Comparative Dose Efficacy Study of
`Atorvastatin Versus Simvastatin,
`Pravastatin, Lovastatin, and Fluvastatin
`in Patients With Hypercholesterolemia
`(The CURVES Study)
`Peter Jones, MD, Stephanie Kafonek, MD, Irene Laurora, PharmD, and
`Donald Hunninghake, MD, for the CURVES Investigators*
`
`The objective of this multicenter, randomized, open-la-
`bel, parallel-group, 8-week study was to evaluate the
`comparative dose efficacy of the 3-hydroxy-3-methyl-
`glutaryl coenzyme A (HMG-CoA) reductase inhibitor
`atorvastatin 10, 20, 40, and 80 mg compared with
`simvastatin 10, 20, and 40 mg, pravastatin 10, 20, and
`40 mg, lovastatin 20, 40, and 80 mg, and fluvastatin 20
`and 40 mg. Investigators enrolled 534 hypercholester-
`olemic patients (low-density lipoprotein [LDL] cholesterol
`>160 mg/dl
`[4.2 mmol/L] and triglycerides <400
`mg/dl [4.5 mmol/L]). The efficacy end points were mean
`percent change in plasma LDL cholesterol (primary), total
`cholesterol, triglycerides, and high-density lipoprotein
`cholesterol concentrations from baseline to the end of
`treatment (week 8). Atorvastatin 10, 20, and 40 mg
`
`The Adult Treatment Panel of the National Choles-
`
`terol Education Program has established guide-
`lines for the evaluation and treatment of elevated
`cholesterol concentrations based on an individual’s
`risk factors for coronary artery disease.1 The low-
`density lipoprotein (LDL) cholesterol treatment goals
`are (1) LDL cholesterol #100 mg/dl for patients with
`CAD; (2) LDL cholesterol ,130 mg/dl in patients
`with $2 risk factors for CAD; (3) LDL cholesterol
`,160 mg/dl in patients with ,2 risk factors for CAD.
`The Adult Treatment Panel recommended bile acid
`resins, nicotinic acid, and the 3-hydroxy-3-methylglu-
`taryl coenzyme A (HMG-CoA) reductase inhibitors as
`first-line drug treatments to achieve these treatment
`goals. Simvastatin, pravastatin, lovastatin, and fluva-
`statin lower LDL cholesterol from 18% to 41% over
`the most commonly used recommended dose range of
`each agent.2–13 A recently approved synthetic HMG-
`CoA reductase inhibitor, atorvastatin, reduces LDL
`cholesterol from 35% to 61% over the dose range of
`
`From Baylor College of Medicine, The Methodist Hospital, Houston,
`Texas; Cardiovascular Medical Research, Parke-Davis, Division of
`Warner Lambert Company, Morris Plains, New Jersey; and Heart
`Disease Prevention Clinic, University of Minnesota School of Medi-
`cine, Minneapolis, Minnesota. This study was supported by Parke-
`Davis, Division of Warner Lambert Company, Morris Plains, New
`Jersey. Manuscript received August 20, 1997; revised manuscript
`received and accepted November 24, 1997.
`Address for reprints: Peter H. Jones, MD, Baylor College of Med-
`icine, 6565 Fannin #A601 Houston, Texas 77030.
`*See Appendix for list of CURVES investigators.
`
`produced greater (p <0.01) reductions in LDL choles-
`terol, 238%, 246%, and 251%, respectively, than the
`milligram equivalent doses of simvastatin, pravastatin,
`lovastatin, and fluvastatin. Atorvastatin 10 mg produced
`LDL cholesterol reductions comparable to or greater than
`(p <0.02) simvastatin 10, 20, and 40 mg, pravastatin
`10, 20, and 40 mg, lovastatin 20 and 40 mg, and
`fluvastatin 20 and 40 mg. Atorvastatin 10, 20, and 40
`mg produced greater (p <0.01) reductions in total cho-
`lesterol than the milligram equivalent doses of simvasta-
`tin, pravastatin, lovastatin, and fluvastatin. All reductase
`inhibitors studied had similar tolerability. There were no
`incidences of persistent elevations in serum transami-
`nases or myositis. Q1998 by Excerpta Medica, Inc.
`(Am J Cardiol 1998;81:582–587)
`
`10 to 80 mg.14 –18 The present multicenter study
`(CURVES) was designed to evaluate the comparative
`dose efficacy of the HMG-CoA reductase inhibitor,
`atorvastatin, with equivalent dose strengths of simva-
`statin, pravastatin, lovastatin, and fluvastatin, in hy-
`percholesterolemic patients after 8 weeks of treat-
`ment.
`
`METHODS
`Study design: This study was a multicenter, open-
`label, randomized, parallel-group, 8-week compara-
`tive study evaluating the efficacy of once-daily doses
`of atorvastatin 10, 20, 40, and 80 mg compared with
`once-daily doses of simvastatin 10, 20, and 40 mg,
`pravastatin 10, 20, and 40 mg, lovastatin 20 and 40
`mg, and fluvastatin 20 and 40 mg, and twice daily
`doses of lovastatin 40 mg (80 mg total daily dose).
`Male and female patients 18 to 80 years old with
`plasma LDL cholesterol concentrations $160 mg/dl
`(4.2 mmol/L) as calculated by the Friedewald formula,
`and triglyceride concentrations #400 mg/dl
`(4.5
`mmol/L) at 2 consecutive visits (weeks 26 and 22)
`were eligible for inclusion.19 Patients with any of the
`following conditions were excluded: primary hypo-
`thyroidism; nephrotic syndrome; type 1 or uncon-
`trolled type 2 diabetes mellitus; hepatic dysfunction;
`serum creatine phosphokinase levels .3 times the
`upper limit of normal; body mass index .32 kg/m2;
`uncontrolled hypertension; myocardial infarction, cor-
`onary angioplasty, coronary artery bypass graft, or
`severe or unstable angina pectoris within the 3 months
`
`582
`
`©1998 by Excerpta Medica, Inc.
`All rights reserved.
`
`0002-9149/98/$19.00
`PII S0002-9149(97)00965-X
`
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`
`before the study; known hypersensitivities to HMG-
`CoA reductase inhibitors; or significant abnormalities
`that the investigator believed could compromise the
`patient’s safety or successful participation in the
`study. Medications known to effect lipid levels, inter-
`act with study medications, or effect clinical labora-
`tory parameters (erythromycin, anticoagulants, iso-
`tretinoin, immunosuppressive agents, lipid-regulating
`drugs, systemic steroids) were not allowed during the
`study.
`Eligible patients were instructed to follow the step
`1 diet for 6 weeks before randomization and through-
`out the duration of the study. After dietary stabiliza-
`tion, patients who qualified were randomized to 1 of
`15 treatment groups, as described above, and were
`treated for 8 weeks. All study medication was taken
`according to recommended dosing. The study was
`performed using a common protocol at 34 sites. An
`appropriate institutional review board at all sites ap-
`proved the protocol and all patients signed written
`informed consent.
`Laboratory methods: Using standardized proce-
`dures, Medical Research Laboratories, Highland
`Heights, Kentucky, performed lipid and clinical labo-
`ratory measurements for all sites. The laboratory was
`certified for standardization of lipid analyses as spec-
`ified by the Standardization Program of the Centers
`for Disease Control and Prevention and the National
`Heart, Lung, and Blood Institute.20 After patients
`fasted overnight (minimum of 12 hours), blood was
`drawn in evacuated tubes containing ethylenediami-
`netetraacetic acid (1 mg/ml). Total plasma cholesterol
`and triglycerides were determined enzymatically with
`the Hitachi 747 analyzer (Boehringer Mannheim Di-
`agnostics, Indianapolis, Indiana).21 Plasma high-den-
`sity lipoprotein (HDL) cholesterol was determined
`enzymatically after LDL and very low density li-
`poprotein cholesterol were selectively removed from
`the plasma by heparin and manganese chloride pre-
`cipitation.22 LDL cholesterol concentration was esti-
`mated by the Friedewald formula.19 Fibrinogen was
`measured by immunonephelometry using an anti-
`serum to human fibrinogen (BNA-100 Behring Diag-
`nostics, Westwood, Massachusetts) in EDTA plasma
`stored at 70°C before analysis.
`Safety: To monitor safety, complete clinical labo-
`ratory determinations were obtained at screening, ran-
`domization, and the end of the active treatment period.
`Physical examinations were performed at the begin-
`ning and end of the study. Adverse events were re-
`corded at each clinic visit. Serum transaminases and
`creatinine phosphokinase concentrations were deter-
`mined at every study visit and as deemed necessary by
`the investigator.
`Statistical methods: Sample sizes were calculated
`based on the 2-sided Dunnett’s test with a significance
`level of 5% and a standard deviation of 13% to detect
`differences in LDL cholesterol reductions of 8% (e.g.,
`simvastatin 10 mg vs atorvastatin 10 mg) to 24% (e.g.,
`fluvastatin 40 mg vs atorvastatin 40 mg) between
`atorvastatin and other reductase inhibitors at each dose
`level with at least 80% power.23 The sample size in
`
`each treatment arm varied greatly due to the large
`range of differences in lipid-lowering efficacy be-
`tween atorvastatin and the other reductase inhibitors.
`Sample sizes were inflated by 5% for enrollment tar-
`gets to allow for potential dropouts.
`The intent-to-treat analysis performed for all effi-
`cacy end points included all randomized patients with
`post-treatment efficacy data for the primary efficacy
`end point of percent change in LDL cholesterol from
`baseline to week 8, and the secondary efficacy end
`points of percent change from baseline to week 8 in
`total cholesterol, triglycerides, and HDL cholesterol.
`Baseline was defined as the mean of measurements at
`week 22 and week 0 (randomization).
`For each lipid parameter, the percent change was
`analyzed using an analysis of covariance model to test
`the treatment effect while controlling for baseline
`lipids. The least-squares means and mean square error
`from this model were used to compare atorvastatin
`with other reductase inhibitors at each dose level using
`Dunnett’s procedure to fix the dose-wise type I error
`rate at 5%.23 An analysis of variance model was used
`to test the assumption of no treatment-by-baseline
`lipid interaction.
`Comparison between the least-squares means from
`the analysis of covariance model were used to evalu-
`ate (post hoc) the effect of each reductase inhibitor at
`all dose levels compared with atorvastatin 10 mg and
`atorvastatin 20 mg.
`Safety was assessed among all patients receiving
`study medication using adverse events (coded using a
`modified COSTART dictionary) and clinical labora-
`tory assessments. Particular attention focused on the
`presence of myopathy or elevated serum transaminase
`levels because these conditions have been associated
`with the use of reductase inhibitors.24
`
`RESULTS
`Patient characteristics: Of the 534 patients random-
`ized to treatment, 518 patients completed the study.
`Sixteen patients (3%) withdrew before the end of the
`study: 8 because of adverse events, 4 for personal
`reasons, and 4 who were lost to follow-up. The intent-
`to-treat analysis included 522 patients who provided
`post-treatment efficacy data. Fifty-nine percent of pa-
`tients (307) were men and 41% (215) were women;
`90% (469) were white. Mean age was 55 years (range
`20 to 80), and 17% of patients had established CAD.
`Effects on serum lipids: Mean baseline LDL choles-
`terol concentrations ranged from 192 to 244 mg/dl
`(5.0 to 6.3 mmol/L) and were similar across treatment
`groups (Table I). When given once daily in equivalent
`(mg) doses, atorvastatin 10, 20, and 40 mg produced
`greater (p #0.01) reductions in LDL cholesterol than
`simvastatin, pravastatin,
`lovastatin, and fluvastatin
`(Figure 1). Atorvastatin administered once daily at 80
`mg reduced LDL cholesterol by 54%, whereas lova-
`statin administered as 40 mg twice daily reduced LDL
`cholesterol by 48%. This difference was not statisti-
`cally significant (p 5 0.17) (Table II).
`Atorvastatin 10 mg produced greater (p #0.02)
`reductions in LDL cholesterol than simvastatin 10 mg,
`
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`TABLE I Baseline Lipid and Lipoprotein Cholesterol Concentrations
`Treatment
`Dose (mg)
`Number of Patients
`Total Cholesterol
`
`Triglycerides
`
`HDL Cholesterol
`
`LDL Cholesterol
`
`Atorvastatin
`Pravastatin
`Simvastatin
`Atorvastatin
`Pravastatin
`Simvastatin
`Fluvastatin
`Lovastatin
`Atorvastatin
`Pravastatin
`Simvastatin
`Fluvastatin
`Lovastatin
`Atorvastatin
`Lovastatin
`
`10
`10
`10
`20
`20
`20
`20
`20
`40
`40
`40
`40
`40
`80
`80
`
`73
`14
`70
`51
`41
`49
`12
`16
`61
`25
`61
`12
`16
`10
`11
`
`298 (7.72)
`309 (8.00)
`289 (7.48)
`297 (7.68)
`315 (8.14)
`313 (8.09)
`322 (8.34)
`334 (8.63)
`286 (7.40)
`299 (7.73)
`300 (7.77)
`275 (7.12)
`301 (7.79)
`296 (7.65)
`306 (7.90)
`
`169 (1.91)
`176 (1.98)
`157 (1.78)
`172 (1.94)
`147 (1.66)
`159 (1.79)
`188 (2.12)
`192 (2.17)
`153 (1.73)
`172 (1.94)
`173 (1.95)
`173 (1.95)
`172 (1.94)
`150 (1.69)
`200 (2.26)
`
`51 (1.33)
`49 (1.26)
`51 (1.31)
`49 (1.28)
`48 (1.25)
`51 (1.32)
`49 (1.26)
`51 (1.32)
`50 (1.29)
`49 (1.28)
`47 (1.20)
`49 (1.26)
`49 (1.26)
`53 (1.37)
`47 (1.21)
`
`213 (5.52)
`226 (5.83)
`207 (5.36)
`213 (5.51)
`237 (6.14)
`230 (5.95)
`236 (6.10)
`244 (6.32)
`206 (5.32)
`215 (5.57)
`219 (5.66)
`192 (4.97)
`219 (5.65)
`213 (5.51)
`219 (5.66)
`
`Values are expressed as mean mg/dl (mmol/L).
`
`FIGURE 1. Percent reduction in low-density lipoprotein cholesterol (LDL-C) after 8
`weeks of treatment with atorvastatin (F), simvastatin ((cid:145)), pravastatin (}), lovastatin
`(n), and fluvastatin (E). *p <0.01 versus atorvastatin at mg equivalent doses; †p
`<0.02 versus atorvastin 10 mg; ‡p < versus atorvastin 20 mg.
`
`dose when simvastatin produced
`greater (p #0.05) elevations in HDL
`cholesterol than atorvastatin (Table II).
`Safety: The overall frequency
`of adverse events was similar be-
`tween treatment groups. Fifty-two
`patients (10%) reported adverse
`events that were judged by the
`investigator to be possibly, prob-
`ably, or definitely associated with
`treatment, most of which were
`mild to moderate in intensity.
`Of
`these,
`the most commonly
`reported events were myal-
`gia
`(1.5%),
`abdominal pain
`(1.3%), diarrhea (1.1%), flatu-
`lence (1%), and nausea (1%).
`Eight patients withdrew from
`the study due to adverse events:
`2 in the atorvastatin group (1%),
`4 in the
`simvastatin group
`(2%), and 1 each in the pravasta-
`tin (1%) and fluvastatin groups
`(4%) (Table IV). The adverse
`events leading to withdrawal included gastrointes-
`tinal complaints, dizziness, depression, myalgia,
`hypertonia, angina, and back pain.
`There were no incidences of persistent (2 measure-
`ments within 1 week) elevations in serum transami-
`nases .3 times the upper limit of normal. There were
`no incidences of elevations in creatine phosphokinase
`.3 times the upper limit of normal or reports of
`myopathy in any treatment group. There were no
`significant changes from baseline in mean fibrinogen
`levels for any of the reductase inhibitors.
`
`DISCUSSION
`The CURVES study is the first trial to compare the
`lipid-lowering efficacy of all marketed HMG-CoA
`reductase inhibitors, including the recently approved
`synthetic HMG-CoA reductase, atorvastatin, across
`their dose ranges. An open-label design was chosen
`
`pravastatin 10 and 20 mg, lovastatin 20 and 40 mg,
`and fluvastatin 20 and 40 mg (Table III). Atorvastatin
`20 mg produced greater (p #0.01) reductions in LDL
`cholesterol than simvastatin 10, 20, and 40 mg, pra-
`vastatin 10, 20, and 40 mg, lovastatin 20 and 40 mg,
`and fluvastatin 20 and 40 mg (Table III).
`As with LDL cholesterol, atorvastatin 10, 20, and 40
`mg produced greater (p #0.01) reductions in total cho-
`lesterol than simvastatin, pravastatin, lovastatin, and flu-
`vastatin at milligram-equivalent doses (Table II). The
`effects on triglycerides were not different between ator-
`vastatin and the other reductase inhibitors except at the
`40-mg dose when atorvastatin produced greater (p
`#0.05) reductions in triglycerides than the 40-mg doses
`of simvastatin, pravastatin, lovastatin, and fluvastatin
`(Table II). Effects on HDL cholesterol, ranging from
`3.0% to 9.9%, were not different between atorvastatin
`and the other reductase inhibitors except at the 40-mg
`
`584 THE AMERICAN JOURNAL OF CARDIOLOGYT
`
`VOL. 81 MARCH 1, 1998
`
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`TABLE II Mean Percent Change (6SD) in Lipoprotein Concentrations
`Treatment
`Dose (mg)
`Number of Patients
`Total Cholesterol
`
`Triglycerides
`
`HDL Cholesterol
`
`LDL Cholesterol
`
`Atorvastatin
`Pravastatin
`Simvastatin
`Atorvastatin
`Pravastatin
`Simvastatin
`Fluvastatin
`Lovastatin
`Atorvastatin
`Pravastatin
`Simvastatin
`Fluvastatin
`Lovastatin
`Atorvastatin
`Lovastatin
`
`10
`10
`10
`20
`20
`20
`20
`20
`40
`40
`40
`40
`40
`80
`80
`
`73
`14
`70
`51
`41
`49
`12
`16
`61
`25
`61
`12
`16
`10
`11
`
`228 (9)
`213 (12)†
`221 (9)†
`235 (6)
`218 (7)†
`226 (8)†
`213 (6)†
`221 (9)†
`240 (8)
`224 (7)†
`230 (10)†
`219 (9)†
`223 (6)†
`242 (7)
`236 (6)
`
`213 (25)
`3 (46)
`212 (30)
`220 (25)
`215 (17)
`217 (22)
`25 (32)
`212 (23)
`232 (19)
`210 (22)†
`215 (29)†
`213 (34)*
`22 (27)†
`225 (22)
`213 (28)
`
`5.5 (12)
`9.9 (13)
`6.8 (9)
`5.1 (11)
`3.0 (8)
`5.2 (10)
`0.9 (8)
`7.3 (12)
`4.8 (12)
`6.2 (11)
`9.6 (13)*
`23.0 (10)
`4.6 (13)
`20.1 (9)
`8.0 (13)
`
`238 (10)
`219 (14)†
`228 (12)†
`246 (8)
`224 (9)**,†
`235 (11)**
`217 (8)**,†
`229 (13)**,†
`251 (10)
`234 (9)**,‡
`241 (13)**,‡
`223 (10)**,†,‡
`231 (7)**,†,‡
`254 (9)
`248 (8)
`
`*p #0.05; †p #0.01, Dunnett’s test of significance compared with atorvastatin at milligram-equivalent doses.
`†Atorvastatin 10 mg statistically significantly better (p #0.02).
`‡Atorvastatin 20 mg statistically significantly better (p #0.01).
`Values are expressed as mean percent change from baseline.
`
`TABLE III Comparison of Percent Change in Low-Density Lipoprotein (LDL) Cholesterol: Atorvastatin 10 and 20 mg Versus All
`Treatments
`
`Treatment Group
`
`Dose (mg)
`
`Number of
`Patients
`
`Mean* Percent
`Change from Baseline
`LDL Cholesterol
`
`p Value vs
`Atorvastatin
`10 mg
`
`p Value vs
`Atorvastatin
`20 mg
`
`Atorvastatin
`Atorvastatin
`Fluvastatin
`Fluvastatin
`Lovastatin
`Lovastatin
`Lovastatin
`Pravastatin
`Pravastatin
`Pravastatin
`Simvastatin
`Simvastatin
`Simvastatin
`
`10
`20
`20
`40
`20
`40
`80
`10
`20
`40
`10
`20
`40
`
`73
`51
`12
`12
`16
`16
`11
`14
`41
`25
`70
`49
`61
`
`*Least-squares mean.
`NS 5 atorvastatin not statistically significantly better.
`
`238
`246
`217
`223
`229
`231
`248
`219
`224
`234
`228
`235
`241
`
`Referent
`—
`0.0001
`0.0001
`0.0019
`0.0197
`NS
`0.0001
`0.0001
`NS
`0.0001
`NS
`NS
`
`—
`Referent
`0.0001
`0.0001
`0.0001
`0.0001
`NS
`0.0001
`0.0001
`0.0001
`0.0001
`0.0001
`0.0083
`
`for this study because of the impracticality of blinding
`15 treatment arms. Efficacy end points were based on
`objective laboratory measurements.
`Atorvastatin 10, 20, and 40 mg produced greater (p
`#0.01) reductions in total and LDL cholesterol than
`the other reductase inhibitors studied at milligram-
`equivalent doses. Atorvastatin 10 mg produced greater
`(p #0.02) reductions in LDL cholesterol than to sim-
`vastatin 10 mg, pravastatin 10 and 20 mg, lovastatin
`20 and 40 mg, and fluvastatin 20 and 40 mg. The
`reduction in LDL cholesterol with atorvastatin 80 mg
`once daily (254%) was numerically, but not statisti-
`cally, greater than lovastatin administered as 40 mg
`twice daily (248%) in a small sample of 10 and 11
`patients, respectively.
`The lipid-lowering effects observed in the present
`study are consistent with those seen in previous com-
`parisons between HMG-CoA reductase inhibitors.
`Simvastatin 10 to 40 mg produced reductions in LDL
`cholesterol of 28% to 41%, pravastatin 10 to 40 mg
`
`produced reductions in LDL cholesterol of 18% to
`34%, lovastatin 20 to 40 mg produced reductions in
`LDL cholesterol of 25% to 38%, and fluvastatin 20 to
`40 mg produced reductions in LDL cholesterol of 18%
`to 27%.2–13 Only the lovastatin 40 mg twice-a-day
`treatment group had a greater reduction in LDL cho-
`lesterol in this study (48%) than anticipated based on
`the results from a large clinical trial—Expanded Clin-
`ical Evaluation of Lovastatin (EXCEL)—in which
`reductions were reported as 40%.25 The greater than
`expected LDL cholesterol reductions in this group
`may be partially explained by the small sample size.
`An HMG-CoA reductase inhibitor’s efficacy is
`measured by its ability to lower LDL cholesterol re-
`gardless of the amount of drug substance needed to
`accomplish this result (potency). Atorvastatin, admin-
`istered in doses of 10 to 80 mg to patients with
`primary hypercholesterolemia, lowers LDL choles-
`terol by 35% to 61%.14 –18 The present study, in con-
`junction with previous comparative studies that have
`
`PREVENTIVE CARDIOLOGY/COMPARATIVE EFFICACY OF ATORVASTATIN 585
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`TABLE IV Withdrawals Due to Adverse Events
`No. of
`Patients
`Withdrawn
`Due to
`Adverse
`Events
`
`Dose
`(mg)
`
`No. of
`Patients
`
`Treatment
`
`Event(s)
`
`Relation to
`Therapy*
`
`their support and efforts related to
`the conduct of the study and the data
`analysis.
`
`Atorvastatin
`Pravastatin
`Simvastatin
`Atorvastatin
`Pravastatin
`Simvastatin
`
`Fluvastatin
`Lovastatin
`Atorvastatin
`Pravastatin
`Simvastatin
`Fluvastatin
`Lovastatin
`Atorvastatin
`Lovastatin
`
`10
`10
`10
`20
`20
`20
`
`20
`20
`40
`40
`40
`40
`40
`80
`80
`
`74
`14
`70
`51
`42
`51
`
`12
`16
`61
`25
`61
`12
`16
`10
`11
`
`1
`0
`1
`1
`1
`2
`
`0
`0
`0
`0
`1
`1
`0
`0
`0
`
`Abdominal pain/diarrhea
`
`Possibly
`
`Depression/dizziness
`Myalgia
`Dizziness
`Hypertonia/nausea
`Abdominal pain/flatulence
`
`Possibly
`Definitely not
`Probably
`Possibly
`Probably
`
`Angina
`Back pain
`
`Unlikely
`Probably
`
`APPENDIX
`CURVES Investigators: W. Virgil Brown, MD,
`Emory University School of Medicine, Atlanta, GA;
`Arthur Bucci, MD, Mercy Heart Institute, Pittsburgh,
`PA; David Capuzzi, MD, PhD, Medical College of Penn-
`sylvania, Philadelphia, PA; Albert Carr, MD, South-
`eastern Clinical Research & Management, Inc., Au-
`gusta, GA; Michael Clearfield, DO, University of North
`Texas, Fort Worth, TX; Stephen Crespin, MD, St.
`Louis, MO; Paresh Dandona, MD, State University of
`New York at Buffalo, Buffalo, NY; Michael Davidson,
`MD, Chicago Center for Clinical Research Inc., Chi-
`cago, IL; Fred Faas, MD, John L. McClellan Memorial
`Veterans Hospital, Little Rock, AR; Keith Ferdinand,
`MD, Margo Morgan Research Center, New Orleans,
`LA; Geoffrey S. Ginsburg, MD, PhD, Beth Israel Hos-
`pital, Boston, MA; Donald B. Hunninghake, MD, Uni-
`versity of Minnesota, Minneapolis, MN; William In-
`sull, MD, Baylor College of Medicine, The Methodist
`Hospital, Houston, TX; Peter H. Jones, MD, Baylor
`College of Medicine, The Methodist Hospital, Houston,
`TX; Stephanie Kafonek,* MD, The Johns Hopkins Uni-
`versity, Baltimore, MD; John P. Kane, MD, University
`of California, San Francisco, CA; Moti L. Kashyap,
`MD, Veterans Administration Medical Center, Long
`Beach, CA; Kent D. Katz, MD, Veterans Administra-
`tion Medical Center, Long Beach, CA; Robert H.
`Knopp, MD, University of Washington, Harborview
`Medical Center, Seattle, WA; Peter Kwiterovich, MD, The Johns Hopkins
`University, Baltimore, MD; Andrew J. Lewin, MD, National Research Institute,
`Los Angeles, CA; Irving K. Loh, MD, Ventura Heart Institute, Thousand Oaks,
`CA; Charles P. Lucas, MD, William Beaumont Hospital, Birmingham, MI; James
`M. McKenney, PharmD, National Clinical Research Inc., Richmond, VA; John
`M. Morgan, Medical College of Pennsylvania, Philadelphia, PA; David T. Nash,
`MD, Syracuse, NY; Stephen D. Nash, MD, Syracuse, NY; Christopher M.
`Rembold, MD, University of Virginia, Charlottesville, VA; Lawrence M.
`Resnick, MD, Veterans Affairs Medical Center, Allen Park, MI; Robert G.
`Robertson, MD, Emory University School of Medicine, Atlanta, GA; Robert J.
`Rosenson, MD, Rush-Presbyterian/St. Luke’s Medical Center, Chicago, IL; F.
`Julie Samuels, MD, National Clinical Research Inc., Richmond, VA; Xavier
`Pi-Sunyer, MD, St. Luke’s/Roosevet Hospital Center, New York, NY; Arkady
`Synhavsky, MD, Kidney Disease & Critical Care, Roseville, MN; Stephen F.
`Weis, DO, University of North Texas, Forth Worth, TX; Stuart R. Weiss, MD,
`The San Diego Endocrine & Medical Clinic Inc., San Diego, CA; James H.
`Zavoral MD, Preventive Cardiology Institute, Fairview Southdale Hospital,
`Edina, MN; Paul Ziajka, MD, PhD, The Florida Lipid Associates, Orlando, FL;
`Jean Bergeron, MD, Hotel-Dieu de Quebec, Quebec, Canada; Jacques Genest,
`MD, Clinical Research Institute of Montreal, Montreal, Quebec Canada; Ruth
`McPherson, MD, PhD, University of Ottawa Heart Institute, Ottawa, Ontario
`Canada.
`
`*Relation to therapy was judged by the investigator.
`
`included atorvastatin, have clearly established atorv-
`astatin as the most efficacious HMG-CoA reductase
`inhibitor for lowering LDL cholesterol.16 –18
`This study was not powered to detect differences in
`effects on triglycerides. The patient population studied
`consisted mostly (74%) of patients with elevated choles-
`terol without elevated triglycerides (mean baseline trig-
`lycerides ranged from 147 to 200 mg/dl [1.66 to 2.26
`mmol/L]). Atorvastatin 10, 20, and 80 mg produced
`numerically, but not statistically, greater reductions in
`triglycerides than the other reductase inhibitors at milli-
`gram-equivalent doses, and statistically greater reduc-
`tions in triglycerides at the 40 mg dose. As with LDL
`cholesterol, the reductions in triglycerides seen in all of
`the treatment groups in the present study are consistent
`with those reported in previous studies.2–18
`Reductase inhibitors are generally well tolerated.24
`Clinically important adverse effects of the drugs in-
`clude increases in serum transaminase concentrations
`and myositis, with or without complicating rhabdo-
`myolysis. In the present study, no patient in any treat-
`ment arm experienced persistent clinically significant
`increases in serum transaminases. Most cases of sig-
`nificant elevations in serum transaminases have been
`reported to occur within the first 2 to 5 months of
`treatment, and the duration of this study (8 weeks)
`may not have been long enough to detect such cases.26
`In rare instances, severe creatine phosphokinase ele-
`vations (.10 times the upper limit of normal) and
`myositis have been associated with the use of reduc-
`tase inhibitors.27 In the present study, no subject ex-
`perienced creatine phosphokinase concentrations .3
`times the upper limit of normal, or myopathy.
`
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`Acknowledgment: We acknowledge and thank Bos-
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`*Stephanie Kafonek, MD, is now Senior Director of Cardiovascular
`Medical Research at Parke-Davis, a Division of Warner-Lambert.
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