Friday, May 25, 2012

The Third International Stroke Trial: IST-3

The Cochrane systematic review of the 11 complete trials of thrombolysis encompasses 3,977 total patients.  IST-3 enrolled 3,035, nearly doubling our cohort of randomized data.  Unfortunately, this influx of new data does very little to resolve any of the outstanding issues regarding stroke care.

Before even looking at the results, it's particularly important to wade through the dense study design and methods - and realize this is a non-blinded study in which patients were enrolled if the treating clinician was "uncertain of the benefits or harms of TPA".  Considering this study began back in 2003, prior to ECASS III, a large chunk of their enrolled patients fell into the 3-4.5 hour time frame, with the remaining majority falling into the up to six hour limit.  The other major area of interest this study was intended to evaluate was the efficacy and safety in patients aged >80 years of age, of which they enrolled 1,616.  And, in a shocking twist, this study actually manages to enroll TPA and control cohorts with nearly identical baseline variables.

IST-3 is negative for the primary endpoint, which is the proportion of patients functionally independent at six months (Oxford Handicap Score 0-2, a scoring system similar to the Modified Rankin Score), with a 95% CI of 0.95 to 1.35.  On ordinal secondary analysis, there are non-significant trends towards improvements in OHS favoring rt-PA, which is probably what you'll hear when people refer to IST-3 as "positive."

Then, regarding the patients aged >80, there is a trend towards benefit with TPA, CI 0.97-1.88.  Unfortunately, in a neutral study, that means there is actually a trend towards harm in ages <80, CI 0.67-1.26.  Likewise, between 4.5-6 hours, there is a trend towards benefit with TPA, CI 0.89-1.93.  Therefore, between 3 and 4.5 hours, there is a trend towards harm with TPA, CI 0.50-1.07.  TPA is also essentially neutral or trends towards harm up until NIHSS 14, with more pronounced benefit shown in severe strokes.

Interestingly enough, the "blinded" phase of the study trended towards favoring control, CI 0.42-1.98, while the open phase favored TPA, CI 0.89-1.45.

So, what does this all mean?  It means, there's still plenty of shades of grey open for interpretation and discussion.  Indeed, when added into the systematic review, IST-3 brings several of the previously significant benefits back into the nonsignificant range.  To me, this reinforces what I've been arguing for awhile - that the focus shouldn't be on massive expansion of TPA eligibility, but specifically targeting those who have the best benefit/harm profile.

As with any major stroke trial, many of the investigators have financial associations with Boehringer Ingelheim.

"The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial"
http://www.lancet.com/journals/lancet/article/PIIS0140-6736(12)60738-7/fulltext

Wednesday, May 23, 2012

Defensive Medicine is Defensive

Sometimes, people order a CTA chest to evaluate for pulmonary embolism because they've used the available evidence to risk-stratify the patient for a pulmonary embolism, and it's an important diagnosis to make.  Sometimes, people order CTAs of the chest to evaluate for pulmonary embolism out of defensive practice, in order to avoid missing a pulmonary embolism.

There are some holes in this paper, considering how few patients in their cohort received the study intervention.  However, the general statistical gist was is that physicians who indicated that defensive medicine played a role in their ordering decisions had a much lower yield on their CTA for PE.  Conversely, elevated Wells/Geneva scores were associated with higher yield CTA.  Positive d-Dimers and patient request were non-significantly positively associated with increased CTA yield.

Not precisely an earthshaking paper, but it does weakly reinforce what we probably already suspected - defensive medicine harms the patient and the healthcare system.

"Ordering CT pulmonary angiography to exclude pulmonary embolism: defense versus evidence in the emergency room"
www.ncbi.nlm.nih.gov/pubmed/22584801

Monday, May 21, 2012

Plain C-Spine Radiography in Children

In adults, the use of plain radiography has largely been replaced in the U.S. by computed tomography over concerns regarding missed injuries - and some literature even argues that, given the right clinical circumstances, even a normal CT scan is inadequate.  But, in children, the harms of radiation exposure are greater, so pediatrics has been more hesitant to move to CT as the first imaging study of the cervical spine in blunt trauma.

Unfortunately, this retrospective PECARN study of children with cervical spine injuries isn't as helpful as one would hope.  The authors identified 204 children, 58 of whom were aged less than 7 years, who sustained a CSI and had plain radiographs of the cervical spine performed.  Of these patients, 127 patients had a definite injury on plain radiography.  41 additional patients had "possible" abnormalities.  Then, 20 films were judged to be inadequate by technique.  And, finally, there were 18 adequate radiographs with normal findings who subsequently had a CSI identified.  The overall sensitivity, then, was 90% (CI 85-94%) - which compares very similarly to the sensitivity in adults from the 34,000 patients in the NEXUS study.

The authors note that most missed injuries fell into two general categories: they were either subtle and non-morbid, or the patients were altered/intubated/focal neurologic findings.  It is probably still reasonable to start with screening plain-film radiography and use clinical judgment to determine when CT may be necessary, but if you're looking for airtight evidence to guide your decision-making, CSI in children is too rare to generate that sort of data.
"Utility of Plain Radiographs in Detecting Traumatic Injuries of the Cervical Spine in Children"