Published online before print April 28, 2003, doi: 10.1161/01.CIR.0000068312.21969.C8
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(Circulation. 2003;107:2409.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia
A Prospective, Randomized, Double-Blind Trial
From Baylor College of Medicine, Houston, Tex (C.M.B.); Radiant Research, Stuart, Fla (J.H.); Istituto di Medicina Interna e Geriatria, Università degli Studi, Palermo, Italy (A.N.); and Schering-Plough Research Institute, Kenilworth, NJ (L.M., L.J.L., R.S., S.S., A.P.L., P.T.S., E.P.V.).
Correspondence to Christie M. Ballantyne, MD, Baylor College of Medicine, 6565 Fannin Street, MS A-601, Houston, TX 77030. E-mail cmb{at}bcm.tmc.edu
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Abstract |
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Background— Despite the established efficacy of statins, many patients do not achieve recommended LDL cholesterol (LDL-C) goals. Contributing factors may be inadequate dosing, increased risk for adverse effects with high-dose monotherapy, and increased potential for intolerance and adverse effects with combinations of available agents.
Methods and Results— In a double-blind study, 628 patients with baseline LDL-C 145 to 250 mg/dL and triglycerides 
350 mg/dL were randomly assigned to receive 1 of the following for 12 weeks: ezetimibe (10 mg/d); atorvastatin (10, 20, 40, or 80 mg/d); ezetimibe (10 mg) plus atorvastatin (10, 20, 40, or 80 mg/d); or placebo. The primary efficacy end point was percentage reduction in LDL-C for pooled ezetimibe plus atorvastatin versus pooled atorvastatin treatment groups. Ezetimibe plus atorvastatin significantly improved LDL-C, HDL cholesterol (HDL-C), triglycerides, total cholesterol:HDL-C, and high-sensitivity C-reactive protein (hs-CRP) compared with atorvastatin alone (P<0.01). Coadministration of ezetimibe provided a significant additional 12% LDL-C reduction, 3% HDL-C increase, 8% triglyceride reduction, and 10% hs-CRP reduction versus atorvastatin alone. Ezetimibe plus atorvastatin provided LDL-C reductions of 50% to 60%, triglyceride reductions of 30% to 40%, and HDL-C increases of 5% to 9%, depending on atorvastatin dose. LDL-C reductions with ezetimibe plus 10 mg atorvastatin (50%) and 80 mg atorvastatin alone (51%) were similar.
Conclusions— Ezetimibe plus atorvastatin was well tolerated, with a safety profile similar to atorvastatin alone and to placebo. When coadministered with atorvastatin, ezetimibe provided significant incremental reductions in LDL-C and triglycerides and increases in HDL-C. Coadministration of ezetimibe and atorvastatin offers a well-tolerated and highly efficacious new treatment option for patients with hypercholesterolemia.
Key Words: lipoproteins • cholesterol • trials • drugs • hypercholesterolemia
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Introduction |
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HMG-CoA reductase inhibitors, or statins, are the most potent and frequently used drugs for treating hypercholesterolemia. Despite their established efficacy, however, the number of patients who attain and maintain LDL cholesterol (LDL-C) levels recommended by the US National Cholesterol Education Program Adult Treatment Panel III (ATP III)1 is suboptimal, indicating a gap between lipid goals and clinical practice.2 Statin doses often are not titrated to achieve goals.2 In the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS),3 only 43% of patients with coronary heart disease (CHD) receiving the initial dose of atorvastatin and even fewer patients receiving initial doses of other statins achieved ATP II goals.
At maximum titration (up to 80 mg), 72% of patients with CHD receiving atorvastatin in ACCESS achieved the ATP II goal,3 but atorvastatin at maximum dosage has been associated with increased incidence of elevated liver enzymes.4 Hepatotoxicity and myalgias have also been reported with high doses of other statins. Concerns about safety may prevent physicians from titrating statin doses high enough to achieve recommended targets.
Tolerance and safety concerns may also limit the use of combination therapy. Although combining lipid-modifying agents that act through complementary pathways may provide more effective LDL-C lowering, combination therapy with available agents (bile acid sequestrants, fibric acid derivatives, statins, and nicotinic acid) may increase risk for intolerance, noncompliance, side effects, or drug interactions.5
Ezetimibe is a novel cholesterol absorption inhibitor6 that prevents the absorption of dietary and biliary cholesterol without affecting the absorption of triglycerides or fat-soluble vitamins. Ezetimibe inhibits cholesterol absorption in the intestine, whereas statins inhibit cholesterol production primarily in the liver. In this multicenter study, we tested the primary hypothesis that the coadministration of ezetimibe with atorvastatin would result in a significantly greater reduction in LDL-C than atorvastatin alone. Also evaluated were the change from baseline for other lipid variables and for C-reactive protein and the proportions of patients reaching ATP III LDL-C goals at final assessment.
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Methods |
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Patients
Men and women
18 years of age were screened for primary hypercholesterolemia, defined as calculated LDL-C7 of 145 to 250 mg/dL, inclusive, and triglyceride levels 350 mg/dL. All patients provided written informed consent. Exclusion criteria included congestive heart failure (defined as New York Heart Association class III or IV heart failure8); uncontrolled cardiac arrhythmias; myocardial infarction, coronary bypass surgery, or angioplasty within 6 months of study entry; history of unstable or severe peripheral artery disease within 3 months of study entry; unstable angina pectoris; uncontrolled or newly diagnosed (within 1 month of study entry) diabetes mellitus; unstable endocrine or metabolic diseases known to influence serum lipids and lipoproteins; known impairment of renal function; active or chronic hepatic or hepatobiliary disease; and known coagulopathy.
Design
This randomized, double-blind, placebo-controlled, balanced–parallel group trial was conducted in conformance with good clinical practices and consisted of 3 phases (Figure 1). The protocol was reviewed and approved by each institution’s independent ethics committee or institutional review board. The 2- to 12-week screening phase included washout of previous lipid-modifying drug therapy (12 weeks for fibrates, 1 year for probucol, and 6 weeks for statins, bile acid sequestrants, nicotinic acid, garlic, fish oil, and other lipid-altering agents) and instruction to follow a Step I9 (or stricter) diet throughout the trial. During the 4-week, single-blind, placebo lead-in phase, blood samples were collected at weeks -4 and -2 to assess for qualifying mean calculated LDL-C, with no single value <145 mg/dL or >250 mg/dL. At week 0, qualifying patients were randomly assigned to 1 of 10 treatments: placebo, ezetimibe (10 mg), atorvastatin (10 mg), ezetimibe (10 mg) plus atorvastatin (10 mg), atorvastatin (20 mg), ezetimibe (10 mg) plus atorvastatin (20 mg), atorvastatin (40 mg), ezetimibe (10 mg) plus atorvastatin (40 mg), atorvastatin (80 mg), or ezetimibe (10 mg) plus atorvastatin (80 mg).
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Random assignment to double-blind treatment occurred at visit 4.Blood samples were collected at baseline and weeks 2, 4, 8, and 12, and lipid measurements were performed in plasma; HDL cholesterol (HDL-C) subfractions, apolipoproteins, and lipoprotein(a) were measured at baseline and week 12. LDL-C was measured directly by ultracentrifugation (ß-quantification; direct LDL-C) and also calculated by the Friedewald equation.7 Total cholesterol and triglyceride levels were quantified enzymatically with the Hitachi 747 analyzer (Roche Diagnostics Corporation). Total HDL-C was determined enzymatically after selective removal of LDL-C and VLDL-C by heparin and manganese chloride precipitation. The HDL3-C subfraction was quantified enzymatically after separation by ultracentrifugation,10 and the HDL2-C subfraction was calculated by subtracting HDL3-C from total HDL-C. Non–HDL-C was calculated by subtracting HDL-C from total cholesterol. Apolipoprotein (apo) A-I and apo B were determined by fixed-rate nephelometry. Lipoprotein(a) was quantified by competitive enzyme-linked immunosorbent assay. Samples collected at baseline and week 12 were quantified for C-reactive protein (CRP) by means of high-sensitivity immunonephelometry11 (hs-CRP; Dade Behring, Inc). All clinical laboratory analyses were conducted at the central laboratory (Medical Research Laboratories). All qualifying lipid determinations, as well as lipid profiles after visit 1, were blinded to the investigators and study sponsor.
Safety was evaluated through patient reports, investigator observations, laboratory tests, ECGs, physical examinations, and vital signs. Alanine transaminase (ALT) or aspartate transaminase (AST) levels 3x the upper limit of normal (ULN) on 2 consecutive visits were considered elevated. Patients were also considered to have 2 consecutive elevations if a single elevation 3xULN occurred during the study and no follow-up measurement was made 2 days after discontinuation of study drug. Myopathy was defined as creatine phosphokinase (CPK) 10xULN with associated muscle symptoms.
Statistical Analysis
The primary efficacy end point was the percentage reduction in direct LDL-C from baseline to final assessment (last available postbaseline direct LDL-C value for each patient) for the intent-to-treat population. The primary efficacy analysis was performed with the use of a 2-way ANOVA model that extracted effects due to atorvastatin dose (0, 10, 20, 40, or 80 mg), treatment (ezetimibe 10 mg or placebo coadministration), and dose-by-treatment interaction for the percentage change in direct LDL-C from baseline to final assessment. The comparisons (pooled ezetimibe [10 mg] plus atorvastatin [10, 20, 40, 80 mg] group versus pooled atorvastatin [10, 20, 40, 80 mg] group and pooled ezetimibe [10 mg] plus atorvastatin [10, 20, 40, 80 mg] group versus ezetimibe [10 mg] group) were performed by using contrast statements under the model to evaluate the primary hypothesis. Consistency of the effect across subgroups (sex, age [<65 years, 65 years], and race [white, nonwhite]) and treatment-by-subgroup interactions were evaluated for the primary variable in the intent-to-treat population by using ANOVA models, including factors for treatment, dose, treatment-by-dose interaction, subgroup, and treatment-by-subgroup interaction. With the planned sample size of 
650 patients (65 patients per treatment group), a difference between percentage reduction of direct LDL-C of any 2 treatment groups 5 percentage points could be detected with 80% power and a significance level of 0.05 (2-tailed), assuming a standard deviation of 10.
Secondary efficacy end points included change from baseline to final assessment for calculated LDL-C, total cholesterol, triglyceride, HDL-C, HDL2-C, HDL3-C, non–HDL-C, lipoprotein(a), apo A-I, apo B, and total cholesterol:HDL-C and direct LDL-C:HDL-C ratios. The proportion of subjects achieving ATP III goals for direct LDL-C at final assessment was summarized. For hs-CRP, percent change from baseline to final median values was compared for the pooled and individual treatment groups by using the Wilcoxon Rank Sum procedure. All statistical analyses were conducted with the use of SAS software (version 8).
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Results |
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Of 1703 individuals screened, 628 met the eligibility criteria and were randomly assigned. The treatment groups were well balanced regarding demographics and baseline characteristics (Table 1). Mean baseline direct LDL-C ranged from 175 to 184 mg/dL across treatment groups. Study treatment was discontinued early in 52 (8%) patients because of adverse events (34 patients), patient request (10 patients), noncompliance with protocol (5 patients), and loss to follow-up (3 patients). There was no trend across treatment groups in the distribution of patients who discontinued or in the reasons for discontinuation.
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Coadministration of ezetimibe plus atorvastatin (pooled treatment groups) resulted in significantly greater mean reductions of direct LDL-C from baseline to final assessment (-54.5%) than either atorvastatin alone (-42.4% for pooled treatment groups; P<0.01 for difference between pools) or ezetimibe alone (-18.4%; P<0.01 for difference between pools) (Table 2). Across individual treatment groups, mean changes in direct LDL-C from baseline to final assessment ranged from -50% to -60% for coadministration versus -35% to -51% for atorvastatin monotherapy (Figure 2A). The incremental mean percentage change with coadministration was statistically significant (P<0.01) compared with each corresponding dose of atorvastatin monotherapy, with effects observed as early as week 2 and maintained throughout the treatment period. Subgroup analysis indicated that the incremental LDL-C reductions with coadministration (all doses) was generally consistent across all subgroups, regardless of sex, age, race, or baseline lipids.
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atorvastatin (40 mg) alone; 
P<0.05 for combination therapy vs corresponding dose of atorvastatin alone.Coadministration of ezetimibe with atorvastatin also significantly reduced the more commonly used calculated LDL-C across all atorvastatin doses (P<0.01; Figure 2B). Although increased doses of atorvastatin were associated with greater reductions in total cholesterol, LDL-C, and triglycerides (Figure 2D), a favorable dose response was not observed for changes in HDL-C (6% increase for 10 mg, 3% increase for 80 mg; Figure 2C), as has been observed in other studies with atorvastatin.4,12 Combination therapy improved the total cholesterol:HDL-C ratio at all atorvastatin doses (P<0.01; Figure 2E). Coadministration of ezetimibe with the starting dose of atorvastatin (10 mg) provided similar reductions to those achieved with the maximal dose of atorvastatin (80 mg) alone for LDL-C (50% and 51%), total cholesterol:HDL-C ratio (43% and 41%), and triglycerides (both 31%) but significantly greater increase in HDL-C (9% versus 3%). Coadministration (pooled groups) also provided greater median reduction in hs-CRP than atorvastatin alone (-41% versus -31%, P<0.01); median reductions across combination therapy groups ranged from 25% to 62% and were generally larger than those observed with statin monotherapy (Figure 3).
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LDL-C was above ATP III target at baseline and below target at final assessment in 85% (215/252) of patients receiving coadministration therapy compared with 73% (180/245) of patients receiving atorvastatin monotherapy. The difference between the 2 pooled treatment groups in the proportion of patients achieving ATP III LDL-C targets was statistically significant (P<0.01).
Coadministration of ezetimibe and atorvastatin was well tolerated. Treatment-related adverse events were reported for 17% (42/248) of patients receiving atorvastatin monotherapy and 23% (58/255) of patients receiving combination therapy (Table 3). Most (90%) adverse events were mild or moderate, and 66% were considered unlikely to be related to study treatment. In general, the types of adverse events resulting in treatment discontinuation (34/628, 5% of patients) or interruption (31/628, 5% of patients) were no more common or severe in any treatment group. No patient died during the study.
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All elevations in hepatic enzymes after random assignment were asymptomatic, and no cases of hepatitis, jaundice, or other clinical signs of liver dysfunction were reported. Consecutive and presumed consecutive elevations in ALT or AST level 3xULN occurred in only 5 patients and did not differ significantly between atorvastatin monotherapy (<1%) and combination therapy (2%) (see Table 3). Of these patients, 1 receiving atorvastatin (80 mg) monotherapy and 2 receiving ezetimibe plus atorvastatin (40 mg) were discontinued from the study; the other 2, receiving ezetimibe plus atorvastatin (10 mg) and ezetimibe plus atorvastatin (20 mg), completed the study.
One patient had CPK elevations 10xULN with associated muscle symptoms. This patient, who received ezetimibe plus atorvastatin (40 mg), reported moderate diffuse myalgias and moderate weakness, coincident with CPK of 403 U/L. Follow-up at a local laboratory indicated values as high as 5379 U/L with ongoing symptoms. After treatment was discontinued, symptoms resolved and CPK level returned to normal (96 U/L).
Other measurements of safety (other laboratory tests, vital signs, ECGs, and cardiopulmonary examinations) did not suggest any clinically meaningful differences between the safety profiles of combination therapy and atorvastatin monotherapy in the study overall or in subgroups defined by sex, age, or race. There was no evidence that ezetimibe worsened statin intolerance or statin-related toxicity.
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Discussion |
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Coadministration of ezetimibe plus atorvastatin was significantly (P<0.01) more effective at reducing LDL-C concentrations than atorvastatin or ezetimibe alone for both the pooled treatment groups and each atorvastatin dose. Reductions in apo B, total cholesterol, and triglycerides, as well as increases in HDL-C, were all significantly greater with combination therapy than atorvastatin alone (P<0.01) or ezetimibe alone (P
0.05). Total cholesterol:HDL-C and LDL-C:HDL-C ratios and non–HDL-C concentration also showed significant improvement with coadministration compared with atorvastatin or ezetimibe alone (P<0.01). Ezetimibe plus the starting dose of atorvastatin (10 mg) lowered direct LDL-C as effectively as the maximum dose of atorvastatin (80 mg) alone (50% and 51%, respectively), reduced median triglycerides by a similar amount (both 31%), but provided significantly greater increases in HDL-C (9% versus 3%). The difference in incremental LDL-C reduction observed in this trial versus the 21% incremental reduction reported with the addition of ezetimibe in subjects already receiving statin therapy13 can be attributed to how incremental change is calculated: change in LDL-C/baseline LDL-C level on no therapy versus change in LDL-C/LDL-C level on statin therapy. In the present study, the incremental LDL-C reduction achieved by coadministration of ezetimibe plus statin compared with the LDL-C level achieved by statin monotherapy was on average 22% (20%, 28%, 21%, and 17% for ezetimibe plus atorvastatin [10, 20, 40, and 80 mg], respectively), which is the same benefit reported when ezetimibe was added to statin therapy in the other study (21%).13 The apparent attenuation in incremental LDL-C lowering observed at the highest dose (80 mg) in the present study may be related to the method of calculation. Although high-dose statin can reduce cholesterol excretion into bile,14 which may theoretically lessen the effect of ezetimibe, this has not been observed with simvastatin (80 mg),15 and further reductions in LDL-C were observed with ezetimibe plus atorvastatin (80 mg) in the present study.
The combination of ezetimibe plus atorvastatin was well tolerated, with an overall safety profile similar to that of atorvastatin alone. All elevations in hepatic enzymes were asymptomatic, and no hepatitis, jaundice, or other clinical signs of liver dysfunction were reported. These findings are consistent with the asymptomatic increases in transaminases that have been observed with all lipid-lowering drugs, including bile acid–binding resins and niacin, which act by different mechanisms,16 and may represent a pharmacodynamic effect due to cholesterol reduction or changes in hepatic metabolism. No cases of rhabdomyolysis were reported in this study, and the low occurrence of reversible increases in CPK level suggests no increased risk of myopathy with the coadministration of ezetimibe and atorvastatin compared with atorvastatin alone. Increases in CPK level have been observed with lipid-lowering therapies, particularly high doses of statins or upward dosage titration.17 Coadministration of ezetimibe with low-dose atorvastatin was a well-tolerated option to high-dose atorvastatin monotherapy.
Study limitations include short duration (12 weeks), which precludes analysis of long-term efficacy and safety, and exclusion criteria that prevent extrapolation of the results to other populations. Because of the low incidence of transaminase elevations in all groups, the sample size was too small to examine whether ezetimibe plus low-dose atorvastatin differs from high-dose atorvastatin monotherapy in liver function test abnormalities.
Coadministration of ezetimibe with the starting dose (10 mg) of atorvastatin provided a 50% reduction in LDL-C, comparable to the 51% reduction obtained with high-dose (80 mg) atorvastatin. Because each doubling of a statin dose provides only 5% to 6% additional LDL-C reduction,16 the need for multiple dosage adjustments may limit the routine use of optimum statin doses in clinical practice. Statin doses are often not titrated to achieve recommended LDL-C goals,2 and at starting doses of statin therapy, most patients do not receive sufficient LDL-C reductions to reach target. In ACCESS overall, at initial doses, LDL-C goals were met in 53% of patients receiving atorvastatin, 38% of patients receiving simvastatin, 28% of patients receiving lovastatin, and 15% of patients receiving pravastatin or fluvastatin.3 Even fewer patients in the highest-risk category of CHD can achieve the ATP goal of LDL-C <100 mg/dL: 6% to 43% of patients with CHD in ACCESS,3 and 1% to 32% of patients with documented atherosclerosis receiving starting doses of atorvastatin, fluvastatin, lovastatin, or simvastatin.18 In ATP III, this highest-risk category has been expanded to include individuals with noncoronary atherosclerosis, diabetes mellitus, and multiple risk factors conferring 10-year CHD risk >20%, doubling the number of individuals with this difficult-to-attain LDL-C goal. The importance of aggressive LDL-C lowering in high-risk patients has been supported by the results of the Heart Protection Study,19 which showed that high-risk individuals with LDL-C lower than the drug initiation threshold also benefited from statin therapy, suggesting that the optimal LDL-C for high-risk patients may be below the goals recommended by the guidelines.
The significant reductions in hs-CRP observed when ezetimibe was added to atorvastatin suggest an added anti-inflammatory effect of the combination, possibly resulting from the overall complex effect of ezetimibe on the lipid profile. Similar reductions in hs-CRP were observed when ezetimibe was added to a variety of statins.13
In clinical practice, ezetimibe coadministered with a statin may enable more patients to achieve recommended target LDL-C levels by offering greater LDL-C lowering with fewer dose titrations as well as a well-tolerated alternative for patients in whom maximal dose statin monotherapy is inadequate. Ezetimibe has also been shown to be efficacious when coadministered with simvastatin. In a similarly designed study,15 the combination of ezetimibe (10 mg/d) and simvastatin (pooled doses of 10, 20, 40, and 80 mg/d) provided significantly greater reductions in LDL-C (13.8%) and triglyceride (7.5%) and increases in HDL-C (2.4%) than simvastatin alone (P<0.01). Combining the different mechanisms of action of these agents (inhibition of cholesterol synthesis by the statin and inhibition of cholesterol absorption across the intestinal wall by ezetimibe) appears to provide substantial incremental reductions in LDL-C, with additional favorable changes in total cholesterol, triglycerides, apo B, and HDL-C.
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Acknowledgments |
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This study was funded by Schering-Plough Research Institute, Kenilworth, NJ, and Merck/Schering-Plough Pharmaceuticals, North Wales, Pa. We thank Arlene Reiss and Kerrie Jara for their assistance in the preparation of this manuscript. This study was conducted by Schering-Plough Research Institute, Kenilworth, NJ, on behalf of Merck/Schering-Plough Pharmaceuticals, North Wales, Pa.
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Footnotes |
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*Study organization is listed in the electronic appendix, which is available in the online-only Data Supplement at http://www.circulationaha.org.
Guest editor for this article was Antonio M. Gotto, MD, Weill Medical College, NY.
Dr Ballantyne has received research grants/contracts from Astra-Zeneca, Merck, Novartis, Pfizer, and Schering-Plough; has served on the Speakers’ Bureaus of Astra-Zeneca, Bristol Myers-Squibb, Kos, Merck, and Pfizer; has received honoraria from Astra-Zeneca, Bristol Myers-Squibb, Kos, Merck, Pfizer, Reliant, and Schering-Plough; and has served as a consultant for Astra-Zeneca, Merck, Reliant, and Schering-Plough. Drs Houri and Notarbartolo have received research grants from Schering-Plough. Drs Melani, Lipka, Suresh, Sun, and Veltri are employees and Dr LeBeaut was an employee of Schering-Plough, Inc, the sponsor of the study. Dr Sager also holds stock and stock options in Schering-Plough.
Received December 23, 2002; revision received February 20, 2003; accepted March 5, 2003.
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 J. J.P. Kastelein, F. Akdim, E. S.G. Stroes, A. H. Zwinderman, M. L. Bots, A. F.H. Stalenhoef, F. L.J. Visseren, E. J.G. Sijbrands, M. D. Trip, E. A. Stein, et al. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia N. Engl. J. Med., April 3, 2008; 358(14): 1431 - 1443. [Abstract] [Full Text] [PDF]
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 A. B. Weinglass, M. G. Kohler, E. O. Nketiah, J. Liu, W. Schmalhofer, A. Thomas, B. Williams, L. Beers, L. Smith, M. Hafey, et al. Madin-Darby Canine Kidney II Cells: A Pharmacologically Validated System for NPC1L1-Mediated Cholesterol Uptake Mol. Pharmacol., April 1, 2008; 73(4): 1072 - 1084. [Abstract] [Full Text] [PDF]
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 K. M. Maki-Petaja, A. D. Booth, F. C. Hall, S. M.L. Wallace, J. Brown, C. M. McEniery, and I. B. Wilkinson Ezetimibe and Simvastatin Reduce Inflammation, Disease Activity, and Aortic Stiffness and Improve Endothelial Function in Rheumatoid Arthritis J. Am. Coll. Cardiol., August 28, 2007; 50(9): 852 - 858. [Abstract] [Full Text] [PDF]
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P. M. Ridker C-Reactive Protein and the Prediction of Cardiovascular Events Among Those at Intermediate Risk: Moving an Inflammatory Hypothesis Toward Consensus J. Am. Coll. Cardiol., May 29, 2007; 49(21): 2129 - 2138. [Abstract] [Full Text] [PDF]
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S. Kinlay Low-Density Lipoprotein-Dependent and -Independent Effects of Cholesterol-Lowering Therapies on C-Reactive Protein: A Meta-Analysis J. Am. Coll. Cardiol., May 22, 2007; 49(20): 2003 - 2009. [Abstract] [Full Text] [PDF]
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C. J. Lavie, R. V. Milani, and J. H. O'Keefe Statin Wars-Emphasis on Potency vs Event Reduction and Safety? Mayo Clin. Proc., May 1, 2007; 82(5): 539 - 542. [Full Text] [PDF]
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M. C. Kontos, S. E. Joyner, C. S. Roberts, F. P. Anderson, J. P. Ornato, J. L. Tatum, and R. L. Jesse Implication of the New Low-Density Lipoprotein Goals in Dyslipidemia Management of Patients With Acute Coronary Syndrome Mayo Clin. Proc., May 1, 2007; 82(5): 551 - 555. [Abstract] [Full Text] [PDF]
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N. V. Deshpande, H. M. Mardikar, and D. Deo A Call for Development of Comprehensive Therapy for Dyslipidemia J. Am. Coll. Cardiol., April 3, 2007; 49(13): 1502 - 1502. [Full Text] [PDF]
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M. Piorkowski, S. Fischer, C. Stellbaum, M. Jaster, P. Martus, A. J. Morguet, H.-P. Schultheiss, and U. Rauch Treatment With Ezetimibe Plus Low-Dose Atorvastatin Compared With Higher-Dose Atorvastatin Alone: Is Sufficient Cholesterol-Lowering Enough to Inhibit Platelets? J. Am. Coll. Cardiol., March 13, 2007; 49(10): 1035 - 1042. [Abstract] [Full Text] [PDF]
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A. Kashani, C. O. Phillips, J. M. Foody, Y. Wang, S. Mangalmurti, D. T. Ko, and H. M. Krumholz Risks Associated With Statin Therapy: A Systematic Overview of Randomized Clinical Trials Circulation, December 19, 2006; 114(25): 2788 - 2797. [Abstract] [Full Text] [PDF]
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 S. Ahmed, C. P. Cannon, S. A. Murphy, and E. Braunwald Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial Eur. Heart J., October 1, 2006; 27(19): 2323 - 2329. [Abstract] [Full Text] [PDF]
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T. A. Pearson, M. A. Denke, P. E. McBride, W. P. Battisti, R. A. Gazzara, W. E. Brady, and J. Palmisano Effectiveness of Ezetimibe Added to Ongoing Statin Therapy in Modifying Lipid Profiles and Low-Density Lipoprotein Cholesterol Goal Attainment in Patients of Different Races and Ethnicities: A Substudy of the Ezetimibe Add-On to Statin for Effectiveness Trial Mayo Clin. Proc., September 1, 2006; 81(9): 1177 - 1185. [Abstract] [Full Text] [PDF]
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 A. J. Tremblay, B. Lamarche, J. S. Cohn, J.-C. Hogue, and P. Couture Effect of Ezetimibe on the In Vivo Kinetics of ApoB-48 and ApoB-100 in Men With Primary Hypercholesterolemia Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1101 - 1106. [Abstract] [Full Text] [PDF]
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 C. D Meyers, Y. S. Moon, H. Ghanem, and N. D Wong Type Of Preexisting Lipid Therapy Predicts LDL-C Response to Ezetimibe Ann. Pharmacother., May 1, 2006; 40(5): 818 - 823. [Abstract] [Full Text] [PDF]
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 A. J. Bergman, J. Burke, P. Larson, A. O. Johnson-Levonas, L. Reyderman, P. Statkevich, S. E. Maxwell, T. Kosoglou, G. Murphy, K. Gottesdiener, et al. Interaction of single-dose ezetimibe and steady-state cyclosporine in renal transplant patients. J. Clin. Pharmacol., March 1, 2006; 46(3): 328 - 336. [Abstract] [Full Text] [PDF]
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K. K. Ray, C. P. Cannon, R. Cairns, D. A. Morrow, N. Rifai, A. J. Kirtane, C. H. McCabe, A. M. Skene, C. M. Gibson, P. M. Ridker, et al. Relationship Between Uncontrolled Risk Factors and C-Reactive Protein Levels in Patients Receiving Standard or Intensive Statin Therapy for Acute Coronary Syndromes in the PROVE IT-TIMI 22 Trial J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1417 - 1424. [Abstract] [Full Text] [PDF]
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M. Garcia-Calvo, J. Lisnock, H. G. Bull, B. E. Hawes, D. A. Burnett, M. P. Braun, J. H. Crona, H. R. Davis Jr., D. C. Dean, P. A. Detmers, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1) PNAS, June 7, 2005; 102(23): 8132 - 8137. [Abstract] [Full Text] [PDF]
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 A. E. Moreyra, A. C. Wilson, and A. Koraym Effect of Combining Psyllium Fiber With Simvastatin in Lowering Cholesterol Arch Intern Med, May 23, 2005; 165(10): 1161 - 1166. [Abstract] [Full Text] [PDF]
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P. M. Ridker, D. A. Morrow, L. M. Rose, N. Rifai, C. P. Cannon, and E. Braunwald Relative Efficacy of Atorvastatin 80 mg and Pravastatin 40 mg in Achieving the Dual Goals of Low-Density Lipoprotein Cholesterol <70 mg/dl and C-Reactive Protein <2 mg/l: An Analysis of the PROVE-IT TIMI-22 Trial J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1644 - 1648. [Abstract] [Full Text] [PDF]
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T. A. Pearson, M. A. Denke, P. E. McBride, W. P. Battisti, W. E. Brady, and J. Palmisano A Community-Based, Randomized Trial of Ezetimibe Added to Statin Therapy to Attain NCEP ATP III Goals for LDL Cholesterol in Hypercholesterolemic Patients: The Ezetimibe Add-On to Statin for Effectiveness (EASE) Trial Mayo Clin. Proc., May 1, 2005; 80(5): 587 - 595. [Abstract] [PDF]
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 N. P. Kadoglou, S. S. Daskalopoulou, D. Perrea, and C. D. Liapis Matrix Metalloproteinases and Diabetic Vascular Complications Angiology, March 1, 2005; 56(2): 173 - 189. [Abstract] [PDF]
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W. Marz, H. Scharnagl, M. M. Hoffmann, B. O. Boehm, and B. R. Winkelmann The apolipoprotein E polymorphism is associated with circulating C-reactive protein (the Ludwigshafen risk and cardiovascular health study) Eur. Heart J., December 1, 2004; 25(23): 2109 - 2119. [Abstract] [Full Text] [PDF]
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S. E. Nissen High-Dose Statins in Acute Coronary Syndromes: Not Just Lipid Levels JAMA, September 15, 2004; 292(11): 1365 - 1367. [Full Text] [PDF]
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 R. J. Chilton Coadministration Therapy in Hypercholesterolemia: A Novel Approach to Achieving Lipid Goals--Introduction J Am Osteopath Assoc, September 1, 2004; 104(9_suppl): 3S - 4S. [Full Text] [PDF]
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C. J. Vaughan and A. M. Gotto Jr Update on Statins: 2003 Circulation, August 17, 2004; 110(7): 886 - 892. [Full Text] [PDF]
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S. M. Grundy, J. I. Cleeman, C. N. Bairey Merz, H. B. Brewer Jr, L. T. Clark, D. B. Hunninghake, R. C. Pasternak, S. C. Smith Jr, N. J. Stone, and Coordinating Committee of the National Cholesterol Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines J. Am. Coll. Cardiol., August 4, 2004; 44(3): 720 - 732. [Abstract] [Full Text] [PDF]
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S. M. Grundy, J. I. Cleeman, C. N. B. Merz, H. B. Brewer Jr, L. T. Clark, D. B. Hunninghake, R. C. Pasternak, S. C. Smith Jr, N. J. Stone, for the Coordinating Committee of the National Cho, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): e149 - e161. [Abstract] [Full Text] [PDF]
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S. M. Grundy, J. I. Cleeman, C. N. B. Merz, H. B. Brewer Jr, L. T. Clark, D. B. Hunninghake, R. C. Pasternak, S. C. Smith Jr, N. J. Stone, for the Coordinating Committee of the National Cho, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines Circulation, July 13, 2004; 110(2): 227 - 239. [Abstract] [Full Text] [PDF]
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A. C. Goldberg, A. Sapre, J. Liu, R. Capece, Y. B. Mitchel, and Ezetimibe Study Group Efficacy and Safety of Ezetimibe Coadministered With Simvastatin in Patients With Primary Hypercholesterolemia: A Randomized, Double-Blind, Placebo-Controlled Trial Mayo Clin. Proc., May 1, 2004; 79(5): 620 - 629. [Abstract] [PDF]
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R. Fux, K. Morike, U.-F. Gundel, R. Hartmann, and C. H. Gleiter Ezetimibe and Statin-Associated Myopathy Ann Intern Med, April 20, 2004; 140(8): 671 - 672. [Full Text] [PDF]
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R. V. Milani, C. J. Lavie, and M. R. Mehra Reduction in C-reactive protein through cardiac rehabilitation and exercise training J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1056 - 1061. [Abstract] [Full Text] [PDF]
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P. M Ridker and on behalf of the JUPITER Study Group Rosuvastatin in the Primary Prevention of Cardiovascular Disease Among Patients With Low Levels of Low-Density Lipoprotein Cholesterol and Elevated High-Sensitivity C-Reactive Protein: Rationale and Design of the JUPITER Trial* Circulation, November 11, 2003; 108(19): 2292 - 2297. [Full Text] [PDF]
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E. M. Balk, J. Lau, L. C. Goudas, H. S. Jordan, B. Kupelnick, L. U. Kim, and R. H. Karas Effects of Statins on Nonlipid Serum Markers Associated with Cardiovascular Disease: A Systematic Review Ann Intern Med, October 21, 2003; 139(8): 670 - 682. [Abstract] [Full Text] [PDF]
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