The Importance of a Controlled Study

by Guy McKhann, M.D.

October 20, 2011

In medicine, people in one field can learn from those in other fields. For people working on the brain, what those working on the heart are doing may provide some leads to new approaches to our problems. The heart people have been ahead of their brain colleagues in techniques for opening up plugged arteries. They have developed catheter-based techniques to place stents in arteries of the heart that are becoming occluded by arteriosclerosis. In this procedure, a catheter is introduced to the area of stenosis (or narrowing) of the artery, a balloon is used to widen the artery, and a stent, or tube, is placed to keep the artery open. Stenting of coronary arteries has become a very common procedure. The question is, if a stenting procedure works so well for the heart, why not use it for the brain?

The arteries in the brain can become occluded from arteriosclerotic disease, just as they do in the heart. If the problem is in one of the big arteries in the neck, like the external carotid artery, which you can feel under your jaw, the artery can be directly operated on and cleaned out. Or, as is being done for the heart, a stenting procedure can be done on these large, brain-directed arteries. However, if the occlusive problem is in the arteries inside the skull, surgical access is limited. Maybe a stent could be used.

Stenting procedures for brain arteries were originally introduced about 10 years ago. Although not yet commonly used in practice, there have been multiple studies involving the technology and outcomes. However, until now, the crucial study had not been done. That is a study comparing two groups of patients with similar, severe disease: one getting the best medical therapy, and the other getting the best medical therapy and a stenting procedure. The investigators doing the study are blind to the results until the study is over.

HealthDay article by Steven Reinberg describes just such a study. The investigators expected that stenting would be better than medical therapy alone. They set up the study anticipating a 35 percent improvement in the stent group, necessitating 382 subjects in each group (764 total) to establish this outcome. They deliberately focused on the more severely involved subjects, those who have had a stroke or transient stroke-like symptoms, with 70-99 percent closure of a major artery of the brain. The study started in November 2008 and by March 2011 the investigators had 451 subjects.

A study such as this one has an outside monitoring team, made up of experts in the area that are not involved in the study. Such a team can break the code and see if there are more problems in one group or another. They can also determine if one group is doing so much better or worse than the other that the study should be stopped. And that’s exactly what happened.

This past April, on the basis of the examination of the results in 451 subjects, the monitoring group stopped the study, but not for the reason people expected. Instead of doing better, the stent group was doing worse. The differences were striking. For the primary outcome at 30 days—that is, the combination of nonfatal stroke, fatal stroke, or death—the rate in the stent group was 14.7 percent and in the medically treated group 5.2 percent, a highly significant statistical difference (P=0.002).

The difference between the two groups was only witnessed in the immediate post-procedure period. After 30 days the rates became equal. The long term effects are not yet known, because these subjects are still being followed. For those who wish to see the details of this study it is in the New England Journal of Medicine. There is also an accompanying thoughtful editorial, “The Challenges of Intracranial Revascularization for Stroke Prevention,” by Dr. Joseph P. Broderick of the University of Cincinnati.

I have been on both sides of the fence in studies similar to this one, both as a participant and as an independent monitor. These types of studies are very difficult to accomplish. There are vested interests who certainly don’t want to see a negative result, including the manufacturers of the equipment, hospitals who stand to make a bundle on these types of procedures, and the medical specialists who perform these procedures. The investigators who carried out this study resisted these outside forces, designed an excellent study, and pulled it off. They are to be congratulated.

The basic problem still exists: Treatment of diseased arteries within the brain needs to be better. The idea of using stents to open up brain arteries may still be a good one, but not in the way used in this study. It is necessary to go back to the drawing board and devise other ways. Those new methods will also have to be evaluated in studies similar to this one.