Nothing But Advantages to Treating Stroke Mimics!

What is the acceptable rate of treatment of stroke mimics with tPA? Zero? A few percent?  No limit?  It’s mostly harmless, after all – with only a ~1% rate of intracerebral hemorrhage. And, thanks to the free-market forces of comparison shopping and collective bargaining power of individual stroke patients, the cost of alteplase has increased >100% in the past decade to ~$6400 per dose. With all this going for it, it’s no wonder the American Heart Association gives a Class II recommendation for empirically treating, rather than pursuing additional diagnostic tests.

The added bonus – the more mimics you treat, the better your stroke outcomes appear!

This retrospective review of 725 tPA-treated patients at three hospitals evaluated the difference in rate of treatment of stroke mimics at an MRI-based “hub” hospital and CT-based “spokes”. Of 514 patients treated at the hub, only 3 (0.3%) were ultimately given a non-stroke diagnosis. Of 211 treated at the spokes, 33 (16%) were stroke mimics. The authors also noted, splitting their review period into 2005-09 and 2010-14, the rate of treatment of stroke mimics at spokes had increased from 9% to 20%.

To no great surprise, clinical outcomes – as measured both by mRS ≤1 five days after discharge and hemorrhagic transformation – significantly favored the spoke hospitals. Outcomes also improved between the time periods compared – hand-in-hand with the increase in treatment of stroke mimics.

These authors go on to mention treatment of stroke mimics has real financial cost to the health system and to individual patients, the misdiagnosis of stroke notwithstanding – growing ever more important as our health system lurches back towards penalties for pre-existing conditions. The authors acknowledge the luxury of having rapid MRI available for stroke, but go on to implicate aggressive efforts to improve door-to-needle times as contributing to misdiagnosis and harmful waste.

But, none of that matters when you can get a shiny promotional merit badge for your stroke center!

“Effects of increasing IV tPA-treated stroke mimic rates at CT-based centers on clinical outcomes”

Correct, Endovascular Therapy Does Not Benefit All Patients

Unfortunately, that headline is the strongest takeaway available from these data.

Currently, endovascular therapy for stroke is recommended for all patients with a proximal arterial occlusion and can be treated within six hours. The much-ballyhooed “number needed to treat” for benefit is approximately five, and we have authors generating nonsensical literature with titles such as “Endovascular therapy for ischemic stroke: Save a minute—save a week” based on statistical calisthenics from this treatment effect.

But, anyone actually responsible for making decisions for these patients understands this is an average treatment effect. The profound improvements of a handful of patients with the most favorable treatment profiles obfuscate the limited benefit derived by the majority of those potentially eligible.

These authors have endeavored to apply a bit of precision medicine to the decision regarding endovascular intervention. Using ordinal logistic regression modeling, these authors used the MR CLEAN data to create a predictive model for good outcome (mRS score 0-2 at 90 days). These authors subsequently used the IMS-III data as their validation cohort. The final model displayed a C-statistic of 0.69 for the ordinal model and 0.73 for good functional outcome – which is to say, the output is closer to a coin flip than a informative prediction for use in clinical practice.

More importantly, however, is whether the substrate for the model is anachronistic, limiting its generalizability to modern practice. Beyond MR CLEAN, subsequent trials have demonstrated the importance of underlying tissue viability using either CT perfusion or MRI-based selection criteria when making treatment decisions. Their model is limited in its inclusion of just a measure of collateral circulation on angiogram, which is only a surrogate for potential tissue viability. Furthermore, the MR CLEAN cohort is comprised of only 500 patients, and the IMS-III validation only 260. This sample is far too small to properly develop a model for such a heterogenous set of patients as those presenting with proximal cerebrovascular occlusion. Finally, the choice of logistic regression can be debated, simply from a model standpoint, given its assumptions about underlying linear relationships in the data.

I appreciate the attempt to improve outcomes prediction for individual patients, particularly for a resource-intensive therapy such as endovascular intervention in stroke. Unfortunately, I feel the fundamental limitations of their model invalidate its clinical utility.

“Selection of patients for intra-arterial treatment for acute ischaemic stroke: development and validation of a clinical decision tool in two randomised trials”

Stem Cells for Stroke Redux

A few months ago, folks at Stanford were claiming miraculous recoveries after implanting stem cells directly into patients’ brains at the site of injury. An interesting concept, to be certain.

Now we have “stem cells lite”, or, at least, the slightly-fewer-holes-in-the-skull version – and it’s apparently just as miraculous.

This is a Phase 2 double-blinded dose-escalation study evaluating treatment with intravenous multipotent adult progenitor cells, with treatment initiated between 24 and 48 hours. Their trial design reflects the nature of a Phase 2 trial, with three cohorts, unbalanced allocation, and dosing differences between groups, but is otherwise fairly straightforward. Until you get to the primary outcome:

“The primary efficacy outcome was the multivariate global stroke recovery at day 90, which assesses global disability, neurological deficit, and activities of daily living and consists of mRS 2 or less; NIHSS total score improvement of 75% or more from baseline; and Barthel index of 95 or more in the multipotent adult progenitor cells treatment group, compared with the placebo treatment.”

Which is to say, they’ve conjured up their own unique black-box composite primary outcome – an outcome they changed midway through the trial.

Why would you need to change the primary efficacy outcome in 2014 for a study that started in 2011? The obvious implication is the results were unfavorable – and, the cursory review of their results table suggests this is a reasonable stance to take.

These authors screened 160 patients at several different sites for eligibility and ultimately randomized 129. Of these, three did not receive the allocated intervention – leaving the remainder for analysis. Patients in each group were generally similar based on NIHSS, time until infusion, and stroke interventions. Sticking to traditional outcomes measured by stroke trials, there was no difference between groups: mRS ≤2 in 37% of the intervention group and 36% of the placebo.  However:

“exploratory analyses suggested an increase in excellent outcome in the multipotent adult progenitor cells arms in the ITT population, and a beneficial clinical effect on long-term 1 year disability.“

This “excellent” outcome is the product of the midstream outcome change combined with their post-hoc data dredging for a feasible positive finding – a combination of patients with mRS ≤1, a NIHSS ≤1, and a Barthel Index ≥95. Then, the bulk of their analysis is further restricted to one year outcomes of those who received their stem cells within 36 hours from stroke onset. With such an obvious “beneficial clinical effect”, is there any question regarding the role of the funding source?

“The funder of the study was involved in study design and in data interpretation. All data collection and analysis were overseen by Medpace. One employee of the funder (RWM) was represented on the writing committee.“


“DCH received grants from Athersys, payments to his university from Medpace for patient enrolment, has a patent on the MultiStem cells through his university and has received licensing revenue through his university. LRW received grants from SanBio and Athersys, and personal fees from SanBio. GAF is a consultant for Athersys; received personal fees from Medpace; and payment from Medpace to his institution for study costs. SS received grants from Athersys. SIS received grants from Athersys, and consulting fees that were paid to the institution from Mesoblast, Aldagen, and Celgene. CAS received grants from Athersys. DC received grants from Athersys.”

The likelihood these results are valid, reproducible, and have a clinically meaningful effect size is nearly zero – but that certainly won’t stop them from throwing good money after bad.

“Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial”

All Aboard the tPA Hype Bus

Indiscriminate use of tPA in those with undifferentiated stroke is a low-value proposition – even if you find the evidence reliable. The utility of tPA for stroke depends on anatomy, time, and tissue status – information the traditional non-contrast head CT does not usually provide. Unfortunately, one of the latest “innovations” in stroke care is simply to do this useless test faster – in a bus, down by the river.

This is the PHAST project out of Cleveland, which, like similar efforts in Berlin, Chattanooga, and Houston, puts a CT scan machine in an oversized ambulance. Many of the initial phases of these projects included a stroke physician physically in the vehicle – but this, as you would expect, takes advantage of telemedicine technology to provide consultation from afar.

The stated hypothesis of this project is “that the MSTU will allow significant reductions in time to evaluation and treatment of patients when compared to a traditional ambulance model in an American urban environment”, which is just mind-numbingly infantile. Of course, pre-hospital administration will be faster than in-house thrombolysis – the interesting data would be with regard to safety and misdiagnosis.

This report is of the first 100 patients evaluated – generated by 317 system alerts. Of these, 33 were given a preliminary diagnosis of probable stroke, 30 possible stroke, 4 transient ischemic attacks, 5 intracerebral hemorrhages, and 28 non-cerebrovascular. Of the 33 probable strokes, 16 received thrombolysis – and, by most of their various metrics, care was accelerated by 20-40 minutes. And, then, no outcomes, safety, or follow-up data is presented – apparently we are simply supposed to operate under the assumption this resource outlay and rush to provide the substrate for potential tPA administration is obviously prudent and effective care.

Probably the only interesting tidbit from this paper was with regard to one of the cases of ICH diagnosed by CT in the prehospital setting. One patient was identified as taking anticoagulation, and prothrombin concentrate complexes were initiated in the pre-hospital setting. The timeliness of anticoagulation reversal is almost certainly beneficial, although the magnitude of effect for the few minutes saved is uncertain.

“Reduction in time to treatment in prehospital telemedicine evaluation and thrombolysis”

Thrombolysis and the Aging Brain

The bleeding complications of thrombolysis are well-described, but frequently under-appreciated in the acute setting. Stroke patients often disappear upstairs after treatment in the Emergency Department quickly enough that we rarely see the neurologic worsening associated with post-thrombolysis hemorrhage.

Risk factors for post-tPA ICH are well-known, but often difficult to precisely pin down for an individual patient. This study pools patients from up to 15 studies to evaluate the effect of leukoariosis on post-tPA hemorrhage. Leukoariosis, essentially, is a cerebral small vessel disease likely related to chronic ischemic damage. It has been long-recognized as a risk factor for increased hemorrhage and poor outcome, independent of age at treatment.

In this study, authors pooled approximately 5,500 patients, half of which were identified to have leukoariosis. The unadjusted absolute risk of symptomatic ICH in those without leukoariosis was 4.1%, while the risk of those with was 6.6%. Then, looking at the 2,700 patients with leukoariosis, those with mild disease had an unadjusted absolute risk of 4.0%, compared with 10.2% for those with moderate or severe. Similar trends towards worse functional outcomes were also seen with regards to worsening leukoariosis.

The moral of the story: the baseline health of the brain matters. When discussing the risks, benefits, and alternatives for informed consent with a family, these substantial risks in those patients with leukoariosis should be clearly conveyed with regards to appropriateness of tPA when otherwise potentially indicated.

“Leukoaraiosis, intracerebral hemorrhage, and functional outcome after acute stroke thrombolysis”

Some Old News About Thrombolysis Before Endovascular Therapy

We’ve spent a little bit of energy on this blog teasing out the appropriate indications for endovascular therapy, and and we’ve used a few of those words to discuss whether thrombolysis prior to is necessary. I am of the opinion: probably not.

It turns out, there are many other prominent neurologists who share that same opinion. Unfortunately, this article is just a rehash of prior data without any new specific insight. Of course, the lay medical press does their typical job of creating definitive, misleading headlines:
Stroke: No Benefit from Adding tPA to Thrombectomy
No Benefit for IV tPA Before Mechanical Thrombectomy in Ischemic Stroke

This is a small post-hoc analysis of the 291 patients undergoing treatment in the SWIFT and STAR trials. Of these, 131 did not receive thrombolysis prior to intervention, with the most common exclusion being either presence of an elevated INR and oral anticoagulation or symptom onset being >4 hours prior to hospital arrival. Other, less common exclusions included blood pressure exclusions, hypoglycemia, and prior strokes. Some patients also received bridging tPA or reduced-dose tPA, as determined appropriate by the interventionalist.

In such a small analysis such as this, little reliable can be made of the results – except to generally say there was no obvious signal confirming nor refuting the appropriateness of thrombolysis prior to intervention. Hemorrhagic complications were similar between groups, as were patient-oriented outcomes. At the least, they offer the appropriate weak conclusion supported by these data: prospective trials are reasonable.

“Combined Intravenous Thrombolysis and Thrombectomy vs Thrombectomy Alone for Acute Ischemic Stroke: A Pooled Analysis of the SWIFT and STAR Studies”

tPA For Wake-Up Strokes – “Safe!”

It’s medical news nonsense time again – this time featuring our old favorite, tPA for stroke.

“Tissue Plasminogen Activators Safe for Patients Who Wake Up with Stroke Symptoms” reports HCP Live, and featured in the ACEP daily e-mail newsletter. Oddly enough, this article was actually initially published back in July before being picked up by the health news blog world here in December.

As the headline suggests, this is an article regarding “wake-up” strokes, those with an unknown time of onset because the patient was last seen normal prior to sleep. The authors hypothesize this might represent an otherwise missed, but eligible, population if their stroke onset was close to waking.

But, in this open-label study spanning 3 years of enrollment, there is absolutely nothing conclusive to be said. During this period, across five centers, these authors managed to enroll only 40 patients – the vast majority of whom had NIHSS less than 10, and four of whom were mimics. Following treatment, six suffered intracerebral hemorrhage, two developed angioedema, and one suffered systemic hemorrhage – and thus, the apparent conclusion, that tPA is “safe” in this population.

In reality, this hardly tells us anything of the sort – generalizing results from this cohort of mostly small strokes to a larger treatment population is obviously inappropriate.  But, the authors state it forms the foundation of future trials – and, no doubt, they are underway already.

“Prospective, Open-Label Safety Study of Intravenous Recombinant Tissue Plasminogen Activator in Wake-Up Stroke”

Endovascular Therapy for Large Ischemic Cores

The vast majority of the important evidence regarding the use of endovascular therapy for stroke has substantial limitations. The critical studies, with the largest magnitude of benefit, used strict imaging criteria to limit interventions to large-vessel occlusions with only small-volume ischemic cores surrounded by large regions of surviving tissue. Further generalizing these data to the remaining stroke population represents a significant challenge.

This small study tries to describe the benefit of endovascular treatment in a population with larger ischemic core volumes, specifically those greater than 50 mL – and it’s useless. They have 56 patients in their retrospective case-control comparison, and are missing long-term follow-up data for 9. Outcomes, yes, are better for the endovascular therapy group – a handful of patients had low or minimal disability, while none of the control patients achieved an mRS 0-2. Safety outcomes, of course, are a total wash in a small sample such as this. This would have made for a great conference abstract, but it is hardly compelling or significant data.

The main notable feature of this study is mostly how it reflects the real-world deployment of this therapy, regardless of the guidelines and current evidence.  Many centers have expanded the use of endovascular intervention for patients beyond the scope of the original trials.  These are very, very weak data – and, even though I don’t disagree in principle with imaging-guided revascularization, the further away from established evidence we drift, the lower value the intervention becomes.

“Endovascular Treatment for Patients With Acute Stroke Who Have a Large Ischemic Core and Large Mismatch Imaging Profile”

Which is Safer – Rivaroxaban or Dabigatran (or Neither?)

The world of anticoagulation turned upside-down with dabigatran, and continued with the Factor Xa inhibitors: rivaroxaban, apixaban, and edoxaban. While RE-LY and its ilk showed, in the settings of controlled clinical trials, that these new agents were potentially superior, or at least non-inferior, to warfarin – which is best? Do we have any idea?

Unfortunately, such comparative effectiveness work is sadly lacking, and we are forced to try and glean safety data indirectly following approval. This study pools Medicare beneficiaries using the new agents for stroke prevention in the setting of nonvalvular atrial fibrillation, and attempts to observe “real world” outcomes.

The winner on stroke prevention: rivaroxaban, by a hair. The winner on bleeding: dabigatran, by a long shot, both intra-cranial and extra-cranial. Overall mortality, then, slightly favored dabigatran.

These data are retrospective and tortured by statistical matching methods, so their reliability is hardly bulletproof. What this does raise are more questions about the appropriate usage of these new agents – and further emphasizes the importance of prospectively performed patient-centered effectiveness research.

“Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation”

Stretch That Thrombectomy Window

It’s the thing to do in stroke – wedge new treatments into practice with a narrow time window and strict eligibility requirements, then expand, expand, expand.

This latest publication/advertising supplement in the Journal of the American Medical Association pools together the endovascular trials MR CLEAN, ESCAPE, EXTEND-IA, REVASCAT, and SWIFT-PRIME for an individual-patient meta-analysis to explore the various nuances of the treatment effect. After much cleaning and tweaking, the authors come around and say “Whoa! We found a benefit out to 7.3 hours from symptom onset, not just the 6 hour limit recommended by the American Heart Association!”

These were all positive trials, so it’s no surprise the overall outcome is positive – nor is these authors ability to drag out favorable outcomes beyond the 6-hour cut-off, considering some of these trials enrolled patients out to twelve hours. However, in their clumsy calisthenics to marry these data to the time-based hypothesis of acute stroke practice, these authors are clearly dancing around the most important bit of evidence emerging from these trials: imaging selection. They spend a handful of sentences discussing the imaging selection eligibility criteria of the included trials, but one benefit of meta-analyses is its use as a tool to obfuscate such inconvenient aspects in favor of words, words, words relating to the methods of their statistical analysis.

As I described in my #smaccDUB talk, you need two things for stroke therapy to be effective: viable tissue and effective reperfusion. These trials – ESCAPE, EXTEND-IA, and SWIFT-PRIME – finally hit that sweet spot with small infarct cores and safe, effective recanalization. Some of that viable tissue absolutely decays over time, so the time-based hypothesis is not entirely untrue, but it’s a low-value oversimplification. As many of use in Comprehensive Stroke Centers have seen, perfusion imaging can direct therapy for patients far outside the general AHA recommendations. The obvious corollary to this, however, is that perfusion imaging similarly identifies patients for whom intervention is futile, regardless of time window. This second point runs contrary, however, to the financial interests at stake here.

The authors do mention imaging-based criteria is being investigated in multiple clinical trials, e.g.: NCT02142283, NCT02586415.  However, these trials are carefully designed not to enroach upon established time-based criteria, and to use imaging only to further extend the treatment windows.

Other fun tidbits:

  • A few patients randomized to endovascular intervention did not receive one. After all, most received pre-intervention tPA – some would be expected to recanalize with medical therapy alone. However, this publication gives another lovely window into our clot-buster that doesn’t bust clots: only 6.8% could be reasonably concluded to have had clot thrombolysis after medical therapy alone. We probably should not be giving tPA to patients for whom endovascular intervention is planned.
  • All five studies cited here were published in the New England Journal of Medicine.  This meta-analysis is in JAMA. Presented without comment.

“Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis”


Coda – there were just a couple relevant conflict of interest disclosures:

Dr Saver reports being an employee of the University of California; serving as an unpaid site investigator in multicenter trials run by Medtronic and Stryker for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled; receiving stock options for services as a scientific consultant regarding trial design and conduct to Cognition Medical; receiving funding for services as a scientific consultant regarding trial design and conduct to Covidien/Medtronic, Stryker, Neuravi, BrainsGate, Pfizer, Bristol Myers-Squibb, Boehringer Ingelheim (prevention only), ZZ Biotech, and St Jude Medical; serving as an unpaid consultant to Genentech advising on the design and conduct of the PRISMS trial; neither the University of California nor Dr Saver received any payments for this voluntary service. The University of California has patent rights in retrieval devices for stroke. Dr Goyal reports receiving grants from Covidien/Medtronic, consulting payments from Covidien/Medtronic, and having patent rights in systems and methods for diagnosing strokes (PCT/ CA2013/000761) licensed to GE Healthcare. Dr van der Lugt reports grant funding from the Dutch Heart Foundation, AgioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/LAMEPRO/Penumbra, Stryker, and Top Medical/Concentric. Dr Menon reports serving as an unpaid member of in the ESCAPE trial, which received support from Covidien/Medtronic, receiving grant support from AstraZeneca, honoraria from Penumbra, a submitted patent for triaging systems in ischemic stroke, and serving on the board of QuikFlo Health. Dr Majoie reports that his institution has received honoraria for his service on a Speaker’s Bureau from Stryker. Dr Dippel reports that his institution has received honoraria for his speaking from Stryker and grant funding from the Dutch Heart Foundation, AgioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/ LAMEPRO, Penumbra, Stryker, and Top Medical/ Concentric. Dr Campbell reports that his institution received a grant to support the EXTEND-IA trial from Covidien/Medtronic. Dr Campbell reports grant funding from the National Health and Medical Research Council of Australia and Medtronic and fellowships from the National Heart Foundation of Australia, National Stroke Foundation of Australia, and Royal Australasian College of Physicians. Dr Nogueira reports receiving fees for service on steering and data safety monitoring committees to Medtronic, Stryker, Penumbra, and Rapid Medical. Dr Demchuk reports receiving grant support and personal fees from Covidien/Medtronic and personal fees from Pulse Therapeutics. Dr Devlin reports that his institutions received clinical trial payments for patients enrolled in clinical trials from Medtronic, clinical trial support from Brainsgate and Genervon, and holding a patent. Dr Frei reports personal fees from Penumbra, Stryker, Codman, MicroVention, and Siemens. Dr Jovin reports receiving fees for service on steering committees from Silk Road Medical, Covidien, Stryker Neurovascular, Air Liquide; personal fees from Neuravi and Johnson & Johnson; nonfinancial support from Fundacio Ictus; and serving on the advisory board for Anaconda. Dr Siddiqui reports personal fees from StimSox, Valor Medical, Neuro Technology Investors, Cardinal Health, Medina Medical Systems, Buffalo Technology Partners, International Medical Distribution Partners, Codman & Shurtleff, Medtronic, GuidePoint Global Consulting, Penumbra, Stryker, MicroVention, W. L. Gore & Associates, Three Rivers Medical, Corindus, Amnis Therapeutics, CereVasc, Pulsar Vascular, the Stroke Project, Cerebrotech Medical Systems, Rapid Medical, Lazarus, Medina Medical, Reverse Medical, Covidien, Neuravi, Silk Road Medical, Rebound Medical, Intersocietal Accreditation Committee; other fees from Penumbra, 3D Separator Trial, Covidien, SWIFT PRIME and SWIFT DIRECT trials, MicroVention, FRED trial, CONFIDENCE study, LARGE trial, POSITIVE trial, COMPASS trial, INVEST trial. Dr van Zwam reports that his institution has received honoraria for his speaking from Stryker and Codman. Dr Davis reports lecture fees and research support from Covidien/Medtronic; travel support from Bristol Myers-Squibb and Pfizer; and advisory board fees from Boehringer Ingelheim and Medtronic. Dr Silver reports personal fees from Boehringer Ingelheim. Dr Donnan reports nonfinancial support from Boehringer Ingelheim; grants from the Australian National Health and Medical Research Council; and fees for service on advisory boards for Boehringer Ingelheim, AstraZeneca, Bristol Myers-Squibb, Pfizer and Merck Sharp & Dohme. Dr Brown reports receiving consulting fees from Medtronic/Covidien and personal fees from the University of Calgary. Dr Mitchell reports that his institution received a grant to support the EXTEND-IA trial from Covidien/Medtronic; his institution has received unrestricted research funding and grants from Codman Johnson and Johnson, Medtronic, and Stryker; and serving as an unpaid consultant to Codman Johnson and Johnson. Dr Davalos reports receiving payments for serving on a multicenter study steering committee and grant funding from Medtronic. Dr Roos reports grant funding from Medtronic. Dr Hill reports unrestricted grant funding for the ESCAPE trial to University of Calgary from Covidien/Medtronic, and active/in-kind support consortium of public/charitable sources (Heart and Stroke Foundation, Alberta Innovates Health Solutions, Alberta Health Services) and the University of Calgary (Hotchkiss Brain Institute, Departments of Clinical Neurosciences and Radiology, and Calgary Stroke Program); personal fees from Merck, nonfinancial support from Hoffmann-La Roche Canada. In addition, Dr Hill has a submitted patent for triaging systems in ischemic stroke, and owns stock in Calgary Scientific, a company that focuses on medical imaging software. No other disclosures were reported.
Funding/Support: The HERMES pooled analysis project is supported by a grant from Medtronic to the University of Calgary.