Review of the Coronary Artery Surgery Study (CASS)

Circulation 68, No. 5, 939-950, 1983

Background  Coronary artery bypass surgery (CABG) had grown in popularity through the 1970s and 1980s. By 1981, approximately 159,000 bypass surgeries had been done.

The goal of the CASS trial was to rigorously evaluate the effect of surgical vs medical therapy on total mortality in well-defined subsets of patients with coronary artery disease.

Patients Eligible patients had to be 65 years of age or below and have angina that was Canadian Cardiovascular Society class I or II with or without a history of myocardial infarction, or had to have a well-documented MI more than 3 weeks before randomization. Clinical criteria for exclusion were prior CABG, unstable or progressive angina, angina more severe than class II (angina occurring after climbing one flight of stairs or walking two blocks is class III), congestive heart failure (New York Heart Association class III or IV), a coexisting illness that would increase the likelihood of death within 5 years, and a variety of practical exclusions that might limit active participation during follow-up.

Angiographic requirements for participation in the trial included the presence of significant operable coronary artery disease, defined as either 70% or greater reduction in the diameter of the right, left anterior descending, or left circumflex coronary artery, or 50% or greater reduction in the diameter of the left main coronary artery. Patients with 70% or greater luminal diameter reduction of the left main were excluded. Also excluded were patients with LVEF (measured by left ventriculography) of less than 35% or those patients who required valve surgery or LV aneurysm repair.

Baseline Characteristics There were 390 patients randomized in both the surgical and medical arm. The mean age was 51 years; 90% were males and 98% were White. Approximately 60% had previous MI, 30% had hypertension and only 3% had congestive heart failure. About 40% were smokers.

Angiographic criteria were well matched—27% had one-vessel disease, 38% had two-vessel disease, and about a third had three-vessel disease. Nearly a third of patients in both groups had proximal LAD disease. The LVEF was more than 50% in 73-74% of patients in both groups. The LVEF was less than 50% in a fifth of patients in both arms.

Procedures CASS authors were quite clear in the screening and randomization process. Slightly more than 16,600 patients were screened for participation in the trial at 11 centers. Figure 1 in the manuscript shows the reasons for exclusion, which included normal or minimal coronary disease (28%), Class 3 or 4 angina (36%), and left main disease more than 70%n (1.5%). Other exclusions totaled 16%.

Ultimately there were 2099 patients eligible to be randomized, however, 1319 patients were not included in the trial due to physician preference.

Randomization was stratified by clinical site, number of diseased vessels, and ejection fraction within three different clinical subgroups. Patients with angina and ejection fractions of at least 0.50 were randomized within group A (n =514), those with angina and EF less than 0.50 were randomized within group B (n=106) and those free of angina after well-documented MI were randomized within group C (n=160).

A total of 954 distal anastomoses were constructed in 357 patients in the surgical group, an average of 2.7 per patient. A total of 334 distal anastomoses were evaluated in the 129 patients; 90% of the grafts were open, 97% of patients had at least one open graft, and in 81% of patients all grafts were patent. Medical therapy consisted mostly of nitrates, and beta-blockers. Statin drugs were not available during the trial.

Endpoint The primary endpoint was all-cause mortality. It was assessed with the intention-to-treat method.

Results There were no significant differences in mortality.

At 5 years, the average annual mortality rate in patients assigned to surgical treatment was 1.1%. The annual mortality rate in those receiving medical therapy was 1.6%. Expressed differently, the rate of death at 5 years was 9.2% in the medical group versus 7.4% in the surgical group.

Annual mortality rates in patients with single-, double-, and triple-vessel disease who were in the surgical group were 0.7%, 1.0%, and 1.5%; the corresponding rates in patients in the medical group were 1.4%, 1.2%, and 2.1%.

There were also no significant differences in survival when patients were grouped according to degree of coronary artery disease (number of vessels) or EF or by a combination of diseased vessels and EF.

Crossovers did occur. Approximately 23% of the 390 patients assigned to the medical group had surgery during the follow-up period (4.7% per year). Of the patients assigned to surgery, 31 of 390 patients (8%) did not have surgery.

Conclusions The CASS authors write in the abstract of the manuscript that they observed excellent long-term survival in both groups and that for patients similar to those in the trial, surgery could be deferred until symptoms worsen.

The CASS trial had caveats. First was that the 780 patients enrolled in the trial were highly selected from a total of more than 16,000 patients in the registry. The CASS registry revealed widely disparate annual mortality in patients managed medically, ranging from 1.3% for those with single-vessel disease and normal EF to 12.5% in those with three-vessel disease and impaired EF.

Another caveat was the lower-than-expected annual mortality in the medical arm of only 1.6%. This was lower than previous surgery trials (3.3% noted in the European Collaborative Study and 4.3% reported in the Veterans Administration Study). CASS authors estimated a 2-4% annual mortality. This reduces the power to find differences in the two groups.

It is interesting however, that for the 1319 patients in whom their physician declined randomization, the outcome in those treated medically was similar to that reported in the randomly assigned patients who received medical therapy.

In conclusion, as early as the 1980s, the CASS study showed that stable coronary artery disease was quite stable, and that revascularization in selected patients did not improve survival over medical therapy.