Diabetes Mellitus and Preferred Method of Coronary Revascularization — The Debate Continues

Diabetes mellitus is a public health problem of increasing importance in both the developed and developing worlds.1 The prevalence of obesity, the metabolic syndrome, and in particular diabetes, continues to increase; the impact on present and future healthcare resources is substantial. Since more than 75% of all diabetic patients die of atherosclerotic coronary heart disease, cardiologists are at the forefront of efforts, along with endocrinologists, to treat patients with established diabetes and coronary heart disease. Efforts to reduce the risk of dying from cardiovascular disease must include aggressive primary prevention, including interventions to reduce the prevalence of obesity and improve nutrition. Specifically, reduced intake of saturated fatty acids and other lifestyle interventions aimed at lowering rates of obesity are the public health interventions most likely to reduce the number of patients with type 2 diabetes and coronary heart disease.2 Similarly, modification of associated coronary heart disease risk factors, including treatment of hypertension and hyperlipidemia, are important primary and secondary prevention interventions in patients with type 2 diabetes mellitus.3 But this epidemic is already upon us. Clinical cardiologists and internists are already faced with a very large number of patients with type 2 diabetes mellitus requiring treatment of established coronary heart disease. Approximately 15–20% of all patients referred for a percutaneous or surgical revascularization procedure have diabetes and this patient population continues to pose a particular challenge for both the interventional cardiologist and the cardiac surgeon.4,5 The preferred method of coronary revascularization remains hotly debated. Although there is no shortage of data addressing this issue, there is little consensus, and much disagreement, regarding the most appropriate manner of revascularization of patients with type 2 diabetes with established coronary heart disease. It is well documented and well known that diabetes is associated with more diffuse and severe coronary atherosclerosis. Specifically, this is characterized by a higher atherosclerosis score (the sum of all angiographically detectable lumen stenoses) and more three-vessel disease.6 Furthermore, diabetes is associated with small reference vessel diameter, an important predictor of both procedural success and major adverse cardiac events following percutaneous coronary intervention (PCI).7 However, diabetes is not a consistent predictor of procedural success and acute (in-hospital) clinical outcomes. A report of the National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty (NHLBI PTCA) Registry did identify diabetes as a univariate predictor of in-hospital death, nonfatal myocardial infarction (MI), and the combined outcomes of death and MI.4 Similarly, a report by Elezi et al. identified diabetes as a risk factor for stent vessel occlusion (a surrogate for coronary stent thrombosis) and Abizaid et al. found that in-hospital mortality was higher amongst patients with insulin-treated diabetes than non-diabetic controls.8,9 But Stein et al. reported the findings of an analysis of the Emory University Hospital database in which diabetes was not a predictor of either procedural success or early (in-hospital) complications.10 Furthermore, despite the aforementioned data from Elezi et al, diabetes has not consistently been identified as a predictor of stent thrombosis. An analysis of more than 4,500 patients enrolled in the Mayo Clinic Percutaneous Coronary Intervention database reported a frequency of stent thrombosis of 0.51% (95% confidence interval 0.32%, 0.76%) and multivariate analysis identified only the number of stents placed, and not diabetes mellitus, as an independent correlate of stent thrombosis.11 Kugelmass et al. contribute to this debate by presenting the results of this large (3,139 patients) registry in this issue of the Journal of Invasive Cardiology. These investigators found no significant difference in any acute outcome between diabetic and non-diabetic patients during the initial hospitalization associated with the index PCI. It is most likely that recent improvements in interventional techniques, including routine coronary stenting, and adjunctive antiplatelet therapy, including dual antiplatelet therapy and periprocedural use of glycoprotein IIb/IIIa inhibitors, may be responsible for the equivalent procedural and early (in-hospital) clinical outcomes.12–14 See Kugelmass et al. on pages 568–574 However, it is an undisputed fact that diabetes is a powerful and consistent predictor of restenosis which drives important differences in the incidence of target vessel revascularization and medium- and long-term clinical outcomes.8,9 Restenosis is the primary cause of the worse clinical outcome in the randomized trials comparing multivessel PCI with coronary artery bypass graft surgery; the difference in outcome has been entirely driven by increased rates of repeat revascularization in the PCI limbs of the randomized controlled clinical trials.15–19 The frequency of death and infarction have been similar in nearly all of the trials, considered separately and together. But there has been a difference in mortality in the subgroup of patients with diabetes in some (though not all) those randomized trials that has persisted in some of the more modern trials in which routine coronary stenting and adjunctive antiplatelet therapy have been employed.5,20–22 There is some evidence to suggest that the difference in mortality in the diabetic subgroup is driven by restenosis,23 particularly following balloon angioplasty, but a more likely explanation for the increased mortality is the progression of coronary atherosclerosis distant from the treated (PCI) segment.24 That observation may explain why, among patients with diabetes, previous coronary bypass surgery, (if an internal mammary artery graft was utilized) has a favorable influence on prognosis after acute MI, but PCI does not.25 This would seem to suggest that progression of atherosclerosis, and particularly plaque rupture, within the bypassed native coronary segment is likely to be of less consequence because the myocardium distal to the lesion is protected by perfusion by a bypass graft. Kugelmass et al. have identified a trend towards more target lesion revascularization (13.6% versus 8.9%; p = 0.07) and target vessel revascularization (17.6% versus 12.7%; p = 0.058) following PCI in patients with, versus those without, diabetes; this is consistent with the data identifying diabetes as a risk factor for restenosis. But there was also an increase in the need for a second PCI in any vessel (31.7% versus 23.0%; p = 0.012), supporting the aforementioned hypothesis that outcomes among patients with diabetes are largely driven by progression of atherosclerosis remote from the treatment site. Uncertainty regarding the preferred revascularization strategy for diabetic patients with multivessel disease persists. Data from the Bypass Angioplasty Revascularization Investigation (BARI) investigators which identified improved survival among patients with diabetes undergoing bypass surgery rather than balloon angioplasty was based on an analysis of only 353 patients. This improved survival among diabetic patients undergoing bypass surgery was not evident in the BARI registry, in which patients and their physicians were responsible for the selection of revascularization strategy, even though most patients in the registry chose to undergo balloon angioplasty.26 Comparison of the baseline measures of atherosclerosis between the balloon angioplasty and surgical groups within the registry identified profound differences and it has been proposed that patients who were eligible for enrollment in the BARI trial were routed prior to randomization according to atherosclerosis severity.24 Specifically, those with limited atherosclerosis were likely to be considered ideal for PCI, those with moderate atherosclerosis were randomized in the BARI trial, and those with severe atherosclerosis were most likely to be considered less suitable for PCI and most suitable for bypass surgery. This is most consistent with routine clinical practice and suggests that PCI remains a feasible option, assuming that atherosclerosis burden has been considered as a determinant of post-procedural clinical outcome. It is clear that further randomized controlled trials addressing this critical question are needed. The BARI 2D trial is randomizing patients in a 2 x 2 factorial design to insulin-providing or insulin-sensitizing medical therapy, and to contemporary PCI or coronary artery bypass surgery (based on physician judgment) versus no revascularization. Similarly, the extraordinary data from the rapamycin and paclitaxel drug-eluting stent trials reveal a significant impact on the incidence and severity of restenosis in patients with diabetes. Indeed, although these drug eluting stents do not eliminate restenosis among patients with diabetes, the benefit is greatest among patients with diabetes when one considers the number needed to treat for benefit to be realized. A beneficial impact of drug eluting stents is supported by observational data from a “real world” registry of contemporary PCI (from the RESEARCH registry, ESC, 2003). Accordingly, the National Institutes of Health (NIH) has agreed to fund the Future Revascularization Evaluation in Diabetic patients: Optimal management of Multivessel disease (FREEDOM), a randomized trial in which patients with diabetes mellitus and multivessel disease will be randomly assigned to undergo multivessel PCI using drug eluting stents versus bypass surgery (on-pump or off-pump, whichever is thought to be most appropriate by the surgeon). While it can be anticipated that the patients in this trial will have far lower restenosis rates than previous trials incorporating balloon angioplasty and bare stent placement, it must be remembered that reducing restenosis will not significantly alter long-term morbidity and mortality resulting from progression of disease at sites remote from the treatment site. Diabetes mellitus is a major public health concern. Physicians are already faced with a large population of diabetic patients who require coronary revascularization, and the number will unquestionably grow. Existing data suggest that PCI remains a safe and appropriate treatment option in selected patients, including multivessel disease patients, particularly when stents, or even better, when drug eluting stents, are employed. However, drug eluting stents do not render the diabetic patient non-diabetic. In patients with more diffuse and severe disease, particularly three vessel disease involving the proximal left anterior descending coronary artery, and especially if the lesions characteristics are suboptimal for PCI (major bifurcation lesions, severe diffuse proximal disease, distal small vessel disease, and others) consideration should be given to bypass surgery as an alternative treatment strategy if (and maybe only if) internal mammary artery grafting is possible. We await the results of the BARI 2D and FREEDOM trials, amongst others, to further clarify the relative risks and benefits of these competing revascularization strategies in the modern era of intensive glycemic control, intensive intravenous and oral peri-procedural antiplatelet therapy, prolonged post-procedural dual antiplatelet therapy, and advances in minimally invasive bypass surgery and complete arterial coronary revascularization.

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