Statin Therapy and Saphenous Vein Graft Disease After Coronary Bypass Surgery: Analysis From the CASCADE Randomized Trial

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1 Statin Therapy and Saphenous Vein Graft Disease After Coronary Bypass Surgery: Analysis From the CASCADE Randomized Trial Alexander Kulik, MD, MPH, Pierre Voisine, MD, Patrick Mathieu, MD, Roy G. Masters, MD, Thierry G. Mesana, MD, PhD, Michel R. Le May, MD, and Marc Ruel, MD, MPH Lynn Heart and Vascular Institute, Boca Raton Regional Hospital, and Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida; Department of Cardiac Surgery, Hôpital Laval, Quebec City, Quebec, Canada; and Divisions of Cardiac Surgery and Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada Background. Current guidelines recommend statin therapy after coronary artery bypass grafting (CABG) to attain low-density lipoprotein (LDL) levels less than 100 mg/dl. Whether achieving LDL levels less than 70 mg/dl improves postoperative graft patency remains unknown. Methods. The CASCADE (Clopidogrel after Surgery for Coronary Artery Disease) trial was a randomized study that evaluated the addition of clopidogrel to aspirin on the development of saphenous vein graft disease after CABG. Patients received the standard of care regarding postoperative statin therapy with targeted LDL levels less than 100 mg/dl. Twelve months postoperatively, patients returned for a coronary angiogram and saphenous vein graft (SVG) intravascular ultrasonogram. In this post hoc analysis, the impact of statin therapy on graft patency and vein graft intimal hyperplasia was assessed. Results. LDL levels significantly declined over the period of the trial (p 0.002). Twelve months postoperatively, 58.4% patients achieved LDL levels less than 70 mg/dl. Twelve-month graft patency was higher for patients with LDL levels less than 100 mg/dl (96.5%) compared with patients with LDL levels >100 mg/dl (83.3%, p 0.03), even after adjustment in multivariate analysis (odds ratio [OR], 5.2; 95% confidence interval [CI], ; p 0.02). However, no improvement in graft patency was noted with further LDL reduction to less than 70 mg/dl (p 1.00). Consistent statin use throughout the trial period was independently associated with less vein graft intimal hyperplasia documented by intravascular ultrasound at 12 months (p 0.04). Conclusions. Statin therapy to achieve LDL levels less than 100 mg/dl was independently associated with improved graft patency in the CASCADE trial. Randomized clinical trials are warranted to prospectively evaluate postoperative LDL reduction to less than 70 mg/dl and its impact on graft patency after CABG. (Ann Thorac Surg 2011;92: ) 2011 by The Society of Thoracic Surgeons Coronary artery bypass grafting (CABG) is an effective therapy for the treatment of ischemic heart disease. However, the long-term results after CABG are compromised by the development of saphenous vein graft (SVG) atherosclerosis and by the progression of native vessel disease [1]. In some series, up to 20% of SVGs become occluded within the first year after CABG [2, 3]. Historically, by 10 years after surgery, only 60% of SVGs remain patent and half of those that are patent have clinically important stenosis [1, 4, 5]. Patients who have previously undergone CABG are therefore at risk for subsequent ischemic events [1, 4, 5]. Although arterial conduits have gained attention in recent years [2, 6], the saphenous vein Accepted for publication April 15, Presented at the Forty-seventh Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31 Feb 2, Address correspondence to Dr Ruel, University of Ottawa Heart Institute, 40 Ruskin St, Ste 3403, Ottawa, ON, Canada K1Y 4W7; mruel@ottawaheart.ca. remains the most commonly used conduit during CABG because of its ease of use and ready availability [7]. The progression of SVG disease, including the development of intimal hyperplasia and the formation of atheromatous plaques, is strongly influenced by hyperlipidemia [4, 8]. Therefore secondary preventive therapy and the use of lipid-lowering agents are critically important after CABG [9]. The current American Heart Association/American College of Cardiology secondary prevention clinical guidelines [10] and the National Cholesterol Education Program Adult Treatment Panel III guidelines [11, 12] recommend statin treatment to achieve low-density lipoprotein (LDL) levels less than 100 mg/dl for all patients after CABG. These recommendations are largely based on the results of the Post-CABG trial. In this trial, lowering LDL levels to less than 100 Dr Ruel discloses that he has a financial relationship with Bristol-Myers Squibb Sanofi Canada Partnership by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg KULIK ET AL 2011;92: STATIN THERAPY AND VEIN GRAFT DISEASE 1285 Abbreviations and Acronyms AtoZ Aggrastat to Zocor Trial CABG coronary artery bypass graft surgery CAD coronary artery disease CASCADE Clopidogrel after Surgery for Coronary Artery Disease Trial CI confidence interval IVUS intravascular ultrasound LDL low-density lipoprotein OR odds ratio PROVE-IT TIMI 22 Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22 Trial SVG saphenous vein graft TNT Treating to New Targets Trial mg/dl with statin therapy significantly reduced the progression of vein graft disease and recurrent cardiovascular events in patients with a history of previous CABG, as compared with LDL levels of 130 mg/dl or more [13 15]. Strong evidence exists to support the use of statins for all patients with coronary artery disease (CAD) [9, 16 18]. Although the current guidelines recommend LDL levels less than 100 mg/dl after CABG, recent studies have illustrated that even more intensive lipid reduction to achieve LDL levels of 70 mg/dl may further improve cardiovascular outcomes [19 23]. However, no study to date has assessed the impact of such aggressive lipid reduction early after CABG. In this context, angiographic and intravascular ultrasound (IVUS) data collected as part of the recent CASCADE (Clopidogrel After Surgery for Coronary Artery Disease) clinical trial [24, 25] provided a unique opportunity to evaluate the relationship between postoperative LDL levels, statin therapy, and the development of SVG disease 12 months after surgery. The goal of this post hoc study was to assess the impact of LDL reduction on graft patency and intimal hyperplasia 12 months after CABG, including the impact of intensive lipid reduction to achieve LDL levels less than 70 mg/dl. Material and Methods CASCADE Trial Design The CASCADE trial was a dual-center randomized placebo-controlled trial that evaluated the addition of clopidogrel to aspirin on the development of SVG disease after CABG. Details of the study design and eligibility criteria have previously been published [24]. In brief, 113 patients who underwent CABG using at least 2 SVGs were enrolled in the trial. The institutional review board of each participating surgical center approved the study protocol, and each patient provided written informed consent before enrollment. During the operation, the size of each target vessel was noted and the quality of each target vessel was rated by the surgeon as good, fair, or poor. Saphenous vein was harvested using open techniques in the CASCADE trial; endoscopic methods were not used. After surgery, patients were randomized to receive either daily aspirin 162 mg plus clopidogrel 75 mg or aspirin 162 mg plus placebo, starting on the day of surgery and for a duration of 12 months. Twelve months after CABG, patients underwent angiography of the bypass grafts and the native coronary arteries. During the same session, intimal hyperplasia of 1 randomly selected SVG was assessed by IVUS [24]. The 40-MHz IVUS catheter (Atlantis SR Pro, Boston Scientific Corporation, Natick, MA) was advanced into the graft and study images were recorded using a validated motorized pullback device at 0.5 mm/sec. Subsequently, using digitized images in a core laboratory, manual planimetric measurements of cross sections spaced at 1.0-mm intervals were obtained in accordance with established standards [26]. Using the aorto-ostial anastomosis as a landmark, the most proximal 40 mm were analyzed. For each cross section analyzed, the lumen and external elastic lamina area were measured and the area of intimal hyperplasia was determined. Mean intimal area per patient was calculated for the 40-mm analyzed segment. Twelve-month angiography was completed in 92 of the 113 enrolled patients (81.4%). IVUS was performed in 90 of the 92 patients (97.8%) who underwent follow-up angiography. IVUS could not be performed in 2 patients because of technical factors (1 patient) or the presence of 2 occluded SVGs (1 patient). As detailed elsewhere, the addition of clopidogrel to aspirin did not significantly reduce the process of SVG intimal hyperplasia or result in improved vein graft patency 12 months after CABG [25]. Patient Follow-Up While enrolled in the CASCADE trial, patients were followed with clinic visits at 1, 6, and 12 months after operation and telephone home assessments at 3 and 9 months. All patients were treated in accordance with current American College of Cardiology/American Heart Association guidelines [10]. This included smoking cessation counseling, aggressive diabetes management, and the administration of aspirin, beta-blockers, angiotensin converting enzyme inhibitors, and statin medications. Patients received the standard of care with respect to statin therapy after operation. In the absence of an absolute contraindication, surgeons and cardiologists were advised to administer statin therapy postoperatively to each patient enrolled in the CASCADE trial in order to achieve an LDL level less than 100 mg/dl, as recommended in the current guidelines [10 12]. The statin type and dose were left to the discretion of the prescribing physician and was not dictated by the trial protocol. Lipid levels were assessed before operation and after operation at 1, 6, and 12 months. Office or telephone

3 1286 KULIK ET AL Ann Thorac Surg STATIN THERAPY AND VEIN GRAFT DISEASE 2011;92: assessments were performed every 3 months to ensure medication compliance, including statin therapy. For the purpose of the present study, consistent statin use was defined as the preoperative and continued postoperative use of statin therapy throughout the 12-month period of the CASCADE trial. Twelve-month clinical follow-up was complete for all patients. Statistical Analysis In this post hoc analysis of the CASCADE trial, we assessed the impact of statin therapy on 12-month graft patency and SVG intimal hyperplasia. Standard descriptive statistical analyses were used, including analysis of variance to examine lipid levels and the use of statin therapy over time. To evaluate the impact of LDL reduction after CABG, graft patency and SVG intimal hyperplasia were compared between patients who achieved LDL levels less than 100 mg/dl and those whose LDL levels were greater than 100 mg/dl, as measured 12 months after surgery. Additional analysis focused on consistent statin use and further LDL reduction to less than 70 mg/dl (compared with 70 to 100 mg/dl). Continuous data are presented as a mean standard deviation and were compared between groups using unpaired 2-sided Student s t tests. Categorical data are presented as proportions and were compared between groups using a Fisher s exact test. Multivariate logistic regression analysis was used to identify independent predictors of improved graft patency, and linear regression analysis was performed to evaluate predictors of SVG intimal hyperplasia. The following factors were considered in the multivariate models: preoperative LDL level, LDL level 12 months after surgery, consistent statin use, age, female gender, body mass index, diabetes, smoking, off-pump surgical procedure, target vessel size, target vessel quality, and surgical center. Stepwise forward selection and backward elimination techniques were used with p 0.20 for entry and removal criteria. Odds ratios (ORs) are reported with 95% confidence intervals (95% CIs), and regression coefficients are reported standard error. All reported p values are 2 sided. Data were analyzed in Intercooled Stata 11.0 (StataCorp LP, College Station, TX). Results Patient Cohort The CASCADE trial cohort consisted of 113 patients who underwent CABG between May 2006 and July The mean age of the cohort was years, and 101 patients (89.4%) were male (Table 1). Most patients had been diagnosed with hypertension (77.9%) or hyperlipidemia (87.6%) before surgery. Ten surgeons at 2 surgical centers performed a mean of grafts (range, 2 to 6 grafts; total 396 grafts), with the majority of patients undergoing on-pump surgical procedures. All patients except 1 received a left internal thoracic artery graft. The mean hospital length of stay after surgery was days. Table 1. Patient Characteristics Variable N 113 Characteristic Age, years Male gender 101 (89.4%) Body mass index, kg/m Diabetes mellitus 33 (29.2%) Current smoker 15 (13.3%) Hypertension 88 (77.9%) Hyperlipidemia 99 (87.6%) Acute coronary syndrome a 21 (18.6%) Heart failure NYHA class (20.4%) Preoperative creatinine, mol/l Preoperative medication use Aspirin 104 (92.0%) Clopidogrel 12 (10.6%) Statin 101 (89.4%) Beta-blocker 87 (77.0%) Angiotensin converting enzyme inhibitor 57 (50.4%) Operative details Number of distal anastomoses Left internal thoracic graft 112 (99.1%) Right internal thoracic graft 22 (19.5%) Cross-clamp time, minutes Cardiopulmonary bypass time, minutes Off-pump procedure 4 (3.5%) Length of stay Duration in intensive care, days Duration in hospital, days a Recent acute coronary syndrome within 1 month. NYHA New York Heart Association. Statin Therapy Before CABG, 89.4% (101/113 patients) received statin therapy. The administration of statin therapy increased to 91.2% (103/113 patients) by the time of surgical discharge (Fig 1) and to 96.0% (95/99 patients) by 12 months after CABG (p 0.15). Consistent statin use throughout the 12-month period of the trial was reported by 62.8% (71/113 patients). There were no adverse effects or complications related to statin therapy in this cohort. Compared with preoperative values, LDL levels significantly declined over the period of the study from mg/dl before operation to mg/dl 12 months after CABG (p 0.002). Twelve months after surgery, 7.9% (7/89) of patients had LDL levels greater than 100 mg/ml, 92.1% (82/89) had LDL levels less than 100 mg/dl, and 58.4% (52/89) achieved LDL levels less than 70 mg/dl. Patients with consistent statin use throughout the trial period achieved significantly lower LDL levels 12 months after operation compared with those who were not consistent users ( mg/dl versus mg/dl; p 0.01). Statin Therapy and Graft Patency Twelve-month patency in the CASCADE trial was 307 of 322 examined grafts (95.3%). Twelve-month internal tho-

4 Ann Thorac Surg KULIK ET AL 2011;92: STATIN THERAPY AND VEIN GRAFT DISEASE 1287 Fig 1. Use of statin therapy during trial enrollment. A trend existed toward increasing use of statin therapy during the period of the trial (p 0.15). racic artery graft patency was 98.2% (110/112), and 12- month SVG patency was 93.8% (196/209). For patients who achieved LDL levels less than 100 mg/dl 12 months after surgery, overall graft patency was 96.5% (277/287) and SVG patency was 95.7% (179/187). In contrast, for patients who had LDL levels greater than 100 mg/dl, overall graft patency was significantly lower at 83.3% (15/18; p 0.03) and SVG patency was significantly lower at 75.0% (9/12; p 0.02). Further reduction in LDL levels to less than 70 mg/dl (52 patients) did not significantly improve graft patency (Fig 2) as compared with those (30 patients) who achieved LDL levels 70 to 100 mg/dl (overall graft patency, 96.2% [179/186] versus 97.0% Fig 2. Impact of low-density lipoprotein (LDL) level on 12-month graft patency. Patients with LDL levels 100 mg/dl had significantly lower graft patency 12 months after surgery. *p 0.03 compared with LDL level 100 mg/dl. # p 0.02 compared with LDL level 100 mg/dl. (SVG saphenous vein graft.) [98/101]; p 1.0; SVG patency, 94.3% [116/123] versus 98.4% [63/64]; p 0.27; LDL less than 70 mg/dl versus LDL 70 to 100 mg/dl). Consistent statin use (71 patients) was not associated with an improvement in graft patency compared with those (42 patients) who were not consistent users (94.0% [220/234]) versus 98.9% [87/88]; p 0.08]. Preoperative LDL levels less than 100 mg/dl were not associated with an improvement in graft patency (p 1.0). Multivariate logistic regression analysis was used to identify factors independently associated with improved graft patency 12 months after CABG. In the multivariate model, LDL levels less than 100 mg/dl 12 months after surgery were associated with significantly higher graft patency (OR, 5.2; 95% CI, ; p 0.02), and poor target vessel quality was associated with lower graft patency (OR, 0.4; 95% CI, ; p 0.04). Reduction in LDL levels to less than 70 mg/dl and consistent statin use were not independently associated with improved graft patency in the multivariate model (p NS). Statin Therapy and Intimal Hyperplasia The mean 12-month SVG intimal area in the CASCADE trial was mm 2, with considerable variation in intimal hyperplasia among the enrolled patients (95%CI, mm 2 ). Vein graft intimal hyperplasia was not reduced in patients who achieved LDL levels less than 100 mg/dl (p 0.7) or less than 70 mg/dl 12 months after surgery (p 1.0), and LDL level (as a continuous variable) was not associated with a reduction in intimal hyperplasia (p 0.9). On univariate analysis, a trend existed toward less intimal hyperplasia in patients who were consistent statin users throughout the trial (p 0.2). In the multivariate linear regression analysis, independent predictors associated with a reduction in SVG intimal hyperplasia included consistent statin use throughout the

5 1288 KULIK ET AL Ann Thorac Surg STATIN THERAPY AND VEIN GRAFT DISEASE 2011;92: trial period ( mm 2 ; p 0.04) and a history of diabetes mellitus ( mm 2 ; p 0.01). Comment Numerous studies have demonstrated that patients with CAD benefit from statin therapy [9, 16 18]. Statins reduce the progression of atherosclerosis, improve survival, and decrease the risk of adverse cardiovascular outcomes across a wide range of cholesterol levels [17, 27]. The benefits of statin treatment appear to be applicable to men and women, as well as to older and younger patients [17]. After surgical revascularization, statin therapy initiated early after CABG is associated with a reduction in all-cause mortality and the incidence of major adverse cardiovascular events [16]. Therefore in the absence of contraindications, essentially all CABG patients are candidates for life-long statin therapy [9]. Recently, several trials reported in the cardiology literature have suggested that high-dose intensive statin therapy may further improve the outcomes in patients with CAD [19 23]. However, no study to date has evaluated whether aggressive lipid reduction to achieve LDL levels less than 70 mg/dl early after CABG improves postoperative graft function. In this post hoc analysis of the CASCADE trial [25], we assessed the impact of early postoperative LDL reduction on graft patency and vein graft intimal hyperplasia 12 months after surgical revascularization. Patients received the standard of care with respect to statin therapy during the period of the trial, with nearly all patients receiving statin treatment. Lowdensity lipoprotein levels declined significantly over time, with the majority of patients achieving LDL levels less than 100 mg/dl 12 months after surgery. Graft patency was significantly improved in patients who achieved LDL levels less than 100 mg/dl. However, no further improvement in graft patency was noted for patients who attained LDL levels less than 70 mg/dl. The results of the current study confirm previous reports documenting an adverse impact of hyperlipidemia on graft patency [4, 8, 13]. The influence of hyperlipidemia on graft thrombosis may relate to the formation of lipid-rich plaque, leading to eventual plaque rupture and acute graft occlusion. However, this mechanism is less likely to play a prominent role within the first 12 months after surgery. Alternatively, hyperlipidemia and elevated LDL levels may contribute directly to a procoagulant milieu. Oxidized LDL has been demonstrated to potently inhibit the synthesis of tissue plasminogen activator and at the same time promote the synthesis of plasminogen activator inhibitor I [1, 28]. Regardless of the mechanism, the current study findings lend further support to the existing clinical guidelines that recommend statin therapy to achieve LDL levels less than 100 mg/dl after CABG [10 12]. Although further reduction in LDL levels to less than 70 mg/dl did not improve graft patency in this post hoc study, a prospective clinical trial would be necessary to provide a comprehensive evaluation of the potential benefits of intensive statin therapy early after CABG. Statin therapy improves coronary endothelial cell function and slows the progression of native artery atherosclerosis [27, 29]. Laboratory studies have also shown that statins inhibit the process of SVG intimal hyperplasia and smooth muscle cell proliferation [30 32]. Similar findings were noted in vivo in the present study. Consistent statin use over the course of the trial was independently associated with a reduction in vein graft intimal hyperplasia as assessed by IVUS 12 months postoperatively. These results add to the growing body of literature documenting the numerous benefits associated with adherence to statin therapy, including improved long-term survival [33 35]. Surprisingly no relationship between LDL level and the extent of intimal hyperplasia was identified in the current study. This may relate to the relatively low LDL levels among the enrolled patients, the wide variability in measured intimal area, and the relatively short (12 months) duration of the trial. We believe the data in the current study point to the complex interaction between lipid levels, statin therapy, and the process of SVG disease, providing a stimulus for further study in the field. More than 20 years of experience has accrued with the use of statin therapy in patients undergoing CABG [9]. Surprisingly, however, they continue to be underused after surgical procedures [36], even in the context of a recent multicenter clinical trial [37]. The current American Heart Association/American College of Cardiology secondary prevention clinical guidelines [10] and the National Cholesterol Education Program Adult Treatment Panel III guidelines [11, 12] recommend statin treatment to achieve LDL levels less than 100 mg/dl for all patients after CABG. These recommendations are based primarily on the results of the Post-CABG trial, a study that evaluated cholesterol treatment with lovastatin 40 mg daily compared with lovastatin 5 mg daily. Published in 1997, the Post-CABG trial enrolled 1351 patients less than 65 years of age who had undergone operations 1 to 11 years previously, with 55% of patients having had CABG greater than 5 years earlier. The Post-CABG trial demonstrated that more aggressive cholesterol treatment to achieve LDL levels less than 100 mg/dl reduces the progression of vein graft disease as well as cardiovascular morbidity and mortality [13 15]. In contrast to the LDL targets achieved in the Post- CABG trial, recent clinical trials have indicated that more aggressive lipid reduction with high-dose statin therapy may further improve the outcomes of patients presenting with stable angina or acute coronary syndrome through a reduction in the incidence of major adverse cardiovascular events (myocardial infarction and stroke) and cardiovascular death [19 23]. Post hoc analyses from these trials have suggested that patients who have previously undergone CABG may also benefit from high-dose statin therapy. In a subgroup analysis of the TNT (Treating to New Targets) trial that focused only on patients with a history of previous CABG, patients who received atorvastatin 80 mg had a lower risk of new cardiovascular events or of requiring repeated coronary intervention compared with patients who received atorvastatin 10 mg

6 Ann Thorac Surg KULIK ET AL 2011;92: STATIN THERAPY AND VEIN GRAFT DISEASE 1289 [38]. Similar findings were also seen in a comparison of intensive statin therapy versus standard statin therapy among patients with a history of previous CABG enrolled either in the PROVE-IT TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis In Myocardial Infarction) trial or the A to Z (Aggrastat to Zocor) trial, although the results did not reach statistical significance (p 0.27) [39]. These subgroup analyses have alluded to a potential benefit associated with aggressive LDL reduction and the use of high-dose statin therapy after CABG. However, these studies remain limited by the lengthy time span between the surgical procedure and study recruitment. For those patients who had undergone CABG several years earlier, it is likely that many had advanced SVG atherosclerotic disease at the time of trial enrollment. Further, no information regarding graft patency is available from these trials. For these reasons it is difficult to compare the patients in CASCADE who were followed for 1 year after CABG to those included in the subgroup analyses described above. Aggressive cholesterol reduction with high-dose statin therapy appears to be safe and effective for patients with CAD [9, 18, 23]. However, as demonstrated in the current study, it remains unclear whether targeting LDL levels to less than 70 mg/dl early after CABG reduces vein graft intimal hyperplasia or improves graft patency. To our knowledge, no randomized trial has prospectively examined the impact of early postoperative high-dose statin therapy after CABG. Limitations We believe the current study is the first to date to evaluate the impact of intensive LDL reduction early after CABG on postoperative graft patency and the development of vein graft intimal hyperplasia. Nevertheless, the results presented must be interpreted within the context of several limitations. The CASCADE trial was originally designed to explore the impact of antiplatelet therapy on the process of SVG disease 12 months after surgery [24]. Patients were not randomized to different postoperative lipid-lowering strategies, as these decisions were left to the discretion of physicians who were following established clinical guidelines [10 12]. Moreover, information regarding the statin type and dose was not prospectively recorded. Therefore, the results of this post hoc analysis must be viewed as exploratory in nature, requiring confirmation from future studies. Because patients in the CASCADE trial were enrolled for 12 months, the impact of aggressive LDL reduction on late graft patency cannot be determined. Finally, because of the relatively small sample size of CASCADE, the current study had limited power in the analysis of patients with LDL levels less than 70 mg/dl and greater than 100 mg/dl. Furthermore, there was insufficient statistical power to evaluate the influence of postoperative LDL levels on clinical outcomes after CABG. Post hoc power calculations revealed that we had 72% power to detect a significant difference in the patency rate between patients who did and those who did not achieve LDL levels less than 100 mg/dl 1 year after surgery. Conclusions In summary, within the CASCADE trial population, statin therapy to achieve LDL levels less than 100 mg/dl was independently associated with improved graft patency. Within the limitations of a small sample size, we did not find an improvement in graft patency with further LDL reduction to less than 70 mg/dl in this cohort. 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Outcomes of patients with acute coronary syndrome and previous coronary artery bypass grafting (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE IT-TIMI 22] and the Aggrastat to Zocor [A to Z] trials). Am J Cardiol 2008;102: DISCUSSION DR ROBERT S. POSTON (Tucson, AZ): I think this is an interesting study because it represents where the placebo group does better than the standard repair. It is kind of a common finding because of using aggressive evidence-based therapies such as this. I am interested in your thoughts about what the mechanism would be for statin reduction causing 1-year graft patency improvement. The things that pop in my mind would be neointimal hyperplasia might be improved. You have data on that. Could you talk about that? The other issue would be that it has an antithrombotic effect, but yet with Plavix you didn t show a difference in this very same trial. So I am interested in what you think the mechanism is.

8 Ann Thorac Surg KULIK ET AL 2011;92: STATIN THERAPY AND VEIN GRAFT DISEASE 1291 DR KULIK: Thank you very much for your interesting questions. With regard to intimal hyperplasia, we did explore the impact of lipid-lowering therapy using the intravascular ultrasound assessments that we have at 1 year for 90 out of these 113 patients enrolled in the CASCADE Trial. Interestingly, we did not find a relationship between LDL levels and the extent of intimal hyperplasia at 1 year. However, patients who were on statins throughout the trial period did have significantly less intimal hyperplasia at 1 year. With respect to the mechanism by which lipid-lowering therapy improves 1 year graft patency, it remains unclear. Statins may improve graft patency by lowering the atherosclerotic burden, decreasing the amount of lipid plaque, and lowering the risk of plaque rupture within a vein graft. Certainly that would be a mechanism that would play an important role over the long term in these patients, but within 1 year, it is doubtful. Interestingly, we know that LDL and, in particular, oxidized LDL, does have prothrombotic effects through the inhibition of tpa. Nevertheless, we cannot conclusively state the mechanism by which lipid-lowering therapy improved graft patency in this study. With respect to clopidogrel and its role as an antithrombotic agent, we did not see any difference in terms of graft occlusion between patients who did or did not receive clopidogrel in the CASCADE trial. Mind you, the CASCADE trial was not powered for the outcome of graft occlusion. DR THOMAS R. CALHOUN (Houston, TX): One wonders how arbitrary the number of 100 is in the LDL level. Obviously your late follow-up will be important, and also in the proposed study that you were doing, one wonders if you could get enough numbers to power it to really draw curves. Do you know what the average LDL was over 100 in that group? In other words, the mean, did you ever average that out and see what the range was? Were most of them up around 200 or was the average about 120? A curve might be drawn that would show the actual cutoff number might be 90 to try to control it. DR KULIK: That is a very interesting question with regard to LDL levels. In the higher group, patients who had LDL levels greater than 100 at 1 year, the average LDL level was 123. The patients were well treated with secondary preventive medications in this study. All patients were on aspirin, and the majority of patients were receiving statin medication. Patients were followed quite rigorously throughout the trial with telephone and clinical follow-up every 3 months. With regard to your comment on powering a study to evaluate the impact of high-dose statin therapy after CABG, if one were to entertain the idea of looking at clinical outcomes at 1 year, powering such a study would not likely be practical; hundreds of thousands of patients would be required. I think first we would need to perform a feasibility study to perhaps look at graft patency first rather than looking at clinical outcomes at 1 year. DR JOSEPH F. SABIK (Cleveland, OH): I would just like to follow-up on Dr. Calhoun s question. We are told by the cardiologists that lower is better, and they don t believe there is a low cutoff for LDL. As opposed to a dichotomous variable, did you look at it as a continuous variable? DR KULIK: We did look at LDL as a continuous variable in this study, particular with respect to the outcome of intimal hyperplasia. For the dichotomous outcome of graft patency, we wanted to explore the impact of the current recommendations, and the guidelines strictly advocate for LDL levels less than 100. So that is why we analyzed the data in such a way. I can appreciate that many cardiologists are advocating for even lower LDL levels, but we found LDL levels less than 70 did not improve graft patency in this study, as compared to LDL levels 70 to 100.