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Previously, we examined the evolution of ischemic stroke treatment beginning with the practice-changing NINDS-2 study. We left off wondering why Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands () produced positive results when three earlier device trials which came before were negative.

Was it the patients?

For an introduction to the issues discussed in this article, see: MR. CLEAN and Memory Lapses.

It is true that the authors of MR CLEAN were far more selective in the patients they included. In fact authors required patients to have an occlusion of distal intracranial carotid artery or middle cerebral artery (M1, M2) or anterior cerebral artery (A1) demonstrated with CT angiography (CTA), magnetic resonance angiography (MRA) or digital subtraction angiography (DSA) before they were enrolled in the trial.

Was it time?

Patients received both IV tPA and endovascular treatments far faster than any of the patients in IMS-3, SYNTHESIS or MR RESCUE. In the MR CLEAN trial patients received their IV tPA on average 85 to 87 minutes after symptom onset and underwent endovascular therapy 196 to 204 minutes after symptom onset.

Was it the devices used?

In contrast to the initial 3 trials, 97% of the endovascular interventions performed in the MR CLEAN cohort utilized a modern retrievable stent device.

Finally, was it simply the play of chance?

Ahead of publication

Currently, we do not have the full publication of MR CLEAN, so a detailed analysis of the results proves difficult. That being said there are a number of interesting points we can take away from the published protocol and results presented during the 9th annual stroke conference.

The authors claimed success in their primary outcome, which they define as "the score on the mRS at 90 days" (11,15). They claim this benefit by citing an adjusted odds ratio of 1.67 (95% confidence interval [CI], 1.21-2.30).

What can we glean from this odds ratio?

What exactly were they measuring and what imbalances were they attempting to adjust that randomization would not account for? In the statistical analysis portion of their protocol the authors only slightly expand on the vague nature of this outcome. The authors used an ordinal analysis in an attempt to quantify the benefits of endovascular therapy over the entire mRS.

They then decided to further adjust these outcomes using multivariable logistic regression in an attempt to "adjust for chance imbalances in main prognostic variables between intervention and control group." The to adjust for were age, stroke severity (NIHSS), time since onset, previous stroke, atrial fibrillation, carotid top occlusion, and diabetes mellitus.

This is the same to magically transform a decidedly negative trial into a statistically positive one. MR CLEAN marks the first time this type of statistical analysis was used as a trial's primary end point rather than a secondary experimental, trial-saving outcome.

Positive, but ...

To be clear this trial was an overwhelming success and this analysis is in no way intended to take away from these findings. Rather to question whether an adjusted ordinal analysis is the appropriate outcome to assess efficacy. We have discussed the problems with ordinal analyses in depth in a prior post, but briefly it is an attempt to mine the data so as to detect smaller changes in outcomes than the more tradition dichotomous cutoff (mRS 0,1, or 2 vs 3,4,5,or 6) is capable of detecting.

On face value this seems like a noble pursuit, but logistically presents a number of problems when employed in a trial. Most importantly, is an ordinal analysis an appropriate measure of functional outcomes? Ordinal analysis is an attempt to examine shifts across an entire functional scale -- minute changes in outcomes that would be missed by a dichotomous measurement.

To accomplish this, one has to assume flawless collection process and intrinsic reliability of the functional assessment tool. We know that the reliability of the mRS is questionable at best. In fact, when two neurologists assess the same patient their results will often .

The MR CLEAN 90 day mRS data were assessed using a structured phone interview conducted by a trained research nurse. This trial employed an open design where the patients were not blinded to their group assignments, using an outcome scale of questionable reliability, collected by a phone interview. Authors then for variables that should have been controlled by the randomization process.

These data are far from flawless. To think you can reduce such data to a granularity that will allow you to extract meaningful outcomes is certainly an error in judgment. Such analysis should be reserved for secondary measures only after a more robust means of appraisal has proven fruitful.

Soft endpoints

Like all the stroke literature, this leaves us trying to compare the soft endpoints of functional neurological outcomes to the hard endpoints of mortality and intracranial hemorrhage (ICH). Despite its success, like NINDS before it, MR CLEAN failed to demonstrate a mortality benefit for endovascular therapies in acute ischemic stroke.

According to reports of data presented at the WSC by , mortality at 90 days was 21% and 22% respectively. Add to that a 5% increase in the rate of serious adverse events (47% vs 42%) in the endovascular therapy group. Despite the claim that the newer endovascular devices were safer and caused less bleeds the rate of clinically relevant ICH was statistically equivalent to the patients who received IV tPA alone (6.0% vs 5.2%).

This is the same rate of ICH seen in both the and trials in which the MERCI retrieval devices were the primary means of clot retrieval. Furthermore, there was a concerning increase in the rate of secondary ischemic strokes in a different vascular territory (5.6% vs 0.4%) and the number of hemicraniectomies performed (6.0 vs 4.9%) in the endovascular treatment group. Though, given the overall functional outcomes at 90 days were markedly improved in the endovascular therapy group these strokes may not be clinically relevant.

More questions

So why did endovascular interventions perform so much better in MR CLEAN than in any of the 3 trials that came before it?

Do modern devices create superior reperfusion with fewer complications?

Interestingly the rate of recanalization in the intervention group at 24 hours was approximately 80% compared with 32% in the IV tPA group alone. When compared with the in IMS-3 the intervention group were found to have approximately 80% with similar recanalizations rates in the IV tPA group as MR CLEAN (35%). Furthermore, the rates of ICH and secondary ischemic infarction seem to be no less than what was observed during IMS-3 and SYNTHESIS. Seemingly these newer devices add little as far as objective effectiveness.

Was it time to reperfusion?

Patients in MR CLEAN received both IV tPA administration as well as endovascular therapy incredibly fast. So fast that some may question the trial's external validity. Despite the fact that patients in MR CLEAN underwent both IV and mechanical reperfusion significantly earlier than patients in IMS-3 and SYNTHESIS, earlier treatment with endovascular therapy did not appear to improve outcomes.

In fact, in MR CLEAN, patients who received IV tPA therapy greater than 120 minutes after their symptom onset did better when randomized to the endovascular intervention arm. Conversely when patients received IV tPA prior than 120 minutes after symptom onset, endovascular therapy demonstrated no added benefit. In both IMS-3 and SYNTHESIS no temporal benefit could be demonstrated for patients receiving endovascular therapy.

Was it the patients MR CLEAN selected that made a difference?

Though MR CLEAN required CT angiographic proof of a large vessel occlusion, the resulting population seems very similar to the patients in IMS-3. The median age and presenting NIHSS was fairly similar (65-66 vs 68-69 and 17-18 vs 16-17 respectively). Even the variation in stroke location was similar with the large majority of the clots located in the M1 segment of the middle cerebral artery (MCA), followed by a third found in the carotid artery terminus and a small minority found in the M2 segment of the MCA.

Anecdote, tPA, placebo

A few final thoughts of interest -- the authors measured change in NIHSS at 24-hour and 1-week intervals. It will be interesting if these findings are expanded upon in the published document, but as far as I can tell from the data presented at the conference, the difference in NIHSS scores between the groups was 2.3 points at 24 hours and 2.9 points at 1 week.

I cannot tell if this difference reached statistical significance but seemingly it is under the threshold of a 4-point improvement on the NIHSS that was deemed clinically relevant by the authors of NINDS in their . If this data does prove to be accurate then it means that the anecdotal stories of patients rising from the cath lab table shortly after clot removal, was just that, anecdote.

Finally, it is important to point out that this trial compared endovascular treatment with standard care, which for all intents and purposes was IV tPA (91% of the control group received IV tPA). It is by no means certain that IV tPA provides any added benefit over placebo alone and some skeptics, such as myself, think there is a suggestion of harm.

An additional control group, comparing placebo with both IV tPA and endovascular therapy is needed. In the subgroup analysis though endovascular therapy performed better than standard care in patients who received tPA, these benefits were not seen when IV tPA was withheld.

Bottom line

Surely we are left with more uncertainty than when we started this line of investigation. Thankfully there are a number of studies currently underway that may provide us the clarity we require. MR CLEAN is the first trial to demonstrate the potential benefits endovascular therapy may provide, but one trial should not define the standard of care, especially when multiple trials have concluded quite the opposite.

The cost and resources needed to create an infrastructure capable of delivering patients to the endovascular suite with the swiftness seen in this cohort would be extraordinary. We should require more than an ambiguous odds ratio, bolstered by further needless statistical adjustments to justify these costs.

, is the chief resident in emergency medicine at Newark Beth Israel Medical Center in New Jersey. In his free time he enjoys riding in TARDISes, defending the Wall, and "chasing the wind." He is a self-described nerd who blogs regularly on nihilism and the art of doing nothing at , where a version of this article originally appeared.