Our EM Journal Club group down here at UT-Houston collaborated to write the Annals of Emergency Medicine monthly Journal Club installment, published in the November issue.
You get the questions now – at least, they’re available online starting today – but you’ll have to wait in suspense for months to hear our “answers”.
I don’t know if it was an editorial decision to put our thinly veiled IST-3 critique on page 666 of this year’s volume, but I can’t imagine it’s just a coincidence….
“rt-PA and Stroke: Does IST-3 Make It All Clear or Muddy the Waters?”
http://www.ncbi.nlm.nih.gov/pubmed/23089093
Category: Stroke
tPA of The Future
“The potential benefits associated with this approach are faster reperfusion, lower risk of hemorrhage, and earlier initiation of fibrinolytic therapy, possibly by first responders.”
Sounds lovely, yes? This is the pie-in-the-sky version of tPA, complete with flying cars and hoverbuses. It’s a “Clinical Implications of Basic Research” article from NEJM covering a Science article about shear-activated nanoparticles.
Essentially, in a mouse model of acute arterial thrombosis and pulmonary embolism, researchers bound tPA to aggregated nanoparticles. In normal vasculature, these aggregates remain unaffected. However, in regions of turbulence and shear associated with stenosis, the aggregates break apart, exposing the biochemically active tPA in greater quantities. The authors, taking cue from the current political season, promise potential 100-fold reductions in dosing of tPA associated with this serendipitously targeted approach rather than standard systemic therapy.
So, someday, instead of taking an aspirin and calling 911 – home thrombolytics?
“The Shear Stress of Busting Blood Clots”
www.ncbi.nlm.nih.gov/pubmed/23034026
“Say Anything”, Regardless of the Data
As we’ve learned from prior publications, the conclusions section of the abstract is the ideal location to “spin” your article to generate news releases. This article, from JAMA Neurology, compares thrombolysis to endovascular intervention for acute carotid artery occlusions and states “Intravenous thrombolysis should be administered as first-line treatment in patients with early cervical ICA occlusion.”
That’s a pretty strong statement, without qualifiers. And, it means it received press coverage from MedPage Today, the ACEP News network, etc.
And, they base that statement on retrospective review of a cohort of 21 patients, 13 of whom received thrombolysis and 8 of whom received endovascular intervention. The tPA patients did better, done and done, OR for early neurologic recovery 77 (95% CI 3 to 500). But, then, Table 2 is a mini-systematic review of prior studies – and it turns out the rate of neurologic recovery is more like 40-50% with endovascular treatment, not the 1 in 8 they found in their retrospective cohort. Indeed, the authors go on to state in the article “These findings are in contrast to the results of previous studies”, and have an entirely reasonable, non-conclusive discussion of their findings in context of the other daa.
But, if you want news coverage, say something “interesting” in your abstract.
“Stroke From Acute Cervical Internal Carotid Artery Occlusion”
http://www.ncbi.nlm.nih.gov/pubmed/23007611
Predicting sICH in Thrombolysis
In contrast to the lunacy of IST-3, this is another piece of work that at least in the right direction – helping us avoid harming patients with thrombolysis.
These authors use the Get With The Guidelines registry as their derivation and validation group to develop a prediction rule for sICH in the setting of thrombolytic use for acute ischemic stroke with in 3 hours of symptom onset. Subsequently, they “externally validate” their rule by applying it retrospectively to the NINDS data set. At the end of it, they come up with a not-so-handy point scale with six clinical features and twenty discrete elements, but basically, these things are bad:
– Older patients
– More severe strokes
– Higher systolic blood pressure
– Elevated blood glucose
– Asian ethnicity
– Male gender
The C-statistic was .71 on their derivation cohort, .70 on their validation cohort, and .68 on the NINDS cohort – which is more or less just OK. In practical, clinical terms, their tool more or less discriminates between folks who are at 1-3% risk of ICH, and then 6-10% risk of ICH. And, I think it’s extremely valuable when discussing risks with our patients to not use blanket generalities, and attempt to tailor the discussion to the individual.
“Risk Score for Intracranial Hemorrhage in Patients With Acute Ischemic Stroke Treated
Empiric Measurement of Bias in Unblinded Trials
This lovely article was passed along to me by David Newman during a discussion of IST-3 – the recently infamous, massive randomized trial of thrombolysis for acute stroke. There are two ways of thinking about IST-3, and how the results are viewed in the literature seems to depend how much funding you receive from Boehringer or Genentech. The first way of thinking seems to be accept the results as published, pick apart the subgroups, do statistical contortions, and then either come out in the “pro” camp (Boehringer) or the “con” camp.
The second way of thinking, supported by this article, is “garbage-in, garbage-out”. The key issue for this approach is that IST-3 is an unblinded, open trial, which introduces bias – treating clinicians and patients who believe TPA is a “promising, yet unproven” treatment (from the uncertainty principle of the study) are perceived as more likely to contribute to favorable reported outcomes when receiving the experimental intervention. This effect is probably even more pronounced given that much of the follow-up scoring for the Oxford Handicap Scale was performed by mail-in questionnaire, rather than standardized expert evaluation – which has rather poor kappa to begin with.
Page three of this article delves into the empiric analysis of the impact of blinding, and the relative likelihood of unblinded trials to report favorable outcomes. Essentially, the relative chance of reporting both favorable and unfavorable outcomes are significantly affected. In clinical terms, this leads to presentation of results in which the benefits are exaggerated and the harms are minimized. In the context of IST-3, this essentially means the likelihood of any hidden positive effects vanishes, while the poor outcomes are underreported – and it’s more “negative” than “neutral”.
The authors also note they are preparing a systematic review of trials with blind and non-blind outcome assessors, which would be particularly apt to IST-3, as well.
“Blinding in Randomized Clinical Trials: Imposed Impartiality”
http://www.ncbi.nlm.nih.gov/pubmed/21993424
Warfarin and tPA Mix – If They’re Subtherapeutic
These authors almost have a conclusion I can’t quibble with – but, rather than “Among patients with ischemic stroke, the use of intravenous tPA among warfarin-treated patients (INR ≥1.7) was not associated with increased sICH risk compared with non-warfarin-treated patients” I would add the caveat to say “after multiple adjustments”.
This is a retrospective registry review published in JAMA, comparing the rate of sICH in warfarin-treated patients with non-warfarin-treated patients who received tPA for ischemic stroke. And, 5.7% of warfarin patients developed sICH vs. 4.6% in the non-warfarin group. However, after adjustments for multiple variables – the warfarin group tended to be older, had more previous strokes, and had higher NIHSS – the OR was 1.01. Not terribly surprising there wasn’t much difference, considering the mean INR in the warfarin cohort was only 1.2. Their confidence intervals start getting very wide above 1.6, but there’s suggestion of a clear association with increasing sICH as the INR increases.
There are plenty of reasons not to give tPA, but subtherapeutic warfarin use probably should not exclude patients from consideration.
“Risks of Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Receiving Warfarin and Treated With Intravenous Tissue Plasminogen Activator”
http://jama.jamanetwork.com/article.aspx?articleid=1199153
The Third International Stroke Trial: IST-3
The Cochrane systematic review of the 11 complete trials of rt-PA for 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
Mobile Stroke Units – Probably Not Helpful
Door to needle times too long? Well, take the needle to the patient, then.
This is an interesting idea that, unfortunately, probably isn’t a good idea. They loaded a CT scanner, a stroke physician, a paramedic, and a mobile laboratory into a truck, and sent it out to meet acute stroke patients in the field. The primary endpoint of the study – alarm to thrombolysis time – was great, with a mean time from alarm to therapy decision of 35 minutes.
The authors are very excited about the concept – as they feel the accelerated time scale in terms of acute stroke thrombolysis represents a paradigm shift in management. Unfortunately, the patient-oriented outcomes – which were not part of the primary endpoint – don’t support their enthusiasm.
All their safety and therapeutic outcomes are underpowered, but, out of their 47 intervention patients and 53 control (in-hospital thrombolysis) patients, 12 vs. 6 were treated stroke mimics and 3 vs. 0 were dead within 7 days. Comorbidities and stroke severity should have favored the intervention group, so, these outcomes are surprising. But, it is underpowered, so more data is needed.
“Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial.”
http://www.ncbi.nlm.nih.gov/pubmed/22497929
TPA is Dead, Long Live TPA
I’m sure this saturating the medical airwaves this morning, but yesterday’s NEJM published a study which they succinctly summarize on Twitter as “In trial of 75 pts w/ acute ischemic #stroke, tenecteplase assoc w/ better reperfusion, clin outcomes than alteplase.”
Well, that’s very exciting! It’s still smashing a teacup with a sledgehammer, but it does appear to be a more functional sledgehammer. Particularly encouraging were the rates of sustained complete recanalization – which were 36% at 24 hours for alteplase and 58% for tenecteplase – and the rates of intracranial hemorrhage – which were 20% for alteplase and 6% for tenecteplase.
However, the enthusiasm promoted by NEJM, and likely the rest of the internet, should be tempered by the fact that there were only 25 patients in each arm, and there is enough clinical variability between groups that it is not yet practice changing. This was a phase 2B trial, and it is certainly reasonable evidence to proceed with a phase III trial.
Unfortunately, in a replay of prior literature, the authors are all affiliated with Boehringer Ingelheim, the manufacturer of tenecteplase.
“A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1109842
Addendum: As Andy Neil appropriately points out, tenecteplase has been studied before – 112 patients over several years, terminated early due to slow enrollment – without seeing a significant advantage.
Pharmaceutical Bias Article in EM News
Imagine my surprise to be paging through Emergency Medicine News this month and stumble upon an article about TPA in stroke – and find that it’s a review of my Western Journal of Emergency Medicine article from last summer.
The EM News article is here:
http://journals.lww.com/em-news/Fulltext/2012/03000/Journal_Scan__Pharma_Bias_Detected_in_Thrombolytic.6.aspx
And my West JEM article is open access, available here:
http://escholarship.org/uc/item/9504g8md