Stent vs. Graft: Choosing the Best Path for the Diabetic Patient with Multivessel Disease
In general, patients with diabetes are at a much higher risk for any kind of revascularization procedure because they have a lot of concomitant disease—both cardiovascular and extra-vascular. Whether undergoing stenting or bypass surgery, diabetic patients as a whole fare worse than nondiabetic patients.
Roxana Mehran, MD, director of outcomes research, data coordination and analysis at the Center for Interventional Vascular Therapy at New York-Presbyterian Hospital/Columbia University Medical Center in New York City, suggests that controlling glycemia might produce better outcomes in diabetic patients who are on both oral agents and insulin. She adds that insulin-dependent diabetics tend to fare worse in stenting than those taking oral agents, which may simply result from the severity of the disease in the insulin-dependent population.
David O. Williams, MD, chief of interventional cardiology at Rhode Island Hospital in Providence, however, suggests that specific lesion characteristics, more than insulin dependence, affect technical success of stenting diabetics. Williams concedes that some patients in this population should not be stented. “If it becomes a toss-up because of the patient’s anatomy, I would favor surgery. Clearly, there are diabetic patients with multivessel disease that can be treated appropriately with angioplasty—not all, but some,” he notes.
In the early 1990s, the NIH-funded BARI (Bypass Angioplasty Revascularization Investigation) trial was the first study to raise a concern about treating diabetics. The study found that diabetic patients with multivessel disease fared better with surgery than balloon angioplasty (see charts, above). At the time, bare-metal stents (BMS) and drug-eluting stents (DES) were not on the market.
Williams points out, however, that there was a patient subset in the BARI registry, who declined randomization, but had the same eligibility. The surgeon and patient decided the treatment. Two-thirds of the patients chose angioplasty and the results were comparable to those who chose surgery, according to Williams.
In the mid-1990s, Mehran and colleagues found that out of nearly 700 patients with multivessel disease, the diabetics did not do as well as the nondiabetics regarding stenting (BMS) versus coronary artery bypass graft (CABG) surgery (J Am Coll Cardiol 2004;43:1348-1355). Researchers from the JACC study also found that many insulin-dependent diabetics had more complications than those in the non-insulin-dependent group. “We know the vascular pathophysiology of atherosclerosis is a little different in patients with insulin-dependent diabetes. We find a lot more negative remodeling in them and their response to angioplasty might be very different from non-insulin-dependent diabetics. It’s very difficult to pinpoint why they are doing worse, but this patient population also has more diffused concomitant disease than non-insulin-dependent diabetic patients,” Mehran says.
Since then, the ARTS trial found no significant difference at five years in mortality and incidence of stroke or MI between stenting (BMS) and CABG in the study population of 1,200 patients with multivessel disease. Overall MACCE was higher in the stent group, driven by the increased need for repeat revascularization (J Am Coll Cardiol 2005; 46:575-81). A subset analysis of the 208 diabetic patients found a higher mortality rate in the stent group compared to the CABG group. Researchers also found that diabetics treated with stenting had a lower event-free survival at five years compared with non-diabetic patients, but the study was not powered to show mortality differences between diabetic and non-diabetic patients. Researchers suggested that differences in outcomes seen between BMS versus CABG for the treatment of multivessel disease are likely to narrow substantially with the advent of DES.
More recently, the HORIZONS AMI trial, which had a diabetic population of 16.5 percent—approximately 600 patients— and used DES, showed a benefit for diabetics who were on the anticoagulant bivalirudin (Angiomax). For the diabetic population, there was no interaction between heparin strata and bivalirudin safety and efficacy in this trial both at 30 days and at one year.
Overall, the trial, which examined 3,600 STEMI patients, showed that diabetic patients fared much worse—higher bleeding complications, more net adverse clinical events, as well as higher mortality rates—than nondiabetics, which Mehran defines as “expected results.”
While some pooled analyses have indicated that patients with diabetes do better with the glycoprotein IIb/IIIa inhibitor abciximab (ReoPro), “we didn’t find that with HORIZONS AMI,” Mehran says.
|Diabetics Do Well with Surgery vs. |
Williams points to the results from the MASS-DAC Registry, presented at the 2008 American Heart Association (AHA) meeting, that showed diabetic patients implanted with DES had an edge over those implanted with BMS. “The carefully worded conclusion said that DES were associated with a lower risk of mortality, MI and revascularization compared to BMS at two years, but the researchers were cautious not to use the words ‘better’ or ‘superior’,” Williams notes. DES always show less repeat revascularization, so initial procedures are more durable. “DES provides an overall benefit for death and MI, but that has not been conclusively proven,” he says.
MASS-DAC also was an observational study, which allows physicians to use judgment about treatment rather than rely on randomization. Williams suggests that physician judgment could play a crucial role. “Patients with multivessel disease, be they diabetics or not, are different, and it’s wrong to put them all in the same group,” he says.
In SYNTAX, for example, which compared DES to surgery, the pathology in the triple-vessel disease subgroup varied, including three vessels partially blocked, two vessels totally blocked and one vessel partially blocked. “In those with the most severe triple-vessel disease, there is no difference for death, MI or repeat revascularization at one year compared to surgery,” Williams notes.
Many clinicians are awaiting the results of the FREEDOM trial for an answer on the long-term clinical outcomes and cost-effectiveness of stenting diabetic patients with multivessel disease. “We perhaps have enough evidence to know that stenting is associated with more overall revascularization,” says Mehran. “Yet, we are confident that death and MI—those hard endpoints—are equivalent between DES and surgery.” As a result, patients might initially prefer a percutaneous approach to surgery, but “we can’t make that recommendation without concrete clinical evidence, which we will not have until we get the results from the FREEDOM trial.”
The NIH-sponsored FREEDOM trial is an international, multicenter, open-label prospective randomized superiority trial of PCI versus CABG in approximately 2,000 diabetic patients in whom revascularization is indicated. Diabetic patients with multivessel disease will be randomized on a one-to-one basis to either CABG or multivessel stenting (two or more vessels) using DES and observed at 30 days, one year and annually for up to five years. The trial is currently 75 percent enrolled.
“This trial also is testing very aggressive medical therapy in both arms of the study,” says Michael Farkouh, MD, a cardiologist at Mount Sinai School of Medicine in New York City, and co-principal investigator of FREEDOM.
Based on the AHA/American Diabetes Association recommendations, the researchers are seeking to achieve a hemoglobin A1c level of less than 7 percent, blood pressure control of 130 over 80 and LDL cholesterol of less than 70 mg/dL. The primary endpoints are death, non-fatal MI and non-fatal stroke at three years. The secondary endpoints will involve quality-of-life metrics and cost-effectiveness at three years.
The researchers have examined previous trials to assess the proper approach for FREEDOM. In the SYNTAX trial, for example, investigators looked at revascularization rates in the small diabetic subpopulation,” but this is not a hard outcome,” Farkouh says. SYNTAX also evaluated patients up to 12 months, and “death in this diabetic population usually occurs later, which is why FREEDOM is following its patients out to five years,” he notes.
Interim clinical practice
While awaiting the outcome of FREEDOM and other more definitive trials, “it will be important for physicians to carefully weigh the previous evidence favoring bypass surgery for patients with diabetes and extensive multivessel disease before concluding that drug-eluting stenting has completely altered the prudent choice,” Spencer B. King, III, MD, Columbia University Medical Center, Center for Interventional Vascular Therapy in New York City, wrote in a Circulation editorial (2005;112:1500-1515).
Williams concurs that while current and previous clinical evidence supports stenting diabetic patients with multivessel disease with DES, it is best to judge each case on an individual basis. Farkouh agrees with Williams, but adds that in patients with three-vessel disease and aggressive diabetes, the evidence points to CABG as the preferred method of revascularization.
“If a diabetic patient with multivessel disease is elective, we should spend the four to six weeks to get their medical risk factors under better control through medical management. If a physician doesn’t have that time because the patient’s risk factors are out of control, I don’t see how PCI is the preferred route—in this case, surgery should be the preferred route because of the greater likelihood of a more complete revascularization, and then you can work on risk factors after the procedure,” Farkouh says.
He also notes that one of the greatest determinates of repeat revascularization is applying the most favorable medical therapy. “We have learned that we need to optimize medical therapy both pre-procedurally and post-procedurally to enjoy the successes of either CABG or PCI.”
Farkouh reiterates that there are patients with severe diabetes and coronary disease who require surgery and others who should clearly receive PCI. “The group in the middle is whom the FREEDOM trial is attempting to determine the proper treatment plan,” he concludes. “Right now, in clinical practice, we still need better data, which is why the treatment plans need to be individualized. We are not ready to accept a wholesale change in practice.”
|Choosing the Right Stent: A Quick Look at Drug-Eluting Stents*|
|Cost Considerations for Treating Diabetics with Multivessel Disease|
|The initial costs associated with coronary artery bypass graft (CABG) surgery are much higher than with PCI, because patients spend time in the ICU and have a prolonged hospital stay. While the length of stay for a stent patient is typically one night, the initial cost benefits gained with stenting could be lost in repeat procedures, especially in the high-risk diabetic population, according to David O. Williams, MD, chief of interventional cardiology at Rhode Island Hospital in Providence.|
J. Dawn Abbott, MD, a cardiologist at Rhode Island Hospital, presented a study at the 2008 American Heart Association conference that found many repeat procedures have nothing to do with the original procedure, but more to do with the progression of the patient’s disease.
An analysis by Cohen et al found that DES are cost-effective in patients estimated to have a clinical restenosis rate greater than 12 to 14 percent (J Am Coll Cardiol 2003;41[Suppl A]:32A). The calculations were strongly dependent on the price of DES and reimbursement, both of which have changed since the publication of the analysis: the price of DES has declined and reimbursement has improved.
The ARTS trial also found that the strategy of multivessel stenting of diabetic patients was less costly than CABG, regardless of diabetic status. The total one-year costs in diabetic patients for stenting and CABG were $12,855 and $16,585, respectively, and $10,164 and $13,082, respectively, for nondiabetics (Circulation 2001; 104:533 -538).
Michael Farkouh, MD, a cardiologist at Mount Sinai School of Medicine in New York City, suggests that the cost-effectiveness of stenting and CABG is comparable in diabetics with multivessel disease, but among nondiabetics who require fewer stents and less revascularization, PCI is most likely more cost-effective.