Long-term treatment of hypercholesterolemia with fluvastatin: A 52-week multicenter safety and efficacy study

Long-Term Treatment of Hypercholesterolemia With Fluvastatin: A 52-Week Multicenter Safety and Efficacy Study JAN DIRKBANGA,M.D., Utrecht,TheNetherlands, BERNARD JACOTOT,M.D., Cr&eil, France, PASCALPFISTER,M.D., Basel, Switzerland, MUNISH MEHRA,M.SC., M.s., Lexington, Kentucky,USA, on behalf of the French-Dutch FluvastatinStudy Group

In this long-term (62-week) open-label extension to an earlier randomized, multicenter, double-blind, placebo-controlled, dose-finding trial, 381 patients with primary hypercholesterolemia received fluvastatin at increasing doses of 10 to 40 mg/day to achieve plasma low-density lipoprotein (LDL) cholesterol normalization, according to the European Atherosclerosis Society guidelines. The aim of the extension study wti to assess the longterm efficacy, safety, and tolerability of fluvastatin. After 52 weeks of therapy, 76% of patients were receiving fluvaatatin at 40 mg/day (mean dose: 36 f 8 mg/day). The mean percent change in LDL-cholesterol levels from baseline was -24.8% (p
From the Utrecht University Hospital, Utrecht, The Netherlands (J.D.B.1; H6pital Henri Mondor. INSERM U32. Cr&eil. France (B.J.): Sandoz Pharma Ltd. Basel. Switzerland (P.P.1, and ClinTrials lncl, Lexington Division, Lexington, Kdntucky; United States WM.). Requests for reprints should be addressed to J.D. Banga, M.D., Utrecht University Hospital, P.O. Box 85 500, 3501 GA Utrecht, The Netherlands.

t is now well recognizedthat raised levels of Iteroltotal and low-density lipoprotein (LDL) choles[1,21and, in particular, lipoparticle (a) [Lp(a)] [3,4] are positive risk factors for coronary artery disease(CAD). Furthermore, the recommendations of the secondAdult Treatment Panel (ATP II) of the U.S. National Cholesterol Education Program [5] now recognizehigh levels of high-density lipoprotein (HDL) cholesterol to be a negative CAD risk factor. Thus, the goal of therapy in the “at-risk” patient is to reduce plasma levels of such atherogenielipids and the LDL:HDL ratio. The European Atherosclerosis Society (EAS) has also devised guidelinesfor the treatment of hyperlipidemia that provide therapeutic goals for normalization of lipid levels [61: LDL cholesterol should be lowered to 5135 mg/dL (3.5mmol/L) in patients with, or 5155 mg/dL (4.0mmol/L) in thosewithout, CAD risk factors. The managementof hypercholesterolemiainitially involves dietary therapy and increasedphysical activity. However, in severe casesor in those with multiple risk factors, drug therapy may be considered. The pharmacokineticsof fluvastatin, a new, entirely synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductaseinhibitor, havebeen describedelsewhere[71.Importantly, >90% of an oral doseis rapidly absorbed.The maximuti blood concentrationof fluvastatin is achieved48 minutes after administration of a single doseand, with repeated doses of 40 mglday, steady-state plasma concentrations are achieved after the first dose. Fluvastatin undergoesextensive hepatic first-pass metabolism and is completely metabolizedprior to excretion,which is mainly via the biIiary/fecal route

VI.

The primary aim of this study was to determine the long-term efficacy of fluvastatin in normalizing LDL-cholesterol levels. The secondaryaim was to assess the long-term safety and tolerability of fluvastatin. This study was an extensionof a dosefinding study in which 431 patients in Holland and in France received either placeboor fluvastatin at 2.5, 5, 10, or 20 mg oncedaily for 6 weeks [8].

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PATIENTSAND METHODS A total of 634 patients with primary hypercholesterolemia (men and women, age 18-70 years) were recruited to the initial dose-finding study from 12 centers in France and five centers in the Netherlands. All subjects gave their informed consent to participate, and the study protocol was approved by ethics committees in both France and the Netherlands. Following 8 weeks of dietary stabilization and 6 weeks of placebo washout (weeks -6 to 0), patients who were eligible to enter the active-treatment phase (weeks 0 to 6) were randomized to receive one of five treatment regimens: placebo, or fluvastatin at 2.5, 5, 10, or 20 mg once daily (at night). Patients were eligible if a food record rating (FRR) [9,10] during the week preceding placebo (week -6) indicated compliance with a prescribed diet, and if plasma LDL-cholesterol and triglyceride levels at weeks -6, -4, and -2 were 2160 mg/dL (4.1 mmol/L) and 5300 mg/dL (3.4 mmol/L), respectively. These lipid levels at week 0 were not taken as inclusion criteria. Patients who were not eligible to enter the initial dose-finding study were those with homozygous familial hypercholesterolemia or hyperlipoproteinemia (World Health Organization classification types I, III, IV, or V). Pregnant or lactating women, or those of childbearing potential not using an intrauterine contraceptive device were also excluded, as were those with either evidence or a history of serious medical or surgical conditions, in particular, cardiovascular, gastrointestinal, ophthalmologic, hepatic, or renal disease. Patients who completed the initial study (n = 424) and whose medical condition remained stable throughout the study were eligible for inclusion in the 52-week extension study. However, those who experienced a drug-related adverse event, a deterioration in hepatorenal function, or a vision-limiting cataract during the initial dose-finding study were excluded. Thus, a total of 381 patients entered the extension study. Treatment Regimens During the &week dietary stabilization phase, patients were to follow either the American Heart Association (AHA) phase I diet, the National Cholesterol Education Program (NCEP) step I diet, or the EAS diet. These fat- and cholesterol-restricted diets were maintained throughout both the initial and extension (E) studies. At week EO (week 6 of the initial study), all patients initially received fluvastatin at 10 mg once daily at least 2 hours after the evening meal, irrespective of their therapy or response to therapy in the initial study. Dosages were increased in 10 mg/ day increments at weeks El2 (20 mg/day), E24 (30 6A-88S

mglday), and E36 (40 mg/day) if necessary to achieve LDL-cholesterol normalization as defined by the EAS guidelines [~135 mg/dL (3.5 mmol/L) with, or 5155 mg/dL (4.0 mmol/L) without, CAD risk factors]. As a result of an amendment to the original protocol, some patients received fluvastatin at 20 mglday from week EO; however, after week E12, the dosage schedules for all patients were identical. A patient was considered to have reached the optimal dose of fluvastatin when LDL-cholesterol levels were normalized. If LDL-cholesterol levels subsequently increased, the patient received dietary counseling, but the dose was not increased. Patients whose LDL cholesterol was neither normalized nor decreased by ~15% from baseline of the initial study (nonresponders) after 8 weeks of 20 mg of fluvastatin despite dietary compliance were discontinued from the study. If a lack of response was due to dietary noncompliance, the patient was given further dietary counseling and continued with fluvastatin at 20 mglday for a further 6 weeks. Dietary compliance was evaluated by a 3-day food record, completed by the patient and scored by a nutritionist physician or dietitian, and adapted to the dietary habits of the appropriate country. These evaluations were made at weeks E24 and E52 as well as at week E36 for those not normalized at week E32. Clinical Investigations A general physical examination was performed at weeks E4, E24, and E52. In addition, at each 4- to 6-week visit, a serum pregnancy test was performed on all women of childbearing potential. Vital signs (body weight, sitting systolic and diastolic blood pressures, and pulse rate) were determined for all patients. A 12-hour fasting blood sample was obtained by venipuncture at weeks E8, E12, E20, E24, E32, E36, E48, and E52 for determination of plasma lipids, including total, HDL, LDL, and very lowdensity lipoprotein (VLDL) cholesterol, and triglycerides (TG). Plasma levels of apolipoprotein (ape) A-I and apo B, and lipoparticle (Lp) A-I, LpAI:A-II, LpE:B, Lp(a):B, and LpC-1II:B were determined every 12 weeks and at endpoint. The samples were collected in tubes (Vacutainer) containing 1 mg/mL sodium-potassium ethylenediaminetetraacetic acid (EDTA). After centrifugation, plasma samples were maintained at 4” C by strict temperature control and shipped within 24 hours of collection to a central laboratory (SERLIA, Pasteur Institute, Lille, France) for analysis within 48 hours of venipuncture. Total, HDL, and VLDL cholesterol and TG levels were determined by enzymatic methods (Boeh-

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ringer Mannheim, Germany) that were standardized according to the National Heart, Lung and Blood Institute (NHLBI, Bethesda, MD)/Centers for Disease Control (CDC; Atlanta, GA) Lipid Standardization Program. Independent quality control of total and HDL cholesterol, and TG determinations, was provided by the Medical Research Laboratories (Cincinnati, OH), using methods from the NHLBI/CDC Part III monitoring program. HDL cholesterol was isolated using the modified heparin, 2 M manganese chloride procedure to precipitate VLDL and LDL cholesterol; VLDL was then isolated by ultracentrifugation. LDL cholesterol was derived using the Friedewald formula (LDL cholesterol = total cholesterol - TG/5 - HDL cholesterol [ll]) when levels are expressed in mg/ dL. (These can be converted to standard international units using the conversion factor 0.02586.) Apo A-I and apo B were measured using an imassay on a laser reader munonephelometric (Behring, Marburg, Germany). Two-site immunoenzymometric assays were used to measure LpA-I:A-II 1121, LpC-III:B, LpE:B and Lp(a):B differential electroimmunoassay [131 whereas (Sebia, Issy-les-Moulineaux, France) allowed quantification of LpA-I [121. Blood and urine samples for safety evaluations were obtained at each visit (every 4-8 weeks). Samples were analyzed at local laboratories for hematology, urinalysis, and secondary biochemical parameters (calcium, inorganic phosphorus, blood urea nitrogen [BUN], uric acid, glucose, total protein, total bilirubin, sodium, potassium, chloride, and creatinine) whereas primary biochemical parameters (aspartate [ASAT] and alanine [ALAT] aminotransferases, creatine phosphokinase [CK], y-glutamyltransferase [ rGT] and alkaline phosphatase) were evaluated using calorimetric tests (Boehringer Mannheim, Germany). An ophthalmologic evaluation comprising lens and nonlens examinations was performed on each patient at weeks E24 and ES2 (or on withdrawal from the study). Particular emphasis was placed on the detection of lens opacities. If a new lens abnormality was reported during the course of the study, ophthalmologic examinations were repeated every 12 weeks until the abnormality was stabilized or resolved. If deterioration continued, the patient was discontinued from the study. Patients were also withdrawn from the study if they experienced a two-line reduction in visual acuity on testing in association with a lens abnormality considered to be treatment-related. Statistical Analyses Analyses were performed at weeks E12, E24, E36, E48, and E52 to assess changes from baseline. June 6,

TABLEI Patient (n = 381) Demographics at Baseline According to Dosage at the End of the Study fluvastatinDose 20 mg/day In q 98) Age lyr; mean! SD1 HeigMicm; meani SD) Weight(kg; mean? SD1 Bodymass index(kg/m’; mean+ SD) Men/women(%I

White 1%) Smoker(%I

52.9t 11.8 167.4 f 8.2

67.6+ 10.5 24.1 f 2.5

43157 95.9 25.5

54.3?:10.7 168.8 + 7.4

70.3? 9.3 24.7i 2.8 44/‘56 100.0 28.2

47.6?12.1 169.1t 9.0 69.3t 10.0 24.2T 2.6 65j35 99.2 25.0

‘atients taking 10 mg/day are included in the 20 mg/day group.

For efficacy parameters, baseline was defined as the mean value of weeks -2 and 0 of the initial study whereas, for laboratory safety parameters, baseline was taken as the value of week 0. Paired t tests were used to detect significant within-group differences in continuous variables, If continuous variables were outside the normal distribution, the nonparametric Wilcoxon signed-rank test was employed. A p value co.05 was considered significant. All biochemistry and hematology data were range-adjusted to provide unit-free intermediate summary statistics: value - LLN Range-adjusted value = ULN _ LLN x JO0 where LLN, ULN = lower, upper limit of normal, respectively. Thus, for all medians, 0 = LLN and 100 = ULN 1141.

RESULTS At baseline, the patients in each treatment group were comparable for most demographic characteristics (Table I) except that the mean age in the 40 mg/day group (47.6 years) was slightly lower than that in the 20 mglday (52.9 years) and 30 mglday (54.3 years) groups, and the proportion of men in the 40 mg/day group (65%) was greater than in the 20 mglday (43%) and 30 mglday (44%) groups. At the end of the extension study, the dosage groups were similar in terms of medical history, coexisting diseases, concomitant medication and compliance with both diet (289%) and study medication (295.6%). Among the 67 patients who were discontinued (17.6%) before completing the extension study, the major reasons for discontinuation were a lack of response to treatment (n = 25), adverse events (n = 18), and a lack of cooperation (n = 11). Efficacy After 52 weeks of treatment, dose titration of fluvastatin resulted in a significant (p
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SYMPOSIUM DN HYPERUPlMMlA/BANGA ETAL TABLEII Effects of Fluvaqin

Treatment (Mean Dose 36 k 8 mg/day) on lipid Parameters Meant SD(mg/dL)

Totalcholesterol LMcbksteroF Triglyceride MM cholesterol HDLchoksterol lDL:HDL chdesterd ratii

na

Baselineb

WeekE52

KcFz

299 299 299 181 299 299

336.9T 14.2 256.6f 74.9 140.4? 59.2 32.3+ 11.8 52.32 13.3 5.2? 2.0

271.2+ 601 192.1f 60.1 125.3+ 61.2 24.4t 10.0 540? 14.7 3.8+ 1.6

-19.1t 9.1’ -24.8+ 10.9 -7.9? 10.6’ -20.5f 27.2’ 3.8+ 13.6’ -26.7+ 13.3’

‘Discrepancies are due to missing data. %ean of weeks -2 and 0 of initial study. ‘LDL cholesterol = total cholesterol - Itriglyceride/ - HDL cholesterol. ‘p 4.001 (from paired ttestfor mean percent change equal to zero, or from Wilcoxon signed-rank test for median percent change equal to zero.) HDL = high-density lipoprotein;LDL = lowdensity lipoprotein; VLDL= very bwdensity lipoprotein.

Effects of Fluvastatin Treatment (Mean Dose 36 + 8 mg/day) on Apolipoproteins

W ApOffl Lp(aI:B LpCiII:B LpE:B w WA

n’

Baselineb

WeekE52

299 299 284 298 298 298 298

185.0?:59.0 136.0t 32.0 26.4k 39.5 20.0t 17.0 44.0i 38.0 45.0+ 19.0 81.0t 23.0

148.0f 49.0 145.0+ 37.0 8.2t 23.4 12.0+ 9.5 40.0i 25.0 45.0+ 19.0 77.0i 18.0

-21.5? 13.3” 6.1t 17.5” -38.6+ 76” -44.3f 49.8 0.0?r86.7 -1.8 t 30.4 -4.0 + 37.6’

Discrepancies are due to missing data. “Week 0 of initial study. ‘p ~0.05; “p
LDL (-24.8%), VLDL (-20.5%), and HDL (+3.8%) cholesterol, and in LDL:HDL-cholesterol ratio (-26.7%) and TG (-7.9%) (Table II). As the number of patients taking higher fluvastatin dosages increased with time (by week E52,75% of patients were taking 40 mglday), the responses in total, LDL, and HDL cholesterol, and in the LDL:HDL cholesterol ratio also increased, suggesting a doserelated effect. At week E52 and all other time points assessed, levels of apo B, apo A-I, Lp(a):B, and LpC-1II:B changed significantly (p
tion, the effect of fluvastatin on TG was significantly greater (p ~0.001) in those who had high baseline values: the mean change in the lowest TG quintile (mean, 73 mg/dL) was +3.4% versus -15.3% in the highest quintile (mean, 237 mg/dL). As for HDL cholesterol, the converse was seen: the mean change in patients in the lowest quintile (mean, 36 mg/dL) was +8.8% compared with +3.3% in those in the highest quintile (mean, 73 mg/dL; p
Changes in the primary biochemical safety parameters are shown in Table IV. Gamma-GT abnormalities were the most frequently observed abnormal laboratory findings. Although the J.&T levels at week F52 in the 40 mglday group showed a sig-

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TABLEIV Percentage of Patients With Newly Occurring or Worsening Biochemical Abnormalities at Any visit (According to Fluvastatin Dose)

n”

Out& Adjusted NormelRangeb(%)

2-3 x ULN 1%)

>3-10 x ULN i%1

>lO x UIN I%1

300 354 214 237 368

2.7 2.0 1.5 3.4

0.0 0.3 0.0 0.0

0.0 0.0

0.0 0.0 0.3 0.0

0.3 0.8 1.5 2.1

0.0 0.0 0.4 0.0

!:! 0.3

Total

300 354 274 237 368

GammaGl 1Omg 20mg 30mg 40mg Total

300 354 214 237 368

11.0 16.4 17.9 13.5

2.3 3.4 3.6 3.4

2.7 3.1 i::

ii 0.0 0.4

CK 1Omg 20mg 30mg 40mg Total

300 354 214 231 368

3.0 5.4 4.4 5.9

0.0 0.3 1.5 1.3

0.0 1.1 0.4 0.0

0.0 0.3 0.0 0.4

ASAT IOmg

20mg 30mg 40mg TOtal AlAT 1Omg 20mg 30mg @w

;:;

0.0 0.0 0.0 0.0

0.0

liscrepancies are due to missing data. .I5 x upper limit of normal IULNL Pabents appear only once rn the total, although fhey may appear at more than one dose. ASAT= aspartate aminotransferase; AfAT = alanine aminotransferase; Gamma&T = gammaglutamyftransferase; CK = creatine phosphokinase. Newly occurring = inside adjusted normal range for worst value before treatment and outside adjusted normal range during treatment; Worsening = outside adjusted normal range for worst value before treatment followed by a 15% increase during treatment.

nificant median increase from baseline (+14.3%; p 3 x ULN) in yGT levels (13 worsening, 8 newly occurring), 15 had elevated baseline values of as high as 2 x ULN (n = 3) or even 3 x ULN (n = 3). One patient receiving 40 mglday developed a yGT level of 409 pmol/L (>lO x ULN, where ULN = 33 pmol/L). One patient was withdrawn from the study because of unexplained elevations in liver enzymes (ALAT, ASAT, rGT) and subsequent jaundice, considered to be a serious adverse event. No other notable liver function abnormalities were recorded. A further young male patient had a notably high (~10 x ULN) CK level and muscle pain on two occasions following heavy exercise (body-building). These elevated levels resolved spontaneously, and the patient remained in the study. After a year of therapy, three patients had-in the same eye and at the same visit-new lens abnormalities (nuclear sclerosis, n = 2; posterior cortical opacities, n = 1) and a notable (240%) concomitant reduction in visual acuity.

Tolerability

A detailed record of all adverse events, both volunteered by the patients or observed by the investigators, was made throughout the study. The most frequently reported adverse events were general disorders or involved the gastrointestinal system. The distribution of the most frequent adverse events certainly or possibly attributable to fluvastatin treatment by the investigators is shown in Table V. There were 18 discontinuations due to adverse events (6 considered to be serious), and 16 serious adverse events overall: angina pectoris (n = 4); myocardial infarction (n = 2); malignant tumors (n = 4); and sudden death, heart failure, peripheral arterial disease, asthma, neuromyopathy, and hepatitis (n = 1 each). Tolerability assessments by both investigators and patients revealed high overall tolerability and no significant differences among the dosage groups.

DISCUSSION This extension study demonstrates the long-term efficacy and tolerability of fluvastatin in the treatment of primary hypercholesterolemia. Fluvastatin

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TABLEV Distribution of the Most Frequent (~1%)Adverse Events Certainly or PossiblyAttributable to Fluvastatin (n = 381) MWMEMt

n

190

AhmiMI piin

12 (3.1)

Ckia

11 (2.91

Headache

8 12.11 8 (2.11 1 Il.81

lnscmnia Nausea Bar&a Pruiis

Fatigue Paresthesia Vertigo

Flatulence kmspecifit pain

6 il.61 5 (1.31 4 (1.0) 4 (1.0) 4 (1.0) 4 (1.01 4 Il.01

at dosesfrom 20 up to 40 mg/day maintained a statistically significant reductionin meanLDL-cholesterol levels throughout 52 weeks of treatment, and the increasingLDL responseover successivedosetitration weeks indicates a possibledose-response relationship. After 52 weeks of treatment, 75% of patients were taking fluvastatin at 40 mg/day and the mean daily dose was 36 & 8 mg; the mean change in LDL cholesterol from baseline was -24.8% (p
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Particular emphasiswas placed on hepatic function becauseof the mode of action and extensive first-pass hepatic metabolism of fluvastatin. Although notable elevations in y-GT were the most frequently reported laboratory abnormality, such rises were usually not accompaniedby elevationsin aminotransferases,and the majority of patients exhibiting abnormally high ?GT levels had shown elevatedvaluesat baseline.Furthermore, ?GT is a nonspecificmarker of hepatobiliary function, and elevations should be interpreted in the context of the various factors known to modify y-GT activity, such as alcohol or drug intake causingmicrosomal enzymeinduction. Hepatitis was diagnosedin a patient who received fluvastatin at 10 mg/day during the initial dose-findingstudy and titrated dosesof fluvastatin (10,20,and 30 mg/day) during the extensionstudy; levels of ASAT (233 U/L), ALAT (566 U/L), and rGT (105 U/L) were all markedly elevated. It is possiblethat the event was related to fluvastatin but, as the patient did not receivefluvastatin again, no definite conclusionscanbe drawn. Headachewas reported by 4.2% of the patients receiving fluvastatin, which was lower than the incidencereported by Steiner et al [18] (8.3%;n = 1,687),which was similar to that with placeboin their study (7.9%; n = 763). Other workers have reported an incidenceof up to 12%with lovastatin [19]. Myopathy has been reported in a small percentageof patients receiving various cholesterollowering drugs 118,201.In the present extension study, the one case of notably high CK levels in associationwith muscle pain occurred in a young man following heavy exerciseand resolved spontaneously.Thus,this event is unlikely to be treatment drug-related. As a result of lens opacities reported in dogs treated with fluvastatin, evidenceof new or worsening lens opacities or nuclear sclerosiswas carefully assessedin all patients. After 52 weeks of treatment, three patients had notable (240%) reductionsin visual acuity and,at the sametime, new ipsilateral lens abnormalities.The extent to which these events are related to the use of fluvastatin remains uncertain. In conclusion,in addition to being safe and well tolerated, long-term (52-week) fluvastatin treatment resulted in a significant improvement in the overall lipid profile in patients with primary hypercholesterolemia. ACKNOWLEDGMENT We extend our thanks to Agnes Marguerie and Henk van den Berg for monitoring the study, Patty Ryan for managing the data, and Pascal Lebel for managing the logistic details at the central laboratory level.

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PARTICIPATING INSTITUTIONS ANDPRINCIPAL INVESTIGATORS The following is a list of members of the FrenchDutch Fluvastatin Study Group and other key investigators: From France: B. Jacotot, N. Lechevanton, Hopital Henri Mondor, Cr&eiZ; B. Anton, M. Krempf, Hopital Hotel-Dieu, Nuntes; F. Berthezene, L. Perrot, Hopital de l’antiquaille, Lyon; B. Chanu, Hopital Saint-Louis, Paris; P. Drouin, M. Floriot, Hopital Jeanne D’Arc, Nancy; P. Douste-Blazy, M. Y. Colomes, M. Denat, Hopital Purpan, Toulouse; M. Farmer, Point Medical, Dijon; J. M. Lecerf, G. Luc, Hopital C. Huriez, Lille; C. Percheron, Hopital Lapeyronie, Montpellier. From The Netherlands: J. D. Banga, T. W. A. de Bruin, J. T. Collet, D. W. Erkelens, Academisch Ziekenhuis, Utrecht; H. Kettner, Medisch Centrum, Middelburg; J. T. A. te Gussinklo, St. Streekziekenhuis, Coevordenl Hardenberg; J. W. Deckers, Academisch Ziekenhuis Dijkzigt, Rotterdam; H. C. Hart, Ziekenhuis Eemland, Lokatie Lichtenberg, Amersfoort. The central laboratory was SERLIA, Pasteur Institute, Lille, France, and the key investigators were J.-M. Bard and J.-C. Fruchart. The statistical analyses and central management were performed by M. Mehra and P. Ryan, ClinTrials Ltd., Lexington, Kentucky, USA. The overall study coordinator was P. Pfister, Sandoz Pharma Ltd., Basel, Switzerland.

REFERENCES 1. Castelli WP, Wilson PWF, Levy D, Anderson K. Serum lipids and risk of coronary artery disease. Atheroscler Rev 1990; 21: 7-19. 2. Dart AM. Managing elevated blood lipid concentrations. Who, when and how? Drugs 1990; 39: 374-87. 3. Schaefer EJ, Lamon-Fava S, Jenner JL, et al. Lipoprotein(a) levels and risk of coronary heart disease in men. The Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994; 271: 999-1003.

4. Rhoads GG, Dahlen G, Berg K, Morton NE, Dannenberg AL. Lpfa) lipoprotein as a risk factor for myocardial infarction. JAMA 1986; 256: 2540-6. 5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second 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. JAMA 1993; 269: 3015-23. 6. Prevention of coronary heart disease: scientific background and new clinical guidelines, Recommendations of the European Atherosclerosis Society prepared by the International Task Force for Prevention of Coronary Heart Disease. Nutr Metab Cardiovasc Dis 1992; 2: 113-56. 7. Tse FLS, Jaffe JM, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol 1992; 32: 630-8. 6. Jacotot B, Banga JD, Pfister P, Mehra M, for the French-Dutch Fluvastatin Study Group. Efficacy, tolerability and safety of a lowdose range of fluvastatin (XU 62-320) in the treatment of primary hypercholesterolaemia. A dose-reponse study in 431 patients. Br J Clin Pharmacol 1994; hn press). 9. Farnier M, Mazencieux S, Brun JM, Fantino M. Inter&t du score alimentaire FRR pour I’evaluation du suivi d’un regime hypoliprdemiant. [Abstr.] Ann Nutr Metabol 1990; 34: 61. 10. Remmel PS, Gorder DD, Hall Y, Tillotson JL. Assessing dietary adherence in the Multiple Risk Factor Intervention Trial (MRFIT). J Am Diet Assoc 1980; 76: 351-6. 11. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentrations of low-density lipoprotein cholesterol in plasma, without the use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502. 12. Koren E, Puchois P, Alaupovic P, Fesmire J, Kandoussi A, Fruchart J-C. Quantification of two different types of apolipoprotein A-kontaining lipoprotein particles in plasma by enzyme-linked differential antibody immunosorbent assay. Clin Chem 1987; 33: 38-43. 13. Vu-Dac N, Mezdour H, Parra HJ, Luc G, Luyeye I, Fruchart J-C. A selective bisite immunoenzymometric procedure for human Lp(a) particle quantification using anti bodies against apofa) and apo B. J Lipid Res 1989; 30: 1437-43. 14. Chuang-Stein C. Summarizing laboratory data with different reference ranges in multicentre clinical trials. Drug Inform J 1992; 26: 77-84. 15. Kostner GM, Gavish D, Leopold B, Bolzano K, Weintraub MS, Breslow JL. HMGCoA reductase inhibitors lower LDL cholesterol without reducing Lpfal levels. Circulation 1989; 80: 1313-9. 16. Thiery J, Armstrong VW, Schleef J, Creutzfeldt C, Creutzfeldt W, Seidel D. Serum lipoprotein Lpla) concentrations are not influenced by an HMGCoA reductase inhibitor. Klin Wochenschr 1988; 66: 462-3. 17. Berg K, Leren TP. Unchanged serum Lpfa) concentrations with lovastatin. [Letter.] Lancet 1989; ii: 812. 18. Steiner A, Weisser B, Vetter W. A comparative review of the adverse effects of treatments for hyperlipidaemia. Drug Safety 1991; 6: 118-30. 19. Henwood JM, Heel RC. Lovastatin: a preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia. Drugs 1988; 36: 429-54. 20. England JF, Viles A, Walsh JC, Stewart PM. Muscle and liver side effects associated with simvastatin therapy. fAbstr.1 Aust N Z J Med 1991; 21 (Suppl 2): 512.

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