Stenting in patients with diabetes: A matter of severity

The role of percutaneous coronary intervention in the treatment of patients with heart disease and diabetes has taken several turns in the last 2 decades, and the debate shows no signs of slowing down.

The discussion began as a question of PCI vs. CABG and evolved with the emergence of the drug-eluting stent (DES). Further questions arose as a new generation of DES was developed. In the background of these discussions has been a steady increase in diabetes incidence, largely spawning from an obesity epidemic in the United States and other parts of the developed world, which has led to a greater focus on medical management of the disease. However, a general decline in CAD has coincided with the increase in diabetes, leaving clinicians with the ongoing task of determining optimal treatment strategies in this patient population.

Cardiology Today Intervention spoke with a number of experts in the area, including Spencer King III, MD, president of Saint Joseph’s Heart and Vascular Institute in Atlanta, who said the future of the discussion may lie, appropriately, in the results of the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial. “The FREEDOM trial, unlike many of the ones that came before it, involves only diabetic patients, and more than 1,800 of them at that,” he said. “The trial will compare outcomes for DES with CABG and will likely provide the most definitive answers to date.”

	Spencer King III

Data from the FREEDOM trial are expected to emerge sometime in 2012. In the meantime, clinicians are left to evaluate patients based on results from a host of trials preceding FREEDOM.

Sifting through history

Harold L. Dauerman, MD, of the University of Vermont College of Medicine, commented on results published by the Bypass Angioplasty Revascularization Investigation (BARI) Investigators, one of the early landmark trials in the debate. “The original BARI trial showed a 15% death rate associated with PCI in diabetic patients,” he said. “After those results came out, the message was clear: Stop doing angioplasty.”

Dauerman said clinicians and patients did not, in fact, stop selecting angioplasty, but that the development of the DES changed the way patients were treated yet again. The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) researchers compared PCI with CABG and concluded that CABG remains the standard of care for patients with three-vessel or left main CAD, even when treated with DES. They said CABG yielded lower rates of major adverse cardiac and cerebrovascular events at 1 year than PCI.

	Harold L. Dauerman

“My concern with the SYNTAX results is that they did not use the everolimus-eluting stent (Xience, Abbott),” Dauerman said. “However, I am still not convinced that the second-generation DES will change the argument, particularly in patients with multivessel disease.”

King agreed. “It is a matter of severity,” he said. “Diabetes influences the approach in patients with left main [disease], but for diabetic patients with more extensive multivessel disease, we still look to surgery. This is not a diabetic problem; this is one of how strong the patient’s heart disease is.”

Feasibility and severity

One-year results from the Coronary Artery Revascularization in Diabetes (CARDIa) trial — which the researchers said was the first randomized trial of coronary revascularization in patients with diabetes — failed to show noninferiority of PCI vs. CABG at 1 year. “However, the CARDIa trial did show that multivessel PCI is feasible in patients with diabetes, but longer-term follow-up and data from other trials will be needed to provide a more precise comparison of the efficacy of these [two] revascularization strategies,” they wrote.

The conversation that clinicians should have with patients is one involving restenosis, according to Dauerman. “We are seeing in SYNTAX and CARDIa that even in patients with multivessel disease, the risks for death or MI are similar, but the restenosis rates are high even with the DES,” he said.

	Kevin J. Beatt

This point was echoed by Kevin J. Beatt, MD, lead in interventional cardiology at Croydon University Hospital in London “There are situations where even patients with multi-lesion disease should be offered stenting, but the decision may be influenced by non-cardiac factors like renal function and risk of stroke,” he said.

Beatt said there are differences in approach between the United States and other parts of the world. “In the United States, multi-lesion diabetics are more likely to have surgery than in Europe. Patients in Europe are more often offered the stenting option, particularly the elderly,” he said.

The BARI 2 Diabetes (2D) trial investigators accounted for simple and complicated patients, according to King. Results of that study indicated no significant difference in mortality or major CV events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision.

“Of note from the BARI 2D results is that the patients selected for PCI were not the patients at highest risk,” King said. “The highest risk patients in BARI 2D got surgery.”

Overlooked variables

Although much attention has been paid to the contrast between PCI and CABG, each of these studies has also dealt with medical interventions, such as dual antiplatelet therapy to treat heart disease, and the effect this has on patients with diabetes.

“In BARI 2D, PCI and medical therapy were equivalent,” King said. “There was no advantage to early stenting.”

Beatt said the problem with current research may be more fundamental. “We have not seen enough data specifically looking at type 2 diabetic patients treated with insulin and separated from type 1 diabetics,” he said. “They represent completely different diseases.”

Another confounding factor in research is the difficulty and complexity of patients involved in trials. “In early studies, we saw patients with less complex disease because we were reluctant to treat diffuse multivessel disease,” Beatt said. “But, increasingly, the patients who get into these trials are difficult ones, as indicated by the increases in stent length we have seen in trials such as SYNTAX and CARDia. This is going to have a serious impact on the results because we have not been on a level playing field over time.”

Beatt said renal complications arising from extended insulin treatment further muddy the picture, as does the risk for stroke in diabetic patients with atrial fibrillation. “Clinical decision-making in this group is difficult,” he said. “It is not just a technical decision to do angioplasty: The whole patient has to be considered.” The 5-year data from SYNTAX and CARDia will also be available next year, Beatt added, and will give a valuable insight into many of the unanswered questions.

Dauerman highlighted a further issue in an editorial published by the Journal of the American College of Cardiology. “The SYNTAX study was a trial of complex, high-risk PCI performed by skilled investigators at high-volume institutions: Can the findings be replicated in community practice?” he wrote.

A final concern is that as patients with diabetes age, they may not be a candidate for surgery, regardless of the severity of their disease, according to Beatt. “We are seeing more and more elderly diabetic patients with calcified disease have increased complications with both surgery and stenting,” he said.

The bigger picture

Beyond stenting, King said that there may be even more basic questions to answer. “There are still questions about what constitutes optimal control of diabetes,” he said. “Very tight blood sugar and glycemic control may not be necessary; there are arguments to be made for both extremely low and moderately low BP; what is the role of insulin sensitizing agents vs. insulin providing agents? These classic medical therapy questions are ongoing.”

King said that it may come down to a message of prevention, particularly in light of the obesity epidemic sweeping the developed world. He noted vast increases in obesity and diabetes in China and India. “It is a public health question on a broad scale,” he said.

In the end, King said the trend toward stenting is leveling off, even declining. “However, surgery has also not picked up,” he said. “The major shift has been that clinicians are willing to treat patients with medical therapy rather than intervention.”

King was also willing to grant that perhaps CAD has decreased in general. “With fewer patients available for analysis, it may be leading us to different results,” he said. “Also, we must consider that preventive therapy in diabetic patients is working, so that gives us a reason to be hopeful.” – by Rob Volansky

References:

• BARI 2D investigators. N Engl J Med. 2009; 360:2503-2515.

• BARI Investigators. N Engl J Med. 1996; 335:217-225.

• Dauerman HL. J Am Coll Cardiol, 2010; 55:1076-1079.

• Kapur A. J Am Coll Cardiol, 2010; 55:432-440.

• Serruys PW. N Engl J Med. 2009; 360:961-972.

Disclosure: Drs. Beatt and King report no relevant financial disclosures; Dr. Dauerman has consulted for and received research grants from Abbott Vascular and Medtronic; and Dr. Marso reports no personal financial disclosures during the past 12 months — all compensation for his research activities, including research grants and consulting fees from The Medicines Company, Novo Nordisk, Abbott Vascular, Amylin Pharmaceuticals, Boston Scientific, Volcano Corporation and Terumo Medical, is paid directly to the Saint Luke’s Hospital Foundation of Kansas City.

Steve Marso

Patients with diabetes often have advanced stages of coronary atherosclerosis and multivessel disease. Their vessels are often diffusely diseased. Even in the era of DES, people with diabetes are at higher risk for restenosis and/or target vessel failure. Perhaps the most compelling difference between people with diabetes and non-diabetes is their future risk of non-fatal MI. Diabetic patients are at two- to fourfold increased risk for non-fatal MI. This leads to much CV morbidity and mortality, including the development of depressed left ventricular systolic function, congestive HF and early mortality.

While the data are not always concordant, people with diabetes also seem to be at increased risk for stent thrombosis. There is clear evidence that DES has decreased the rate of binary restenosis compared with the bare-metal stent. However, it’s my impression of the data that people with diabetes continue to have increased risk of restenosis, even now in the second-and-third generation DES platforms.

– Steve Marso, MD
Cardiology Today Intervention Editorial Board member