November 9, 2011 — Final results of a randomized trial show no additional benefit to the medical therapy of extracranial-intracranial (EC-IC) bypass surgery in patients with symptomatic atherosclerotic internal carotid artery occlusion (AICAO) with hemodynamic cerebral ischemia.
The procedure had previously been shown in a randomized trial not to provide benefit, but the hope here was to better select patients at risk by confirming the presence of cerebral ischemia using positron emission tomography (PET) before surgery. The trial was stopped for futility in 2010.
Final results of the Carotid Occlusion Surgery Study (COSS) were published in the November 9 issue of JAMA. The findings were first presented in February at the International Stroke Conference.
The COSS results confirm both the importance of hemodynamic factors in the pathogenesis of recurrent stroke in patients with symptomatic AICAO and the accuracy of PET measures of oxygen extraction fraction in identifying those at high stroke risk because of poor collateral circulation, lead author William J. Powers, MD, from the University of North Carolina School of Medicine, Chapel Hill, and colleagues conclude.
The stroke rate they saw of 23% at 2 years in these patients receiving medical therapy is comparable to that faced by patients with 70% to 99% symptomatic carotid artery stenosis.
"Nevertheless, the results of the COSS showed that EC-IC bypass surgery provided no additional benefit over medical therapy for preventing recurrent stroke," they conclude.
Subgroup at Risk
It is estimated that AICAO causes approximately 10% of transient ischemic attacks and between 15% and 25% of ischemic strokes in the carotid territory, the authors note. The 2-year risk for subsequent ipsilateral stroke on medical therapy is between 10% and 15%.
EC-IC bypass was developed in the 1960s with the hope of reducing the risk for subsequent stroke by improving hemodynamics distal to the occlusion, but the well-known results of the EC-IC Bypass Study published in 1985 in the New England Journal of Medicine, showed no benefit from the procedure.
However, Dr. Powers and colleagues note, "[t]his trial was criticized for failing to identify the subgroup of patients with hemodynamic cerebral ischemia due to poor collateral circulation for whom surgical revascularization might be of greatest benefit."
The current trial was a randomized, parallel-group, open-label but blinded adjudication trial of 195 patients with symptomatic AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia ipsilateral to the occlusion, confirmed using PET.
All patients received antithrombotic therapy and risk factor intervention; 97 were randomly assigned, in addition, to receive EC-IC bypass, anastamosis of the superficial temporal artery branch to a middle cerebral artery cortical branch.
The primary outcome for those randomly assigned to surgery who actually received surgery was a composite of 30-day stroke and death from surgery and ipsilateral ischemic stroke within 2 years of randomization. Primary outcome for those not assigned to surgery or who were randomly assigned to surgery but did not receive it in the end was the composite of all stroke and death from randomization to randomization plus 30 days, and ipsilateral ischemic stroke within 2 years of randomization.
The study was terminated early on June 24, 2010, by the data and safety monitoring board because, the researchers note, the prespecified statistical boundary for declaring futility had been crossed. In addition, they write, "given the unexpected relatively low rate of observed primary end points in the nonsurgical group, a clinically meaningful difference in favor of surgery would not be detectable without a substantial increase in sample size, which was not feasible."
Two-year rates for the primary endpoint were not significantly different for the surgical and nonsurgical groups, with a difference of only 1.7% in favor of the surgery. Conversely, 30-day rates for ipsilateral ischemic stroke were higher in the surgical group by 12.4%.
Table. COSS: Primary Endpoint
|Endpoint||Surgical Group||Nonsurgical Group||P (Z Test)||Difference|
|Primary endpoint at 2 years (% [95% confidence interval])||21 (12.8 - 29.2)||22.7 (13.9 - 31.6)||.78||1.7|
|30-day ipsilateral ischemic stroke (% [n])||14.4 (14/97)||2.0 (2/98)||—||12.4|
The lower stroke risk seen in this trial for the nonsurgical group is similar to the overall better outcomes reported in recent studies of patients with asymptomatic carotid artery stenosis treated medically, the authors note — improvements that have been attributed to strides made with therapies such as statins.
"These observations reaffirm the hazard of using even the most carefully studied historical controls to infer therapeutic efficacy and the necessity of performing randomized controlled trials to establish clinical benefit," Dr. Powers and colleagues conclude.
"Although improved hemodynamics in participants who survived EC-IC bypass surgery without perioperative stroke was associated with low risk of recurrent stroke, the better-than-expected efficacy of medical therapy in the nonsurgical group was sufficient to nullify any overall benefit of surgery," they write.
In a statement from the University of North Carolina, Dr. Powers points out that it may be possible to stent these vessels with much lower risk than with bypass surgery. The 30-day postoperative morbidity and mortality in this trial was 15%, which is not statistically different than the 12% reported in the previous EC-IC Bypass Trial.
Those patients who made it through 30 days, however, had a significantly lower risk for stroke — on the order of a 75% reduction. This study, then, proves that if blood flow can be restored to the brain on the side of the blockage, stroke risk can be reduced.
"The trick now is to figure out how to do that with a procedure that doesn't carry such a high risk of stroke itself that it negates the benefit," Dr. Powers notes in the statement. "And that's the real question: Whether or not these catheter-related procedures will be effective at doing that."
Opening Vessels but Not Improving Outcomes?
In an accompanying editorial, Joseph P. Broderick, MD, from the University of Cincinnati College of Medicine, and Philip M. Meyers, MD, from Columbia University, New York City, point out that COSS "joins the list of stroke trials in which a successful outcome as measured by an important biologic marker of brain perfusion — improved oxygen extraction ratio after the bypass procedure — was not reflected in improved clinical outcome at 2 years."
In an interview with Medscape Medical News, Dr. Broderick pointed out that the patients in this trial were selected as being at higher risk for stroke on the basis of demonstrated "misery perfusion" — regions of the brain that are underperfused relative to the metabolic demand.
"Unfortunately, with every procedure there's up-front risk — you can't get away from that," he said. The hope is that a reduced risk over time will justify the initial risk of the surgery, but in this case, it did not.
EC-IC bypass may still be used in the future in highly selected patients, he added, but only a very small number. "What this study suggests is even when you try to select it out by imaging, it's hard to really make the case for the procedure, at least the way we currently do it, with its current risk."
Reimbursement for the procedure may also be an issue given these results, he noted.
The editorial also examined some of the larger issues around reimbursement, particularly for use of devices that get regulatory approval and reimbursement before their value in improving stroke outcomes has really been demonstrated. The result is that enrolment in trials attempting to show the clinical benefit of these devices is significantly slowed, as patients opt not to be randomized or physicians opt not to randomize their patients.
"That's a hard thing to deal with, because the more you use it, the more you're convinced it works," Dr. Broderick said. "We know that these devices open up arteries, and it's a visually compelling thing when you see someone whose artery was closed open up with one of the devices." The problem is that recanalization may not actually provide benefit to the patient.
A case in point is the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, which was recently published in the New England Journal of Medicine and reported by Medscape Medical News at that time. The decision by the Center for Medicare and Medicaid Services not to reimburse intracranial stenting outside of a randomized trial expedited completion of the trial, and ultimately showed no benefit from the procedure, Dr. Broderick noted.
COSS was supported by grants from the National Institute of Neurological Disorders and Stroke. Dr. Powers has reported receiving salary and other support from US Public Health Service grants that supported this research. Disclosures for coauthors appear in the article. Dr Broderick reports having received consulting fees from Genentech and consulting fees as a member of the data and safety monitoring board for the NEST 3 trial. Consulting fees and honoraria for Dr. Broderick are placed in an educational/research stroke fund within the Department of Neurology. Dr. Broderick is the principal investigator of the National Institute of Neurological Disorders and Stroke–funded IMS 3 trial, as well as the National Institute of Neurological Disorders and Stroke–funded University of California SPOTRIAS Center. Dr. Meyers is the external interventional safety monitor for the IMS 3 trial.
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Cite this: EC-IC Bypass Fails Again to Reduce Stroke After TIA - Medscape - Nov 09, 2011.