PCCs for Non-Warfarin ICH?

This quick post comes to you from the EMedHome weekly clinical pearl, which was forwarded along to me with a “Good stuff?” open-ended question.

The “good stuff” referred to a series of articles discussing the “CTA spot sign”, referring to a radiologic marker of ongoing extravasation of blood following an intracranial hemorrhage. As logically follows, ongoing bleeding into a closed space has been associated with relatively increased hematoma growth and poorer clinical outcomes.

However, the post also highlighted – more in an informational sense – an article highlighting potential use of prothrombin concentrate complexes for treatment of bleeding, regardless of anticoagulation status. We are all obviously familiar with their use in warfarin-related and factor Xa-associated ICH, but this article endeavors to promote a hypothesis for PCC use in the presence of any ICH with ongoing radiologically apparent bleeding.

The evidence produced to support their hypothesis? A retrospective 8 patient cohort of patients with ICH and CTA spot sign, half of whom received PCCs and half who did not. Given the obvious limitations regarding this level of evidence, along with problems of face validity, there is no reason to revisit their results. The EMedHome pearl seemed to suggest we ought to be aware of this therapy in case a specialist consultant requested it. Now, you are aware – expensive, unproven, and not indicated without a substantially greater level of evidence to support its use.

“Role of prothrombin complex concentrate (PCC) in Acute Intracerebral Hemorrhage with Positive CTA spot sign: An institutional experience at a regional and state designated stroke center”

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”



Ah, the CLEAR trial – a trial evaluating the efficacy of intraventricular injections of alteplase for intracerebral hemorrhage with acute obstructive hydrocephalus. In other words, treating brain bleeds with an agent responsible for brain bleeds. It is not quite as nonsensical as it seems, however, as improved resolution of the intraventricular blood is linked to improved outcomes.

This trial, however, performed over the course of six years and enrolling 500 patients, fails to find anything reliable in favor of alteplase – a rather inconsequential end to a decade’s worth of build-up from the initial and phase II trial. At the end of the day, there was no significant difference between either treatment with regard to the primary outcome, patients attaining a mRS of 0-3.

It should also be noted the preliminary results from this trial were presented last year at the International Stroke Conference with breathless coverage:
CLEAR III: tPA Clot Removal Hope for Intraventricular Hemorrhage

Along with the lead author stating “This treatment saves lives. Our results suggest that physicians should begin to think about using it for stable hemorrhagic stroke patients.”

Which, now that we can all review the results together, is obviously not the case – nor is it their conclusion in the published article. These results do raise some questions – mortality was lower in the intervention group, and patients with improve clot evacuation also tended to do better – regarding potential subgroups for benefit. However, without further prospective data to confirm these signals, this intervention should continue to be reserved for controlled trials.

“Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial”

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”

No Mandate for Hyperbaric Therapy in CO Poisoning

The new year – actually, the end of the old year – brings us a new update on the management of carbon monoxide poisoning, as distilled into an ACEP Clinical Policy statement. There are three elements to their update, addressing specific management questions in the context of carbon monoxide toxicity:

  • Don’t rely exclusively on non-invasive means for CO measurement.
  • Hyperbaric oxygen therapy is neither proven nor disproven of benefit.
  • Cardiac testing provides useful prognostic information.

The most impactful recommendation of the three is the one for HBO therapy, which is either dismissed out-of-hand or pursued with such zealotry that eligible patients are airlifted to far-flung dive chambers for treatment. In theory, HBO therapy helps reduce the delayed neuropathology and cognitive burden related to lipid peroxidation and other toxic metabolites. However, these authors appropriately synthesize the low-quality evidence into a conclusion that HBO therapy has no proven advantage to high-flow oxygen.

As with any therapy for which the evidence is poor, there are proponents on both sides and substantial practice variation. This Clinical Policy does not state HBO is inappropriate or not beneficial for carbon monoxide poisoning, merely the evidence is inconclusive. Sometimes, when the evidence is insufficient to provide an answer, the magnitude of benefit is small or clinically unimportant. In this case, I’m not even sure such a conclusion regarding the scope of benefit can be made – the foundational evidence is simply too unreliable to make any practice-influencing recommendations.

“Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Acute Carbon Monoxide Poisoning”

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”

No CT Before LP?

There are a couple schools of thought regarding the need for a CT before an LP in the setting of infectious cerebral disease. The traditionalist school of thought: herniation. The pragmatist school: no big deal.

This article falls on the side of “no big deal”, which was probably the bias of the authors prior to its conception. These authors looked at comatose children in Malawi with suspected malaria. They analyzed the mortality outcomes of 1,827 patients, including 1,470 who received an LP and 357 who did not. Unadjusted mortality was higher in those who did not receive an LP, for which the authors attempted to adjust using propensity-based analyses, or by directly comparing those who had documented brain swelling on MRI or with papilledema. Using their admittedly small numbers in their retrospective cohort, they did not find any signals of harm relating to overall mortality or herniation precipitated by LP within 12 hours of procedure.

We probably will only ever get this level of evidence regarding the safety of LP in the critically ill with elevated ICP secondary to infection. Adverse events are rare, regardless, and it will always be difficult to shake out the confounding features of the malignant infection. I tend to agree with these authors that LP is safe in a stable patient without localizing neurologic signs, but it is entirely reasonable to take the opposite view.

“Safety of lumbar puncture in comatose children with clinical features of cerebral malaria”