By: Norman Bauman for Veins1
"You can look after patients in your own community," said Roger M. Greenhalgh, MD, professor of surgery at Imperial College, London. But if you do clinical trials properly, "you can bring the optimal treatment to a large population of patients all over the world."
And now Dr. Greenhalgh was in New York, at the VEITHSymposium™ on vascular surgery, to bring his results to North America.
Dr. Greenhalgh is a vascular surgeon. Many people around the world have a life-threatening vascular disease, with major arteries blocked or swollen and ready to burst. The disease can be cured by an operation, which could also kill them. Is it safer to have the operation or not? There is often traditional surgery and a less-invasive procedure. Is the less-invasive procedure as good? Dr. Greenhalgh helps them decide.
Coronary artery disease
For coronary artery disease, in which the arteries that supply the heart are blocked by atherosclerosis, outcomes have "enormously improved" in his lifetime, said Dr. Greenhalgh.
Heart surgeons learned to open the patient's chest and bypass blocked arteries with an artery or vein from somewhere else. Then they developed a less-invasive technique: Feed a catheter through the artery in the groin, up the aorta, and into the coronary artery. A pressurized balloon at the end opens the coronary artery. This is called balloon angioplasty.
Surgeons are trying to develop less-invasive techniques, like catheters and balloons, for everything they do.
Stroke and carotid arteries
For those who don't die of a stroke, it causes "the most terrible conditions you can imagine, being alive but paralyzed without being able to speak," said Dr. Greenhalgh. "Of all the endpoints from my patients who are suffering, that was the worst."
Many strokes are caused by atherosclerotic plaque that builds up in the carotid arteries on either side of the neck. The plaque can eventually block the flow of blood in the artery. But even before then, pieces of plaque can break off and travel up to the brain, where they block smaller arteries and cause strokes. A small temporary stroke, typically a temporary loss of vision, or a temporary paralysis on one side of the body, is a warning that a big, permanent stroke will follow.
Strokes can be significantly reduced by smoking cessation, medication and surgery. In an endarterectomy, the surgeon simply cuts open the carotid artery at the neck and removes the plaque. "I operate on literally hundreds of patients for carotid procedures," said Greenhalgh. "I probably did more carotid procedures than most surgeons in Britain." He also followed up the results of his surgery to find out when and why it succeeds or fails. He compared cigarette smokers with non-smokers, for example.
In the 1980s, carotid endarterectomy was a big fad. Surgeons performed 130,000 procedures a year in the United States, but it was controversial. It reduced strokes, but the surgery itself seemed to cause strokes. Doctors didn't know whether it did more good or harm. So it fell out of favor, and fewer procedures were requested.
Finally, doctors in North America and Europe decided to find out. They took 3,200 patients who had small temporary strokes, gave them aspirin, and randomly assigned them to surgery or no surgery.
The results were dramatic. In 1991, after 18 months, the Americans and Canadians could see that the surgery made such a difference in the worst patients that they ended the study for them, and made carotid endarterectomies the standard of care. Among patients with severely blocked carotid arteries in the control group, 12 percent had a major stroke or died. But with surgery, only 5 percent did. The National Institutes of Health mailed a special alert to doctors. The European study confirmed those results. They also identified patients in whom the surgery didn't work. Surgery has marginal benefit for patients with moderately blocked arteries and no benefit for patients with mildly blocked arteries.
"I was so struck by the impact of that trial," recalled Dr. Greenhalgh. "It rippled across the United States and across Europe," and changed the practice of medicine. Carotid endarterectomies were now performed more frequently than ever before. "I realized it wasn't enough to manage a few people in my immediate environment, I had to learn clinical trial methodology in order to influence the larger group of people."
Sadly, his own father-in-law "suffered a terrible stroke on the right side," said Dr. Greenhalgh. "He had an artery which, if only the disease had been spotted a couple of weeks earlier, could have been corrected."
Surgeons have tried to figure out less-invasive catheter and balloon techniques to replace endarterectomy. They haven't worked too well.
Abdominal aortic aneurysms
Another common cause of death is abdominal aortic aneurysm. All the blood in the body flows through the aorta, which starts at the heart, and travels through the middle of the chest and the abdomen - not an easy place for a surgeon to reach. Then the aorta splits into a branch for each leg.
In men over 65, the wall of the aorta sometimes weakens and enlarges. This is called an aneurysm. Usually it just enlarges a bit and doesn't cause any more problems. But if the aneurysm gets large enough, it balloons out and ruptures. When it ruptures, the person usually dies. In the United States, this causes 15,000 deaths a year.
If a doctor identifies an abdominal aortic aneurysm, a surgeon can repair it. The surgery is invasive. The surgeon makes a long vertical cut in the belly, moves aside other organs, cuts out the weakened aorta, and sews in a fabric replacement graft. The surgery has a death rate of two to four percent but afterwards, the results are excellent.
A lot of men over 65 have enlarged aortas. Which ones need this dangerous surgery? Dr. Greenghalgh's colleagues in England, and the Veterans Administration hospitals in America, decided to find out.
Doctors can easily measure an aorta with ultrasound. A normal aorta is 2.2 centimeters (almost an inch). In 5 percent of those men, the aorta is 3 centimeters or more. Some aortas will grow larger and rupture, and some won't. By the time they reach 5.5 centimeters, they're very likely to rupture, and most surgeons would operate. Some surgeons want to be aggressive, and operate when they reach 4 centimeters. Is that wise?
The British and American investigators separately selected patients with aneurysms four to 5.4 centimeters. They randomized them into surgical or non-surgical treatment. After eight years the surgical and non-surgical patients did equally well, in England and the United States. So now we know, Dr. Greenhalgh says, that you can safely wait until the aneurysm reaches 5.5 centimeters. But then, the death rate goes up to 25 percent a year, so you'd better operate quickly.
Surgeons developed a less-invasive catheter and balloon procedure for abdominal aortic aneurysms like the procedure used in the heart. They repair the aorta from the inside instead of the outside. In endovascular aneurysm repair, or EVAR, they feed a catheter up from the branch of the aorta that goes through the leg, and then up the aorta to the aneurysm. Then they feed a folded graft up the catheter, with a balloon inside. The balloon opens the graft like an umbrella and presses it against the artery walls. The graft can have hooks to hold it in place. The death rate for EVAR surgery is less than for open surgery but sometimes the hooks come loose, which is like having an aortic rupture after all.
Is the less-invasive surgery safer than conventional surgery, as in the heart? Or is it more dangerous, as in carotid arteries? The British National Health System wanted to find out. They commissioned a study to find out, and appointed Dr. Greenhalgh to manage it. Starting in 1999, they randomized 1,000 patients into conventional open surgery and EVAR groups. The initial results were good: 1.7 percent of the patients with EVAR died, compared to 4.7 percent of the patients with open surgery, a three percent improvement. The long-term results were not so good: After four years, the EVAR stents held up. But the death rate was about the same in either group: 26 percent for EVAR, and 29 percent for open surgery. The statisticians said that the three percent difference over four years wasn't significant.
So there was a three percent improvement in survival at the beginning, and for a year or so afterwards, but by the end of four years, about the same number of people were alive. It's good, but not as good as they hoped. Over four years, EVAR "is just ahead of open repair," says Dr. Greenhalgh. It gives you an immediate survival advantage. And it's less invasive – there is no big incision in your abdomen.
"It may well be that a potential grandfather is awaiting the birth of his first grandchild," said Dr. Greenhalgh. "And it may well be that a 30-day mortality and greater certainty of being alive at a certain date is very important."
EVAR was originally developed for people who are too sick for conventional surgery. Most patients with aneurysms smoked cigarettes, for example, so their lung capacity was reduced too.
Dr. Greenhalgh's team randomly assigned these sick patients to EVAR or no surgery. The results weren't good. The EVAR surgical death rate was nine percent. After four years, the death rate was the same in each group, 64 percent. (These were very sick patients.)
"The result of the endovascular aneurysm trial, to my disappointment, is that we are not able to show the mortality benefit," said Dr. Greenhalgh.
"So my focus would change," said Dr. Greenhalgh. Instead of operating quickly, he first treats the underlying condition which is causing the patient to be at such high risk.
A life in science
Dr. Greenhalgh decided early in his career that surgery would be a way to combine his interests in science, his manual dexterity, and his compassion for people. His youthful interests were woodworking and piano, and he enjoyed difficult technical challenges. "I was never so happy as playing the church organ on three keyboards and with my feet at the same time," he said.
In 1969 when he was a training surgeon, the "great contributions" of American vascular surgeons were spreading through the U.K., said Dr. Greenhalgh. "I saw patients who would have otherwise had their legs amputated, have operations which would prevent strokes," and walk out.
"I have always had this urge to understand the dilatation of the aorta," said Dr. Greenhalgh. Why do some people get aneurysms and not others? The aorta is made of collagen, a tough, fibrous protein, and elastin, a stretchy protein. A normal aorta keeps these proteins in balance by creating and destroying them. One genetic defect seems to overproduce an enzyme that destroys them, which would weaken the aorta. We shall develop drugs to inhibit that enzyme, he said. "In the future, the dilating process will be overcome."