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Effects of Laropiprant on Nicotinic Acid-Induced Flushing in Patients With Dyslipidemia† John F. Paolini, MD, PhDa,*, Yale B. Mitchel, MDa, Robert Reyes, BAa, Uma Kher, PhDa, Eseng Lai, MD, PhDa, Douglas J. Watson, PhD, MSPHb, Josephine M. Norquist, MSb, Alan G. Meehan, PhDa, Harold E. Bays, MDc, Michael Davidson, MDd, and Christie M. Ballantyne, MDe Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D2, which leads to poor patient compliance and suboptimal dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin D2 receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)–induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n ⴝ 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n ⴝ 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERNinduced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;101:625– 630) Elevated low-density lipoprotein (LDL) cholesterol is a key risk factor for atherosclerotic coronary heart disease. Statins reduce coronary heart disease mortality by approximately 1/3. To further reduce the residual coronary heart disease event risk in dyslipidemic patients, the regulation of other lipid parameters beyond low-density lipoprotein cholesterol alone may be of benefit. Niacin (nicotinic acid) lowers low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a), and it is the most effective agent approved for increasing high-density lipoprotein cholesterol levels.1 As monotherapy or in combination with other lipid-altering agents, niacin reduces cardiovascular events and atherosclerosis progression in a Merck Research Laboratories, Rahway, New Jersey; bMerck Research Laboratories, North Wales, Pennsylvania; cLouisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky; dChicago Center for Clinical Research, Chicago, Illinois; and eBaylor College of Medicine, Houston, Texas. Manuscript received June 19, 2007; revised manuscript received and accepted October 3, 2007. This study was supported by a grant from Merck & Company, Inc., Rahway, New Jersey. *Corresponding author: Tel: 732-594-2246; fax: 732-594-9866. E-mail address: [email protected] (J.F. Paolini). † A list of study investigators appears in the Appendix. 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.10.023 patients with cardiovascular disease and dyslipidemia.1–3 However, clinical lipid efficacy in dyslipidemic patients requires titration over 12 weeks to niacin doses of ⱖ1 g/day, which are frequently associated with flushing.2– 8 This cutaneous adverse reaction limits patient acceptance of niacin and the widespread use of the drug in the management of patients with coronary heart disease and dyslipidemia. Indeed, a recent retrospective observational study of prescription patterns of extended-release niacin (ERN) use in 14,386 dyslipidemic patients in a clinical practice setting in the United States reported that ⬍15% of newly initiated ERN users were still receiving ERN therapy at the end of 1 year, and of those, ⬍15% were receiving doses of ⱖ1.5 g.9 These clinical practice data clearly illustrate the need for the development of a novel method of administering niacin that is better tolerated. Niacin-induced flushing is mediated primarily by prostaglandin D2, which activates prostaglandin D2 receptor 1, leading to cutaneous vasodilatation.10 Laropiprant (LRPT; MK-0524) is a once-daily, selective prostaglandin D2 receptor 1 antagonist.11 The present placebocontrolled study in dyslipidemic patients assessed whether LRPT would (1) reduce niacin-induced flushing at the initiation of ERN therapy and during long-term maintenance therapy and (2) support a novel, accelerated ERN dosing paradigm: initiating ERN at the 1-g dose and advancing rapidly to the 2-g therapeutic dose. www.AJConline.org 626 The American Journal of Cardiology (www.AJConline.org) Table 1 Demographics and baseline characteristics Demographic/Baseline Parameter Age (yrs) Gender Women Men Race White Black Hispanic Other Body mass index (kg/m2) Low-density lipoprotein cholesterol (mg/dl) High-density lipoprotein cholesterol (mg/dl) Median triglycerides (mg/dl) Non-high-density lipoprotein cholesterol (mg/dl) Fasting plasma glucose (mg/dl) Statin therapy Placebo (n ⫽ 68) ERN 1 g ¡ ERN 2 g (n ⫽ 72) LRPT (Pooled Doses) ⫹ ERN 1 g ¡ ERN 2 g (n ⫽ 272) All Patients (n ⫽ 412) 52.1 ⫾ 10.4 54.3 ⫾ 10.6 52.5 ⫾ 11.0 52.8 ⫾ 10.8 21 (30.9) 47 (69.1) 26 (36.1) 46 (63.9) 109 (40.1) 163 (59.9) 156 (37.9) 256 (62.1) 55 (80.9) 5 (7.4) 5 (7.4) 3 (4.4) 29.7 ⫾ 5.4 129.6 ⫾ 49.7 46.8 ⫾ 12.6 152 163.7 ⫾ 54.3 99.4 ⫾ 17.6 21 ⫾ 30.9 57 (79.2) 8 (11.1) 6 (8.3) 1 (1.4) 29.3 ⫾ 5.4 132.0 ⫾ 44.3 45.5 ⫾ 11.4 163 168.4 ⫾ 45.5 99.8 ⫾ 16.6 30 ⫾ 41.7 226 (83.1) 26 (9.6) 13 (4.8) 7 (2.6) 30.2 ⫾ 5.7 129.1 ⫾ 39.7 48.0 ⫾ 13.0 158 164.0 ⫾ 43.8 100.2 ⫾ 21.3 91 ⫾ 33.5 338 (82.0) 39 (9.5) 24 (5.8) 11 (2.7) 29.9 ⫾ 5.6 129.7 ⫾ 42.2 47.3 ⫾ 12.7 160 164.7 ⫾ 45.9 100.0 ⫾ 20.0 142 ⫾ 34.5 Data are expressed as mean ⫾ SD or number (percentage) except as noted. Methods This study enrolled dyslipidemic men and women aged 18 to 75 years for whom treatment with niacin was appropriate as determined by the investigator. Exclusion criteria included conditions or medications (including aspirin [with the exception of the use of aspirin 81 mg/day for cardioprotection] and nonsteroidal anti-inflammatory drugs) that might have confounded or interfered with the reporting of flushing; diseases, conditions, or medications that could have affected lipid levels; patients with newly diagnosed (within 6 months of randomization) or poorly controlled type 1 or type 2 diabetes mellitus (glycosylated hemoglobin ⬎8.5%); patients with histories of gout who were not taking allopurinol; patients taking niacin ⬎50 mg/day; inability to complete an electronic diary on a daily basis; triglycerides ⱖ500 mg/dl; alanine aminotransferase and/or aspartate aminotransferase ⱖ1.5 times the upper limit of normal; creatinine phosphokinase (CK) ⱖ2 times the upper limit of normal; thyroxine ⬍4 g/dl; thyroid-stimulating hormone ⬎10 U/ml; or any of the contraindications specified in the product label for Niaspan (Abbott Laboratories, Abbott Park, Illinois).12 This was a 2-part study. In part A of the study, 154 dyslipidemic patients were randomized to either LRPT 150 mg/day or placebo for 4 weeks, followed by a 1-week washout and crossover to the other treatment for an additional 4 weeks. Patients who completed part A (n ⫽ 122) were washed out for 2 weeks and then entered part B, together with 290 additional dyslipidemic patients who were randomized directly into part B (after a 2-week placebo run-in), for a total of 412 patients in part B. All part B patients were randomized to placebo, ERN 1 g (Niaspan, with no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients were instructed to take study therapy with their evening meals. In part B of the study, patients reported flushing Figure 1. Maximum GFSS in week 1, presented as percentage of patients. intensity daily with the validated Flushing Symptom Questionnaire13 using a handheld electronic diary. The Flushing Symptom Questionnaire is composed of 11 questions that assess aspects of the frequency, severity, duration, and bother of flushing. One of the 11 items assesses the intensity of all 4 flushing symptoms (skin redness, warmth, tingling, and itching) in the aggregate using an 11-point numerical rating scale, termed the Global Flushing Severity Score (GFSS), which was labeled with the following intensity categories: none (score 0), mild (score 1 to 3), moderate (score 4 to 6), severe (score 7 to 9), and extreme (score 10). The study protocol was reviewed and approved by the appropriate ethics committees and institutional review boards. All patients provided written informed consent. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice standards. The key efficacy end points in part A of the study were the percent change from baseline in low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyc- Preventive Cardiology/Laropiprant Reduces ERN-Induced Flushing 627 Figure 2. Mean ⫾ SE percentage of days during which patients had moderate or greater flushing (GFSS ⱖ4), by study week. Figure 3. Percent change from baseline at week 8 for high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Data are expressed as mean ⫾ SE percent change from baseline for high-density lipoprotein cholesterol and low-density lipoprotein cholesterol and as median ⫾ SE percentage change from baseline for triglycerides. erides. In part B of the study, flushing intensity was assessed using the GFSS during treatment initiation (week 1) and maintenance treatment (weeks 2 to 8). Additional end points in part B included the percent change from baseline in low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Safety assessments included the collection of adverse experiences, physical examination, vital signs, and 12-lead electrocardiography. Laboratory safety measurements included blood chemistry, hematology, and urinalysis. Blood chemistry included aspartate aminotransferase, alanine aminotransferase, CK, serum creatinine, and fasting plasma glucose. Efficacy analyses of lipid and flushing end points were performed in the all-patients-treated analysis population, which included all patients who had taken ⱖ1 dose of randomized medication and who had lipid measurements or GFSS measurements for ⱖ1 day after the first dose of treatment. Efficacy end points were analyzed using an analysis-of-variance model with terms for treatment and center. Results The demographics and baseline characteristics were generally similar across the treatment groups in this study (Table 1). Of the 412 patients who entered part B, a total of 63 (15.3%) discontinued the study drug before completing the trial: 9 of 68 patients (13.2%) taking placebo, 14 of 72 patients (19.4%) taking ERN alone, and 40 of 272 patients (14.7%) taking LRPT plus ERN. Treatment with LRPT plus ERN 1 g led to a significant reduction relative to ERN 1 g alone in the intensity of 628 The American Journal of Cardiology (www.AJConline.org) ERN-induced flushing reported during the treatment initiation period as determined by the percentage of patients with maximum GFSS ⱖ1 (mild or greater flushing) during week 1 (p ⬍0.001 for between-group comparison for LRPT plus ERN 1 g vs ERN 1 g alone across all doses of LRPT tested; data not shown). All steps of the step-down trend test were significant, indicating that there was no apparent dose-response relation for the reduction in the maximum intensity of acute ERN-induced flushing with LRPT (data not shown); therefore, data for the LRPT plus ERN group were pooled across LRPT doses for subsequent analyses. In addition to evaluating GFSS ⱖ1 (any ERN-induced flushing), the effects of treatment in the treatment initiation period (week 1) in part B on the clinically important ERN-induced flushing intensity categories of moderate or greater flushing (GFSS ⱖ4), were also examined. Treatment with LRPT plus ERN led to a smaller percentage of patients reporting maximum scores of moderate or greater ERN-induced flushing compared with ERN alone (Figure 1). During the maintenance treatment period in part B, treatment with LRPT plus ERN led to a significant reduction in ERN-induced flushing relative to ERN alone, as determined by the percentage of days with GFSS ⱖ1 during weeks 6 to 8 (p ⬍0.001 for between-group comparison for LRPT plus ERN 1 g vs ERN 1 g alone across all doses of LRPT tested; data not shown). The higher frequency of moderate or greater flushing in the ERN alone group relative to that in the placebo group reported in week 1 of part B persisted throughout the maintenance period to week 8 (Figure 2). During weeks 6 to 8, the incidence of moderate or greater ERN-induced flushing in patients treated with LRPT plus ERN was similar to that for patients treated with placebo (Figure 2). In part B, the incidence of discontinuation because of flushing in the LRPT plus ERN group (8 of 272 [2.9%]) was numerically lower than that for the ERN alone group (5 of 72 [6.9%]); no patients in the placebo group discontinued because of flushing in part B. At week 8 in part B, treatment with LRPT had no significant effect on the beneficial lipid-altering effects of ERN (Figure 3). In part A of the study, treatment with LRPT 150 mg alone had no effect relative to placebo on mean high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels and median triglycerides levels (data not shown). In part B, the overall safety profile of the LRPT plus ERN group was generally comparable with that for the ERN alone group. There were no deaths or drug-related serious adverse experiences in this study. The incidence of discontinuations because of drug-related adverse experiences that were not associated with flushing was similar across the 3 groups (data not shown). In part A, the incidence of discontinuation because of drug-related adverse experiences in the LRPT 150 mg group was similar to that for the placebo group (data not shown). There were no cases of hepatitis in this study. No patients in part A had consecutive or presumed consecutive alanine aminotransferase and/or aspartate aminotransferase elevations ⱖ3 times the upper limit of normal (data not shown). In part B, consecutive or presumed consecutive alanine aminotransferase and/or aspartate aminotransferase eleva- tions ⱖ3 times the upper limit of normal were reported by 5 of 268 patients (1.9%) taking LRPT plus ERN, 0 of 72 patients (0%) taking ERN alone, and 0 of 68 patients (0%) taking placebo (p ⫽ 0.588 for LRPT plus ERN vs ERN alone). Of the 5 cases reported in the LRPT plus ERN group, 2 were drug related. None of the cases were associated with clinical symptoms, and all reversed with treatment discontinuation; there was no evidence of a relation to LRPT dose. There were no cases of myopathy (i.e., muscle symptoms associated with CK ⱖ10 times the upper limit of normal) or rhabdomyolysis in the study. In part B, CK elevations ⱖ10 times the upper limit of normal were reported in 6 of 269 patients (2.2%) taking LRPT plus ERN, 1 of 72 patients (1.4%) taking ERN alone, and 1 of 68 patients (1.5%) taking placebo (p ⬎0.999 for LRPT plus ERN vs ERN alone). These CK elevations were asymptomatic and generally transient and reversible, resolving either during continued study treatment or after the discontinuation of study treatment; there was no evidence of a relation to LRPT dose. Three of the 6 cases in the LRPT plus ERN group (1.1% of the 269 patients in that group) were determined by the investigators to be possibly drug related; the other 3 cases in the LRPT plus ERN group as well as the 2 cases in the ERN alone and placebo groups were determined to be not drug related. One additional patient in the LRPT plus ERN group had an asymptomatic CK elevation ⱖ10 times the upper limit of normal that had started during part A (when the patient was randomized to placebo) and continued into part B. In part A and part B, the laboratory adverse experience of fasting blood glucose increased was reported at a similar incidence across the treatment groups (data not shown). In part B, there were small least squares mean increases from baseline at week 8 in fasting plasma glucose of 3.4, 7.4, and 8.7 mg/dl in the placebo, ERN alone, and LRPT plus ERN groups, respectively (p ⫽ 0.556 for LRPT plus ERN vs ERN alone). No clinically meaningful differences in change from baseline at week 8 were observed across the treatment groups in pulse rate, electrocardiographic results, systolic blood pressure, diastolic blood pressure, body weight, or body mass index (data not shown). Discussion In the present study, ERN coadministered with the prostaglandin D2 receptor 1 antagonist LRPT was given according to a new paradigm of initiation at ERN 1 g/day for 4 weeks and then advanced to 2 g/day for another 4 weeks in dyslipidemic patients. Treatment with LRPT plus ERN was well tolerated and led to a significant reduction in ERNinduced flushing at the initiation of therapy and with the long-term maintenance of therapy, without affecting niacin’s beneficial effects on lipids. In addition, there was a lower incidence of discontinuations because of flushing with LRPT plus ERN compared with ERN alone. Patients treated with LRPT plus ERN experienced a significantly lower incidence of ERN-induced flushing, including clinically meaningful moderate or greater flushing, compared with those taking ERN alone during the treatment initiation and maintenance periods. Treatment with LRPT plus ERN led to an immediate and significant reduction in Preventive Cardiology/Laropiprant Reduces ERN-Induced Flushing the percentage of patients experiencing moderate or greater ERN-induced flushing compared with ERN alone during week 1 (the initiation of therapy) at ERN 1 g. Whereas ERN-induced flushing persisted in the ERN alone arm throughout the 8 weeks of the study, LRPT plus ERN treatment provided a sustained reduction in ERN-induced flushing throughout the maintenance treatment period (weeks 2 to 8 in part B). The incidence of moderate or greater ERN-induced flushing for LRPT plus ERN during weeks 6 to 8 of the study approximated that of patients treated with placebo. Study therapy was dosed with the evening meal rather than at bedtime to ensure adequate time during the wakeful hours to fully assess the effects of LRPT on ERN-induced flushing. Although this trial had been designed as a doseranging study, all LRPT doses tested were maximally effective in reducing ERN-induced flushing. Fewer patients discontinued because of flushing in the LRPT plus ERN group compared with the ERN alone group; because of the small size of this study, demonstration of statistical significance was not intended. In this study, patients receiving ERN therapy had a relatively high level of treatment compliance compared with what would typically be expected in actual clinical practice9 because of intensive follow-up through daily downloading of their electronic diaries, frequent clinic visits, drug intake accountability, and patient education regarding the occurrence of flushing and the importance of remaining in the trial through to completion. As a result, the low incidence of discontinuations in the LRPT plus ERN group in the first week of therapy indicates that the attenuation in flushing over this period was due to an actual beneficial effect of LRPT rather than a potential confounding effect of early discontinuations with initiation at the ERN 1 g dose. LRPT plus ERN therapy had no significant effect on the high-density lipoprotein cholesterol–increasing or low-density lipoprotein cholesterol– and triglycerides-lowering effects of ERN, and LRPT alone had no effect relative to placebo on high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or triglycerides level. LRPT, given alone or coadministered with ERN, was generally well tolerated. The incidence of consecutive or presumed consecutive alanine aminotransferase and/or aspartate aminotransferase elevations ⱖ3 times the upper limit of normal in the LRPT plus ERN group was not significantly different from that in the ERN alone group. None of the drug-related alanine aminotransferase and/or aspartate aminotransferase elevations in the LRPT plus ERN group were associated with clinical symptoms, and there was no evidence of a relation to LRPT dose for these elevations. There were no cases of myopathy reported in this study, and the incidence of CK elevations ⱖ10 times the upper limit of normal in the LRPT plus ERN group was also not significantly different from that in the ERN alone group. Slight alterations in glycemic regulation have been reported with ERN therapy and other niacin products.14 The small increase in mean fasting blood glucose in the LRPT plus ERN group was not significantly different from that in the ERN alone group, indicating that LRPT had no clini- 629 cally meaningful impact on the known glycemic effects of ERN. In summary, the reductions in flushing seen with LRPT support a novel dosing paradigm for ERN therapy that should facilitate the more widespread use of niacin therapy at a more effective dose and thereby reduce the risk for cardiovascular disease in patients with dyslipidemia. Acknowledgment: We wish to thank Olga Kuznetsova for statistical input in the development of the study, Kelly McQuarrie for development and support of the electronic diary, Sally Thompson-Bell and her team (Abigaile Betteridge, Robin Roberts, and Andrew Trovato) for facilitating the timely completion of the trial, and Dr. Jonathan Tobert for his input and guidance during the early phase of the LRPT clinical development program. Appendix Study Investigators: Stephen Aronoff, MD, Central Research Institute of Dallas, Dallas, Texas; Christie Ballantyne, MD, Baylor College of Medicine, Houston, Texas; Harold Bays, MD, L-MARC Research Center, Louisville, Kentucky; Eliot A. Brinton, MD, University of Utah School of Medicine, Salt Lake City, Utah; David Capuzzi, MD, Lipid Disorders Research Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Scott Conard, MD, Tiena Health Research, Irving, Texas; Michael Davidson, MD, Radiant Research Chicago, Chicago, Illinois; Adrian Dobs, MD, Johns Hopkins University, Baltimore, Maryland; Samuel Engel, MD, Soundview Research Associates, Norwalk, Connecticut; Alan Forker, MD, Saint Luke’s Lipid & Diabetes Research Center, Kansas City, Missouri; Neil Fraser, MD, Troy Internal Medicine, Troy, Michigan; Elizabeth Gallup, MD, Radiant Research Kansas City, Overland Park, Kansas; Linda M. Gaudiani, MD, Marin Endocrine Associates, Greenbrae, California; Henry Ginsberg, MD, Columbia University, New York, New York; Charles Harper, MD, Atlanta, Georgia; David Hassman, MD, Comprehensive Clinical Research, Berlin, New Jersey; Charles Herring, MD, New Hanover Medical Research Associates, Wilmington, North Carolina; Victor N. Howard, MD, Heart Center Research Casa Grande Medical Plaza, Port Charlotte, Florida; William Insull, MD, Baylor College of Medicine, Houston, Texas; Michael B. Jacobs, MD, Radiant Research Las Vegas, Las Vegas, Nevada; Scott Kleber, MD, Laureate Clinical Research Group, Atlanta, Georgia; Robert Knopp, MD, Northwest Lipid Research Center, Seattle, Washington; Michael J. Koren, MD, Jacksonville Center for Clinical Research, Jacksonville, Florida; William Kraus, MD, Duke University, Durham, North Carolina; Wayne Larson, MD, Radiant Research Tacoma, Lakewood, Washington; Andrew Lewin, MD, National Research Institute, Los Angeles, California; Thomas W. Littlejohn, MD, Piedmont Medical Research Associates, Winston-Salem, North Carolina; Barry Lubin, MD, Hampton Roads Center for Clinical Research, Inc., Norfolk, Virginia; James McKenney, PharmD, National Clinical Research, Inc., Richmond, Virginia; Thomas Pearson, MD, Strong Heart Program Rehabilitation 630 The American Journal of Cardiology (www.AJConline.org) Center, Rochester, New York; Terry Poling, MD, Heartland Research Associates, LLC, Wichita, Kansas; George Raad, MD, Metrolina Medical Research, Charlotte, North Carolina; Jennifer Robinson, MD, University of Iowa College of Public Health, Lipid Research Clinic, Iowa City, Iowa; Eli Roth, MD, Sterling Research Group, Ltd., Cincinnati, Ohio; Mohammed Saad, MD, University of California, Los Angeles, Diabetes Center, Alhambra, California; Edward Schwager, MD, Carondelet Medical Group, Tucson, Arizona; Evan A. Stein, MD, Metabolic & Atherosclerosis Research Center, Cincinnati, Ohio; Allen Sussman, MD, Rainier Clinical Research Center, Inc., Renton, Washington; Melvin Tonkon, MD, Apex Research Institute, Santa Ana, California; Philip Toth, MD, MidWest Institute for Clinical Research, Indianapolis, Indiana; Kris Vijayaraghavan, MD, Scottsdale Cardiovascular Research Institute, Scottsdale, Arizona; Mervyn Weerasinghe, MD, Rochester Clinical Research, Inc., Rochester, New York; Scott Yates, MD, North Texas Medical Research, The Colony, Texas; James Zavoral, MD, Radiant Research Minneapolis, Edina, Minnesota; Howard Zisser, MD, Sansum Medical Research Institute, General Research, Santa Barbara, California. 1. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421. 2. The Coronary Drug Project Research Group. 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