SGEM#137: A Foggy Day – Endovascular Treatment for Acute Ischemic Stroke

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Date: November 21st, 2015

Guest Skeptic: Dr. Rory Spiegel is an Emergency Medicine resident in New York City. Rory is doing a resuscitation fellowship at Stony Brook University School of Medicine. He also writes a blog called EM Nerd about nihilism, medicine and the art of doing nothing.

Case: An 78-year-old woman presents to your emergency department with right arm weakness and slurred speech for the last two hours. She has a history of hypertension and diabetes. A CTA is performed that shows an Intracranial arterial occlusion of the left M1 middle cerebral artery segment.

Background: Prior to the publication of MR CLEAN and the four trials published in its wake, the data regarding endovascular therapy has been consistently negative. Over the past year five RCTs examining endovascular therapy for acute ischemic stroke have been published. In direct contrast to the three trials published in 2013, all of the recent trials were impressively positive.

Because of methodological flaws, the true size of benefit these interventions provide is still unclear. Without an understanding of this effect size, it is difficult to assess whether this benefit justifies the resources required to support its implementation on a national level.

Clinical Question: Do endovascular therapies for acute ischemic stroke lead to improved neurological outcomes when compared to medical therapies alone and what is the effect size?

Reference: Badhiwala, JH et al. Endovascular Thrombectomy for Acute Ischemic Stroke A Meta-analysis. JAMA 2015

Population: Varied depending on primary trial’s inclusion and exclusion criteria. Essentially, patients presenting with signs and symptoms of acute ischemic stroke with either clinical or radiographic evidence of large vessel occlusion conducive to endovascular intervention.
Intervention: Various endovascular therapies including intra-arterial tPA and clot retrieval devices.
Comparison: Optimal medical therapy which included the use of IV tPA in the majority of the patients.
Outcome: The authors chose to examine functional neurological status at 3-months, as assessed by an ordinal analysis of the modified Rankin Scale (mRS).

Author’s Conclusions: “Among patients with acute ischemic stroke, endovascular therapy with mechanical thrombectomy vs. standard medical care with tPA was associated with improved functional outcomes and higher rates of angiographic revascularization, but no significant difference in symptomatic intracranial hemorrhage or all-cause mortality at 90 days.”

Quality Checks for Therapeutic Systematic Reviews:

The clinical question is sensible and answerable. Sensible Yes, Answerable, with the current data, No.
The search for studies was detailed and exhaustive. Yes
The primary studies were of high methodological quality. Variable
The assessment of studies were reproducible. Yes
The outcomes were clinically relevant. Questionable
There was low statistical heterogeneity for the primary outcomes. No
The treatment effect was large enough and precise enough to be clinically significant. Large Yes. Precise No.

Key Results: In their pooled analysis, the authors found a shift towards improved functional outcomes at 90-days in the patients randomized to receive endovascular therapy when compared to standard care.

Odds Ratio 1.56 (95% CI, 1.14–2.13 p=0.005)

Functional independence at 90 days (mRS 0-2) was seen in 44.6% (95% CI, 36.6%-52.8%) in the treatment group compared to 31.8% (95% CI, 24.6%-40.0%) in the standard care grow. This translates into a 12% risk difference (3.8%-20.3%; p = 0.005).

The authors also found no difference in the following secondary outcomes:
- Symptomatic intracranial hemorrhage 5.7% vs. 5.1% (OR, 1.12; 95% CI, 0.77-1.63; P=0.56)
- 90-day all-cause mortality 15.8% vs.17.8% (OR, 0.87; 95% CI, 0.68-1.12; P=0.27).

Though the question of whether endovascular therapy for acute ischemic stroke is an important one, whether it was answerable through a meta-analysis of the current literature is far less clear.

The assumed benefit to performing a meta-analysis is that the summation of these data sets provides a more accurate description of the true effect size than each individual data set can provide.

These trials examined different populations, using different inclusion criteria and different endovascular treatment strategies; essentially they examined different populations.

Heterogeneity: A way to quantify heterogeneity is by using the I2 test. This study had high heterogeneity (I2=75.9) for its primary outcome. This questions whether the data should have been combined in a meta-analysis.
- The assumed benefit to performing a meta-analysis is that the summation of these data sets provides a more accurate description of the true effect size than each individual data set can provide. This supposition rests on the notion that all the studies included in the meta-analysis are examining the same study population, and that the variance of results is due to random errors in sampling.
- This is what is known as a “fixed effect” model. Unfortunately most data is not so homogeneous. It is common for the variations observed between trials to be due to more than just random error, but to considerable differences in the populations being compared. In such cases, the results of a direct-pooled analysis will likely deviate from reality. Statistical models that attempt to account for these random deviations should be utilized. These are known as “random-effect” models (Cornell et al 2014).
- The authors used the I2 index to assess the degree of variation between studies. I2 describes the extent of variation across trials that cannot be explained by random chance. An I2 score of 0% implies all of the variation observed between trials can be accounted for by random errors in sampling. Conversely, if the I2 is 75%, only 25% of the variation can be accounted for by sampling error with the remaining variation (75%) due to heterogeneity between trials (Higgins et al BMJ 2003). In the Badhiwala et al meta-analysis the I2 = 75.9%, so they correctly did a random effect model.
Included Studies: Though the authors search for studies was exhaustive, they were very particular in which trials they selected. In fact, it seems the authors knew which trials would be included in the analysis before conducting it, and the systematic review was merely perfunctory.
Stopping Early: A number of the more recent studies included in this analysis were stopped early. This was after the positive results seen in the MR CLEAN trial. Due to this premature stoppage of these trials, the data is likely to be a distortion of reality. This makes it even harder to interpret the point estimate of effect size.
Time is Brain: One of the subgroups the authors examined in their secondary analysis was whether time to randomization had any effect on the efficacy of endovascular therapy. Specifically they looked at time from symptom onset to randomization. They examined the effect size of endovascular therapy as compared to standard care depending on whether patients were randomized before or after three hours from symptom onset. Temporality did not seem to affect outcomes. Once again calling into question the time is brain mantra so frequently proclaimed.
Ordinal Analysis: The authors utilized an ordinal analysis of the modified rankin Scale (mRS) for their primary outcome. An ordinal analysis is a statistical attempt to assess the shift of outcomes across the entire mRS. This statistical manipulation assumes the reliability of the scale used to measure functional status. It has been shown that when two neurologists assess the same patient, their mRS assessment may vary wildly. This scale is hardly granular enough to apply an ordinal analysis with any accuracy. We have a classic example in the stroke literature where a dichotomous outcome (alive/independent vs. dependent/dead) showed no statistical difference, but a secondary ordinal analysis showed a difference (SGEM#29).

Comment on Authors’ Conclusion Compared to SGEM Conclusion: The authors are likely correct in their assertion that endovascular therapy for acute ischemic stroke leads to improved functional outcomes when compared to medical therapy alone, and yet the true effect size is unknown.

SGEM Bottom Line: Despite its methodological rigor, Badhiwala et al’s meta-analysis brings us no closer to certitude. It serves to place an objective number on the current ambiguous state of the data concerning endovascular therapy for acute ischemic stroke. The inherent value of the statistical manipulations in this pooled data set is unclear. This analysis provides little utility over our unstructured judgment of each respective trial’s importance, while validating our suspicion that these trials are examining very different populations.

Dr. Rory Spiegel

Case Resolution: Rory works at a stroke centre and would activate the stroke team in his hospital. It is more difficult in the community setting where the patient would need to be transferred to a stroke center for care. This added another layer of complexity to the question of how to best manage this patient.

Clinical Application: The recent trials on endovascular therapy for acute ischemic stroke have demonstrated that there is likely a subset of stroke patients who will benefit from reperfusion therapy. This is a small portion of patients that present to the emergency department with acute ischemic stroke. They also demonstrate that this subset of patients is more accurately identified with the use of advanced perfusion imaging rather than an empiric time since symptom onset that we have more traditionally used. The true extent of this benefit is still unclear.

What Do I Tell The Patient? This is difficult. I might say…It appears you are having a stroke. There is a blockage of blood flow to part of your brain. You do have some treatment options. Each option carries potential benefit and potential harm. One involves a clot-busting drug to try and dissolve the clot. Another option is a special type of surgery called endovascsular surgery. It can potentially remove the blockage and restore the blood flow. Both have the risk of bleeding and in some cases even death. But they each also have the potential to improve your weakness and speech. Another option is to do nothing and see if you get better. This too is not without risk. However, the stroke team will be here soon. They can talk with you about your various options in more detail. I am around and happy to answer any question you may have to the best of my ability.

A Few more thoughts from the EM Nerd: Even the biggest cynics must concede there is a signal of benefit demonstrated throughout the recent trials examining endovascular therapy for acute ischemic stroke. How much of this is due to the true effect of the treatment in question, and how much is in fact due to statistical noise is far more difficult to discern.

That has not stopped the AHA from making some recommendations for the use of endovascular therapy. More concerning was their whole-hearted support of the development of a regionalized system capable of instituting the use of endovascular therapy at a national level (Power et al 2015).

Regional systems of stroke care should be developed. These should consist of:
- Healthcare facilities that provide initial emergency care including administration of intravenous r-tPA, including primary stroke centers, comprehensive stroke centers, and other facilities.
- Centers capable of performing endovascular stroke treatment with comprehensive periprocedural care, including comprehensive stroke centers and other healthcare facilities, to which rapid transport can be arranged when appropriate (Class I; Level of Evidence A). (Revised from the 2013 guideline)
They go on to say:
- It may be useful for primary stroke centers and other healthcare facilities that provide initial emergency care including administration of intravenous r-tPA to develop the capability of performing emergency noninvasive intracranial vascular imaging to most appropriately select patients for transfer for endovascular intervention and reduce time to endovascular treatment (Class IIb; Level of Evidence C). (Revised from the 2013 guideline)

Keener Kontest: Last weeks’ winner was Shawn Murphy a Physician Assistant from Parry Sound. He knew “Staying Alive” by the Bee Gees has been suggested as a song to think about when performing chest compressions.

Listen to the podcast for the question this week. If you know the answer, then send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.