FREEDOM: CABG Superior to PCI in Diabetic Patients With Coronary Disease

November 04, 2012

LOS ANGELES — Patients with diabetes and multivessel coronary artery disease treated with CABG surgery had significantly lower rates of death from any cause, nonfatal MI, or nonfatal stroke when compared with diabetic patients treated with PCI, according to the long-awaited main results of the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial[1].

Presented at the American Heart Association (AHA) 2012 Scientific Sessions today and simultaneously published in the New England Journal of Medicine, the researchers, led by Dr Michael Farkouh (Mount Sinai School of Medicine, New York), believe the results have the potential to immediately alter clinical practice and potentially have an impact on the clinical guidelines for the management of patients with diabetes.

Presenting the results to the media, senior investigator Dr Valentin Fuster (Mount Sinai School of Medicine) concluded that in diabetic patients with complex disease, "CABG was of significant benefit as compared with PCI." In addition to the reduction in the primary composite end point, CABG was also associated with a significant reduction in the risk of MI and all-cause mortality, while PCI was associated with a lower risk of stroke. For the FREEDOM investigators, CABG surgery should be the preferred method of revascularization for patients with diabetes and multivessel coronary artery disease.

According to Dr David Williams (Brigham and Women's Hospital, Boston, MA), an interventional cardiologist who was not affiliated with the trial, the results of FREEDOM will definitively affect his clinical practice. Asked if he would be less likely to perform PCI in patients with diabetes, Williams said the answer is yes.

"I think the study is very convincing, and I think the guidelines will likely recognize that," said Williams. "There have been trends showing this before, such as the BARI-2D study with similar information showing that surgery was definitely better than medicine. I think that if you look at the anatomy--and all coronary disease is not the same--the anatomy [of diabetics] is imposing, and I think most of these patients go to surgery anyway. But I think this provides meaningful information to help us with these decisions."

Dr Alice Jacobs (Boston University, MA), who commented on the study but was not affiliated with it, noted that the 2010 guidelines on myocardial revascularization already state that CABG should be considered over PCI when the extent of coronary disease justifies a surgical approach (class IIa, level of evidence B). The 2011 PCI and CABG guidelines also suggest CABG over PCI in patients with multivessel disease who also have diabetes.

"Faced with a patient who is a candidate for either procedure, I would think long and hard about performing PCI at this point," said Jacobs.

Dr Subodh Verma (University of Toronto, ON) agreed, telling heartwire that the debate over PCI vs CABG in diabetic patients should end now, given the clear results from FREEDOM. Verma, a surgeon, stressed that the debate over PCI and CABG is not a war between interventionalists and surgeons, and these new data highlight the importance of collaboration and cooperation to provide the best patient care. The data also clearly show that for patients with diabetes and multivessel disease, "surgery is the best option for patients," a finding that has important implications given the obesity epidemic and rising rates of diabetes in the developed world.

Significant Reduction in Clinical Events

Sponsored by the National Heart, Lung, and Blood Institute, FREEDOM enrolled 1900 patients with diabetes and coronary artery disease, a majority of whom had three-vessel disease, to treatment with CABG surgery or PCI with sirolimus-eluting and paclitaxel-eluting stents. Newer-generation stents could be used as long as they were FDA-approved. Dual antiplatelet therapy was recommended for at least 12 months, and patients were followed for a minimum of two years.

During a median follow-up of 3.8 years, the primary end point occurred in 205 patients in the PCI arm and 147 patients in the CABG arm. The five-year primary end-point event rates were significantly lower in the CABG-treated patients, as was the five-year rate of all-cause mortality and MI. Following revascularization, the five-year rate of all-cause mortality, MI, and stroke was 26.6% in the PCI-treated patients and 18.7% among patients who underwent CABG surgery, a statistically significant relative risk reduction of 30%. Stroke rates were significantly higher in the CABG arm, mainly because of the excess of stroke in the surgery patients that occurred within the first 30 days. Of the strokes, most (87%) were ischemic strokes and 13% were hemorrhagic.

FREEDOM: Primary End Point Five Years After Randomization

Outcome PCI (%) CABG (%) p
Primary end point (all-cause death, nonfatal MI, or nonfatal stroke) 26.6 18.7 0.005
All-cause death 16.3 10.9 0.049
MI 13.9 6.0 <0.001
Stroke 2.4 5.2 0.03
Cardiovascular death 10.9 6.8 0.12

The researchers observed no significant interaction based on SYNTAX score, with the absolute difference in the primary end point between PCI and surgery similar in patients with a low, intermediate, and high SYNTAX score. Given the wide variability of the patients enrolled in FREEDOM, as evidenced by the wide distribution of SYNTAX scores at baseline, the trial represents real-world practice and should be considered a strength of the study, according to the investigators.

Putting the Results Into Clinical Practice

Speaking with heartwire , Dr Robert Harrington (Stanford University, CA) said FREEDOM is consistent with previously published data and that CABG in this patient population appears to be a better revascularization option. While there might be some argument made that the drug-eluting stents used were not the most contemporary stents on the market, Harrington said this push-back argument is usually made by the losing side.

"I would think that's a stretch to say that's the reason for the difference," said Harrington. "I don't think we see any evidence that one stent is superior to any other with regard to the end points measured here or that it would make any difference."

Dr Eric Bates (University of Michigan, Ann Arbor) told heartwire that when looking strictly at the clinical trial and the previously published evidence, FREEDOM supports the superiority of CABG over PCI. However, he said that from a clinical-practice point of view, many interventionalists are able to identify low-risk and high-risk patients and as a result are able to direct them to the most appropriate revascularization treatment. For this reason, some of registry data have shown that clinical events were similar in diabetic patients undergoing CABG surgery or PCI.

"It's not PCI vs CABG," said Bates. "These are complementary revascularization procedures, and these trials show that CABG should be an important part of the discussion, but on an individual patient level, there are factors such as the risk of stroke, frailty, renal function, pulmonary function, patient preference, operator experience, and other variables that go into making an individualized patient decision."

To heartwire , Dr Christopher White (Ochsner Medical Center, New Orleans, LA), the president of the Society for Cardiac Angiography and Interventions (SCAI), called the FREEDOM study unassailable in terms of its design, saying the results definitely tilt the balance in favor of CABG surgery in diabetic patients with multivessel disease. He added, however, that the results apply to those included FREEDOM--that is, patients who were candidates for surgery and for stenting. He noted that nearly 33 000 patients were screened and one-tenth were eligible for inclusion in the trial, of whom 1900 provided informed consent.

"But the prima facie evidence, based on the randomized-controlled-trial data, is that if I run into a patient tomorrow who would have gotten randomized in FREEDOM, they should have surgery and not stenting," said White.

To heartwire , Verma said the results have immediate clinical implications, given that the two therapies are not equivalent when it comes to the treatment of diabetics with coronary artery disease. He added that it will be an interesting experiment to watch how these results filter down into clinical practice and change care. Equally important will be the long-term data to determine whether the benefits of CABG over PCI are maintained over time or possibly widen.

Informed Consent

In an editorial accompanying the FREEDOM paper[2], Dr Mark Hlatky (Stanford University School of Medicine, CA) said the controversy surrounding the optimal revascularization strategy in patients with diabetes "should finally be settled." The results of the FREEDOM study "suggest that patients with diabetes ought to be informed about the potential survival benefit from CABG for the treatment of multivessel disease."

To heartwire , Hlatky said that an informed patient might decide that he wants to live longer but is "scared to death of surgery" and that a "stroke bothers me more than dying," so they elect to undergo PCI. However, in order to have a knowledgeable patient, the patient should be informed before they enter the catheterization laboratory. In addition to an informed patient, the clinicians also need to be aware of the data. The experts heartwire spoke with cited the "heart team" that is now frequently used when assessing patients as candidates for transcatheter aortic-valve implantation (TAVI).

"The heart team, which was popularized with the TAVI experience, is very useful," said Harrington. "Unless you have people presenting the data in a fair and balanced way, it's quite easy to tip the balance one way or the other based on the conversation. So, if you're the proverbial man with the hammer, everything looks like a nail, and that's going to create challenges."

White said that many patients will simply object to bypass surgery, even those who meet the inclusion criteria for FREEDOM. Like Hlatky, White stressed that it is up to the physician to inform the patient of the mortality benefit with CABG surgery, and this conversation needs to take place before the patient is in the cath lab with a coronary angiogram revealing multiple coronary artery disease lesions.

"What happens is, they're on the table, and you see these things on the angiogram that you can fix with a stent with a low amount of risk," said White. "The question is, should you fix them or should you stop and say, 'You know what, you're a diabetic, you have multivessel disease, and that FREEDOM trial said you'd be better off with surgery. I want you to talk to my surgeon.' Well, some patients can get kind of cross, saying, 'I thought I told you, I don't want surgery.' You really need to have these conversations up front, before the angiogram is ever done."

The Financial Implications of FREEDOM

In addition to presenting the data at the meeting, the FREEDOM investigators also conducted a cost-effectiveness analysis. Led by Dr Elizabeth Magnuson (Saint Luke's Mid America Heart Institute, Kansas City, MO), the researchers examined the cost-effectiveness of the two treatment strategies by assessing the incremental cost-effectiveness ratio as expressed as the quality-adjusted life-year (QALY) gained.

Overall, the total cost of CABG surgery was reported at $34 467 while the cost of PCI was $24 845, a significant difference of $8622. Based on the total costs, the cost differential between the two procedures narrowed from $8622 at year 1 to $3641 at year 5. At five years, CABG improved the quality-adjusted life expectancy by approximately 0.03 years while also increasing the total costs by approximately $3600 per patient. Over the course of a lifetime, assuming a life expectancy of 12 years following the procedure, CABG was associated with 0.66 QALYs gained and approximately higher costs of $5400 per patient. This resulted in an incremental cost-effectiveness ratio of $8132 per QALY gained.

The researchers note that even by the most conservative estimates, limiting the cost-effectiveness analysis to the five-year study period, the incremental cost-effectiveness ratio was approximately $27 000 per QALY gained. Traditionally, procedures, devices, and drug therapy are considered cost-effective if the incremental cost-effectiveness ratio is less than $50 000 per QALY gained.

Farkouh reports consulting for Genentech, Pfizer, Sanofi, and Eli Lilly and receiving grants from Genentech and Merck. Disclosures for the coauthors are listed on www.nejm.org . Hlatky reports consulting for the American College of Cardiology (ACC); Blue Cross Blue Shield; Partners Healthcare System; and Kaiser Permanente of Northern California; receiving grants from the AHA; National Heart, Lung, and Blood Institute (NHLBI); St Jude Medical; and HeartFlow; receiving payment for lectures including serving on speakers' bureaus from the ACC; royalties from Up-to-Date; and receiving other fees from the Consumers Union, the Medicines Company, Gilead, Genentech, the NHLBI, Altarum Institute, and California Park Medical Center.

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