My correspondence regarding this article was published in Stroke a couple days ago. I’d like to say the author response is earth-shattering and insightful, but while it is not, they were kind enough to respectfully reply.
Sadly, the correspondence and response is available only to subscribers – but I have PDFs available for educational purposes….
“Letter by Radecki Regarding Article, ‘Safety of Thrombolysis in Stroke Mimics: Results From a Multicenter Cohort Study'”http://stroke.ahajournals.org/content/early/2013/08/08/STROKEAHA.113.002040.full.pdf+html
Category: Stroke
tPA Proponents Want to Have It Both Ways
I’m sure I sound like a bit of a broken record – yet again covering further attempts by the stroke neurology literature to continue expanding use of tPA for acute stroke beyond its initial, narrowly selected treatment population. This observational, retrospective review from SITS-ISTR would like you to know:
“…this is the first observational study demonstrating that intravenous alteplase therapy within 4.5 to 6 hours of stroke onset for patients compliant with other EU approval criteria resulted in comparable rates of SICH, mortality, and functional independence to treatment initiated within 3 hours. This observation persisted in the multivariate analysis after adjustment for baseline imbalances.”
No difference in outcomes between 0-3h, 3-4.5h, and 4.5-6h – in both guideline-compliant and protocol-violation cohorts, and both adjusted and unadjusted results. The authors, all receiving honoraria or grant support from Boehringer Ingelheim would like you to believe this analysis, also funded by Boehringer Ingelheim, supports a benefit for tPA up to six hours.
…but didn’t we just cover Jeff Saver’s JAMA article that “proved” an obvious time-to-treatment effect, favoring faster treatment?
Which of these observational, retrospective, registry reviews provides us the truth? Is there a time-to-treatment effect that decays benefit with time, or, as this registry suggests, no difference between any time frames?
I suppose it depends on your specific professional conflicts-of-interest.
“Results of Intravenous Thrombolysis Within 4.5 to 6 Hours and Updated Results Within 3 to 4.5 Hours of Onset of Acute Ischemic Stroke Recorded in the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register (SITS-ISTR)”
www.ncbi.nlm.nih.gov/pubmed/23689267
Continuing Debate Over Thrombolysis
The debate spurred by Jeanne Lenzer’s report on conflicts of interest by guideline writers continues.
Drs. Grotta, Hoffman, Saver, Newman, Solomon, Klauer, Marchidann, Sandercock, Quinn and myself all contribute to the back-and-forth regarding the future of tPA in stroke, while Dr. Geisler and Bracken respond regarding the data for use of steroids in spinal cord trauma. Some truly amazing responses by leading physicians on both sides of the issues.
“Why we can’t trust clinical guidelines”
Rewriting The Inconvenient Rules on tPA
Stroke neurologists spent the first decade of the tPA era explaining away negative studies and excluding patients from meta-analyses secondary to “protocol violations”, emphasizing that strict adherence to NINDS criteria supports clear benefit to tPA. As we’ve seen, however, the new push is rather to take back the night, expanding the treatment window out to 4.5 hours, 6 hours, the extreme elderly, and all sorts of previously excluded patients.
But we don’t need evidence to do that – we just need Genentech to fly a select group of experts out to a meeting so they can issue a report in support of throwing out the previous exclusion criteria: The Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force. The astute reader might already recognize the prevailing bias just from the acronym for their group.
This is the first report, specifically addressing “rapidly improving stroke symptoms”. I agree with the general concept – if a severely disabled patient has shown some improvement, but are still profoundly limited – it is reasonable to consider them a candidate for treatment. The original NINDS group was interested primarily in excluding TIAs – folks they thought would go on to have zero residual disability. However, these authors are already over the cliff on treating nearly every improving and mild stroke symptom. In true flabbergasting lunacy, a majority of surveyed participants wouldn’t even randomize patients who rapidly improved to an NIHSS of 0 into a clinical trial comparing outcomes with tPA vs. placebo – unless the patient had zero disability, they would simply treat.
I’m no longer surprised by such extreme viewpoints. After all, here are the authors’ significant COIs:
Broderick: Genentech, Novo Nordisk, Schering Plow, PhotoThera
Grotta: none
Kasner: Genentech
Khatri: Genentech (for a study called “Potential for rtPA to Improve Strokes with Mild Symptoms”!), Penumbra, Jannsen, Lake Biosciences, Medical Dialogues
Levine: Genentech
Meyer: Genentech, The Medicines Company
Panagos: Genetench
Romano: Genentech
Scott: none
Kim: none
“Logistical support for the in-person meeting was provided by Infusion, An InforMed Group Company, who was funded by Genentech, Inc. Travel funds (lodging, airfare, and food) to this meeting were also provided to some participants by Genentech, Inc.”
I cannot fathom why stroke neurologists are still befuddled by continued skepticism towards their tPA recommendations when they persist in pumping out recommendations saturated by bias.
“Review, Historical Context, and Clarifications of the NINDS rt-PA Stroke Trials Exclusion Criteria : Part 1: Rapidly Improving Stroke Symptoms”
www.ncbi.nlm.nih.gov/pubmed/23847249
23.4% – The Next Great Hypertonic Saline
Mannitol and hypertonic saline are the most commonly used medications to ward off the catastrophic complications of malignant increased intracranial pressure. Hypertonic saline, in my experience, has typically been 3%, but there are multiple different concentrations in use.
These authors perform a systematic review and meta-analysis of 23.4% saline. After all, the theory goes, a more osmotically powerful concentrated solution will exert greater physiologic effects. They identified 11 articles, six of which they included in a meta-analysis to identify an effect size for intracranial pressure reduction. Using the pooled data, the measured effect was a 55.6% (CI 44%-67%) decrease in ICP within 60 minutes. Their systematic review uncovered few adverse effects of 23.4% – transient hypotension and rare hemolytic anemia – and even reported acute reversal of herniation syndromes with good neurologic outcomes.
There is a ton of heterogeneity between studies – both in dosing of 23.4% saline, co-administration of mannitol, and underlying pathophysiology of ICP. Most studies are also tiny, ranging between 8 and 68, and either retrospective reviews or prospective non-random selection. Many studies did not report patient-oriented outcomes, so it’s hard to truly compare this practice to the current standard of care.
That being said, it seems interesting for potential use as “rescue” therapy when the alternative is permanent cerebral asphyxiation – and further study is needed to describe the appropriate (if any) population for use.
For reference: the salinity of seawater is about 3.5%, the Great Salt Lake varies between 5-27%, and the Dead Sea is approximately 33.7%. Definitely not appropriate for a peripheral intravenous line!
“High-Osmolarity Saline in Neurocritical Care: Systematic Review and Meta-Analysis”
BMJ, Clinical Guidelines & tPA
A little hullabaloo today regarding a new report in the BMJ regarding problems with the creation of clinical practice guidelines, including a substantial portion of the article devoted to the conflicts of interest swirling about the use of tPA in acute ischemic stroke.
There have already been personal attacks – even from ACEP’s official twitter account – against the author. These seem to be motivated by the author’s coverage of the new ACEP/AAN clinical practice guidelines for tPA – and miss the overall point that patients are best protected and served by guidelines that are formulated in the absence of conflict-of-interest. tPA for acute stroke, erythropoetin endorsement by the National Kidney Foundation, the errant one-man crusade for steroids in spinal cord trauma, and cholesterol treatment guidelines are all discussed in the context of cautionary tales regarding the influence of conflict-of-interest.
Whichever side of the expand/limit tPA in acute stroke debate you fall upon, the issues of sponsorship bias, one-sided panelists on a still-controversial practice, and lack of open peer review for the ACEP/AAN guidelines ought to be unacceptable. Patients and practicing clinicians benefit from healthy debate and recognition of the limitations of the science, which seems clearly to have been lacking in the creation of these guidelines.
“Why we can’t trust clinical guidelines”
http://www.bmj.com/content/346/bmj.f3830
Time-to-Treatment Effect “Confirmed”
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
tPA Equally (In)Effective for Wake-Up Stroke
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
Beware Observational Conclusions
“High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.”
Jerry Hoffman has mentioned the exercise to, while reading, expand any instance of the word “may” to “may or may not” – to help erase the positive bias of speculative conclusions. And, this is one of those perfect circumstances where the lukewarm endorsement from this abstract conclusion ought to be predicated with a pound of cautionary conditionality.
These authors call their study SAMURAI-ICH, and it’s a prospective, observational study regarding the safety of early blood pressure reduction in intracerebral hemorrhage. What this really means is they thought aggressive BP lowering was going to be awesome – despite only having various bits of inconclusive evidence – so they made wholesale practice changes, and then started a registry to monitor outcomes. So, you can see the bias already.
And, verily, there is an association between their ability to lower blood pressure in ICH and favorable outcomes. Now, their “favorable outcomes” cohort was also young, less disabled at baseline, and had smaller ICH hematoma volume. Through the magic of statistical models, they attempt to control for all the various prognostic catastrophes, and thusly they arrive at their significant association.
But, finally, this observation doesn’t in the slightest explain whether the blood pressure control improved outcomes – or whether it was simply easier to lower blood pressure in patients whose cerebrovascular physiology was less deranged by smaller insults, and who went on to have good outcomes. Aggressive antihypertensive treatment “may or may not” ameliorate clinical outcomes, indeed.
Beware observational conclusions!
“Systolic Blood Pressure After Intravenous Antihypertensive Treatment and Clinical Outcomes in Hyperacute Intracerebral Hemorrhage : The Stroke Acute Management With Urgent Risk-Factor Assessment and Improvement-Intracerebral Hemorrhage Study”
www.ncbi.nlm.nih.gov/pubmed/23704107
INTERACT2: ICH Half-Truths
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