N Engl J Med 2012;367:2375-2384
Background: The first large trial to compare PCI vs CABG was SYNTAX. In the subgroup of patients with diabetes, which made up approximately 25% of the trial population, PCI was associated with a higher rate of adverse events compared to CABG, primarily driven by higher rates of repeat revascularization in the PCI group.
The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial sought to assess the optimal revascularization strategy for patients with diabetes and multivessel coronary artery disease.
Patients: Eligible patients had diabetes and multivessel coronary artery disease defined as a stenosis of 70% or more in two or more major coronary arteries supplying at least two separate territories.
Patients with left main stenosis of 50% or more were excluded as well as patients with severe congestive heart failure, prior CABG or valve surgery, stroke within 6 months, significant bleeding within 6 months, 2 or more chronic total occlusions in major coronary territories that are targets for revascularization, and patients with STEMI within 72 hours.
Baseline characteristics: The trial randomized 1,900 patients – 953 randomized to PCI and 947 to CABG.
The average age of patients was 63 years and 71% were men. The average HbA1c was 7.8 and 32% were using insulin. Approximately 26% had prior myocardial infarction and 16% were current smokers. The average left ventricular ejection fraction was 66%.
Approximately 83% had three vessel disease and 6% of the lesions were classified as chronic total occlusions. The SYNTAX score was low (22 or less) in 35% of the patients, intermediate (23 - 32) in 45% and high (33 or more) in 20%.
Procedures: Patients were randomized in a 1:1 ratio to undergo CABG or PCI using drug-eluting stents. The use of arterial conduits was encouraged for patients undergoing CABG.
Dual antiplatelet therapy with aspirin and clopidogrel was recommended for at least 12 months following PCI.
Endpoints: The primary endpoint was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke. Secondary analysis was performed based on the SYNTAX score and study center location; north America vs not.
Analysis was performed based on the intention-to-treat principle. The estimated sample size was 1,900 patients to be followed up for at least 2 years. This sample size would provide 80% power to detect a 27% relative risk reduction in one treatment group based on an estimated event rate of 21.5% in the arm with higher event rate.
It’s important to note that the initial sample size was 2,400 patients but this was amended twice due to slow recruitment.
Authors performed 3 interim analyses and therefore, the p value to indicate statistical significance for the primary outcome was adjusted to be 0.044.
Results: Among 32,966 patients who were screened for inclusion, 3,309 (10%) were found eligible. Among eligible patients, 1,900 consented to the trial and were randomized. The breakdown for excluding patients was not provided. The median follow up time was 3.8 years (interquartile range: 2.5 - 4.9). In the PCI arm, the average number of lesions stented per patient was 3.5 and 34% underwent a staged procedure. In the CABG arm, the average number of vessels grafted was 2.9 and 94% had a left internal mammary artery graft.
At 5-years, the primary outcome was lower in the CABG arm (18.7% vs 26.6%, absolute difference 7.9%, 95% CI: 3.3 – 12.5; p= 0.005). All-cause death was lower with CABG (10.9% vs 16.3%; p= 0.049) as well as myocardial infarction (6.0% vs 13.9%; p< 0.001). When examining the Kaplan-Meier curves for the primary endpoint as well as death (figure 1 of the manuscript), the curves start to diverge, in favor of surgery, at approximately 2-years of follow up.
Stroke was higher with CABG (5.2% vs 2.4%; p= 0.03). Excess stroke in the CABG arm was largely within 30-days after the procedure (1.8% vs 0.3%).
Major bleeding within 30-days after revascularization was not significantly different between both treatment groups (3.6% with CABG vs 2.4% with PCI; p= 0.13). Acute renal failure requiring dialysis within 30-days after revascularization was higher with CABG (0.8% vs 0.1%; p= 0.02).
There were no significant subgroup interactions that included the SYNTAX score, sex, 2- or 3-vessel disease and study center location; north America vs not.
Conclusion: In patients with diabetes and multi-vessel stable coronary artery disease, CABG was superior to PCI in reducing the primary endpoint that consisted of death from any cause, nonfatal myocardial infarction, and nonfatal stroke with a number need to treat (NNT) of approximately 13 patients over an average follow-up period of 3.8 years. All-cause death and myocardial infraction were significantly lower with CABG with a NNT of approximately 19 and 13, respectively. Stroke was higher with CABG with a number needed to harm (NNH) of 36 patients. CABG also increased the risk of acute renal failure requiring dialysis within 30-days after revascularization with a NNH of approximately 143.
A key difference between this trial and the early CABG trials is the frequent use of internal mammary grafts in FREEDOM (94% vs 10%). Internal mammary grafts are resistant to atherosclerosis and have high patency rates. One possible explanation for the divergent results between this trial and SYNTAX, which also used arterial grafts frequently, is the follow up time. In SYNTAX, patients were followed for 1 year while FREEDOM followed patients up to 5 years and the curves for the primary outcome and death favoring CABG started to diverge at approximately 2 years.
When deciding between CABG and PCI for patients meeting the trial's eligibility criteria, it’s important to consider the early risks associated with surgery, with the benefits of CABG becoming more apparent after 2 years.