Adjunctive Metabolic Intervention at the Time of Coronary Revascularization

Recent studies have underscored the importance of optimal glycemic control at the time of coronary revascularization, both in the setting of PCI and with CABG. A prospective single-center analysis correlated HbA1c and the 12-month TVR rate in 179 diabetic patients undergoing PCI and demonstrated that diabetic patients with optimal glycemic control (i.e., HbA1c <7%) had a TVR rate similar to that of nondia-betic patients (n = 60): 15% versus 18%.65 Those with HbA1c greater than 7% had a significantly higher TVR

rate (34%). In a multiple logistic regression analysis, HbA1c greater than 7% was identified as significant independent predictor of TVR (OR = 2.9). In addition, optimal glycemic control was associated with a significantly lower rate of cardiac rehospitalization and recurrent angina at 12 months. Opposing these results, a single-center retrospective analysis of prospectively acquired registry data addressing outcomes after PCI among 1373 diabetic patients stratified for baseline HbA1c found comparable results in terms of "death" and "death or MI" in various HbA1c strata (HbA1c <8.0%, 8.0% to 10.0%; HbA1c >10%, unknown).66

The importance of strict blood glucose control at the time of CABG was underscored in a single-center experience involving 3554 diabetic patients treated either with subcutaneous insulin (1987-1991) or with continuous insulin infusion (1992-2001).67 The latter group had a lower in-hospital mortality rate (2.5% versus 5.3%). In a multivariate regression model, continuous insulin infusion was identified as an independent protective factor against death (OR = 0.43).67 Another single-center prospective study randomized 141 diabetic patients undergoing CABG to either tight glycemic control (target serum glucose concentration, 125 to 200 mg/dL) using glucose-insulin-potassium infusion or standard therapy (target, <250 mg/dL) using intermittent subcutaneous insulin beginning before anesthesia and continuing for 12 hours after surgery.68 Patients allocated to glucose-insulin-potassium achieved lower serum glucose levels, had significantly less perioperative atrial fibrillation, and had a significantly shorter postoperative length of stay. In addition, the active treatment group showed a significant survival advantage over the initial 2 years after surgery and significantly fewer episodes of recurrent ischemia or wound infections at follow-up.

Another concept aimed at improving the outcomes of diabetic and nondiabetic patients undergoing PCI relies on modulation of the PPAR-y receptor, which is expressed by all major cell lines in the vasculature, including endothelial cells, smooth muscle cells, and monocyte/macrophages. Thiazolidinediones (TZD) bind with high affinity to and activate the PPAR-y receptor, thereby enhancing the insulin-mediated glucose transport into adipose tissue and skeletal muscle (insulin sensitizers). Troglitazone, rosigli-tazone, and pioglitazone inhibit vascular smooth muscle cell proliferation in vitro at drug levels therapeutic for antidiabetic therapy.69 In a small randomized trial, the administration of troglitazone after coronary stenting was associated with a reduction of restenosis on IVUS follow-up.70 However, the drug was withdrawn from the market after reports of severe hepatotoxicity. Recently, a positive effect on restenosis was reported with rosiglitazone. Among 95 diabetic patients, randomization to TZD for 6 months after PCI was associated with a significant reduction in restenosis compared with controls (17.6% versus 38.2%; P = .03). Baseline and follow-up HbAic levels did not differ between the two groups.71

In a randomized, placebo-controlled, double-blind trial, the effect of 6 months of pioglitazone treatment on neointima volume measured by IVUS was studied in 50 nondiabetic patients undergoing BMS-based PCI.72 Compared with controls, subjects receiving pioglitazone had significant reductions in both neo-intima volume within the stented segment and binary restenosis rate. Importantly, in this study population of nondiabetic patients, pioglitazone treatment did not significantly change fasting blood glucose, fasting insulin, HbA1c levels, or lipid parameters. These data bolster the hypothesis that TZD, in addition to their metabolic effects, exhibit direct antirestenotic effects in the vasculature.

The clinical relevance of long-term therapy with insulin sensitizers in association with coronary revas-cularization in diabetic patients is being tested in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D), an NHLBI-sponsored trial investigating 2368 diabetic patients with mild angina or documented myocardial ischemia and at least 1 significant (>50%) coronary lesion on angiography.73 Patients were enrolled between 2001 and 2005 and randomly assigned, in a 2 x 2 factorial design, to two glucose management regimens (insulin-sensitizing or insulin-providing) and to either medical therapy or mechanical revascularization (CABG or PCI). The primary end point is 5-year mortality. Aspirin, statins, P-blockers, and angiotensin-converting enzyme (ACE) inhibitors are mandatory if not contraindicated.

It remains a source of discussion what the best revascularization strategy for diabetic patients with mul-tivessel CAD may be. The scarce data available have been accumulated over the years from post-hoc analysis of randomized trials (Table 2-6) and from singlecenter or multicenter registries.74 Particular emphasis has been placed on the results of the Bypass Angioplasty Revascularization Investigation (BARI) trial, a

Years

Figure 2-7. Kaplan-Meier estimates of survival for diabetic patients randomized in the BARI trial according to treatment assignment. The survival curves for PTCA and CABG among nondiabetic patients are virtually superimposed and here represented as a single line. CABG, coronary artery bypass surgery; DM, diabetes mellitus; PTCA, percutaneous transluminal coronary angioplasty. (Adapted from BARI investigators: Seven-year outcome in the Bypass Angioplasty Revascularization Investigation [BARI] by treatment and diabetic status. J Am Coll Cardiol 2000;35:1 122-1 129.)

Years

Figure 2-7. Kaplan-Meier estimates of survival for diabetic patients randomized in the BARI trial according to treatment assignment. The survival curves for PTCA and CABG among nondiabetic patients are virtually superimposed and here represented as a single line. CABG, coronary artery bypass surgery; DM, diabetes mellitus; PTCA, percutaneous transluminal coronary angioplasty. (Adapted from BARI investigators: Seven-year outcome in the Bypass Angioplasty Revascularization Investigation [BARI] by treatment and diabetic status. J Am Coll Cardiol 2000;35:1 122-1 129.)

study that randomized patients with multivessel disease to CABG or PTCA between 1988 and 1991. Among the 353 diabetic patients enrolled, CABG demonstrated a greater survival benefit than PTCA, and this difference persisted to 7 years (76.6% versus 55.7%, respectively; P = .0011) (Fig. 2-7).75 Conversely, the survival curves of nondiabetic patients randomized to CABG or PTCA remained virtually superimposed. Subgroup analyses of the small diabetic group of patients enrolled in the Emory Angioplasty vs. Surgery (EAST) and the Coronary Angioplasty vs. Bypass Revascularization Investigation (CABRI) trials showed a trend for better long-term survival benefit for CABG compared with PTCA (see Table 2-6). In contrast, the Randomized Intervention Treatment of Angina (RITA-1) trial showed a trend toward more deaths among diabetic patients who underwent CABG compared with balloon-only PCI. In a meta-analysis including the subgroup of diabetic patients (n = 537) of EAST, CABRI, and BARI, the absolute survival benefit for CABG was 8.6% at 4 years.76 At 6.5 years, however, the difference was no longer significant. The applicability of these results is limited by the fact that the trials were conducted before the availability of coronary stents and GP IIb/IIIa inhibitors. In addition, there was no systematic use of ACE inhibitors, P-blockers, aspirin, or statins.

With respect to stenting, the only randomized study comparing stent-based PCI with CABG that had a sufficient number of diabetic patients was the Arterial Revascularization Therapy Study (ARTS).77 At 5 years, comparable results were obtained with PCI and CABG in 208 diabetic patients. The respective

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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