Patients with diabetes present unique challenges for the interventional cardiologist, particularly since trials such as BARI demonstrated that patients with diabetes experienced higher rates of mortality with PCI compared with coronary artery bypass graft (CABG) surgery. Determining the optimal approach for these patients is important, given that 26 million US adults have diabetes and another 79 million seem well on their way based on the presence of metabolic syndrome.

As PCI has evolved, does the benefit still lean more towards surgery? After all, PCI today is a lot different compared to the BARI trial era, which enrolled patients between 1988 and 1991. Back then, patients were randomized to PCI (otherwise known as plain old balloon angioplasty) or bypass surgery. Diabetes was not a factor for patient stratification before randomization in BARI, but alarming differences in survival rates caught the attention of the data safety monitoring board. After 5 years of follow-up,¹ overall survival was similar for the two revascularization strategies; however, after 7 years of follow-up, survival in the CABG group was statistically superior.² The results switched again for 10-year survival, which was equivalent for both strategies in the overall population. However, the 10-year risk of cardiac death was 1.7 times higher with percutaneous angioplasty for the subgroup with diabetes.³

The BARI findings led to an alert from the National Heart, Lung, and Blood Institute (NHLBI), recommending that patients with diabetes and multivessel disease undergo CABG as the preferred mode of revascularization. In fact, however, clinical practice did not change appreciably on the basis of the alert or the subsequent trial publication.

FREEDOM Trial

Several smaller studies suggested the same thing as BARI, such as ARTS (with a historical control arm), CARDia (an underpowered randomized trial), and SYNTAX (a subgroup analysis). All reported excess rates of major adverse cardiovascular and cerebrovascular events in patients with diabetes assigned to PCI.

Each of those studies had serious limitations, leaving many interventionalists to await the results of the landmark FREEDOM trial (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease).⁴ The NHLBI-sponsed study was led by principal investigator, Valentin Fuster, MD, PhD.

From April 2005 through April 2010, a total of 32,966 patients were screened and, of the 3,309 trial-eligible patients, 1,900 provided written informed consent. These patients had diabetes and multivessel disease and were randomly assigned to either CABG surgery or PCI with drug-eluting stents (DES). The mean SYNTAX score was 26.2±8.6.

The primary composite outcome of death, MI, and stroke at 5 years was significantly higher with PCI versus CABG (26.6% vs. 18.7%; p = 0.005), driven by significant reductions in all-cause mortality (16.3% vs. 10.9%; p = 0.049) and MI (13.9% vs. 6.0%; p< 0.001) for CABG patients; strokes were lower in the PCI arm (2.4% vs. 5.2%; p = 0.03).

The results of the FREEDOM trial have yet to be fully digested but seem to show a clear benefit from CABG in patients with diabetes with predominantly 3-vessel disease, regardless of SYNTAX score. Speaking at AHA.12, Sidney Smith, MD, University of North Carolina, Chapel Hill, said, “For those of us who see patients with diabetes who need revascularization, coronary artery bypass surgery for two- or three-vessel disease will give better results than drug-eluting stents.”

“There is the potential with this study to change clinical practice,” said Alice Jacobs, MD, Boston University School of Medicine. “Results from FREEDOM add to the consistent evidence base supporting CABG as the preferred strategy for patients with diabetes and multivessel coronary disease.”

However, Robert H. Jones, MD, from Duke University, Durham, North Carolina, cautioned that “PCI is probably a better approach for a young patient.... Save the surgery for later, because you don’t want to have to re-do it 10 years down the line.”

New Data From VA CARDS

It has been months since the publication of the FREEDOM trial, surely there are new data. Indeed, results have been published now from the prospective, multicenter Veterans Affairs Coronary Artery Revascularization in Diabetes Study (VA CARDS).⁵ Investigators randomly assigned 198 eligible diabetic subjects with severe coronary artery disease to either CABG or PCI with DES. Participating patients had either single-vessel proximal or multivessel left anterior descending coronary artery disease.

The primary outcome measure was a composite of nonfatal MI or death, but enrollment was slower than expected and the study was underpowered for its primary endpoint, which showed no significant difference. However, at a mean follow-up of 2 years, all-cause mortality was 5% for CABG and 21% for PCI (HR = 0.30) while the risk of nonfatal MI was 15% for CABG and 6.2% for PCI (HR = 3.32), both of which were statistically significantly different.

In a commentary that accompanied the VA CARDS results,⁶ Stephen G. Ellis, MD, of the Cleveland Clinic, questioned how the results from an incomplete and underpowered study that showed “statistically significant” rates of 2-year mortality favoring CABG should be interpreted. In particular, a study in wich death was not the primary endpoint, and in which there was a nearly statistically significant imbalance in initial LV function favoring CABG.

He noted that it is important to assess the consistency of results across trials and venues. In terms of VA CARDS, CARDIA, FREEDOM, and SYNTAX, he said, “Considering that, at last count, there were 159 deaths in the CABG groups and 244 deaths in the PCI groups from these four relatively contemporary trials, one cannot ignore these findings.”

On the basis of the current body of evidence, Dr. Ellis wrote that CABG should be preferred over PCI in patients with diabetes and multivessel disease with complex anatomy (exemplified by SYNTAX scores >22) and perhaps even for all patients with diabetes and multivessel disease.

References

1. The BARI Investigators. N Engl J Med. 1996;335:217-25.
2. The BARI Investigators. J Am Coll Cardiol. 2000;35:1122-9. http://content.onlinejacc.org/article.aspx?articleid=1126377
3. The BARI Investigators. J Am Coll Cardiol. 2007;49:1600-6. http://content.onlinejacc.org/article.aspx?articleid=1188902
4. Farkouh ME, Domanski M, Sleeper LA, et al. N Engl J Med. 2012;367:2375-84.
5. Kamalesh M, Sharp TG, Tang X, et al. J Am Coll Cardiol. 2013;61:808-16. http://content.onlinejacc.org/article.aspx?articleid=1653065
6. Ellis SG. J Am Coll Cardiol. 2013;61:817-9. http://content.onlinejacc.org/article.aspx?articleid=1653074

To listen to an interview with Valentin Fuster, MD, PhD, about the results of the FREEDOM trial, visit youtube.cswnews.org. The interview was conducted by Spencer B. King III, MD.