Rosiglitazone could improve clinical outcomes after coronary stent implantation in nondiabetic patients with metabolic syndrome

Although coronary stent implantation is a useful treatment for coronary artery disease (CAD), in-stent restenosis remains a major limitation of this technique.¹ Thiazolidinediones (TZDs), a peroxi- some proliferators activated receptor-γ(PPAR-γ) agonist, is used in the treatment of patients with type 2 diabetes as an insulin sensitizing agent.² Recent studies have shown that TZDs could reduce in-stent restenosis and improve clinical outcomes in patients with type 2 diabetes after coronary stent implantation.^3-5 It remained unclear whether nondiabetic patients with metabolic syndrome after stenting could also benefit from the treatment with TZDs. Therefore, we investigated the influence of rosiglitazone on nondiabetic patients with metabolic syndrome after coronary stent implantation.

METHODS

Patients
Patients with metabolic syndrome who have stable or unstable angina or documented silent myocardial ischaemia undergoing coronary stent implantation were recruited to this randomized, double-blind, placebo controlled trial. Inclusion criteria were the presence of a significant stenosis (>50%) in a native coronary artery suitable for stent implantation and age younger than 75 years. Patients with metabolic syndrome were diagnosed according to the new International Diabetes Federation (IDF) definition.⁶ Patients with diabetes were excluded from this study. A person to be defined as having the metabolic syndrome must have central obesity (defined as waist circumference >90 cm for men and >80 cm for women) plus any two of the following three factors (1) raised triglyceride level: >1500 mg/L (1.7 mmol/L), or specific treatment for this lipid abnormality; (2) reduced high density lipoprotein (HDL) cholesterol: < 400 mg/L (1.03 mmol/L) in men and < 500 mg/L (1.29 mmol/L) in women, or specific treatment for this lipid abnormality; (3) raised blood pressure: systolic BP >130 or diastolic BP >85 mmHg, or treatment of previously diagnosed hypertension. Patients with any of the following were excluded: unsuccessful reperfusion after coronary stent implantation (final Thrombolysis In Myocardial Infarction flow grade 2 after stent implantation); acute myocardial infarction; a history of coronary revascularization within 6 months; contradictions to treatment with rosiglitazone or platelet inhibitors; active liver disease or impaired liver function (serum alanine transaminase levels >2.5 times the upper limit of normal); congestive heart failure or left ventricular ejection fraction <40%; or major, life threatening illness. Subjects were randomized to receive placebo or rosiglitazone 4 mg daily. The first dose was given 1 day before stenting and treatment was continued until the 9 months followup. All other cardiovascular medications were given according to standard treatment, including clopidogrel 75 mg/d for 4 weeks for bare stents and 9 months for drug eluting stents (DES) after the procedure.

Stent implantation
Before stent implantation, all patients received aspirin (100 mg/d) and clopidogrel. Patients who were not taking clopidogrel received a 300 mg loading dose 1 day before stenting. Coronary stent implantation was performed by physicians who were unaware of the patients' treatment assignment. All patients underwent coronary stent implantation with the Driver stent (Medtronic Inc., USA), BX Velocity stent (Cordis Co., USA) or Cypher stent (Cordis Co., USA). Stents were implanted followed balloon dilatation according to standard protocols. The balloon size, the inflation pressure and the stent size were determined by the operator to obtain near zero diameter stenosis by visual evaluation.

Clinical followup
Major adverse cardiac events (MACE) at 9 months were defined as cardiac death or target lesion revascularization (TLR). TLR was considered if the stenosis of the target vessel was at least 50 percent of the luminal diameter based on a quantitative analysis with either signs or symptoms of myocardial ischaemia, or if there was stenosis of at least 70 percent diameter in the absence of ischaemia. Other adverse events included hepatic dysfunction and heart failure up to 9 months after stenting. Myocardial infarction (MI) was defined by an elevation of cardiac biomarkers (creatine kinase MB >2 times the upper limit of normal) and/or ST segment elevation on the ECG. Liver enzyme levels were measured every 4 weeks during the study, hepatic dysfunction was diagnosed when serum alanine transaminase levels >3 times the upper limit of normal.

Statistical analysis
Results are presented as mean±standard deviation (SD) for continuous variables and as percentages for categorical data. Differences in continuous variables between the treatment groups were assessed using unpaired Student's t test; categorical variables were compared using Fisher exact test or χ² test. Statistical analysis was performed with SPSS 11.0 software, P<0.05 was considered statistically significant.

RESULTS

Baseline characteristics
Three hundred and sixty patients with metabolic syndromes were initially enrolled in the study. One hundred and eighty patients were randomized to each group. The stent implantation was successful in 175 patients in the rosiglitazone group (97.2%) and 172 patients in the control group (95.6%). However, only 297 patients (152 patients in the rosiglitazone group and 145 patients in the control group) completed the followup. Baseline clinical characteristics were similar in both treatment groups, without statistically significant differences (Table 1). There were more target lesions of the left anterior descending (LAD) in the rosiglitazone group and more circumflex and right artery in the control group. There were no significant differences in the number of target lesions, lesion type, the reference vessel diameter and minimal lumen diameter in the two groups.

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Table 1. Patient and lesion characteristics

Procedural results
The number of stents, deployment pressure, the diameter and length of the stents used in the procedure was comparable (Table 2). Final percent stenosis and final minimal luminal diameter after stenting were similar in the two groups. Approximately one third of patients in each group received glycoprotein IIb/IIIa platelet receptor inhibitors.

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Table 2. Procedure results

Clinical outcomes
Nine-month clinical follow-up was obtained for all patients. The incidence of MACE was significantly lower in the rosiglitazone group than in the control group (7.2% vs14.5%, P=0.044). This lower MACE rate was attributable primarily to fewer TLR procedures performed in the rosiglitazone group. As compared with the control group, rosiglitazone reduced the risk of target vessel revascularization at six months by 61 percent (4.6% vs 11.7%, P=0.024). At 6-month followup, there was no death in either group. Hepatic dysfunction was observed in 7 patients from the rosiglitazone group (4.6%) and 3 patients from the control group (2.1%) (Table 3). The incidence was slightly higher in the rosiglitazone group, but the difference was not significant (P=0.337). The incidence of heart failure was low and not significantly different between the two groups (2.6% vs 1.4%, P=0.685)

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Table 3 Clinical outcomes at 6 months

DISCUSSION

The present study demonstrated that the treatment with rosiglitazone could significantly reduce MACE over the 9 months after stent implantation in nondiabetic patients with metabolic syndrome. Previous studies have shown that TZDs treatment could reduce restenosis and neointima formation after coronary stent implantation, which resulted in the improvement of clinical outcomes.^3-6 However, these studies recruited patients with type 2 diabetes mellitus and it remained unclear whether nondiabetic patients with metabolic syndrome would have the same benefits.

Metabolic syndrome was characterized by insulin resistance, which were associated with a proinflam- matory state and endothelial dysfunction.^7-10 There is an increasing body of evidence to suggest that inflammation plays a pivotal role in the process of neointimal growth and stent restenosis.^11-15 It was the reason why the incidence of clinical restenosis was higher in patients with metabolic syndrome compared with normal patient after coronary stent implantation.¹⁶ TZDs directly improve insulin resistance acting via the nuclear transcription factor peroxisome proliferator activated receptor (PPAR)- γand can counterbalance the action of proinflam- matory effect on restenosis in patients with metabolic syndrome.^17,18 Experimental animal studies showed that TZDs could inhibit the growth factor induced vascular smooth muscle cell (VSMC) migration and proliferation, which is the key event in the progression of neointimal tissue growth after coronary stent implantation.^19,20 Moreover, animal data have demonstrated that TZDs reduced intimal hyperplasia through the enhancement of cytokine induced apoptosis in VSMC.²¹ These studies suggest that rosiglitazone treatment reduces in-stent restenosis through two mechanisms: inhibiting neointimal tissue growth,and inducing regression of developed neointimal tissue after coronary stent implantation.

Patients randomly assigned to be treated with rosiglitazone did not experience increased heart failure compared with the placebo. Similarly, there was no significant difference in the incidence of hepatic dysfunction between the two groups. This result is consistent with the previous study which showed that the proportion of rosiglitazone treated patients with serum ALT levels >3 times the upper limit of normal was similar to that in patients receiving placebo. These results suggest that rosiglitazone could be safely used to the treatment of patients without impaired hepatic function.²²

Major limitations of this study were a single centre study with a relative small number of patients recruited and the findings are based on a relatively short term observational study. However, the present study provides important new information regarding the effectiveness of rosiglitazone on antirestenosis in patients with metabolic syndrome. These data encourage the undertaking of a large, long term and multicentre study to further evaluate its antirestenotic effect in patients with metabolic syndrome undergoing coronary stent implantation.

In conclusion, rosiglitazone treatment in nondiabetic patients reduced the incidence of MACE and improved the clinical outcomes at 9 months after coronary stent implantation.

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