Category: Medication Safety

The holy grail of tPA proponents, the time-to-revascularization theory, is the subject of this most recent article in JAMA.  This is a data mining exercise from the Get With The Guidelines-Stroke Registry – and, actually, there’s not a lot to say.  They evaluate 55,000 patients from the registry, and there are significant differences between the cohorts receiving tPA between 0-90, 91-180, and 181-270 minutes – so all their outcomes are dependent on multiple statistical adjustments.

And, when I say multiple, I mean overwhelming:

The variables used in the risk models were patient-level and hospital-level risk adjustors that were expected to be predictive of outcome, based on empirical analysis, prior literature, and clinical judgment.

Patient-level factors included age, race/ethnicity, sex, medical history (including atrial fibrillation, prosthetic heart valve, previous stroke or TIA, coronary heart disease or prior myocardial infarction, carotid stenosis, peripheral vascular disease, hypertension, dyslipidemia, diabetes, and current smoking), stroke severity (NIHSS), an age-by-NIHSS interaction term, arrival time during regular work hours (7 AM-PM Monday-Friday), arrival mode (ambulance, private vehicle), and select classes of vascular risk prevention medications prior to admission.

Hospital-level factors included hospital size, region, teaching status, rural location, certified primary stroke center status, average number of patients treated with tPA annually, and average number of annual stroke dis- charges. All variables were included in the predictive models without use of a stepwise or other formal variable selection process.

The pharmaceutical industry conflict-of-interest disclosure is even longer.

These folks could have made these data say whatever they desired with their statistical weighting.  They report a positive association with time-to-treatment and improved outcomes; the astute reader may interpret this as they are wont.

It is also worth mentioning the earlier time-to-treatment populations are probably more likely to include stroke mimics and TIAs – both of which tend towards excellent outcomes, with or without tPA.  The percentage of stroke mimics treated with tPA ranges between 6.5% and 15.5% at academic centers using MRI as imaging confirmation, and has been estimated to be as high as 25% to 29% in community settings.  The GWTG-Stroke registry specifically fails to account for stroke mimics in their coding instructions – a patient that receives tPA and rapidly improves is to be coded as “aborted stroke”, even though contemporary evidence throws this concept into doubt.

Regardless, the percentage of stroke mimics confounding the results likely dwarfs the magnitude of effect of the proposed time-to-treatment association reported by these authors.

“Time to Treatment With Intravenous Tissue Plasminogen Activator and Outcome From Acute Ischemic Stroke”
http://jama.jamanetwork.com/article.aspx?articleid=1697967

This is a, yet another, study in Stroke of folks claiming it is “safe” to use thrombolysis on patients who are found to have suffered a stroke while sleeping – the so-called “wake-up stroke” population.

The specific claim made is “This retrospective analysis of data in thrombolysed consecutive acute ischemic stroke patients shows no significant differences in mortality, functional outcomes, or bleeding rates between WUIS patients with no early ischemic change on CT and those treated within 4.5 hours of stroke onset.”

…because their sample size is so small the absolute differences are still within the statistical variation expected by chance.  This is, unfortunately, a recurring theme I see in these stroke publications, many of which are retrospective registry reviews.  Their groups are statistically not different, but this is owing to failed statistical power in study design, as opposed to clinically meaningful equivalence.  This is a major difference between retrospective and prospective studies – in which prospective studies choose specific absolute differences necessary to define clinically meaningful equivalence, and then perform power and sample size calculations based on these constraints.

Their outcomes are, incidentally, also simply terrible.  They publish a figure comparing outcomes with their wake-up stroke population to their 0-4.5 hour thrombolysis reference group – a 326 patient reference group with 18% mRS 0-1 and a 26% mortality.  But then, they further break out the 197 patients from that group that received tPA within the ECASS III license criteria, showing that compliance with guidelines leads to 32% mRS 0-1 and 18% mortality.  This therefore implies the other 129 patients – the ones who received tPA outside the license criteria – had utterly dismal functional outcomes and frighteningly high mortality.

Someone needs to go down to King’s College and check up on them and make sure all this off-label use isn’t just costly killing fields.

“A Case-Controlled Comparison of Thrombolysis Outcomes Between Wake-Up and Known Time of Onset Ischemic Stroke Patients”
http://www.ncbi.nlm.nih.gov/pubmed/23723307

There have been dueling schools of thought regarding atraumatic intracerebral hemorrhage: let the brain autoregulate its own blood supply and don’t artificially lower the blood pressure, or use intravenous agents to lower blood pressure because there’s evidence it decreases hematoma expansion.  However, until now, there’d been no evidence that decreased hematoma size correlated with meaningful patient-oriented outcomes.

So, what are they saying about INTERACT2, the open-label, randomized trial of intensive BP control (SBP <140 mmHg) versus guideline-concordant BP control (<180 mmHg)?

@medwireNews INTERACT2 contradicts “longstanding dogma”, supports intensive BP reduction in ICH #eurostroke2013 

@MedscapeNeuro INTERACT2: Intensive Blood Pressure Lowering Benefits ICH 

@IctusClnic #ESCLondon2013 Surely INTERACT2 will have a great impact in blood pressure management after intracranial hemorrhage.

Pfffft.

The primary outcome was reduction in death or major disability (modified Rankin scale 3 to 6) at 90 days.  Unadjusted outcome was statistically negative, 52.0% to 55.6% (OR 0.87, 95% CI 0.75 to 1.01), but favoring intensive BP control.  Their secondary outcomes, which uses the conceptually messy tool of ordinal analysis, essentially magnified the effect of that 3.6% absolute difference in mRS outcomes and goes on to show that folks with less disability end up happier and more functional.

However, the baseline functional characteristics favored the intensive BP group, with median NIHSS score of 10 vs. 11.  68% of the cohort was from China – which has uncertain effects on external validity.  Over seven different intravenous antihypertensives – including the most popular agent, urapidil – were used for BP lowering, further muddling precise treatment guidance.  Most ICH was small volume hemorrhage, and BP treatment didn’t seem to have much different on hematoma expansion – so it’s hard to say why the intensive control group seemed to have a trend towards superiority.

And, finally, even though approximately half of the 1436 assigned to guideline-recommended treatment group had baseline systolic BP >180 mmHg, only 303 of them received an anti-hypertensive agent within 1 hour of study assignment.  It might be more appropriate to describe this study as “intensive” vs. “poorly guideline-concordant” BP control – would outcomes have been more favorable if more of the guideline-concordant group actually had their systolic BP lowered below 180 mmHg?

In any event, to call this a practice-changing paradigm is a only a half-truth.  It does appear safe, at least, to make a brisk and reasonable effort to lower BP in atraumatic, intracerebral hemorrhage.  Whether “intensive” control is needed with a nicardipine infusion, such as in the upcoming Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial, is still uncertain.

“Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage”
http://www.nejm.org/doi/full/10.1056/NEJMoa1214609