April 27th, 2015

Through the Fog of Data on Endovascular Therapy for Acute Ischemic Stroke

The original version of this post appears on Rory J. Spiegel’s blog EM Nerd.

Reading the literature on endovascular therapy for acute ischemic stroke is like being on a small seafaring vessel trying to map the shoreline through dense fog. The fog occasionally lifts, and you glimpse the shore, only for obscurity to return. Recent publications on endovascular therapy for acute ischemic stroke have shown a definitive benefit of mechanical reperfusion therapy, but each study is so incomplete that it’s hard to see anything more than a general appearance of benefit. The premature truncation of trials, too early to definitively characterize the benefits and risks, obscures the finer details.

The MR CLEAN trial, published earlier this year in the NEJM and discussed ad nauseam in previous posts, marked the first of what is now a litany of trials demonstrating a benefit of endovascular therapy in acute ischemic stroke (1). MR CLEAN’s release resulted in the subsequent premature cessation of a number of key trials examining endovascular therapy. Although all of those trials boast impressive results, each stopped enrollment prematurely, not due to a preplanned interim analysis but rather because of MR CLEAN’s positive results. ESCAPE and EXTEND-IA were the first to halt enrollment and hastily publish their results (2,3).

More recently, the NEJM has reported findings from the next two trials that were prematurely stopped after MR CLEAN’s success. The first is the SWIFT-PRIME trial, by Saver et al (4). This trial’s initial results were presented at the 2015 International Stroke Conference, alongside those from EXTEND-IA and ESCAPE. Like its counterparts, SWIFT-PRIME enrolled patients who presented with large ischemic infarcts and radiographically identified occlusions in the terminal internal carotid artery (ICA) or the first branch (M1) of the middle cerebral artery (MCA). In addition, patients had to have a favorable core-to-ischemic penumbra ratio on perfusion imaging. Patients were enrolled if they were able to undergo endovascular interventions within 6 hours after symptom onset.

Like ESCAPE and EXTEND-IA, SWIFT-PRIME had impressive results. The authors boast a 25% absolute difference in the number of patients with a modified Rankin Scale (mRS) score of 0­–2 at 90 days. Though notable, the definitive magnitude of effect is hardly concrete. The authors cite a number needed to treat (NNT) of 4 to have one more patient alive and independent at 90 days, and an NNT of 2.6 to have one patient less disabled. These calculations derive from the dichotomous and ordinal analyses, respectively. Although the authors cite impressive P values (<0.001), the confidence interval surrounding this 25% point estimate is far broader (11%–38%). Therefore, the NNT is somewhere between 2.6 and 9 patients.

EXTEND-IA and ESCAPE have similarly wide confidence intervals surrounding their point estimates (4). EXTEND-IA’s confidence interval is 8% to 50% surrounding a point estimate of 31% (2); ESCAPE has a confidence interval of 13% to 34% surrounding its 23.7% point estimate (3). All three of these trials were stopped early secondary to MR CLEAN’s results. And though both EXTEND-IA and ESCAPE came close to reaching their predefined sample sizes, SWIFT-PRIME was stopped before its first interim analysis (with fewer than 200 patients enrolled) (4).

Like EXTEND-IA, ESCAPE, and SWIFT-PRIME, the second of the relevant trials just published in NEJMthe REVASCAT trial, by Jovin et al., was also stopped prematurely secondary to the publication of MR CLEAN. In fact, even though REVASCAT failed to reach the prospectively determined efficacy threshold for stopping the trial, at the first interim analysis, the data and safety monitoring board felt that, given the MR CLEAN data, there was a loss of equipoise and that further randomization would be unethical (5).

Despite its apparent success, REVACAT has results that are far less impressive than those from EXTEND-IA, ESCAPE, or SWIFT-PRIME. The REVASCAT trial planned to enroll 690 patients presenting to the emergency department (at 4 centers across Catalonia) with symptoms consistent with a large-vessel stroke that could be treated with endovascular therapy within 8 hours after symptom onset. Unlike EXTEND-IA, ESCAPE, or SWIFT-PRIME, the REVASCAT trial did not use perfusion imaging to select patients with favorable areas of salvageable tissue. Rather, it employed CT angiography to identify occlusion in the ICA or the M1 branch of the MCA — and it utilized the less accurate ASPECT score, derived from the initial noncontrast CT, to assess potential for viable ischemic tissue (5).

REVASCAT enrolled 206 patients before its premature termination. And like the three trials before it, it showed a statistically significant improvement in mRS at 90 days in the patients who underwent endovascular therapy. The REVASCAT trial cites an absolute increase in the number of patients with an mRS of 0–2 by 15.5%. This is surrounded by a confidence interval of 2.4% to 28.5%. Furthermore, unlike the previous three trials, which either boast an outright survival benefit or demonstrate trends in favor of endovascular therapy, REVASCAT showed an impressive 4.8% absolute increase in the rate of death within 7 days after randomization (5).

The results of REVASCAT are far from positive. If it were not part of the optimistic fervor that currently surrounds endovascular therapy, REVASCAT might even be considered a negative trial. Why were the results of REVASCAT far less impressive than those of EXTEND-IA, ESCAPE, and SWIFT-PRIME? Was it just random chance, the true effect size of endovascular therapy falling somewhere between the two extremes of the 13.5% difference observed in MR CLEAN and the 31% in EXTEND-IA? Or, rather, was it that the patient populations selected in EXTEND-IA, ESCAPE, and SWIFT-PRIME led to trials’ success? EXTEND-IA, ESCAPE, and SWIFT-PRIME all used some form of advanced imaging to determine the size of viable ischemic tissue (2,3,4). MR CLEAN and REVASCAT used only the CTA to identify a reachable lesion, and the noncontrast CT to determine tissue viability (1,5). If any one of those trials were followed to completion, the results would be likely to yield a better understanding of which patients will benefit from endovascular therapy and the exact magnitude of this benefit.

This is a problem of certainty. Our faith in endovascular interventions was so unyielding that at the first sign of success we claimed victory and discontinued any further scientific inquiries. The bloated results from EXTEND-IA, ESCAPE, and SWIFT-PRIME are the consequences of this premature resolution. We know that trials stopped early for benefit are likely to overestimate the effect size of the treatment in question. In fact, the smaller the sample size is at the time of closure, the greater the amplification will be (6). In 1989, Pocock et al. showed this to be a mathematical inevitability (7), later validated by Bassler et al. in a meta-analysis of 91 trials stopped prematurely for benefit (8). Bassler et al. revealed that the degree of embellishment was directly related to the size of the sample population at trial cessation and independent of the quality of the trial or the presence of a predetermined methodology for early stoppage.

Although the exact patient population that stands to benefit from endovascular therapy is unclear, it is certainly a small fraction of the overall patients who present to the ED with acute ischemic stroke. All patients enrolled in the REVASCAT trial were also included in a national registry known as SONIA. SONIA catalogued 2576 patients (only 15.6% of all stroke patients seen) with some form of reperfusion therapy during the period when REVASCAT enrolled patients (5). The vast majority of those patients (2036; 79%) received only t-PA; Of the 540 patients (21%) who underwent endovascular therapy, only 111 (24%) were eligible for enrollment in the REVASCAT trial. Only 4.3% of the patients in the SONIA registry, and only 0.3% of all stroke patients during the 2-year period, were eligible for inclusion in REVASCAT (5). This accounts for a small minority of the stroke patients presenting to the ED with symptoms consistent with acute ischemic stroke. Notably, the REVASCAT trial’s eligibility criteria are more inclusive than those used in EXTEND-IA, ESCAPE, and PRIME-SWIFT, which if you believe were successful because of their inclusion criteria, would account for an even smaller portion of stroke patients presenting to the ED. In the SWIFT-PRIME trial, it took 2 years and 39 centers to recruit 196 patients (4). That comes out to 0.2 patients per center per month. EXTEND-IA and ESCAPE recruited only 0.3 and 1.44 patients per center per month, respectively (2,3).

Even the greatest skeptics will find it difficult to deny the definite treatment effect observed in the recent trials of endovascular therapy in acute ischemic stroke. The magnitude of this effect has yet to be defined. Its borders are obscured by the murkiness of small sample sizes, extreme selection bias, and prematurely stopped trials. This invasive procedure also has clear harms. Both the REVASCAT trial and the earlier trials of endovascular therapy (IMS-III, SYNTHESIS, and MR RESCUE) demonstrated that when performed on the wrong patient population, endovascular therapy will not only fail to provide benefit, but it may also be harmful (5,9,10,11).

In short, this is simply not a yes or no question. The resources required to build an infrastructure capable of supporting endovascular therapy on a national level are daunting. Although we have reached a certain degree of clarity that endovascular therapy for acute ischemic stroke provides benefit, how well and in whom remains murky. The overeager truncation of important trials has left us adrift in a sea of fog, unsure whether the shoreline is a warm, welcoming beachfront or a rocky coast set to demolish our vessel upon arrival.

Sources Cited

  1. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372(1):11-20.
  2. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372 (11): 1009-18
  3. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372(11): 1019-30
  4. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; Apr 17: epub ahead of print
  5. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 Hours after symptom onset in ischemic stroke. N Engl J Med 2015; Apr 17: epub ahead of print
  6. Guyatt GH, Briel M, Glasziou P, Bassler D, Montori VM. Problems of stopping trials early. BMJ 2012; 344:e3.
  7. Pocock SJ, Hughes MD. Practical problems in interim analyses, with particular regard to estimation. Control Clin Trials 1989; 10(suppl 4):209-21S.
  8. Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA 2010; 303(12):1180-7.
  9. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013; 368(10):893-903.
  10. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368(10):904-13.
  11. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; 368(10):914-23.


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