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 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 cross sectional study"