Effects of Statins on Restenosis After Coronary Stent Implantation

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1 Angiology Volume 58, Number 1, Effects of Statins on Restenosis After Coronary Stent Implantation Hirotoshi Kamishirado, MD, *Teruo Inoue, MD, FACC,* Masashi Sakuma, MD, Tatsuhiro Tsuda, MD, Terumi Hayashi, MD, Kan Takayanagi, MD, FACC, and Koichi Node, MD,* Ichikawa, Saga, and Koshigaya, Japan, and Boston, MA, USA Experimental data and preliminary clinical studies suggest that lipid-lowering drugs might have a beneficial effect on restenosis after coronary angioplasty. Recently, statins have been focused on prevention of restenosis after coronary stent implantation. However, their benefit has not yet been established. The authors studied the effects of statins on stent restenosis. We compared retrospectively the quantitative coronary angiographic (QCA) variables between 62 dyslipidemic patients treated with statins (pravastatin or fluvastatin) and 62 normolipidemic patients, as a control, treated without statins after undergoing successful coronary stent implantation with 6-month follow-up angiography from May 1999 to December Major cardiac events were about the same in both groups. Each of the QCA variables before and immediately after coronary stenting was similar in the 2 groups. At follow-up angiography, however, minimal lumen diameter (MLD) (2.12 ±0.73 vs 1.78 ±0.7; p <0.01) was larger in the statin group than in the normolipidemia group. Both restenosis rate (15% vs 31%; p = 0.05) and target lesion revascularization rate (10% vs 24%; p = 0.05) were lower in the statin group than in the normolipidemia group. Statin reduced restenosis rate. The efficacy of statins appears to be dependent on their pleiotropic effects on vascular wall rather than on lipid-lowering effects. Introduction Angiology 58:55 60, 2007 From the Kamishirado Heart Clinic, Ichikawa, Japan; the *Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, Saga, Japan; the Department of Cardiovascular Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA; and the Department of Cardiology, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Japan Correspondence: Hirotoshi Kamishirado, MD, Kamishirado Heart Clinic, Sugano, Ichikawa-city, Chiba , Japan [email protected] DOI: / Sage Publications Although several clinical trials have provided a wealth of data documenting the benefits of cholesterol-lowering therapy with 3-hydroxy-3- methylgutaryl coenzyme A reductase inhibitors (statins) to reduce the incidence of cardiovascular events in patients with coronary artery disease, statins did not appear to reduce the restenosis rate after balloon angioplasty. 1-3 However, Walter et al 4 reported data supporting a beneficial effect of statin therapy on restenosis development after coronary stent implantation, which seems to have a different mechanism from that after balloon angioplasty. This effect is suggested to be derived from the statins effect on the vascular wall,

2 56 Angiology Volume 58, Number 1, 2007 namely, inhibiting intimal proliferation, in addition to their lipid-lowering effects. Recently, the Lescol Intervention Prevention Study (LIPS) 5 showed that statins reduced the risk of major adverse cardiac events in patients undergoing their first successful percutaneous coronary intervention (PCI). However, the effects of statins for prevention of restenosis have not yet been established. This study aims to elucidate whether or not statins are beneficial for reducing restenosis after coronary stent implantation, and if so, whether or not the effects depend on their lipidlowering effects. Methods Study Patients Sixty-two consecutive patients who received fluvastatin 20 mg/day (n = 37) or pravastatin 10 mg/day (n = 37) for hyperlipidemia after undergoing elective planned coronary stenting for a single lesion from May 1999 to December 2002 were eligible retrospectively for this study. Twenty-five patients (40%) were receiving statin therapy already before the PCI procedure and were continued on statin therapy. In 37 other patients (60%), statin therapy was initiated the day after PCI and continued throughout the study period. The criterion of statin initiation was an elevated fasting total cholesterol level ( 220 mg/dl) or low-density lipoprotein (LDL) level ( 140 mg/dl) on at least 2 separate times. Patients who received other lipid-lowering drugs were excluded. We attempted to perform single stenting in all patients, and patients undergoing unavoidable multiple stenting were excluded. Patients who underwent stenting for chronic total occlusion lesions or left main coronary artery stenosis were also excluded. The other criteria for exclusion were contraindications to antiplatelet agents, complicating congestive heart failure, inability to follow the protocol, known bleeding disorders, thrombocytopenia (<150,000/mm 3 ), and severe hepatic or renal dysfunction (serum aspartate aminotransferase 60 IU/mL or serum creatinine 2.0 mg/dl). Sixty-two normolipidemic patients undergoing coronary stenting with matched age, gender, lesion, and PCI procedures were selected as control subjects. Our clinical research was performed according to the principles of the Declaration of Helsinki, and informed consent was obtained from each patient. Our institutional review board approved this study. Stent Implantation Procedure The coronary stenting procedure was performed using the standard Judkins technique with the femoral approach. All patients were premedicated intravenously with 5,000 to 10,000 units of bolus heparin, and 5 mg of intracoronary isosorbide dinitrate was repeatedly injected as needed during the procedure. Five different types of stents were used including: Palmaz-Schatz stents (Cordis, A Johnson & Johnson Company, Miami, FL), GFX stents (Arterial Vascular Engineering Inc, Santa Rosa, CA), NIR stents (Boston Scientific, Maple Grove, MN), Multilink stents (ACS, Guidant, Temecula, CA), and S670 stents (Medtronic AVE, Santa Rosa, CA). These stents were all standard length (16 mm), and patients undergoing implantation with shorter or longer stents (9 mm, 24 mm, or 30 mm) were excluded. Procedural success was defined as successful stenting at the desired position with 25% residual stenosis (visual estimation) and normal antegrade flow. Follow-up coronary angiography was performed 6 months after the stenting or earlier if clinically indicated. As poststent antiplatelet therapy, ticlopidine 200 mg/day, was given for 1 month and aspirin, 81 mg/day, indefinitely. Quantitative Coronary Angiography Two experienced angiographers blinded to the treatment regimen analyzed the angiographic results using an on-line quantitative coronary angiography (QCA) analysis system (QUANTOCOR, Siemens, Erlangen, Germany). The measurements were performed on the end-diastolic frames by a single investigator who was unaware of the study design. Reference diameter, lesion length, and minimal lumen diameter (MLD) were measured before and immediately after stenting, and at the time of follow-up angiography. We determined the acute gain (minimal lumen diameter after stenting minus minimal lumen diameter before the procedure), late lumen loss (minimal lumen diameter after stenting minus minimal lumen diameter at follow-up angiography), and the late loss index (the average ratio of late lumen loss to acute gain) for each lesion. Restenosis was defined as >50% diameter stenosis of the treated lesion. Target lesion revascularization (TLR) was performed in patients with visually estimated stenosis of 90% or that of 75% with symptoms. The vi-

3 Kamishirado Statin Therapy After Stent Implantation 57 sual estimation of the percent stenosis was based on the nomenclature of the American Heart Association and performed by 2 independent observers unaware of the patients assigned groups. Statistical Analysis Data are expressed as mean ± SD. Comparison of clinical and angiographic variables between the 2 groups was performed with Wilcoxon rank-sum test for continuous variables and the chi-square test for categorical variables. QCA results were compared by using analysis of variance (ANOVA) for repeated measures. Differences were considered statistically significant at p values <0.05. Results Patient Background and Hyperlipidemia The backgrounds of the 62 statin patients and 62 control patients are shown in Table I. The location and type of target lesions, and stent types used, were similar in the statin and control patients (Table I). Baseline total cholesterol, lowdensity lipoprotein levels, and triglyceride levels were significantly higher in statin than in control patients. At 6-month follow up, total cholesterol, low-density lipoprotein levels, and triglyceride levels were similar in statin and control patients (Table II). Table I. Baseline characteristics. control statin (n = 62) (n = 62) p Age, yr 63.2 ± ±9.90 NS Gender, male/female 49/13 46/16 NS Diagnosis, AP/OMI 35/27 28/34 NS Risk factor, n (%) Hypertension 25 (40%) 34 (55%) NS Diabetes mellitus 20 (32%) 19 (31%) NS Smoking 45 (72%) 35 (56%) NS Obesity 20 (32%) 29 (47%) NS Lesion location, LAD/CX/RCA 38/14/10 27/17/18 NS Lesion type, A/B 1 /B 2 /C 13/21/14/14 8/18/21/15 NS Long lesion (>20 mm), n (%) 07 (11%) 09 (14%) NS Stent type, n (%) Palmaz-Schatz 09 (14%) 10 (16%) NS Multilink 20 (32%) 11 (18%) NS GFX 3 (5%) 09 (14%) NS NIR 18 (29%) 14 (23%) NS S (19%) 18 (29%) NS AP = angina pectoris, OMI = old myocardial infarction, NS = not significant.

4 58 Angiology Volume 58, Number 1, 2007 Table II. Changes in hyperlipidemia. Control Statin Baseline 6 Months Baseline 6 Months Total cholesterol, mg/dl 189 ± ± ±48 *199 ±41* Low-density lipoprotein, mg/dl 121 ± ± ±39 *124 ±37* High-density lipoprotein, mg/dl 046 ± ± ± ±11 Triglycerides, mg/dl 128 ± ± ±88 *124 ±59* *p <0.01 vs baseline, p <0.01 vs control. Table III. QCA results. Control Statin (n = 62) (n = 62) p Lesion length, mm 13.9 ± ± Baseline Reference diameter, mm 2.78 ± ± MLD, mm 0.80 ± ± Percent diameter stenosis 70.9 ± ± Poststenting MLD, mm 2.58 ± ± Percent diameter stenosis 19.6 ± ± Acute gain, mm 1.79 ± ± Follow-up angiography MLD, mm 1.78 ± ± Percent diameter stenosis 36.9 ± ± Late lumen loss, mm 0.80 ± ± Loss index 0.44 ± ± Restenosis, n (%) 19 (31%) 09 (14%) Target lesion revascularization, n (%) 15 (24%) 06 (10%) QCA = quantitative coronary angiography; MLD = minimal lumen diameter.

5 Kamishirado Statin Therapy After Stent Implantation 59 Effects of Statins After Stent Implantation Table III summarizes the QCA results. Each of the QCA variables before and immediately after coronary stenting was similar in the 2 groups. At follow-up angiography, however, MLD (2.12 ±0.73 vs 1.78 ±0.70 mm; p <0.01) was larger in the statin group than in the control group. Late lumen loss (0.51 ±0.67 vs 0.80 ±0.71 mm; p <0.05) was smaller in the statin group than in the control group. The restenosis rate (15% vs 31%; p <0.05) and target lesion revascularization rate (10% vs 24%; p <0.05) were lower in the statin group than in the control group. Discussion The major finding of this study is that statin therapy was associated with a significant reduction in angiographic late loss, and consequently, in the restenosis and target lesion revascularization rates after coronary stent implantation. These results suggest that a statin had an outstanding effect for preventing restenosis development after coronary stent implantation. Although several reports have shown a failure of statins to reduce restenosis rates after balloon coronary angioplasty, 1-3 Walter et al 4 demonstrated data supporting beneficial effects of statins on restenosis development after coronary stenting. It has been suggested that the mechanism of restenosis after stenting differs from that after balloon angioplasty. Restenosis after coronary stenting is almost entirely due to neointimal hyperplasia, 6 whereas balloon angioplasty is followed by a chronic shrinkage process as the major mechanism of restenosis. 7 Recently, it has been reported that statins exert many pleiotropic effects on the vascular wall, in addition to their lipid-lowering effect. These include improvement of endothelial function, 8 enhancing the stability of atherosclerotic plaques, 9 inhibiting vascular smooth muscle cell proliferation, 10,11 inhibiting platelet aggregation, 12 reducing vascular inflammation, 13 and everting antioxidative action. 8,14 These beneficial effects of statins may contribute to reduction of neointimal hyperplasia and restenosis after coronary stenting. In this study, for the control patients without statin administration, we selected normolipidemic patients. Nevertheless, the restenosis rate was lower in the statin group than in the normolipidemic controls. These results suggest that the pleiotropic effects of statins might be a greater contributor to restenosis reduction than the lipid-lowering effects. A large angiography study has shown statins reduce narrowing of the minimal coronary lumen diameter, which was accompanied by a decrease in cardiovascular events. 15 This is consistent with a number of studies demonstrating the beneficial effects of various statins on coronary atherosclerosis within 2 years of therapy The Lipoprotein and Coronary Atherosclerosis Study (LCAS) 15 was conducted to determine whether lipid-lowing therapy with statins would reduce the progression of coronary atherosclerotic lesions and/or new coronary lesion formation in patients with coronary artery disease and moderately elevated LDL cholesterol. In addition, the LIPS study showed that statin treatment in patients with normal cholesterol levels undergoing their first successful percutaneous coronary intervention reduced the risk of major adverse cardiac events. 5 This evidence may greatly support the results of our study. Study Limitation This study has several potential limitations. First, the number of study patients was small and the study was performed as a retrospective analysis. Thus, prospective randomized trials with a larger sample size are needed. Second, 40% of the patients were being treated with statin therapy already. Third, multiple stents with different struts, designs, and different metal compositions could unpredictably affect the results of immediate success and late follow-up. Therefore, our patients were intentionally randomized in a homogeneous population treated with the same type of stent, as mentioned previously. Finally, only QCA was used to evaluate restenosis after coronary stenting, which provides little information on vascular remodeling. In a further investigation of the mechanism of coronary restenosis, intravascular ultrasound study should be used. Conclusion The results of this study demonstrate that statin therapy was associated with a significant reduction in restenosis development after coronary stent implantation. The effect of statins appears

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