The Evidence that Established Coronary Artery Bypass Surgery is Worth Studying
The study of the week goes back in history to look at the surgery vs medicine trials in patients with severe coronary heart disease. Wow.
(Editor’s note. I had accidentally limited comments to paid subscribers. Comments are now open to all.)
Two quick stories as background.
I remember caring for an older man who presented with a minor heart attack. We got him squared away easily. I was then struck by his history because more than a decade before this presentation, doctors had discovered severe multi-vessel coronary disease and they had recommended bypass surgery. They told him he would die without it. He refused. And he didn’t die. He lived another decade with little trouble—on a few tablets.
Second story: When I trained in cardiology, I recall being upset that veterans with severe coronary artery disease had to wait weeks to have their coronary bypass surgery (CABG). My angst was for naught. Had I looked back at the seminal trials, I would not have worried. In fact, the seminal trials of CABG vs medical therapy are quite surprising.
In this week’s study of the week, let’s look back at those seminal trials. Buckle up.
The Coronary Artery Surgery Study (CASS) trial came first. It started in 1975 and was published in 1983. Patients with amenable coronary disease were randomized to either bypass surgery (n =390) or medical therapy (n=390). The primary endpoint was death. The survival curve showing no difference over 12 years is below.
A year later, the NEJM published the VA Cooperative trial. The trial procedures were similar. CABG vs meds in nearly 700 patients. The eleven-year rates of survival were 57 vs 58% respectively. The survival curves graphically show the lack of CABG benefit over meds.
The European Coronary Surgery Study reported four later in 1988. Once again, CABG was compared to meds in 767 men. “Twelve years after assignment to treatment, there were 201 deaths — 109 in the medically treated group and 92 in the surgically treated group.”
The survival curves below show a definite benefit for surgery at 5 years, but over the next five years, the curves come together. In the end, that difference in 17 deaths barely reached statistical significance at a P-value of 0.043.
I know what you may be thinking. Mandrola, you are off your rocker. These are old trials. Modern trials must have been better. Modern heart surgery uses the left internal mammary artery whereas older surgery used mostly vein grafts.
Ok. Let me show you a big modern trial.
The STICH trial, published in 2011, randomized about 1200 patients with impaired LV systolic function and severe coronary artery disease amenable to surgery to CABG or medicine alone. The primary outcome was death.
Death occurred in 41% of patients (244) in the medical arm vs 36% (218) in the surgical arm. The edge to surgery did not reach statistical significance. This, despite the fact that patients had severe multi-vessel disease and bad ventricular function. About 70% of these patients had proximal LAD disease—the widow-maker.
The STICH trialists amended their study protocol and followed these patients for 10 years. They called the extension study STITCHES.
The survival curves are similar, but since more patients died, (or had outcome events in statistical parlance), the small advantage in death now reached statistical significance. It should be noted, however, that after a decade, in a trial of 1200 patients, the difference in deaths was only 39.
You might wonder how bypass surgery became established as a common everyday procedure despite all these non-significant trials. Recall also that this was an era where medical therapy included only nitrates and aspirin.
I look forward to any comments from surgeons, but I see three main reasons.
One was that subgroups within these non-significant trials did better with surgery. Yet we all know the limits of subgroups, especially when taken from trials with non-significant primary endpoints.
Another reason was crossovers. Each of these trials were labeled CABG vs Meds. But many patients in the medical arm eventually crossed over to surgery. The intention-to-treat principle holds that cross-over patients are analyzed in the medical arm. That surely reduces any surgical advantage. Another way to consider these trials would be immediate vs delayed surgery.
The other savior for bypass surgery came from a Canadian research team from McMasters University. Professor Salim Yusef organized a study wherein he and colleagues got the authors of these studies to share individual patient level data for a meta-analysis.
It’s now known simply as the “Yusef meta-analysis.” Lancet published the study and here is the main survival curve:
When you combined the studies, about 1300 patients were randomized in each group. The CABG group had a significantly lower mortality than the medical treatment group: at 5 years (10.2 vs 15.8%; odds ratio 0.61 [95% Cl 0.48-0.77], p = 0001), at 7 years (15.8 vs 21.7%; 0.68 [0.56-0.83], p<0.001), and 10 years (26.4 vs 30.5%; OR 0.83 [0.70-0.98] p =0.03.
Yusef and colleagues also noted the subgroup findings. The risk reduction with surgery was greater in patients with left main disuse and in those with disease in three vessels.
I was struck by the meta-analysis authors’ contention that each of the trials were underpowered. They recommended larger trials. But that is hard for me understand because each of the CABG vs Medical trials were carried out for decade—and each had many outcome events.
This post is not meant to question the value of coronary bypass surgery. If I had severe angina, heart failure, left main or multi-vessel proximal disease with LV dysfunction, I would strongly consider bypass surgery. If I were unstable and had severe disease, I’d consider CABG.
The main take-home of this post is to emphasize the extreme (near-miraculous) stability of stable coronary disease. Had this fact been better appreciated at the time, I think it would have reduced our enthusiasm for many things we do in cardiology.
The clear stability of stable coronary disease is surely why no trial of stenting or angioplasty of stable disease has ever shown a survival advantage.
This stability of coronary disease is another reason why I am not enthusiastic about early detection of disease with coronary artery scans.
I hope some heart surgeons happen by this column and offer their comments. JMM
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