A major study to test the hypothesis that extracranial-intracranial (EC/IC) arterial bypass surgery will reduce subsequent ipsilateral ischemic stroke at two years, despite perioperative stroke and death, is currently underway at 22 centers in the United States. This randomized, non-blinded, controlled clinical trial, known as the Carotid Occlusion Surgery Study (COSS), is funded by the National Institute of Neurological Disorders and Stroke. However, recruitment has been so slow that this important study is in danger of being closed down.

Carotid artery occlusion is estimated to cause 61,000 first ever strokes and 19,000 transient ischemic attacks (TIAs) per year in the United States. The overall rate of subsequent stroke is 7 percent per year for all stroke victims and 5.9 percent per year for those suffering ipsilateral ischemic strokes. These risks persist in the face of platelet inhibitory drugs and anticoagulants. Prevention of subsequent stroke in patients with carotid artery occlusion remains a difficult challenge.

PET to ID Stroke's Cause
The technique of EC/IC arterial bypass surgery was developed in the late 1960s and applied to patients with carotid occlusion in an attempt to prevent subsequent stroke by improving the hemodynamic status of the cerebral circulation normally supplied by the occluded vessel. In 1977 an international multicenter randomized trial of EC/IC bypass showed no benefit for the prevention of subsequent stroke among 808 patients with symptomatic carotid occlusion. This trial, however, has been criticized for failing to identify and separately analyze the subgroup of patients with hemodynamic compromise in whom surgical revascularization might be beneficial. Unfortunately, at the time that this trial was conducted there was no reliable and proven method for identifying a subgroup of patients in whom cerebral hemodynamic factors were of primary importance in causing subsequent stroke.

Neuroimaging techniques now have made it possible to evaluate cerebral hemodynamics in patients with carotid occlusion. Two prospective natural history studies have demonstrated that patients with symptomatic carotid artery occlusion who have increased oxygen extraction fraction (OEF) measured by positron emission tomography (PET) also have a high rate of subsequent stroke within the next two years if they are maintained on medical therapy. Depending on the precise clinical and PET criteria used, the two-year ipsilateral stroke rates ranged from 26 percent to 57 percent. In contrast, the comparable stroke rates in the patients with normal OEF were 5 percent to 15 percent, corresponding to absolute rate differences of 21 percent to 42 percent, and relative rate differences of 75 percent to 80 percent. Since EC/IC bypass has been shown to return areas of increased OEF to normal in patients with carotid occlusion, it is important to perform a new trial that is restricted to patients with symptomatic carotid occlusion and increased OEF identified by PET to determine if EC/IC bypass can produce comparable reductions in stroke risk.

Comparing the Costs
We created a Markov chain model to compare the costs and effectiveness of medical treatment alone in patients with symptomatic carotid occlusion to their treatment using PET screening followed by EC/IC bypass if their OEF was elevated. PET screening followed by EC/IC bypass was shown to prolong quality-adjusted survival when compared to medical therapy alone. Over a 10-year span, the gain in quality-adjusted years was 49 per 100 patients screened, with minor cost savings. This result is not surprising given the high cost of stroke in the medically treated patients. Finally, the cost of PET was more than offset by reducing the number of operations performed on patients who were at low risk for subsequent stroke, thus reducing the attendant risk and expense.

Thus, there is good scientific, clinical and economic evidence to proceed with the COSS as quickly as possible.

Assisting in the COSS
We ask all of our neurosurgical colleagues to assist in this important study by referring their eligible patients to participating centers. Major eligibility criteria are:

• atherosclerotic occlusion of one or both carotid arteries;
  
• hemispheric TIA or mild-to-moderate stroke (modified Barthel index of 12 or greater) in the territory of an occluded carotid artery within 120 days; and
  
• increased cerebral OEF measured by PET image in the cerebral hemisphere distal to the symptomatic carotid artery occlusion. COSS will pay the costs of PET and of the EC/IC bypass surgery. Further details and a list of participating centers can be found at www.cosstrial.org, or by contacting Carol Hess, the project coordinator, at carol@npg.wustl.edu.
  

We will not get another chance to prove the value of EC/IC bypass for stroke prevention. Failure to complete this study will permanently consign the bypass procedure to the history books and to the list of procedures not reimbursed by Medicare.

William J. Powers, MD, principal investigator, and Robert L. Grubb Jr., MD, principal neurosurgical investigator, are at Washington University, St. Louis, Mo. William R. Clarke, PhD, principal investigator of the Biostatistics and Data Management Center and Harold P. Adams Jr., MD, are at the University of Iowa, Iowa City, Iowa.