Category: Neurology

No More Excuses For Not Giving TPA

Rather than restrict TPA for acute ischemic stroke to the small cohort of patients identified by strict exclusion criteria in the few completed randomized trials, the current crusade is to continue to try and give it to more patients on the fringes of eligibility.

This article promotes giving TPA to patients with “minor or rapidly improving” strokes, because the lead author (sponsored by Genentech) sees this classification of patients is responsible for 50% of the documented reasons why patients were excluded from receiving TPA.  In fact, if patients with mild and improving strokes received TPA, it would immediately double the rate of TPA use – and provide potentially excellent outcomes at 90 days for the manufacturers.

They base their assertions on a retrospective, uncontrolled evaluation of the discharge disposition of patients in this “minor or rapidly improving” cohort – and observe that only 72% of patients in this group were discharged home.  In their mind, patients could do much better (as measured by disposition location) if they had received TPA – and their final conclusion is that this exclusion criteria should be further studied so that it may be revoked.

But, their conclusions are a preposterous farce conjured out of fictionalization of the data.  Considering the median age of their cohort was 72, 30% of whom had prior stroke/TIAs, 26% were diabetic, 76% were hypertensive, etc. – the sheer fact that only 28% went to rehab/SNF/died is probably rather good performance.  The authors also admit they had no information regarding the initial residence of this mostly elderly cohort and have no idea if the patients discharged to nursing facilities originally resided there.  Finally, the article additionally states “outcomes for patients with mild/rapidly improving stroke were better than for rtPA-treated patients with mild stroke (NIHSS score of 0 to 5) but worse for patients with a final diagnosis of TIA.”

Yes, they compared this mild stroke cohort data to the mild stroke cohort data that received TPA, and all outcomes – adjusted and unadjusted for NIHSS – significantly favored the non-TPA cohort.

….so the obvious conclusion is to find a way to give more of them TPA.

Lunacy.  Another example of bad literature undermining trust in a probably efficacious treatment.

“Outcomes in Mild or Rapidly Improving Stroke Not Treated With Intravenous Recombinant Tissue-Type Plasminogen Activator”
www.ncbi.nlm.nih.gov/pubmed/21903949

ED Blood Pressure Management In Acute Stroke Is Terrible

This is a non-TPA article regarding the medical management of hypertension in acute ischemic stroke in the Emergency Department.

The authors remind us that for every 10 mmHg drop in SBP <150 mmHg, there is a 17.9% increase in risk for death at 14 days.  They additionally remind us that antihypertensive therapy is only recommended for BP >220/120 mmHg, with a 15-25% goal decrease in the first 24 hours.

This is a retrospective review of cases from 16 Cincinnati region hospitals looking at the blood pressure observed in the ED along with any treatment.  They found 1739 cases, 1520 of whom did not receive treatment and 219 who did.  It turned out that 2.6% of the non-treated patients should have had some blood pressure lowering – oops.  But, amazingly even worse, only 31.5% of patients who did receive treatment actually required lowering.

Of the 217 patients that were treated, 52 of them had greater than a 20% drop in blood pressure in the Emergency Department.  So, we treat a lot of blood pressure that shouldn’t be treated – and when we treat it, it is not uncommon to treat it too aggressively.

Stop it!

“Emergency Department Adherence to American Heart Association Guidelines for Blood Pressure Management in Acute Ischemic Stroke”
http://www.ncbi.nlm.nih.gov/pubmed/22033993

TPA Is “Safe” In Prior Stroke and Diabetics

Another recent Journal Watch article about TPA – relaying the manufacturer-sponsored message that TPA can, in fact, be given to the patients who were excluded from ECASS III because of diabetes or prior stroke.

Papers like this are fabulous.  I am 100% in agreement with the physiologic premise that timely reperfusion of the ischemic penumbra is beneficial in acute stroke.  I am less enthusiastic about using systemic thrombolysis, because it’s akin to smashing a teacup with a sledgehammer.  But, until PCI-like therapy is available/safe for the brain, it’s all we have.

I am really tired of endless papers from the TPA literature with authors falling all over themselves to present fundamentally flawed data as definitive evidence.  In this paper, the authors take the non-randomized TPA population from the SITS-ISTR – and compare it to the non-randomized, non-thrombolyzed population from the VISTA registry.  Why is this a problem?  Because even though the relative differences are large, the absolute differences are small – and we’ve already see that what makes the largest absolute difference is stroke after-care, and that all stroke centers are not created equal.  The authors acknowledge this, but then justify their results by stating that their numbers are similar to prior, retrospective, non-randomized comparisons performed on subsets of registry data.  It’s a self-fulfilling prophecy.

They conclude with “Hence, we find no justification to exclude patients from receiving alteplase for acute ischemic stroke if they have a [prior stroke] and also have [diabetes mellitus]” – which is true, unless it bothers you that the mRS 6 (dead) group nearly doubles when TPA is given to the stroke/diabetes groups.  Imagine what the reaction to ECASS III would be if TPA wasn’t 52% good outcome vs 6.7% death – and was one of these 29% good outcome vs. 23% death, or 25% good outcome vs. 28% death comparisons from the registry data (totally different baseline severity vs. ECASS III, just throwing the numbers out there for hyperbole).

…and, the obligatory:

“Dr. Mishra reports no disclosures. Dr. Ahmed is an employee of SITS International, which received a grant from Boehringer Ingelheim for the SITS-MOST/SITS-ISTR study with alteplase. Dr. Davalos has received speaker or consultancy honoraria from AstraZeneca, Boehringer Ingelheim, Lundbeck Inc., ev3, Ferrer, and Talecris Biotherapeutics. Dr. Iversen has served on scientific advisory boards for Boehringer Ingelheim and Allergan, Inc.; and has received research support from the Danish National Advanced Science Foundation. Dr. Melo reports no disclosures. Dr. Soinne serves on speakers’ bureaus for and has received speaker honoraria from Boehringer Ingelheim, Pfizer Inc, and Siemens; and has served as a consultant for Boehringer Ingelheim. Dr. Wahlgren serves as Chairman of the SITS Scientific Committee; has served on scientific advisory boards for Boehringer Ingelheim and ThromboGenics NV; has received funding for travel and speaker honoraria from Boehringer Ingelheim, Lundbeck Inc., and Ferrer; and serves on the editorial boards of Stroke and Cerebrovascular Diseases. Dr. Lees serves on scientific advisory boards for Boehringer Ingelheim, Talecris Biotherapeutics, Lundbeck Inc., Ferrer, and PhotoThera; and has received speaker honoraria from Boehringer Ingelheim, Lundbeck Inc., ThromboGenics NV, and Talecris Biotherapeutics.”
I want to use TPA to treat stroke without reservations, but the literature is broken.  Still hoping IST-3 will help define a low-risk population that benefits.
“Thrombolysis outcomes in acute ischemic stroke patients with prior stroke and diabetes mellitus”

ED Nursing Hand-Offs & Stroke Outcomes

Yet again, in the “little things matter more” series of dull, but important, Emergency Department literature.  TPA or no, what matters more in terms of their ultimate outcome is everything that happens down the line.

This is a retrospective review of consecutively-collected prospective registry data for acute ischemic stroke patients in Louisiana, looking at patients who were present in the ED during shift change.  They simply reviewed and compared the outcomes of 366 consecutive patients, looking at good outcome, neurologic worsening, discharge status, and development of pneumonia.

There are, unfortunately, huge, irreconcilable differences between the shift-change and non-shift change groups – the group that was in the ED had milder strokes and was less likely to have TPA 9.5% vs. 4.5% – but still ended up developing more pneumonia.  After their mathematical adjustments for various baseline differences, being present during shift change ended up with a five-fold increased odds of developing pneumonia, resulting in decreased likelihood of discharge to home or rehab.  The authors attribute this primarily to non-adherence with stroke unit dysphagia precautions, which is probably reasonable.  This is just retrospective and observational, but it probably identifies an important operations issue for the Emergency Department.

So, perhaps it does matter whether you give TPA or not – if TPA gets them out of the ED faster, that will help more than anything.

“Emergency Department Shift Change Is Associated With Pneumonia in Patients With Acute Ischemic Stroke”
http://stroke.ahajournals.org/content/42/11/3226.short

The Cure For Bleeding is More Bleeding?

Intraventricular TPA for intraventricular hemorrhage – I wouldn’t call it counter-intuitive, but I would certainly call it unusual.
This is a small placebo-controlled, randomized, blinded, prospective trial enrolling 48 patients with intraventricular hemorrhage requiring placement of an intraventricular catheter for CSF drainage.  They were testing the theory that low-dose TPA would assist in clot breakdown, thus speeding recovery.  There are probably not significant differences between groups – although the placebo group was oddly mostly women.  Also fascinatingly, the predicted mortality of each group was ~74% – and ended up being 23% in the placebo group and 19% in the TPA group.  Serious adverse events including 61% in the TPA group and 36% in the TPA group.  Due to the small sample size of the cohort, none of these differences reached statistical significance.
Unfortunately, the screaming major flaw in this study is that they do not truly have a control group – a true control would be standard care without the use of placebo administration through the intraventricular catheter.  Their rate of ventriculitis (8% and 9%) is higher than the typically expected rate for intraventricular catheter placement (probably below 5%), and is consistent with prior studies that showed increased incidence of ventriculitis when the catheter is used for administration of drugs or irrigation.  So, the safety profile and minimal outcome trend in favor of the TPA group can’t truly be evaluated because it isn’t being compared to the current standard of care, which is leaving the catheter alone for drainage only.
The authors conclude these results support further evaluation – which is already ongoing in the CLEAR III trial – and that the treatment met their pre-defined safety profile cut-offs.  Unfortunately, yet again, propagating their skew on the data is motivated by financial interests – Johns Hopkins has applied for a use patent and Genentech is behind the rtPA licensing and funding.  
“Low-Dose Recombinant Tissue-Type Plasminogen Activator Enhances Clot Resolution in Brain Hemorrhage”

Ethanol – Miracle Drug (For Stroke)

From China, in Stroke, an animal model (poor rats, as usual) of MCA ischemia, collagenase-induced ICH, and post-TPA ICH.  Rats received either 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg ethanol after two hours of MCA occlusion.  Performance on various foot, balance, and parallel behavioral testing significantly favored the ethanol treatment group with initial and sustained reduction in errors as compared to the no-treatment group.

No difference was found between groups in induced ICH volume, and in their (small) series, no increase in ICH after TPA administration.  A transient increase in expression of hypoxia-inducible factor 1-alpha favoring ethanol was seen at 3 hours after reperfusion, gone by 24 hours.

I cannot wait to see the day where we give IV ethanol for acute stroke.

“Beer, the cause and solution to all the world’s problems.”

“Neuroprotective Effect of Acute Ethanol Administration in a Rat With Transient Cerebral Ischemia”

Conflict of Interest in TPA Literature

Another tiny bit of self-promotion – a new publication published today.  Stems essentially from a literature review I did after clawing through ECASS-III and noting that 12 of the 14 investigators were paid, sponsored, or employed by the manufacturers of alteplase – which muddied my estimation of the reliability of the conclusions.  Turns out, ECASS-III wasn’t the only one….

“Pharmaceutical Sponsorship Bias Influences Thrombolytic Literature in Acute Ischemic Stroke”

CTA Contrast Probably Increases ICH With TPA

…although the authors of this study draw the opposite conclusion.

In an effort to decrease the administration of TPA to stroke mimics and TIAs, some institutions are moving to the use of CT angiographic and perfusion studies after the initial non-contrast scan.  Previous studies have suggested an association between iodinated contrast administration and ICH after TPA.

These authors beg to differ.  In their study cohort, they retrospectively evaluate 319 patients receiving TPA for acute stroke, 69 of whom receive contrast and 243 who do not.  Depending on whether the ECASS or SITS-MOST definition of symptomatic ICH is used:
 ECASS – 4 of 69 (5.8%) with contrast, 12 of 243 (4.9%) without contrast
 SITS-MOST: 3 of 69 (4.4%) with contrast, 9 of 243 (3.7%) without contrast

…and that small absolute difference does not reach statistical significance because their numbers are so small.  This does not prevent the authors from stating “we found no association of either IV contrast administration or contrast dose with SICH in our series of patients treated with IV rtPA.”  They’re not wrong – but they barely address how underpowered their study is, or how every baseline characteristic (age, stroke severity, comorbid conditions) favored their contrast group, yet they still trended towards increased ICH.

Does the author of every TPA article live in a distortion field that blinds them to reasonable consideration of safety issues and study limitations?

“Iodinated Contrast Media and Cerebral Hemorrhage After Intravenous Thrombolysis”
http://stroke.ahajournals.org/content/42/8/2170.short?rss=1

A Third of TPA Patients Do Not Have Stroke

…but they almost all do well!  Only 5.1% of patients without stroke who receive TPA end up with intracerebral hemorrhage – so it’s OK that we give TPA to a ton of patients without a confirmed diagnosis of stroke, right?

This is a retrospective Finnish registry study of 1,104 consecutive TPA patients enrolled in a prospective cohort.  Of these, 119 had basilar artery occlusion, which is angiographically proven prior to treatment, and are excluded from their analysis, and a couple others were excluded for other reasons.  This left 985 patients who were initially diagnosed with ischemic stroke, and, eventually, 14 of those patients were diagnosed as a stroke mimic such as migrane, epilepsy, or a demyelinating disorder.  The authors then go on to say that stroke mimics such as these accounted for a mere 1.4% of all TPA patients, and none of them had ICH.

But, this isn’t exactly a true reading of their data.  The authors also state that 275 of their patients had “neuroimaging negative ischemic stroke”, which is to say, their follow-up MRI detected no sign of infarct.  Now, there is a false-negative rate on DWI MRI for stroke, but it’s in the range of 5% for acute infarcts, and generally involves small lacunar, small cortical, and some posterior circulation strokes.  Not only that, it’s reasonable to suggest that around 40% of TIAs actually have DWI or FLAIR sequence abnormalities as well.

So, some of their “neuroimaging negative ischemic stroke” group probably does have ischemic stroke with false negative MRI – but not 30% of the study population.  And, some of their neuroimaging positive group is likely false positive from TIA as well.  These numbers for stroke mimics are also far below other reported case series, which have estimated 10-30% incidence, depending on whether TIAs are included.

I absolutely cannot fathom this line of reasoning and distortion Neurology is developing in justify recklessly pushing TPA onto a larger population.

“Stroke Mimics and Intravenous Thrombolysis”
http://www.ncbi.nlm.nih.gov/pubmed/22000770

Stroke After-Care Is Far More Important

Somewhere in the rush to but up billboards and focus the medical establishment on experimental revascularization interventions for acute stroke (e.g., time is brain), we’ve overlooked what truly matters – follow-up care after the ischemic event.  This is a lovely study that reminds us of what we probably knew once, but have forgotten – that even in the absence of acute therapy, simple protocols to prevent fever, prevent hyperglycemia, and prevent aspiration pneumonia lead to profound differences in the number of patients with zero or minimal disability after stroke.

This is a prospective interventional study in which acute stroke units in New South Wales Australia were randomized to either no protocolized intervention, or an intervention with nursing protocols named above.  At the end of the three-year intervention period, 42% of the control group had mRS 0 or 1 at 90 days, and 58% of the intervention group had mRS 0 or 1 at 90 days.  There were small differences in the type of stroke, education level, and prior ability to work that probably favored the intervention group, but the differences at baseline were far smaller than the magnitude of the treatment effect.  In short, a basic nursing protocol intervention improved outcomes more than any other intervention for acute stroke.

“Implementation of evidence-based treatment protocols to manage fever, hyperglycemia, and swallowing dysfunction in acute stroke (QASC): a cluster randomised controlled trial.”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61485-2/fulltext