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Pleiotropic Effect of Lovastatin, With and Without Cholestyramine, in the Post Coronary Artery Bypass Graft (Post CABG) Trial
Pleiotropic Effect of Lovastatin, With and Without Cholestyramine, in the Post Coronary Artery Bypass Graft (Post CABG) Trial Michael Domanski, MDa,*, Xin Tian, PhDb, Jerome Fleg, MDa, Sean Coady, MSc, Christine Gosen, BSa, Ruth Kirby, RN, BSa, Vandana Sachdev, MDd, Genell Knatterud, PhDe, and Eugene Braunwald, MDf This study evaluated patients in the Post Coronary Artery Bypass Graft (Post CABG) trial for evidence of statin pleiotropic effects in preventing atherosclerotic progression in saphenous vein grafts (SVGs). We studied 1,116 of the 1,351 patients in the Post CABG trial who were randomized to aggressive (low-density lipoprotein [LDL] cholesterol target <85 mg/dl) or moderate (target LDL cholesterol <140 mg/dl) lovastatin treatment and who had sufficient data available. The generalized estimating equation models, adjusting for important covariates, were applied to estimate the odds ratios (ORs) and probability of substantial atherosclerotic SVG progression (decrease in lumen diameter >0.6 mm) and the difference in minimum lumen diameter change between treatment groups. Aggressive lovastatin treatment compared with moderate treatment was associated with a significant decrease in risk of significant SVG atherosclerotic progression after adjustment for baseline cholesterol level, LDL cholesterol on treatment, high-density lipoprotein cholesterol, and triglyceride changes on treatment and other independent predictors (OR 0.68, 95% confidence interval 0.49 to 0.94, p ⴝ 0.019). Results were similar when the change or percent change from baseline of LDL cholesterol level on treatment was adjusted for rather than on-treatment LDL cholesterol and in the subset achieving a year-1 LDL cholesterol level from 90 to 135 mg/dl (OR 0.64, 95% confidence interval 0.42 to 0.98, p ⴝ 0.042). Mean decrease in minimum lumen diameter was also significantly smaller in the aggressive than the moderate treatment arm (ⴚ0.256 vs ⴚ0.343 mm, p ⴝ 0.042). In conclusion, aggressive versus moderate lovastatin treatment appeared therapeutic in slowing the atherosclerotic process in SVGs from Post CABG patients, independent of its greater LDL cholesterol–lowering effect. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102:1023–1027) Lipid-lowering therapy with statins decreases myocardial infarction incidence,1– 6 improves survival,4,6 and retards progression of atherosclerosis in patients with coronary artery disease.7,8 Attenuation of atherosclerotic progression with statin treatment in saphenous vein bypass grafts (SVGs) and in native vessels has been demonstrated in patients after coronary artery bypass grafting (CABG).9 The importance of decreasing low-density lipoprotein (LDL) cholesterol with statins has thus been clear for some time. In addition, there is an awareness of non-LDL cholesterol– lowering effects of statins that may be therapeutic.10 –20 The relevance of these “pleiotropic” effects to SVGs, however, has not been investigated. To search for pleiotropic effects of statin therapy in SVGs, we examined data on patients a Atherothrombosis and Coronary Artery Disease Branch, bOffice of Biostatistics Research, cEpidemiology Program, and dCardiovascular Diseases Branch, National Heart, Lung, and Blood Institute, Bethesda, and e Maryland Medical Research Institute, Baltimore, Maryland; and fHarvard Medical School, Boston, Massachusetts. Manuscript received March 6, 2008; revised manuscript received and accepted May 20, 2008. The Post Coronary Artery Bypass Graft Trial (Post CABG) was supported by research contracts with the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and Merck & Company, West Point, Pennsylvania. *Corresponding author: Tel: 301-435-0550; fax: 301-480-1336. E-mail address: [email protected] (M. Domanski).
0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.05.053
with previous CABG surgery who were randomized into a study of moderate versus intensive LDL cholesterol lowering with lovastatin, the Post Coronary Artery Bypass Graft (Post CABG) trial.9 Methods The Post CABG trial has been described previously.9 Briefly, using a 2 ⫻ 2 factorial design, this multicenter, blinded trial randomized 1,351 patients 1 year to 11 years after CABG to aggressive- or moderate-intensity treatment to lower LDL cholesterol levels with lovastatin (and, if necessary, cholestyramine) and to treatment with low-dose warfarin or placebo after baseline angiography. At baseline, patients were required to have ⱖ2 patent SVGs with stenosis ⬍75% in men and ⱖ1 patent SVG in women, ejection fractions 0.30, LDL cholesterol levels 130 to 175 mg/dl, and triglyceride levels ⬍300 mg/dl. Of 1,351 enrolled patients, 116 had type 2 diabetes mellitus requiring pharmacologic treatment with sulfonylureas or insulin. Lovastatin was initially given in doses of 40 mg/day in the aggressive treatment arm and 2.5 mg/day in the moderate treatment arm. Lipid levels were measured in clinical center laboratories certified by the Centers for Disease Control and Prevention, and the results were sent to the coordinating center. The co-ordinating center issued recommendations to titrate the lovastatin doses to reach target www.AJConline.org
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Table 1 Baseline characteristics by lipid-lowering treatment arms Variable
Aggressive Treatment (n ⫽ 570)
Moderate Treatment (n ⫽ 546)
p Value
Age (yrs) Men Previous myocardial infarction No. of grafts 1 2 3 ⱖ4 Years since CABG operation Minimum graft diameter (mm) Maximum graft stenosis (%) Ejection fraction (%) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Total-to-HDL cholesterol ratio Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean arterial pressure (mm Hg) Diabetes Current smoker Warfarin treatment assignment
61.7 ⫾ 7.3 527 (92.5%) 273 (47.9%)
61.1 ⫾ 7.4 513 (94.0%) 263 (48.2%)
0.20 0.32 0.92 0.15
98 (17.2%) 288 (50.5%) 168 (29.5%) 16 (2.8%) 4.8 ⫾ 2.5 2.9 ⫾ 0.6 10.7 ⫾ 11.6 56.2 ⫾ 11.8 155.5 ⫾ 20.7 39.1 ⫾ 9.4 157.3 ⫾ 65.0 6.0 ⫾ 1.3 134.6 ⫾ 17.7
107 (19.6%) 294 (53.9%) 128 (23.4%) 17 (3.1%) 4.8 ⫾ 2.6 2.9 ⫾ 0.6 11.7 ⫾ 12.1 57.3 ⫾ 11.9 155.0 ⫾ 19.9 39.1 ⫾ 9.8 159.5 ⫾ 72.2 6.1 ⫾ 1.4 133.8 ⫾ 17.3
0.58 0.50 0.16 0.13 0.70 0.98 0.60 0.66 0.44
79.5 ⫾ 8.9
80.3 ⫾ 8.8
0.18
97.9 ⫾ 10.5
98.1 ⫾ 10.4
0.74
48 (8.4%) 60 (10.5%) 282 (49.5%)
37 (6.8%) 58 (10.6%) 270 (49.5%)
0.30 0.96 0.99
Values expressed as mean ⫾ SD or frequency (percentage). No characteristics differed significantly between the 2 treatment arms by t tests or chi-square tests. Averages for angiographic variables were obtained by averaging over grafts within each patient and then averaging over all patients. HDL ⫽ high-density lipoprotein.
LDL cholesterol levels ⬍85 mg/dl in the aggressive treatment arm and ⬍140 mg/dl in the moderate treatment arm. If a patient’s LDL cholesterol level decreased ⬍60 mg/dl in the aggressive treatment arm or ⬍130 mg/dl in the moderate treatment arm, the dose of lovastatin was decreased. If necessary to achieve the LDL cholesterol goal, cholestyramine, in a dose of 8 g/day, was added. At the first annual visit after enrollment, patients assigned to the aggressive treatment arm were receiving a mean ⫾ SD of lovastatin 76 ⫾ 12.6 mg/day; 30% of this arm was also given cholestyramine 8 g/day. Patients assigned to the moderate treatment arm were receiving a mean of lovastatin 4 ⫾ 1.3 mg/day; 5% were also given cholestyramine 8 g/day. The prescribed doses of lovastatin and cholestyramine remained constant after this visit for most patients, and adherence to prescribed lovastatin was 85% to 90%. Follow-up angiography was performed 4 to 5 years (mean 4.3) after baseline. The primary prespecified angiographic outcome was the percent of grafts per patient that had substantial progression of atherosclerosis, defined by a decrease ⱖ0.6 mm lumen diameter at the site of greatest change at follow-up. These substantial changes included new lesions of ⬎15% stenosis in grafts with no pre-existing lesion, progression of ⱖ1 lesion present at baseline, or new occlusion. The secondary outcome was the mean change per patient of the minimum
Figure 1. Probability of atherosclerotic graft progression after aggressive versus moderate LDL cholesterol–lowering treatment according to ontreatment LDL cholesterol levels at 1 year, adjusted for baseline LDL cholesterol. Numbers below graph represent mean ⫾ SD for LDL cholesterol and the number of patients in each LDL cholesterol subgroup by treatment arm. Aggressive LDL cholesterol lowering decreased the risk of atherosclerotic graft progression (OR 0.74, 95% CI 0.54 to 0.99, p ⬍0.05).
lumen diameter (MLD) of each graft. All grafts were considered occluded in patients who died without having a follow-up angiogram. Interpreters of angiographic findings were blinded to treatment assignment and patient compliance. Progression of graft atherosclerosis was decreased from 39% of grafts per patient in the moderate treatment group to 27% in the aggressive treatment group.9 The goal of this secondary analysis of the Post CABG data was to determine whether lovastatin treatment resulted in a therapeutic effect (decrease of atherosclerotic graft progression) in addition to that afforded by LDL cholesterol lowering. In this analysis, therefore, the effect of lovastatin treatment on graft progression was examined after adjustment for baseline characteristics, baseline lipid levels, LDL cholesterol achieved on treatment, high-density lipoprotein cholesterol change, and triglyceride change at 1 year. The same analysis was also performed on a subset of patients in the 2 treatment groups whose LDL cholesterol levels achieved on treatment were in the overlapping range between the 2 groups. Continuous variables were expressed as mean ⫾ SD and compared by unpaired t test. Discrete variables and odds ratios (ORs) were compared using chi-square analysis. A 2-tailed p value ⬍0.05 was required to reject the null hypothesis. The generalized estimating equation (GEE) regression models were applied to estimate the OR and probability of substantial graft progression and the difference of the mean MLD change for the aggressive versus moderate LDL cholesterol–lowering treatment, respectively. The logit-link function was chosen to relate the dichotomous response variable of substantial graft progression to the baseline patient and graft variables and on-treatment cholesterol level changes. The identity link function was chosen to relate the continuous response variable to the change in MLD. Because grafts were not ordered and the numbers of grafts varied (1 to 5) for individual patients, the compound symmetry (exchangeable) working correction was used, although the GEE method is robust to the correlation matrix
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Table 2 Estimated odds ratios (95% confidence intervals) of significant atherosclerotic graft progression for lovastatin aggressive treatment compared with moderate treatment
All Post CABG patients (n ⫽ 1,116/2,344 grafts) Aggressive treatment (n ⫽ 570/1,218 grafts) Moderate treatment (n ⫽ 546/1,126 grafts) Subset with year-1 LDL cholesterol 90–135 mg/dl (n ⫽ 518/1,096 grafts) Aggressive treatment (n ⫽ 266/574 grafts) Moderate treatment (n ⫽ 252/522 grafts)
No. of Patients/Grafts With Progression
Adjusted Percent Grafts With Progression*
Adjusted OR* (95% CI)
p Value†
220/307 280/415
23.5% 31.3%
0.68 (0.49⫺0.94)
0.019
121/169 121/181
25.0% 34.3%
0.64 (0.42⫺0.98)
0.042
* Estimated from regression models that included LDL cholesterol level achieved on treatment, high-density lipoprotein cholesterol and triglyceride changes on treatment at year 1, and other baseline variables such as age, gender, previous myocardial infarction, years since CABG, ejection fraction, baseline LDL cholesterol, high-density lipoprotein cholesterol, ratio of total to high-density lipoprotein cholesterol, triglycerides, mean arterial pressure, number of grafts, minimum diameter and maximum stenosis of graft, diabetes, current smoking status, and warfarin treatment. † The p value for chi-square test of the hypothesis that the OR is 1.
mis-specification. The GEE analytic procedures used individual graft information for each patient, adjusting for the correlation of outcomes among the grafts in each patient and different numbers of grafts per patient.21 Multivariate GEE models were adjusted for baseline covariates including age, warfarin treatment, diabetes, and baseline prognostic factors previously reported22 such as gender, lipid profiles, years since CABG operation, previous myocardial infarction, ejection fraction, mean arterial pressure, smoking status, and the number of grafts and 2 graft measurements, maximum stenosis and minimum graft diameter (Table 1). It was found in the main trial that the mean LDL cholesterol level decreased significantly by the first annual visit and remained nearly constant for the subsequent annual visits, with mean differences ⱕ4.5 mg/dl within each treatment group.9 Accordingly, the LDL cholesterol level at year 1 was used as the LDL cholesterol level achieved on treatment in the regression model. Change or percent change of LDL cholesterol from baseline to year 1, high-density lipoprotein cholesterol and triglyceride changes on treatment at year 1, LDL cholesterol level at year 2, and interaction between treatment group and LDL cholesterol change were also examined in the model. To examine potential pleiotropic effects of lovastatin on SVG progression, we compared the risk of graft progression for patients with similar on-treatment LDL cholesterol level in the 2 lovastatin treatment arms. Because the distributions of LDL cholesterol level5 on treatment were significantly different for the 2 treatment arms, the GEE regression models were applied to the subset of patients in the 2 arms who had an LDL cholesterol achieved at year 1 in the range of 90 to 135 mg/dl, where 90 and 135 mg/dl were the median LDL cholesterol levels at year 1 for the aggressive and moderate arms, respectively. Statistical analyses were performed using SAS 9.0 (SAS Institute, Cary, North Carolina). Results Of the 1,351 patients enrolled in the Post CABG trial, 95 patients had missing graft outcome variables. Of the remaining 1,256 patients, 98 patients had missing graft measurements for minimum diameter and maximum stenosis, 34 additional patients had missing LDL cholesterol levels at
Table 3 Estimated mean change of minimum lumen diameters for the lovastatin aggressive treatment and moderate treatment, adjusted for other covariates Mean MLD Change* (mm)
All Post CABG patients (n ⫽ 1,116/2,236 grafts) Aggressive treatment (n ⫽ 570) Moderate treatment (n ⫽ 546) Subset with year-1 LDL cholesterol 90–135 mg/dl (n ⫽ 518/ 1,031 grafts) Aggressive treatment (n ⫽ 266) Moderate treatment (n ⫽ 252)
p Value†
Adjusted
Difference
⫺0.256
0.087 (0.003–0.170)
0.042
0.115 (0.001–0.229)
0.047
⫺0.343
⫺0.244 ⫺0.359
* Estimated from regression models that included the same covariates as models presented in Table 2. † The p value for the t test of the hypothesis that the difference is 0.
year 1, and 8 patients had missing ejection fractions. Patients with missing outcome data or graft measurements were deleted; thus, 1,116 patients (2,344 subject– graft measurements) were included in the analysis. Table 1 lists the means ⫾ SDs and percentages for potential prognostic factors for graft progression. At baseline, all patient and graft measurements were similar and balanced between the 2 treatment arms. After 1 year on treatment, lovastatin decreased LDL cholesterol levels significantly. For the aggressive treatment arm, the LDL cholesterol level was decreased to a mean ⫾ SD of 93 ⫾ 22 mg/dl (39.5% decrease from baseline); for the moderate treatment arm, the LDL cholesterol level was decreased to 136 ⫾ 23 mg/dl (11.6% decrease from baseline). Figure 1 shows the estimated percent of grafts with substantial progression within a given narrow range of LDL cholesterol levels achieved on treatment at year 1 for each lova-
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statin treatment arm after adjustment for baseline LDL cholesterol using the GEE regression model. Aggressive treatment decreased the risk of substantial graft progression significantly compared with moderate treatment (OR 0.74, 95% confidence interval [CI] 0.54 to 0.99, p ⫽ 0.046). Table 2 presents results from the GEE models, controlling for baseline characteristics listed in Table 1 and cholesterol level changes on treatment at year 1. Assignment to the aggressive lovastatin arm contributed a significant decrease in the risk of significant graft worsening after adjustment for baseline LDL cholesterol, LDL cholesterol on treatment, high-density lipoprotein cholesterol and triglyceride changes on treatment, other independent baseline predictors, and warfarin treatment. Assignment to warfarin versus placebo had no effect on risk of graft worsening (p ⫽ 0.4). Regression results were equivalent when the change of LDL cholesterol on treatment was adjusted for and were similar if LDL cholesterol levels at years 1 and 2 and cholestyramine use were adjusted for in the model. The interaction between LDL cholesterol on treatment and the lovastatin treatment arm was not significant (p ⫽ 0.14). As presented in Table 3, mean MLD change was significantly smaller in patients in the aggressive treatment arm, consistent with a beneficial effect on progression of graft atherosclerosis. The GEE regression analysis was repeated in the subset of patients with 1-year LDL cholesterol values of 90 to 135 mg/dl, the median LDL cholesterol levels at year 1 for the aggressive and moderate arms, respectively. At 1 year, only 4% of patients in the aggressive arm had LDL cholesterol levels ⬎135 mg/dl and 1.5% of patients in the moderate arm had LDL cholesterol levels ⬍90 mg/dl. Thus, the subset with LDL cholesterol at year 1 in the range of 90 to 135 mg/dl included nearly ½ of patients in the 2 treatment arms. Mean ⫾ SD LDL cholesterol levels at year 1 were 103.9 ⫾ 11.6 and 118.6 ⫾ 11.6 mg/dl in the aggressive and moderate arms, respectively, for this subset. Distributions of baseline characteristics in the subset were not significantly different from those in the entire treatment arms listed in Table 1. In these overlapping subsets, there were 9 (3.4%) and 15 (6.0%) total deaths, 11 (4.1%) and 5 (2.0%) myocardial infarctions, and 24 (9.0%) and 21 (8.3%) composite end points (death, nonfatal myocardial infarction, stroke, CABG, or percutaneous coronary intervention) in the aggressive and moderate treatment arms, respectively. None of these event rates differed significantly between groups. Applying the same regression models to this subset provided similar results (Tables 2 and 3). If percent change from baseline of LDL cholesterol on treatment was adjusted in the model instead of LDL cholesterol level on treatment, as in Table 2, the estimated risk ratios of significant graft worsening in the aggressive versus moderate arm were comparable (OR 0.70, 95% CI 0.51 to 0.97, p ⫽ 0.032, for all patients; OR 0.64, 95% CI 0.41 to 0.97, p ⫽ 0.037, for the subset, with LDL cholesterol levels 90 to 135 mg/dl). Discussion The Post CABG trial demonstrated that higher-dose lovastatin therapy, resulting in a lower serum LDL cholesterol, was more effective in preventing atherosclerotic disease progression in SVGs than lower-dose lovastatin therapy that produced more modest LDL cholesterol lowering.9 In the
present analysis, the effect of high- versus low-dose lovastatin persisted even after controlling for baseline and ontreatment LDL cholesterol levels and other known risk factors for graft progression.22 Results of this study suggest the presence of a dose-dependent therapeutic effect of lovastatin treatment on SVG atherosclerotic progression that is independent of LDL cholesterol lowering. This is the first study to show such an association in SVGs. Emerging data support an additional beneficial effect of statin therapy unrelated to lowering serum LDL cholesterol. Of 708 postinfarction patients in the Cholesterol and Recurrent Events (CARE) trial, those with higher levels of C-reactive protein and serum amyloid A benefited more from pravastatin therapy than those with lower levels of these inflammatory markers despite similar lipid profiles.12 In that analysis and in the prospective Pravastatin Inflammation/C-reactive protein Evaluation (PRINCE) trial,13 the pravastatin-associated change in C-reactive protein was not significantly correlated with the LDL cholesterol decrease. Several studies have demonstrated improvement in endothelial dysfunction from statin therapy that was only weakly correlated with degree of LDL cholesterol lowering.14 –16 A recent study by Landmesser et al14 reported that, with equal lowering of LDL cholesterol with simvastatin and ezetimibe, only simvastatin improved endothelial function. Associations between statin therapy and decreased incidence of diabetes17 and progressive renal disease18 provide further evidence of a protective effect not related to lipid lowering. In a retrospective analysis from the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, Scirica et al19 showed that atorvastatin 80 mg/day decreased the rate of heart failure hospitalization, independent of recurrent myocardial infarction or previous myocardial infarction, compared with pravastatin 40 mg. In a nationwide observational sample of 61,931 Medicare beneficiaries, Foody et al20 demonstrated that statins were associated with lesser total mortality in patients with heart failure, independent of the presence or absence of coronary artery disease and serum cholesterol. Given that much of the purported clinical evidence for the pleiotropic effect of statins is derived from retrospective analyses, this remains a topic of ongoing controversy that requires validation in prospective clinical trials. Statins have manifold actions apart from LDL cholesterol lowering that might be beneficial. For example, statins decrease the formation of isoprenoids, important molecules in the prenylation and membrane localization of Rho, Ras, and Rac proteins.23 This effect attenuates cell proliferation and hypertrophy10 and increases nitric oxide through decreased inhibition of endothelial nitric oxide synthase activity and increased nitric oxide bioavailability.10 These latter effects are thought to explain the observed improvement in endothelial function with statin therapy.14 –16 Statins decrease oxidant stress, evidenced by decreases in serum peroxides and increases in the activity of antioxidant enzymes such as paraxonase24 and superoxide dismutase.10 Statins also decrease lipoprotein associated phospholipase A2 (Lp-PLA2),25 an atherogenic lipoprotein that hydrolyzes oxidized lipids and proinflammatory molecules and localizes in the necrotic core and fibrous cap of vulnerable plaques. In many studies, statin therapy has reversibly decreased inflammatory
Coronary Artery Disease/Pleiotropic Effects of Statins
markers, including C-reactive protein,10,12,13 tumor necrosis factor receptors,11 tumor necrosis factor ␣,11 endothelin-1,11 and interleukin-18,26 and increased antiinflammatory molecules such as interleukin-10.27 Integrin-dependent adhesion molecules have decreased with statin therapy in some studies.10 Atherosclerotic plaques may be stabilized by a statin-associated, LDL-independent increase in collagen content caused by a decrease in matrix metalloproteinase-9,26 decreased foam cell formation, and decreases in CD36.28 Statins also decrease thrombosis through inhibition of the coagulation cascade and increased fibrinolysis resulting from effects on multiple substrates, including decreases in thrombin activatable fibrinolysis inhibitor (TAFI),16 platelet P-selectin,29 platelet membrane Rho A expression,30 and plasminogen activator inhibitor 1 (PAI-1) and increases in tissue-type plasminogen activator.16 This retrospective analysis used multivariate analysis in a subgroup of all-randomized patients; therefore some residual confounding by unmeasured variables cannot be excluded. Although the LDL cholesterol levels achieved in the 2 treatment arms were suboptimal by current standards, this should not diminish the validity of the intergroup comparisons. 1. Cannon C, Braunwald E, McCabe C, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–1504. 2. Pedersen T, Faergeman O, Kastelein J, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J. Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin versus usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized, controlled trial. JAMA 2005;294:2437–2445. 3. La Rosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK. Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435. 4. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440 –1445. 5. Gotto AM Jr, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477– 484. 6. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet 2005;366:1267–1278. 7. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN, REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071–1080. 8. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, et al, ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556 –1565. 9. Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162. 10. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109(suppl):III39 –III43.
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11. Ray KK, Cannon CP. The potential relevance of the multiple lipidindependent (pleiotropic) effects of statins in the management of acute coronary syndromes. J Am Coll Cardiol 2005;46:1425–1433. 12. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E, for the Cholesterol and Recurrent Events (CARE) Investigators. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998;98:839 – 844. 13. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001;286:64 –70. 14. Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirschhoff N, Schuls S, Manes C, Fischer D, de Groot K, Fliser D, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005;111:2356 –2363. 15. Marchesi S, Lupattelli G, Siepi D, Schillaci G, Vaudo G, Roscini AR, Sinzinger H, Mannarino E. Short-term atorvastatin treatment improves endothelial function in hypercholeterolemic women. J Cardiovasc Pharmacol 2000;36:617– 621. 16. Guven GS, Atalar E, Yavuz B, Beyazit Y, Kekilli M, Kiliarslan A, Sahiner L, Oz G, Ozer N, Aksoyek S, Hazned Aroglu IC, Sozen T. Simvastatin treatment improves endothelial function and increases fibrinolysis in patients with hypercholesterolemia. J Natl Med Assoc 2006;98:627– 630. 17. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, et al. Pravastatin and the development of diabetes: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103:357–362. 18. Buemi M, Senatore M, Corica F, Aloisi C, Romeo A, Cavallaro E, Floccari F, Tramontana D, Frisina N. Statins and progressive renal disease. Med Res Rev 2002;22:76 – 84. 19. Scirica B, Morrow D, Cannon C, Ray KK, Sabatine MS, Jarolim P, Shui A, McCabe CH, Braunwald E; PROVE-IT-TIMI 22 Investigators. Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE-IT-TIMI 22 study. J Am Coll Cardiol 2006;47:2326 –2331. 20. Foody J, Shah R, Galusha D, Masoudi F, Havranek E, Krumholz H. Statins and mortality among elderly patients hospitalized with heart failure. Circulation 2006;113:1086 –1092. 21. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13–22. 22. Domanski MJ, Borkowf CB, Campeau L, Knatterud GL, White C, Hoogwerf B, Rosenberg Y, Geller Nl; Post CABG Trial Investigators. Prognostic factors for atherosclerosis progression in saphenous vein grafts: the Post Coronary Artery Bypass Graft (Post CABG) trial. J Am Coll Cardiol 2000;36:1877–1883. 23. Liao J. Isoprenoids as mediators of the biological effects of statins. J Clin Invest 2002;110:285–288. 24. Tomas M, Senti M, Garcia-Faria F, Vila J, Torrents A, Covas M, Marrrugat J. Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2000;20:2113–2119. 25. Resch U, Tatzber F, Budinsky A, Singzinger H. Reduction of oxidative stress and modulation of autoantibodies against modified low-density lipoprotein after rosuvastatin therapy. Br J Clin Pharmacol 2006;612: 262–274. 26. Leu HB, Chen JW, Wu TC, Ding YA, Lin SJ, Charng MJ. Effects of fluvastatin, an HMG-CoA reductase inhibitor, on serum levels of interleukin-18 and matrix metalloproteinase-9 in patients with hypercholesterolemia. Clin Cardiol 2005;28:423– 428. 27. Fichtlscherer S, Breuer S, Heeschen C, Dimmeler S, Zeiher AM. Interleukin-10 serum levels and systemic endothelial vasoreactivity in patients with coronary artery disease. J Am Coll Cardiol 2004;44:44 – 49. 28. Fuhrman B, Koren L, Volkava N, Keidar S, Hayek T, Aviram M. Atorvastatin therapy in hypercholesterolemic patients suppresses cellular uptake of oxidized LDL by differentiating monocytes. Atherosclerosis 2002;164:179 –185. 29. Cha JK, Jeong MH, Kim JW. Statin reduces the platelet P-selectin expression in atherosclerotic ischemic stroke. J Thromb Thrombolysis 2004;18:39 – 42. 30. Casani L, Sanchez-Gomez S, Vilahur G, Badimon L. Pravastatin reduces thrombogenicity by mechanisms beyond plasma cholesterol lowering. Thromb Haemost 2005;94:1035–1041.
0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.05.053
with previous CABG surgery who were randomized into a study of moderate versus intensive LDL cholesterol lowering with lovastatin, the Post Coronary Artery Bypass Graft (Post CABG) trial.9 Methods The Post CABG trial has been described previously.9 Briefly, using a 2 ⫻ 2 factorial design, this multicenter, blinded trial randomized 1,351 patients 1 year to 11 years after CABG to aggressive- or moderate-intensity treatment to lower LDL cholesterol levels with lovastatin (and, if necessary, cholestyramine) and to treatment with low-dose warfarin or placebo after baseline angiography. At baseline, patients were required to have ⱖ2 patent SVGs with stenosis ⬍75% in men and ⱖ1 patent SVG in women, ejection fractions 0.30, LDL cholesterol levels 130 to 175 mg/dl, and triglyceride levels ⬍300 mg/dl. Of 1,351 enrolled patients, 116 had type 2 diabetes mellitus requiring pharmacologic treatment with sulfonylureas or insulin. Lovastatin was initially given in doses of 40 mg/day in the aggressive treatment arm and 2.5 mg/day in the moderate treatment arm. Lipid levels were measured in clinical center laboratories certified by the Centers for Disease Control and Prevention, and the results were sent to the coordinating center. The co-ordinating center issued recommendations to titrate the lovastatin doses to reach target www.AJConline.org
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Table 1 Baseline characteristics by lipid-lowering treatment arms Variable
Aggressive Treatment (n ⫽ 570)
Moderate Treatment (n ⫽ 546)
p Value
Age (yrs) Men Previous myocardial infarction No. of grafts 1 2 3 ⱖ4 Years since CABG operation Minimum graft diameter (mm) Maximum graft stenosis (%) Ejection fraction (%) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Total-to-HDL cholesterol ratio Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean arterial pressure (mm Hg) Diabetes Current smoker Warfarin treatment assignment
61.7 ⫾ 7.3 527 (92.5%) 273 (47.9%)
61.1 ⫾ 7.4 513 (94.0%) 263 (48.2%)
0.20 0.32 0.92 0.15
98 (17.2%) 288 (50.5%) 168 (29.5%) 16 (2.8%) 4.8 ⫾ 2.5 2.9 ⫾ 0.6 10.7 ⫾ 11.6 56.2 ⫾ 11.8 155.5 ⫾ 20.7 39.1 ⫾ 9.4 157.3 ⫾ 65.0 6.0 ⫾ 1.3 134.6 ⫾ 17.7
107 (19.6%) 294 (53.9%) 128 (23.4%) 17 (3.1%) 4.8 ⫾ 2.6 2.9 ⫾ 0.6 11.7 ⫾ 12.1 57.3 ⫾ 11.9 155.0 ⫾ 19.9 39.1 ⫾ 9.8 159.5 ⫾ 72.2 6.1 ⫾ 1.4 133.8 ⫾ 17.3
0.58 0.50 0.16 0.13 0.70 0.98 0.60 0.66 0.44
79.5 ⫾ 8.9
80.3 ⫾ 8.8
0.18
97.9 ⫾ 10.5
98.1 ⫾ 10.4
0.74
48 (8.4%) 60 (10.5%) 282 (49.5%)
37 (6.8%) 58 (10.6%) 270 (49.5%)
0.30 0.96 0.99
Values expressed as mean ⫾ SD or frequency (percentage). No characteristics differed significantly between the 2 treatment arms by t tests or chi-square tests. Averages for angiographic variables were obtained by averaging over grafts within each patient and then averaging over all patients. HDL ⫽ high-density lipoprotein.
LDL cholesterol levels ⬍85 mg/dl in the aggressive treatment arm and ⬍140 mg/dl in the moderate treatment arm. If a patient’s LDL cholesterol level decreased ⬍60 mg/dl in the aggressive treatment arm or ⬍130 mg/dl in the moderate treatment arm, the dose of lovastatin was decreased. If necessary to achieve the LDL cholesterol goal, cholestyramine, in a dose of 8 g/day, was added. At the first annual visit after enrollment, patients assigned to the aggressive treatment arm were receiving a mean ⫾ SD of lovastatin 76 ⫾ 12.6 mg/day; 30% of this arm was also given cholestyramine 8 g/day. Patients assigned to the moderate treatment arm were receiving a mean of lovastatin 4 ⫾ 1.3 mg/day; 5% were also given cholestyramine 8 g/day. The prescribed doses of lovastatin and cholestyramine remained constant after this visit for most patients, and adherence to prescribed lovastatin was 85% to 90%. Follow-up angiography was performed 4 to 5 years (mean 4.3) after baseline. The primary prespecified angiographic outcome was the percent of grafts per patient that had substantial progression of atherosclerosis, defined by a decrease ⱖ0.6 mm lumen diameter at the site of greatest change at follow-up. These substantial changes included new lesions of ⬎15% stenosis in grafts with no pre-existing lesion, progression of ⱖ1 lesion present at baseline, or new occlusion. The secondary outcome was the mean change per patient of the minimum
Figure 1. Probability of atherosclerotic graft progression after aggressive versus moderate LDL cholesterol–lowering treatment according to ontreatment LDL cholesterol levels at 1 year, adjusted for baseline LDL cholesterol. Numbers below graph represent mean ⫾ SD for LDL cholesterol and the number of patients in each LDL cholesterol subgroup by treatment arm. Aggressive LDL cholesterol lowering decreased the risk of atherosclerotic graft progression (OR 0.74, 95% CI 0.54 to 0.99, p ⬍0.05).
lumen diameter (MLD) of each graft. All grafts were considered occluded in patients who died without having a follow-up angiogram. Interpreters of angiographic findings were blinded to treatment assignment and patient compliance. Progression of graft atherosclerosis was decreased from 39% of grafts per patient in the moderate treatment group to 27% in the aggressive treatment group.9 The goal of this secondary analysis of the Post CABG data was to determine whether lovastatin treatment resulted in a therapeutic effect (decrease of atherosclerotic graft progression) in addition to that afforded by LDL cholesterol lowering. In this analysis, therefore, the effect of lovastatin treatment on graft progression was examined after adjustment for baseline characteristics, baseline lipid levels, LDL cholesterol achieved on treatment, high-density lipoprotein cholesterol change, and triglyceride change at 1 year. The same analysis was also performed on a subset of patients in the 2 treatment groups whose LDL cholesterol levels achieved on treatment were in the overlapping range between the 2 groups. Continuous variables were expressed as mean ⫾ SD and compared by unpaired t test. Discrete variables and odds ratios (ORs) were compared using chi-square analysis. A 2-tailed p value ⬍0.05 was required to reject the null hypothesis. The generalized estimating equation (GEE) regression models were applied to estimate the OR and probability of substantial graft progression and the difference of the mean MLD change for the aggressive versus moderate LDL cholesterol–lowering treatment, respectively. The logit-link function was chosen to relate the dichotomous response variable of substantial graft progression to the baseline patient and graft variables and on-treatment cholesterol level changes. The identity link function was chosen to relate the continuous response variable to the change in MLD. Because grafts were not ordered and the numbers of grafts varied (1 to 5) for individual patients, the compound symmetry (exchangeable) working correction was used, although the GEE method is robust to the correlation matrix
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Table 2 Estimated odds ratios (95% confidence intervals) of significant atherosclerotic graft progression for lovastatin aggressive treatment compared with moderate treatment
All Post CABG patients (n ⫽ 1,116/2,344 grafts) Aggressive treatment (n ⫽ 570/1,218 grafts) Moderate treatment (n ⫽ 546/1,126 grafts) Subset with year-1 LDL cholesterol 90–135 mg/dl (n ⫽ 518/1,096 grafts) Aggressive treatment (n ⫽ 266/574 grafts) Moderate treatment (n ⫽ 252/522 grafts)
No. of Patients/Grafts With Progression
Adjusted Percent Grafts With Progression*
Adjusted OR* (95% CI)
p Value†
220/307 280/415
23.5% 31.3%
0.68 (0.49⫺0.94)
0.019
121/169 121/181
25.0% 34.3%
0.64 (0.42⫺0.98)
0.042
* Estimated from regression models that included LDL cholesterol level achieved on treatment, high-density lipoprotein cholesterol and triglyceride changes on treatment at year 1, and other baseline variables such as age, gender, previous myocardial infarction, years since CABG, ejection fraction, baseline LDL cholesterol, high-density lipoprotein cholesterol, ratio of total to high-density lipoprotein cholesterol, triglycerides, mean arterial pressure, number of grafts, minimum diameter and maximum stenosis of graft, diabetes, current smoking status, and warfarin treatment. † The p value for chi-square test of the hypothesis that the OR is 1.
mis-specification. The GEE analytic procedures used individual graft information for each patient, adjusting for the correlation of outcomes among the grafts in each patient and different numbers of grafts per patient.21 Multivariate GEE models were adjusted for baseline covariates including age, warfarin treatment, diabetes, and baseline prognostic factors previously reported22 such as gender, lipid profiles, years since CABG operation, previous myocardial infarction, ejection fraction, mean arterial pressure, smoking status, and the number of grafts and 2 graft measurements, maximum stenosis and minimum graft diameter (Table 1). It was found in the main trial that the mean LDL cholesterol level decreased significantly by the first annual visit and remained nearly constant for the subsequent annual visits, with mean differences ⱕ4.5 mg/dl within each treatment group.9 Accordingly, the LDL cholesterol level at year 1 was used as the LDL cholesterol level achieved on treatment in the regression model. Change or percent change of LDL cholesterol from baseline to year 1, high-density lipoprotein cholesterol and triglyceride changes on treatment at year 1, LDL cholesterol level at year 2, and interaction between treatment group and LDL cholesterol change were also examined in the model. To examine potential pleiotropic effects of lovastatin on SVG progression, we compared the risk of graft progression for patients with similar on-treatment LDL cholesterol level in the 2 lovastatin treatment arms. Because the distributions of LDL cholesterol level5 on treatment were significantly different for the 2 treatment arms, the GEE regression models were applied to the subset of patients in the 2 arms who had an LDL cholesterol achieved at year 1 in the range of 90 to 135 mg/dl, where 90 and 135 mg/dl were the median LDL cholesterol levels at year 1 for the aggressive and moderate arms, respectively. Statistical analyses were performed using SAS 9.0 (SAS Institute, Cary, North Carolina). Results Of the 1,351 patients enrolled in the Post CABG trial, 95 patients had missing graft outcome variables. Of the remaining 1,256 patients, 98 patients had missing graft measurements for minimum diameter and maximum stenosis, 34 additional patients had missing LDL cholesterol levels at
Table 3 Estimated mean change of minimum lumen diameters for the lovastatin aggressive treatment and moderate treatment, adjusted for other covariates Mean MLD Change* (mm)
All Post CABG patients (n ⫽ 1,116/2,236 grafts) Aggressive treatment (n ⫽ 570) Moderate treatment (n ⫽ 546) Subset with year-1 LDL cholesterol 90–135 mg/dl (n ⫽ 518/ 1,031 grafts) Aggressive treatment (n ⫽ 266) Moderate treatment (n ⫽ 252)
p Value†
Adjusted
Difference
⫺0.256
0.087 (0.003–0.170)
0.042
0.115 (0.001–0.229)
0.047
⫺0.343
⫺0.244 ⫺0.359
* Estimated from regression models that included the same covariates as models presented in Table 2. † The p value for the t test of the hypothesis that the difference is 0.
year 1, and 8 patients had missing ejection fractions. Patients with missing outcome data or graft measurements were deleted; thus, 1,116 patients (2,344 subject– graft measurements) were included in the analysis. Table 1 lists the means ⫾ SDs and percentages for potential prognostic factors for graft progression. At baseline, all patient and graft measurements were similar and balanced between the 2 treatment arms. After 1 year on treatment, lovastatin decreased LDL cholesterol levels significantly. For the aggressive treatment arm, the LDL cholesterol level was decreased to a mean ⫾ SD of 93 ⫾ 22 mg/dl (39.5% decrease from baseline); for the moderate treatment arm, the LDL cholesterol level was decreased to 136 ⫾ 23 mg/dl (11.6% decrease from baseline). Figure 1 shows the estimated percent of grafts with substantial progression within a given narrow range of LDL cholesterol levels achieved on treatment at year 1 for each lova-
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statin treatment arm after adjustment for baseline LDL cholesterol using the GEE regression model. Aggressive treatment decreased the risk of substantial graft progression significantly compared with moderate treatment (OR 0.74, 95% confidence interval [CI] 0.54 to 0.99, p ⫽ 0.046). Table 2 presents results from the GEE models, controlling for baseline characteristics listed in Table 1 and cholesterol level changes on treatment at year 1. Assignment to the aggressive lovastatin arm contributed a significant decrease in the risk of significant graft worsening after adjustment for baseline LDL cholesterol, LDL cholesterol on treatment, high-density lipoprotein cholesterol and triglyceride changes on treatment, other independent baseline predictors, and warfarin treatment. Assignment to warfarin versus placebo had no effect on risk of graft worsening (p ⫽ 0.4). Regression results were equivalent when the change of LDL cholesterol on treatment was adjusted for and were similar if LDL cholesterol levels at years 1 and 2 and cholestyramine use were adjusted for in the model. The interaction between LDL cholesterol on treatment and the lovastatin treatment arm was not significant (p ⫽ 0.14). As presented in Table 3, mean MLD change was significantly smaller in patients in the aggressive treatment arm, consistent with a beneficial effect on progression of graft atherosclerosis. The GEE regression analysis was repeated in the subset of patients with 1-year LDL cholesterol values of 90 to 135 mg/dl, the median LDL cholesterol levels at year 1 for the aggressive and moderate arms, respectively. At 1 year, only 4% of patients in the aggressive arm had LDL cholesterol levels ⬎135 mg/dl and 1.5% of patients in the moderate arm had LDL cholesterol levels ⬍90 mg/dl. Thus, the subset with LDL cholesterol at year 1 in the range of 90 to 135 mg/dl included nearly ½ of patients in the 2 treatment arms. Mean ⫾ SD LDL cholesterol levels at year 1 were 103.9 ⫾ 11.6 and 118.6 ⫾ 11.6 mg/dl in the aggressive and moderate arms, respectively, for this subset. Distributions of baseline characteristics in the subset were not significantly different from those in the entire treatment arms listed in Table 1. In these overlapping subsets, there were 9 (3.4%) and 15 (6.0%) total deaths, 11 (4.1%) and 5 (2.0%) myocardial infarctions, and 24 (9.0%) and 21 (8.3%) composite end points (death, nonfatal myocardial infarction, stroke, CABG, or percutaneous coronary intervention) in the aggressive and moderate treatment arms, respectively. None of these event rates differed significantly between groups. Applying the same regression models to this subset provided similar results (Tables 2 and 3). If percent change from baseline of LDL cholesterol on treatment was adjusted in the model instead of LDL cholesterol level on treatment, as in Table 2, the estimated risk ratios of significant graft worsening in the aggressive versus moderate arm were comparable (OR 0.70, 95% CI 0.51 to 0.97, p ⫽ 0.032, for all patients; OR 0.64, 95% CI 0.41 to 0.97, p ⫽ 0.037, for the subset, with LDL cholesterol levels 90 to 135 mg/dl). Discussion The Post CABG trial demonstrated that higher-dose lovastatin therapy, resulting in a lower serum LDL cholesterol, was more effective in preventing atherosclerotic disease progression in SVGs than lower-dose lovastatin therapy that produced more modest LDL cholesterol lowering.9 In the
present analysis, the effect of high- versus low-dose lovastatin persisted even after controlling for baseline and ontreatment LDL cholesterol levels and other known risk factors for graft progression.22 Results of this study suggest the presence of a dose-dependent therapeutic effect of lovastatin treatment on SVG atherosclerotic progression that is independent of LDL cholesterol lowering. This is the first study to show such an association in SVGs. Emerging data support an additional beneficial effect of statin therapy unrelated to lowering serum LDL cholesterol. Of 708 postinfarction patients in the Cholesterol and Recurrent Events (CARE) trial, those with higher levels of C-reactive protein and serum amyloid A benefited more from pravastatin therapy than those with lower levels of these inflammatory markers despite similar lipid profiles.12 In that analysis and in the prospective Pravastatin Inflammation/C-reactive protein Evaluation (PRINCE) trial,13 the pravastatin-associated change in C-reactive protein was not significantly correlated with the LDL cholesterol decrease. Several studies have demonstrated improvement in endothelial dysfunction from statin therapy that was only weakly correlated with degree of LDL cholesterol lowering.14 –16 A recent study by Landmesser et al14 reported that, with equal lowering of LDL cholesterol with simvastatin and ezetimibe, only simvastatin improved endothelial function. Associations between statin therapy and decreased incidence of diabetes17 and progressive renal disease18 provide further evidence of a protective effect not related to lipid lowering. In a retrospective analysis from the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, Scirica et al19 showed that atorvastatin 80 mg/day decreased the rate of heart failure hospitalization, independent of recurrent myocardial infarction or previous myocardial infarction, compared with pravastatin 40 mg. In a nationwide observational sample of 61,931 Medicare beneficiaries, Foody et al20 demonstrated that statins were associated with lesser total mortality in patients with heart failure, independent of the presence or absence of coronary artery disease and serum cholesterol. Given that much of the purported clinical evidence for the pleiotropic effect of statins is derived from retrospective analyses, this remains a topic of ongoing controversy that requires validation in prospective clinical trials. Statins have manifold actions apart from LDL cholesterol lowering that might be beneficial. For example, statins decrease the formation of isoprenoids, important molecules in the prenylation and membrane localization of Rho, Ras, and Rac proteins.23 This effect attenuates cell proliferation and hypertrophy10 and increases nitric oxide through decreased inhibition of endothelial nitric oxide synthase activity and increased nitric oxide bioavailability.10 These latter effects are thought to explain the observed improvement in endothelial function with statin therapy.14 –16 Statins decrease oxidant stress, evidenced by decreases in serum peroxides and increases in the activity of antioxidant enzymes such as paraxonase24 and superoxide dismutase.10 Statins also decrease lipoprotein associated phospholipase A2 (Lp-PLA2),25 an atherogenic lipoprotein that hydrolyzes oxidized lipids and proinflammatory molecules and localizes in the necrotic core and fibrous cap of vulnerable plaques. In many studies, statin therapy has reversibly decreased inflammatory
Coronary Artery Disease/Pleiotropic Effects of Statins
markers, including C-reactive protein,10,12,13 tumor necrosis factor receptors,11 tumor necrosis factor ␣,11 endothelin-1,11 and interleukin-18,26 and increased antiinflammatory molecules such as interleukin-10.27 Integrin-dependent adhesion molecules have decreased with statin therapy in some studies.10 Atherosclerotic plaques may be stabilized by a statin-associated, LDL-independent increase in collagen content caused by a decrease in matrix metalloproteinase-9,26 decreased foam cell formation, and decreases in CD36.28 Statins also decrease thrombosis through inhibition of the coagulation cascade and increased fibrinolysis resulting from effects on multiple substrates, including decreases in thrombin activatable fibrinolysis inhibitor (TAFI),16 platelet P-selectin,29 platelet membrane Rho A expression,30 and plasminogen activator inhibitor 1 (PAI-1) and increases in tissue-type plasminogen activator.16 This retrospective analysis used multivariate analysis in a subgroup of all-randomized patients; therefore some residual confounding by unmeasured variables cannot be excluded. Although the LDL cholesterol levels achieved in the 2 treatment arms were suboptimal by current standards, this should not diminish the validity of the intergroup comparisons. 1. Cannon C, Braunwald E, McCabe C, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–1504. 2. Pedersen T, Faergeman O, Kastelein J, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J. Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin versus usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized, controlled trial. JAMA 2005;294:2437–2445. 3. La Rosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK. Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435. 4. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440 –1445. 5. Gotto AM Jr, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477– 484. 6. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet 2005;366:1267–1278. 7. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN, REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071–1080. 8. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, et al, ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556 –1565. 9. Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162. 10. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109(suppl):III39 –III43.
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