Category: Neurology

Ever since the narrow approval and strict inclusion criteria of the first trials for alteplase in stroke, our benevolent corporate overlords have been doing their utmost to expand its indications – all while continuing to unilaterally boost its price. This includes sponsoring “expert” convocations to whittle down contraindications, as well as sponsoring, and then cancelling, trials destined to futility.

This is another example of the latter.

This is the remnants of PRISMS, a trial testing the alteplase versus aspirin in a randomized, placebo-controlled trial of mild stroke. In this trial, “mild stroke” included a NIHSS of ≤5 and the absence of any disabling deficits. That is to say, rather, every patient entered in this trial met, in theory, the primary outcome of an mRS of 0-1 at entry. The trial expected to find an advantage to treatment of 9% and incidence of sICH of 2%, a NNT of 11, NNH of 50, and a requirement of 948 patients for the statistical power to validate such findings.

The trial, however, was stopped after 313 patients due to “slow enrollment”. Of these, 32 were lost to follow-up, leaving 281 available for 90-day assessment without imputation. The bulk of patients ranged in NIHSS 1 to 3, with sensory symptoms, facial palsy, and dysarthria the most frequently represented stroke symptoms. Of those with 90-day follow-up, 83.1% of the aspirin arm achieved mRS 0-1, compared with 77.5% of those randomized to alteplase. Conversely, 3.4% of these mild strokes were ultimately mRS 4-6 – a typical definition of “poor outcome” – in the aspirin arm, compared with 10% of those randomized to alteplase. The 5 patients with sICH following alteplase administration contributed to these poor outcomes, compared with none following administration of aspirin.

So, very clearly, there is no evidence here to support a presumption of benefit from alteplase administration, but quite clearly evidence of harm. The authors – with hardly any conflict-of-interest to speak of – go to great lengths to assure us:

“The findings from the current trial cannot be extrapolated to all patients with lower stroke severity based on an NIHSS score of 0 to 5.”

Please continue, they say, treating this population despite the virtual absence of evidence. Even more comically, they also conclude this ought not be the last word in this patient population:

“… the very early study termination precludes any definitive conclusions, and additional research may be warranted.”

Although these authors go to great lengths to assure us there was no tomfoolery at work in the sponsor’s decision to terminate the trial, it strains credibility to suggest Genentech would be so willing to abandon potential profit relating to an expanded indication. Such decisions to cut their losses would hardly be warranted if an expectation of potential return were in store.

At the very least, this clearly shows not only diminishing returns, but likely harms relating to the use of alteplase in minor stroke. Given the sparse RCT data in this realm – NINDS, for example, included only 58 cases with a NIHSS below 5, and nearly 3,000 patients were actively excluded from other RCTs – these data still ought to move the needle of equipoise with regard to treating a spectrum of low NIHSS, but potentially disabling, deficits.  It would be entirely defensible not to treat this population while awaiting robust trial evidence in support.

Also: 13% stroke mimics!

“Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits”

https://jamanetwork.com/journals/jama/fullarticle/2687354

What happens when you wake up and you’re paralyzed from a stroke? Well, usually nothing. “Unknown time of onset” takes you – for better or worse – out of the game for alteplase, but not necessarily for endovascular therapy should a large-vessel occlusion be identified. Those large vessel occlusions, in the setting of a favorable CT perfusion profile, seem to benefit from endovascular therapy.

But, getting back to the “wake up stroke” – these have had our neurologists gnashing their teeth for some time. They have hypothesized many of these strokes have occurred just before waking and might otherwise be eligible for treatment. Absent reliable presenting information regarding the time of onset, these authors look to MRI – using presence of DWI lesion without corresponding FLAIR signal as a surrogate for tissue viability/stroke recency. Exclusion criteria in addition to the usual alteplase culprits were extremes of age, premorbid functional disability, NIHSS >25, thrombectomy candidates, and those with infarct volumes greater than 1/3rd the MCA territory. The primary outcome was 0 or 1 on the mRS at 90 days, like most trials.

These authors in this multicenter, placebo-controlled planned to enroll 800 patients, but ran out of money after five years and 503 patients. To get to these 503, the authors needed to screen 1362 potential strokes. These 859 exclusions were for various reasons, but over half were because the FLAIR matched the DWI lesion – indicated a completed infarct. Another 137 had negative DWI – i.e., not stroke – and various others had hemorrhage, failed to meet criteria for infarct size, or a scattering of other exclusions. Even despite these exclusions, another 79 snuck through as protocol violations, including 48 who should have been excluded based on imaging criteria.

Now, the meat: About 95% of those included were of the “wake up” variety, nearly all from overnight sleep. Baseline clinical features were generally well-matched. Median NIHSS was 6 in each group, although median lesion volume on DWI was 2.0 mL in the alteplase cohort as compared to 2.5 with placebo. At 90 days, 53.3% of the alteplase cohort achieved an mRS of 0-1 as compared with 41.8% with placebo. Bleeding complications, as typical, favored the placebo cohort – with absolute advantages ranging from 1.6% to 3.6%, depending on the definition of hemorrhage used. Death at 90 days also favored placebo at 1.2% versus 4.1%.

It is difficult to know what to do with these data unless your system is specifically equipped to replicate the conditions of this trial with rapid MRI. Even then, there are some oddities and specific warnings to unpack. If adhering to this protocol, the majority of patients screened will not be eligible for treatment. The number of patients who had completed their infarction was similar to those who had DWI/FLAIR mismatch, and another third had other imaging or clinical findings excluding them from treatment. Incorporating MRI into workflow may not yet represent a high-value approach.

Then, the authors performed a pre-specified subgroup analysis stratifying based on NIHSS – and the 109 analyzed patients with a NIHSS >10 did terrible. Only 13.5% of those in the tPA cohort and 12.3% of those receiving placebo achieved mRS 0 or 1. Unpacking these stratifications further, the authors provide us a whole host of breakdowns:

Generally, not too much should be read into these secondary outcomes, but they are useful for generating equipoise for other investigations.  That said, these data should be at least a useful cautionary tale regarding the value of tPA in the setting of mild, but disabling stroke – as these 175 patients represent at least six times more patients than from NINDS, and are of higher quality evidence than any of the Get With the Guidelines publications trying to build the case for tPA in mild stroke.

One takeaway that should definitely not be generated from this is: “well, if there’s an absolute increase in good outcome of 12% on those screened with MRI, then treating all ‘wake up’ patients after screening with just CT could generate about a 6% absolute benefit, and that should be offered to patients.”  Unfortunately, I suspect we will hear such calls – probably based on parsing out the low NIHSS patients in the subgroups above, and trying to toss out the ~30% with a large-vessel occlusion identified on MRA as patients who should be triaged to endovascular.  Again, trying to pick and choose the secondary outcomes that suit your narrative is fraught with peril, and the fact remains such a treatment strategy is also likely to generate harms greater than those seen in this trial.  These data ought to have a very narrow application – but shareholders and executives don’t realized dividends when alteplase isn’t flying off the shelves for expanded indications.

“MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset”
https://www.nejm.org/doi/full/10.1056/NEJMoa1804355

This article is mostly a story about tenecteplase, but, effectively, it’s also a scathing indictment of alteplase – you know, the miraculous “clot-buster” we’ve been using for the past 23 years.

Because, despite rumors to the contrary, it doesn’t actually bust clots.

This isn’t news to anyone who actually follows the stroke literature closely. Indeed, the entire endovascular/thrombectomy industry is constructed upon this edifice of failure. And, as we see in this 202-patient study comparing recanalization rates after large-vessel occlusion, tenecteplase appears to be more efficacious than alteplase – 22% vs. 10%.

That is to say, in a population of 24 ICA occlusions, 3 basilar occlusions, 60 M1 occlusions, and 14 M2 occlusions, alteplase successfully “busted the clot” in 10. Most of the difference in recanalization was driven by the M1 and M2 patients, where tenecteplase had a 26% success rate and alteplase languished at 8%. These rates for alteplase are a little lower than most prior literature, so it is reasonable to be suspicious of the superiority margin associated with tenecteplase.

But, regardless, as you can see, both are dismal – and, for the past 20+ years, prior to the advent of even limited endovascular availability, we’ve just been pushing alteplase on these large vessels to no beneficial effect – except to Genentech and their shareholders.

“Tenecteplase versus Alteplase before Thrombectomy
for Ischemic Stroke”
https://www.nejm.org/doi/full/10.1056/NEJMoa1716405