One gets the sense when reading the literature on endovascular therapy for acute ischemic stroke that they are on a small seafaring vessel attempting to map the shoreline through a dense fog. There are moments when the fog lifts and you catch a glimpse of the topographic details of the shore, and then the cloud again rolls in obscuring any further ascertainment. Similarly the recent publications of endovascular therapy for acute ischemic stroke have demonstrated there is a definitive benefit to mechanical reperfusion therapy, and yet each publication in itself is so incomplete, it is difficult to perceive anything more than this general appearance of benefit. The finer details are obscured by the premature truncation of trials, too early to definitively characterize the benefits and risks of endovascular therapy.
MR CLEAN, 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 benefit for endovascular therapy in acute ischemic stroke (1). Its release resulted in the subsequent premature stoppage of a number of key trials examining endovascular therapy. Although all these trials boast impressive results, each stopped their enrollment prematurely, not due to a preplanned interim analysis, but rather due to 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 on the findings from the next two trials prematurely stopped due to MR CLEAN’s success.
The first of these studies is the SWIFT-PRIME trial published by Saver et al (4). This trial’s initial results were presented earlier this year alongside EXTEND-IA and ESCAPE at the 2015 International Stroke Conference. Like its counterparts, this trial examined patients presenting with large ischemic infarcts and radiographically identified occlusions in the terminal internal carotid (ICA) or first branch (M1) of the middle cerebral artery (MCA). Additionally patients had to demonstrate a favorable core-to-ischemic penumbra ratio on perfusion imaging. Patients were enrolled if they were able to undergo endovascular interventions within 6-hours of symptom onset.
Like ESCAPE and EXTEND-IA, the results of SWIFT-PRIME are impressive. Authors boast a 25% absolute difference in the number of patients with a mRS of 0-2 at 90 days. Though notable, the definitive magnitude of effect is hardly concrete. The authors cite an 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 are used using their 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%). Meaning 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). Likewise 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 pre-defined sample size, SWIFT-PRIME was stopped before its first interim analysis (n<200) (4).
Like EXTEND-IA, ESCAPE and SWIFT-PRIME, the second trial just published in NEJM, the REVASCAT trial, by Jovin et al was stopped prematurely secondary to the publication of the MR CLEAN data. In fact, even though it failed to reach the prospectively determined efficacy threshold for stopping the trial, at the first interim analysis, the data and safety board felt that given the MR CLEAN data, there was a loss of equipoise and further randomization would be unethical (5). Despite its apparent success the results of the RAVASC trial are far less impressive than either EXTEND-IA, ESCAPE or SWIFT-PRIME. The REVASC trial planned to enroll 690 patients presenting to the Emergency Department in 4 centers across Catalonia with symptoms consistent with a large vessel stroke that could be treated with endovascular therapy within 8 hours of 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 employed CTA to identify occlusion in the ICA or M1 branch of the MCA, and utilized the less accurate ASPECT score, derived from the initial non-contrast CT, to assess potential for viable ischemic tissue (5).
REVASCAT enrolled 206 patients before its premature termination. And like the three trials before it demonstrated 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 a 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 that either boast an outright benefit in mortality or demonstrate trends in favor of endovascular therapy, REVASCAT demonstrated an impressive 4.8% absolute increase in the rate of death within the first 7 days after randomization (5).
The results of REVASCAT are far from positive. If they were not included in the optimistic fervor that currently surrounds endovasacular therapy, it might even be considered a negative trial. Why were the results REVASCAT far less impressive than 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% seen in EXTEND-IA? Or rather was it that the patient population selected in EXTEND-IA, ESCAPE and SWIFT-PRIME led to their success? EXTEND-IA, ESCAPE and SWIFT-PRIME all utilized 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 non-contrast CT to determine tissue viability (1,5). If any one of these trials were followed to completion the results likely would provide us with a better understanding of who 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 demonstrated in EXTEND-IA, ESCAPE, and SWIFT-PRIME are the result of this premature resolution. We know that trials stopped early for benefit are likely to over-estimate the effect size of the treatment in question. In fact the smaller the sample size at the time of closure, the greater the amplification (6). In 1989, Peacock et al demonstrated this to be a mathematical inevitability (7). Later validated by Bassler et al in a meta-analysis examining 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 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 Emergency Department with acute ischemic stroke. All patients enrolled in the REVASC 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 over the time period REVASCAT enrolled patients (5). The vast majority of these patients 2036(79%) received only tPA. 540 (21%) patients underwent endovascular therapy. Of these only 111 (24%) were eligible for enrollment into 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 the REVASCAT trial (5). This accounts for a small minority of the stroke patients presenting to the Emergency Department with symptoms consistent with acute ischemic stroke. Of note the criteria used in the REVASCAT trial to determine eligibility 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 the Emergency Department. 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 most skeptical will find difficulty denying there is a definite treatment effect observed in the recent trials examining 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. There are also clear harms associated with this invasive procedure. Both the REVASCAT trial and the earlier trials examining endovascular therapy (IMS-3, SYNTHESIS and MR RESCUE) demonstrated that when performed on the wrong patient population, not only will endovascular therapy fail to provide benefit, it may in fact be harmful (5,9,10,11). 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. Though 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 if the shoreline we paddle towards is a warm welcoming beachfront or a rocky coast prepared to demolish our vessel upon arrival.
- 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.
- Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection. N Engl J Med. 2015.
- Goyal M, Demchuk AM, Menon BK, et al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. N Engl J Med. 2015.
- 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
- Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. N Engl J Med. 2015;
- Guyatt GH, Briel M, Glasziou P, Bassler D, Montori VM. Problems of stopping trials early. BMJ. 2012;344:e3863.
- Pocock SJ, Hughes MD. Practical problems in interim analyses, with particular regard to estimation. Control Clin Trials 1989;10(suppl 4):209-21S.
- 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.
- 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.
- Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(10):904-13.
- 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.