Registry Data Challenge CABG Survival Advantage in Diabetics vs PCI Using Contemporary Stents

July 09, 2015

NEW YORK, NY — In patients with diabetes mellitus and multivessel disease, PCI with a current-generation stent is associated with a lower risk of death and stroke in early follow-up but an equivalent risk of death and a higher rate of MI and need for repeat revascularizations in the long term when compared with CABG surgery[1].

These are the main findings from an analysis of more than 16,000 patients included in the New York State PCI and cardiac surgery registries. Importantly, the results did not support the long-term mortality advantage with CABG that was observed in the National Institutes of Health (NIH)–sponsored Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial.

"There was a debate after FREEDOM, mostly about the applicability of FREEDOM to what we do today," lead investigator Dr Sripal Bangalore (New York University School of Medicine) told heartwire from Medscape. "These trials take such a long time to be done and by the time you have the final results, the stents that were used in the trial are no longer used. So there is the question of how [the results] translate to current-day practice."

Published July 8, 2015 in Circulation: Cardiovascular Interventions, the analysis included FREEDOM-like patients with diabetes mellitus and multivessel disease, of whom 7326 underwent PCI with an everolimus-eluting stent and 8763 underwent CABG. In FREEDOM, PCI was performed primarily with sirolimus-eluting and paclitaxel-eluting stents. The purpose of the New York State registry analysis was to investigate the comparative effectiveness of CABG vs PCI using the everolimus-eluting stent.

Dr Michael Farkouh (University of Toronto, ON), who led the FREEDOM trial along with Dr Valentin Fuster (Icahn School of Medicine at Mount Sinai, New York), said he has a "real skepticism" that the newer-generation stents can close the mortality gap between CABG and PCI over the long term. The registry analysis, he said, is too short to differentiate a long-term benefit of CABG over PCI.

Currently, in patients with diabetes and multivessel disease, CABG is a class 1 indication, both in the US and in Europe, and this recommendation for CABG over PCI is based primarily on the results of FREEDOM. As reported by heartwire , the primary end point of all-cause mortality, nonfatal MI, and nonfatal stroke in FREEDOM was significantly reduced by 30% among those treated with CABG compared with PCI.

"The reason it is a class 1 indication is that there was also a mortality benefit with CABG compared with PCI," said Bangalore. "We wanted to see whether there would be a mortality benefit if we compared CABG with newer-generation stents. The way PCI and CABG treat coronary artery disease is completely different, and I don't think that at any point in time PCI would be better than CABG, but at least we might be able to bridge the gap between CABG and PCI with the newer stents."

In the first 30 days, PCI significantly reduced the risk of all-cause mortality by 42% and significantly reduced the risk of stroke by 86% compared with CABG. In long-term follow-up, PCI with the everolimus-eluting stent was associated with a similar risk of all-cause mortality compared with CABG (10.5% in the PCI arm vs 10.23% in the CABG arm; P=NS) but a statistically significant 24% lower risk of stroke. The need for revascularization in long-term follow-up was significantly increased among the PCI-treated patients.

Regarding the relative risks of MI in the registry analysis, the researchers observed a significantly elevated risk with PCI compared with CABG in the first 30 days (hazard ratio [HR] 2.44; P=0.02) and in the long term (HR 1.64; P<0.0001). However, Bangalore said the increased risk for MI with the everolimus-eluting stent was observed in patients with three-vessel disease but not in those with two-vessel coronary disease. The increased risk of MI was not observed in the subgroup of PCI-treated patients who underwent complete revascularization.

"It was interesting in the sense that if you look at the primary end point of our study, which was all-cause mortality, there was actually no difference in mortality long term," said Bangalore. "FREEDOM showed a mortality benefit with CABG, but we did not. FREEDOM also found an increased risk of stroke with CABG, and that's exactly what we found in our analysis."

In FREEDOM, the 5-year mortality rate in the PCI-treated patients was 16.3% vs 10.9% in the CABG arm, a statistically significant difference. It should be noted that FREEDOM was not powered for all-cause mortality, but a follow-up meta-analysis conducted by Dr Subodh Verma (University of Toronto, ON) and colleagues, which was published in the Lancet in 2013, did show CABG reduced the risk of death from any cause by 33% compared with PCI. When restricted to drug-eluting stents alone, the researchers found a 35% relative reduction in all-cause mortality with CABG.

Follow-Up Not Long Enough, Says FREEDOM Investigator

Speaking with heartwire , Farkouh does not believe the results of the registry analysis contradict the FREEDOM trial but rather are consistent with what they observed and what has been observed in other trials. The short-term advantage of PCI over CABG—with the lower up-front risk of death and stroke—has been shown previously.

Regarding the lack of survival advantage of CABG over PCI long-term, Farkouh noted that in FREEDOM, the median follow-up among surviving patients was nearly 4.8 years and the primary end point was a 5-year Kaplan-Meier estimate of clinical events. In contrast, the average follow-up in the registry analysis was 3 years.

"You need 4 or 5 years before the mortality signal emerges," said Farkouh. "To me, this is completely consistent with FREEDOM. You have more MIs in the PCI group, more stroke in the CABG group, but mortality is the real driver, and the problem is you haven't followed the people long enough for the mortality signal to emerge."

Farkouh suggests the newer stents might provide some advantages over the older-generation models, particularly in regard to stent thrombosis. To Farkouh, the main problem in diabetic patients with multivessel disease remains the nontarget lesions that are not revascularized during PCI. These lesions, he said, are responsible for most clinical events after the first 18 months, but they remain amenable to medical management, something most diabetic patients aren't getting.

For example, Farkouh and colleagues previously reported that very few patients with diabetes achieve optimal control of four major risk factors (LDL-cholesterol level, blood pressure, glycemic control, and smoking cessation). In clinical trials, the percentage of diabetic patients achieving control of all four risk factors at 1-year follow-up ranged from 8% in FREEDOM to 23% in BARI 2D.

"We know that they're not treated optimally, and we know that these other medical risk factors are playing a role in long-term outcomes," said Farkouh.

For Bangalore, he said that if physicians are faced with a diabetic patient with multivessel disease, a conversation about the risks and benefits of both revascularization approaches is warranted. With CABG, there is an up-front risk of death and stroke, while there is a long-term risk of repeat procedures with PCI.

"If there's a therapy that provides a mortality benefit, we need to be offering it to all patients," said Bangalore. "And that's what FREEDOM would suggest. If you were to go solely based on those results, every patient with diabetes and multivessel disease should be undergoing CABG. But now, with this study, we think there's unlikely to be a mortality benefit with the newer-generation stents, which kind of evens the playing field. And patient preference matters, especially when many will say 'No way, there's a risk of stroke, I don't want it—I'd rather come back for a repeat procedure than to have a stroke.' "

The study was funded by Abbott Vascular. Bangalore reports consulting/speaking fees from Abbott Vascular and receiving a research grant from Abbott Vascular. Disclosures for the coauthors are listed in the article. Farkouh previously reports receiving consulting fees from Genentech, Pfizer, Sanofi, and Eli Lilly and grant support to his institution from Genentech and Merck.


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