatic. Because NIHSS score predicts bleeding, we can compare to the NINDS trial TPA group, whose median NIHSS score of 14 compared with this trial's median of 13.  The NINDS trial showed a 10.8% rate of ICH and about 4% mortality at 7 days.

Seems like a treatment with triple the ICH and double the mortality, and that isn't proven superior, shouldn't support the conclusion of "potentially safe" or that "Further study of this treatment combination appears warranted."

"The Argatroban and Tissue-Type Plasminogen Activator Stroke Study : Final Results of a Pilot Safety Study"

Monday, January 23, 2012

Progress In Combating Publication Bias

...if from abysmally terrible to embarrassingly bad represents progress.

A certain subgroup of trials registered with ClinicalTrials.gov are required to report their results within one year of conclusion of study.  These mandatory-reporting requirements include clinical trials of FDA-approved drugs, devices, or biological agents that have at least one study site in the U.S.  In the future, this will expand to include unapproved drugs.  These requirements, ideally, should help reduce publication and sponsorship bias by ensuring result availability regardless of ability to obtain publication or the desire of a pharmaceutical corporation to publish negative results.

And, so far, these authors discover that it is a tremendous success - trials subject to the mandatory reporting complied with the requirement in twice as many of identified trials as compared with registered trials that were not required to report results.

Unfortunately, twice as many was only 22% compared with 10%.  So, there's still quite a ways to go before we have full transparency in clinical trial reporting - but it's "progress."

"Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study"