Impact of Glycemic Control on Occurrence of No-Reflow and 30-Day Outcomes in Diabetic Patients Undergoing Primary Angioplasty fo

Primary percutaneous transluminal coronary angioplasty (PTCA) has been consistently demonstrated to be superior to thrombolytic therapy and is currently the recommended therapy for myocardial infarction (MI).¹ However, no-reflow phenomenon develops in up to 10–15% of MI interventions.² The occurrence of no-reflow is associated with a high incidence of death and adverse events.^2–5 Diabetes mellitus is a strong predictor of adverse outcomes after PTCA.⁶ Although optimal glycemic control has been shown to reduce the incidence of microvascular complications, its effect on macrovascular complications has been controversial.⁷ A recent study suggested that optimal glycemic control at the time of elective PTCA was associated with a lower incidence of repeat revascularization.⁸ However, the impact on the incidence of no-reflow during primary angioplasty remains unclear. Since diabetes mellitus is associated with several factors that may contribute to the occurrence of no-reflow, including endothelial dysfunction, platelet activation and prothrombotic state,^9,10 we postulate that optimal glycemic control is associated with a lower risk of no-reflow and consequently, better clinical outcomes among diabetic patients undergoing primary angioplasty. In this study, we sought to determine the association between glycemic control and the occurrence of no-reflow as well as 30-day outcomes in diabetic patients undergoing primary angioplasty for MI. Patients and Methods Study population. The PTCA registry at the National University Hospital, Singapore, was used to gather patient data for this analysis. Patients who underwent primary angioplasty for MI at our institution from January 2001 to June 2004 were recruited for analysis. The diagnosis of MI was based on chest pain lasting ? 30 minutes, ST-segment elevation ? 2 mm in at least 2 contiguous ECG leads, and a > 3-fold increase in serum creatine kinase (CK) levels. Patient survivals and clinical events were collected prospectively by dedicated research nurses through telephone interviews and/or clinical record reviews. All procedures were performed according to standard techniques, and the interventional strategy was left to the discretion of the individual operator. Before the procedure, weight-adjusted heparin was administered to achieve an activated clotting time (ACT) of > 300 seconds, or 200–250 seconds when a platelet glycoprotein (GP) IIb/IIIa inhibitor was used. All patients were on life-long aspirin administration and received a loading dose of clopidogrel (300 mg). All patients who received coronary stents received clopidogrel maintenance (75 mg/day) for ? 1 month. Definition. No-reflow during the procedure was defined as Thrombolysis In Myocardial Infarction (TIMI) flow 11 Glycosylated hemoglobin (HbA1c) level was used to determine the degree of glycemic control. All HbA1c values used for analysis were obtained within 8 weeks from the date of the primary angioplasty procedures. Whenever two or more tests were done, the one performed closest to the primary angioplasty procedure date was used for analysis. Patients were divided into two groups according to the HbA1c value: optimal control (HbA1c ? 7%) and suboptimal control (HbA1c > 7%). This was in accordance with the American Diabetic Association guideline.¹² An adverse event was defined as death, re-MI (clinical symptoms or new electrocardiographic changes, associated with re-elevation of the CK and CK-MB levels of > 1.5 times the previous value if within 48 hours, > 3 times the upper normal limit if after 48 hours), repeat revascularization, stroke or re-admission for angina or angina-equivalent. Thirty-day mortality and adverse event rates were determined for each group. Statistical analysis. All statistical analyses were carried out using SPSS (version 11.5). Associations between no-reflow groups, glycemic control groups and categorical variables were assessed using Chi-square or Fisher’s exact tests. The Mann Whitney U-test was carried out for the continuous variables. Logistic regression analysis predicting the occurrence of no-reflow, 30-day survival and adverse event-free survival between groups, adjusting for relevant covariates, was performed. Results A total of 183 diabetic patients underwent primary angioplasty for MI during the study period. The mean (SD) age was 58.3 (11.1) years, and 71% were male. The relative proportion of various ethnic groups was 52% (Chinese), 19% (Malay), 26% (Indian) and 3% (others), in accordance with the country’s ethnic group profile. Complex lesion (ACC/AHA B2/C) accounts for 77% of the target lesions. All patients underwent coronary stent implantation. Intravenous GP IIbIIIa inhibitor was administered in 29% of the patients. The HbA1c level was determined during the index admission in 93% of the patients. In the remaining 7%, it was determined 8 weeks from, but not during, the index admission. No-reflow occurred in 17.5% (95% CI 12.7–23.6) of the study patients (n = 32). The baseline demographic characteristics and angiographic details of the patients with and without no-reflow are shown in Tables 1 and 2, respectively. Thrombus-laden lesions (Odds ratio [OR] 4.49, 95% Confidence interval [CI] 1.93–10.32) and baseline TIMI flow Diabetic patients with optimal versus suboptimal glycemic control. Among the study’s diabetic patients, glycemic control was optimal in 20.2% (95% CI 15.0–26.6, n = 37) and suboptimal in 79.8% (95% CI 73.4–85.0, n = 146). The median HbA1c of the optimal and suboptimal glycemic control groups were 6.5% and 8.5%, respectively. There were differences in the demographic characteristics between the two groups (Table 3). Compared to the suboptimal glycemic control group, the optimal glycemic control group was older, more likely to have hypertension (OR 7.69, 95% CI 2.26–26.32), previous history of stroke (OR 17.54, 95% CI 1.90–166.77), renal failure (OR 5.29, 95% CI 3.91–7.14), and higher baseline creatinine. Despite these differences, the optimal and suboptimal glycemic control groups had similar angiographic findings (Table 4). Glycemic control and no-reflow phenomenon. No-reflow during PTCA occurred in 16% of the optimal glycemic control group and 18% of the suboptimal glycemic control group, respectively (p = 0.820). When we divided the patients according to the occurrence of no-reflow, the mean HbA1c levels were similar in those with or without no-reflow (8.6 ± 1.8% versus 8.4 ± 1.8%, p = 0.524) (Figure 1). After adjusting for age, gender, history of hypertension, hyperlipidemia, smoking status, previous PTCA, left ventricular function, baseline hemoglobin, platelet, creatinine, ACC/AHA lesion characteristics, lesion eccentricity, thrombus, ostial lesion, lesion contours, bifurcation and baseline TIMI flow, multivariate analysis showed that optimal glycemic control was not significantly associated with a lesser occurrence of no-reflow (OR 1.27, 95% CI 0.19–8.29; p = 0.807). HbA1c was also entered as a continuous variable, but it was not a significant predictor for occurrence of no-reflow (OR 1.2, 95% CI 0.79–1.82; p = 0.405) after the same adjustment. The peak CK levels (3,208 ± 3,440 versus 2,881 ± 3,435 U/L; p = 0.4) and CKMB levels (232 ± 191 versus 178 ± 183 mg/L; p = 0.2) of the optimal and suboptimal glycemic control groups were similar. Procedural success, defined as final TIMI 3 flow and Glycemic control and 30-day outcomes. The optimal glycemic control group had a 30-day survival rate similar to that of suboptimal glycemic control (90% versus 93%; p = 0.698). Similarly, the 30-day event-free survival rate of the optimal glycemic control group and the suboptimal glycemic control group were not significantly different (84% versus 86%; p = 0.695). Multivariate analysis revealed that optimal glycemic control was not a significant independent predictor of 30-day survival (OR 0.6, 95% CI 0.12–37.39; p = 0.606) and event-free survival (OR 0.9, 95% CI 0.28–5.46; p = 0.790) after adjusting for relevant demographic characteristics and angiographic findings. Insulin versus non-insulin-requiring diabetic. Among the study patients, 7% (n = 13) were insulin-requiring and 93% (n = 170) were non-insulin-requiring. In comparison with the non-insulin requiring diabetics, the insulin-requiring diabetics had a similar occurrence of no-reflow (non-insulin-requiring versus insulin-requiring, 18% versus 15%; p = 1.000) and slightly lower 30-day survival (93.3% versus 83.3%; p = 0.221) and 30-day event-free survival (87.1% versus 69.2%; p = 0.093). After adjusting for relevant demographic characteristics and angiographic findings, insulin- or non-insulin-requiring diabetes was not significantly associated with 30-day survival (OR 24.15, 95% CI 0.34 to > 100; p = 0.142) and event-free survival (OR 3.13, 95% CI 0.48–20.33; p = 0.233). Discussion The purpose of the present study was to investigate the effect of optimal glycemic control on the occurrence of no-reflow and clinical outcomes in diabetic patients undergoing primary angioplasty for MI. The major finding is that optimal glycemic control, defined as HbA1c ? 7%, is not associated with a lesser occurrence of no-reflow or better 30-day outcomes. No-reflow during primary angioplasty has been shown to be associated with worsened short- and long-term outcomes.^3,4 In accordance with previous reports, our results show that the occurrence of no-reflow is associated with a 5-fold lower 30-day survival rate. In light of these findings, various pharmacological and device therapies have been investigated to reduce the occurrence of no-reflow. However, the effect is so far only modest Diabetes mellitus is associated with an increased risk of developing cardiovascular disease and is a well-recognized risk factor for adverse outcomes after PTCA.⁶ It is a common practice to enforce optimal glycemic control in diabetic patients, hoping that it will reduce the risk of vascular complications. Yet, little information exists regarding the effect of glycemic control on outcomes in this high-risk patient population undergoing primary angioplasty. We postulated that optimal glycemic control was associated with a lower risk of developing no-reflow phenomenon during primary angioplasty. This was based on the fact that chronic hyperglycemia was associated with several factors that have been proposed to contribute to the occurrence of no-reflow. It was demonstrated that insulin resistance, with or without overt hyperglycemia, inhibits endothelial nitric oxide synthase activity, and thereby causes endothelial dysfunction.⁹ Increased concentrations of von Willebrand factor, factor VII, factor VIII, and plasminogen activator inhibitor type 1 are all associated with the diabetic state resulting in potentiation of the coagulation cascade and platelet activation.¹⁰ A recent study suggests that acute hyperglycemia is a strong independent predictor of no-reflow phenomenon during primary angioplasty.¹³ However, acute hyperglycemia occurs in both diabetic and non-diabetic patients, and in fact, less than one third of the patients had diabetes mellitus in that study. In the present study, we exclusively studied diabetic patients and focused on the importance of long-term glycemic control. HbA1c, which is expressed as a percentage of the hemoglobin covalently-bonded with a glucose molecule, provides an index of the average glucose concentration over the life of the hemoglobin molecule (6 weeks) and a reliable assessment of the glycemic control. Our use of HbA1c level ? 7% to define optimal glycemic control was based on recent recommendation, and is consistent with other related studies.⁸ In contrast to our postulation, multivariate analysis revealed that optimal glycemic control was not associated with a lesser occurrence of no-reflow in the present study. Furthermore, there was no impact on 30-day survival and event-free survival rates. The finding of thrombus-laden lesion and baseline TIMI flow 14 which did not support the routine use of this device in all patients undergoing primary PCI, we propose the selective use of a distal protection device to minimize the likelihood of embolization in these high-risk patients. Study limitations. There were several limitations in our study. The number of patients was relatively small and may not be powered to detect the difference. With the exception of HbA1c levels, all data were prospectively entered, but the HbA1c data were retrospectively collected for the purpose of this study. We did not collect data on the myocardial blush scores (MBG) and TIMI frame count. These assessments are often time-consuming and require sophisticated equipment and trained personnel for their accuracy and reproducibility. In contrast, epicardial TIMI flow can be reliably determined with visual inspection of angiograms by most interventional cardiologists during the procedure. In conclusion, our results suggest that optimal glycemic control, defined as HbA1c ? 7%, is not associated with a lesser occurrence of no-reflow or better 30-day outcomes among diabetic patients undergoing primary angioplasty for MI. Acknowledgement. The authors would like to thank the Publication Support Unit of the National University Hospital, Singapore, for their help in the preparation of this manuscript. Email: leerch@hotmail.com

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