Safety profile of atorvastatin-treated patients with low LDL-cholesterol levels

Atherosclerosis 149 (2000) 123 129 www.elsevier.com/locate/atherosclerosis Safety profile of atorvastatin-treated patients with low LDL-cholesterol levels Rebecca G. Bakker-Arkema *, James W. Nawrocki, Donald M. Black Parke-Da is Pharmaceutical Research, Di ision of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105-1047, USA Received 10 November 1998; received in revised form 30 June 1999; accepted 14 July 1999 Abstract Data pooled from 21 atorvastatin clinical trials have been analyzed to establish the safety of reducing low density lipoprotein cholesterol (LDL-C) levels below currently recommended minimum targets in hypercholesterolemic patients. Safety data for atorvastatin-treated patients with at least one LDL-C value 80 mg/dl (2.1 mmol/l) (n=319) during treatment (mean LDL-C level throughout treatment was 91 mg/dl [2.4 mmol/l]) were compared to those from all atorvastatin-treated patients (n=2502) and patients treated with lovastatin, simvastatin or pravastatin (n=742). The frequency of treatment-associated adverse events (AEs) in the atorvastatin LDL-C 80 mg/dl (2.1 mmol/l) subgroup (24%) was comparable to the frequencies observed for all atorvastatin-treated patients (20%) and for patients receiving the other statins (24%). Patient withdrawals due to treatment-associated AEs (constipation, dyspepsia and flatulence being the most common) were consistent and low across treatment groups. No treatment-associated deaths occurred in any group. Safety data for 21 atorvastatin-treated patients with LDL-C 50 mg/dl (1.3 mmol/l) were also analyzed and found to be similar to all atorvastatin-treated patients and patients treated with the other statins. While recognizing the short-term nature of the data (all patients who received atorvastatin were treated for 1 year and approximately 30% were treated for 6 months), this analysis suggests that reducing LDL-C levels below 80 (2.1 mmol/l) or 50 mg/dl (1.3 mmol/l) with atorvastatin does not alter its safety profile, as measured by frequency of AEs, which remains similar to those of other statins. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Statins; Low cholesterol; LDL-C; Safety; Hypercholesterolemia 1. Introduction * Corresponding author. Tel.: +1-734-622-5243; fax: +1-734-622-7334. Hypercholesterolemia is now recognized as being a major causal factor in the development of coronary heart disease (CHD). Clear evidence, based on epidemiological and observational studies, shows that individuals with elevated plasma concentrations of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) and with reduced concentrations of high density lipoprotein cholesterol (HDL-C), are at increased risk of CHD [1 4]. By reducing the plasma levels of LDL-C, either through diet modification and/or with pharmacological intervention, the risk of cardiovascular morbidity and mortality can be significantly reduced. In particular, a number of studies have shown that the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) to lower LDL-C levels is associated with clinical benefits in terms of decreased risk of cardiovascular events [5 9]. As a result of these studies, guidelines set by the US National Cholesterol Education Program (NCEP) [10] and new guidelines from the Second Joint Task Force of European and other Societies on Coronary Prevention (Joint European Societies) [11] recommend statins as a first-line drug therapy for the management of hypercholesterolemia. The introduction of more effective lipid-lowering agents, such as the statins, has meant recommended minimum LDL-C targets, such as those set out in the NCEP guidelines ( 100 mg/dl [2.6 mmol/l] for patients with established CHD [10]), are more likely to be achieved. Although the degree of CHD risk reduction obtained by reducing LDL-C levels beyond these targets is not certain, the recent Post Coronary Artery 0021-9150/00/$ - see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0021-9150(99)00294-4

124 R.G. Bakker-Arkema et al. / Atherosclerosis 149 (2000) 123 129 Bypass Graft trial, where LDL-C levels were reduced below 100 mg/dl (2.6 mmol/l), suggests there are significant clinical benefits [12]. An ongoing trial, the Treating to New Targets study, is designed to clarify this point further by comparing major cardiovascular end-points in two patient groups: one that achieves an average LDL-C of approximately 100 mg/dl (2.6 mmol/l) and one that achieves an average LDL-C of approximately 75 mg/dl (1.9 mmol/l) [13]. Atorvastatin is a relatively recent addition to the statin class, which has been shown to reduce LDL-C levels by up to 61% from baseline [14]. Despite this aggressive lipid-lowering, studies have shown that atorvastatin has a similar safety profile to other statins and is well tolerated in a variety of patient populations including elderly patients, women and patients with type 2 diabetes [15,16]. As available safety data from patients with LDL-C levels below 100 mg/dl is scarce, this subgroup analysis of data pooled from 21 atorvastatin clinical trials has been conducted to establish whether reducing LDL-C levels below 100 mg/dl (2.6 mmol/l) compromises safety in dyslipidemic patients. 2. Methods 2.1. Pooled studies database Data were pooled from 21 clinical trials that completed as of 1 January 1996. The vast majority of these studies have been published, and the data were all that the authors had access to there was no bias, selective reporting or omission of key data. In the majority of trials (15/21), eligible patients had hypercholesterolemia (Fredrickson type IIa) with LDL- C levels 135 mg/dl (3.5 mmol/l) and triglyceride (TG) levels 200 mg/dl (2.3 mmol/l) or mixed dyslipidemia (Fredrickson type IIb) with LDL-C levels 135 mg/dl (3.5 mmol/l) and TG levels 200 mg/dl (2.3 mmol/l); the remaining studies included patients with other types of dyslipidemia including homozygous familial hypercholesterolemia, hypertriglyceridemia, or type 2 diabetes. 2.2. Patient selection 2.2.1. Inclusion criteria Most trials included men and postmenopausal or surgically sterilized women of any race, aged between 18 and 80 years of age and with body mass index (BMI) upper limits ranging from 30 to 38 kg/m 2. Women of childbearing potential were allowed entry provided they planned not to become pregnant during the course of the study and were practicing a reliable method of birth control deemed acceptable by the investigator. 2.2.2. Exclusion criteria Patients with significant renal dysfunction, nephrotic syndrome, dysproteinemias or uncontrolled hypertension were generally excluded from participation in the studies, as were patients suffering from metabolic or endocrine diseases known to influence serum lipid or lipoprotein levels. Patients were also excluded from studies if they were pregnant or nursing, or if they had active liver disease or hepatic dysfunction defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than a range from 1.5 times to three times the upper limit of normal, depending on the nature of the study and possible risk-benefit relationships. A current or recent history of substance abuse, including consumption of excessive amounts of alcohol, or the taking of any prohibited medication, precluded patients from entering studies. Prohibited medication, unless it was a study treatment, included niacin, probucol, psyllium ( 2 tablespoons/day), fibrates, bile acid sequestrants, fish oils, or any other HMG-CoA reductase inhibitors. It was also a requirement that patients did not receive active medication in another clinical study concurrently or within 30 days of screening except for atorvastatin extension studies. Some studies excluded patients with a history of myocardial infarction, coronary angioplasty, coronary artery bypass graft, or severe or unstable angina pectoris within the 3 months prior to study entry. 2.3. Study designs After screening, most studies (15/21) entered patients into a dietary baseline phase of 4 6 weeks. During this period, patients followed the US National Institute of Health s (NIH) NCEP Step 1 diet, which limits cholesterol to less than 300 mg/day, saturated fats to less than 10% of total calories and total fat to less than 30% of total calories. This allowed values for specific lipid parameters to be established while maintaining dietary intervention and enabled the exclusion of patients whose lipid levels could be managed effectively by alterations to their diet alone. Upon completion of the baseline phase, qualifying patients were allocated to study treatment. The majority of studies (18/21) were randomized, blinded, and well controlled. Only three studies, involving a total of 52 patients (the majority with homozygous or heterozygous familial hypercholesterolemia), were randomized and uncontrolled. Eleven studies had a parallel group design in which patients maintained a single dosage level of treatment throughout the trial. Ten studies were dose titration or treatment change studies in which patients received a fixed dosage of treatment during the first 4 16 weeks of the study, after which the study medication dosage was doubled or treatment was changed.

R.G. Bakker-Arkema et al. / Atherosclerosis 149 (2000) 123 129 125 The majority of studies compared the efficacy and safety of atorvastatin with other statins (simvastatin, lovastatin, pravastatin). The primary endpoint in most studies was the change from baseline of various lipid parameters, predominantly LDL-C. 2.4. Treatment with statins Patients received doses of atorvastatin 2.5 80 mg/ day (only 1% of patients received doses below 10 mg/day), lovastatin 20 80 mg/day, simvastatin 10 40 mg/day and pravastatin 20 40 mg/day. Active treatment periods ranged from 4 to 52 weeks. 2.5. E aluation of safety The majority of patients had lipid levels recorded every 6 weeks (minimum 2 weeks; maximum 12 weeks). Safety data for atorvastatin-treated patients with at least one LDL-C value 80 mg/dl (2.1 mmol/l) at any point in the treatment phase of the study were compared to those from all atorvastatin-treated patients and from patients treated with lovastatin, simvastatin or pravastatin. In addition, safety data for atorvastatintreated patients with at least one LDL-C value 50 mg/dl (1.3 mmol/l) were also analyzed. Patients may have received concomitant colestipol. In the evaluation of safety, 17 of the 21 studies were multicenter trials that used central laboratories and the remaining four were single-center trials that used local laboratory facilities. For each study, the designated laboratory determined the normal range for laboratory parameters. Evaluations were performed on fasting (minimum of 12 h) venous blood samples drawn 6 18 h post-dosing. Full clinical laboratory evaluations (routine hematology and blood chemistry testing) were conducted for every patient at designated visits. Measurements of plasma AST, ALT and creatine phosphokinase (CPK) levels (plus other safety parameters) were performed more often. Physical examinations and electrocardiograms were carried out at baseline and at the end of studies. At every visit, investigators questioned patients about adverse experiences and rated them as definitely, probably, possibly, probably not, or definitely not drug related. During these assessments, investigators involved in 18 of the 21 studies were not aware of the specific drug used. Version IV of the COSTART dictionary [17] was used to convert adverse events recorded in investigators terms to preferred terms and body systems. The safety evaluation included all patients randomized to treatment. All collected information was included and missing data were not imputed. Only persistent (two consecutive measurements) transaminase values greater than 3 times the upper limit of normal and persistent CPK values greater than 10 times the upper limit of normal (with concurrent muscle pain, tenderness, or weakness) were summarized from the trials. This evaluation of safety is consistent with clinical practice. 2.6. Statistical methods The data presented is descriptive without statistical testing. Due to the low rates of adverse events with statins, the number of patients in the various subgroups was not sufficient to allow meaningful statistical testing.results 2.7. Patient characteristics The pooled dataset included data from a total of 3244 patients. Of these patients, 2502 received atorvastatin and 742 received other statins (lovastatin, n=260; simvastatin, n=310; or pravastatin, n=172). Throughout the treatment period, the 2502 atorvastatin-treated patients had an average LDL-C value of 125 mg/dl (3.2 mmol/l) with 99.8% of patients having had at least one LDL-C value over 80 mg/dl (2.1 mmol/l). A subgroup of 319 atorvastatin-treated patients had at least one LDL-C value 80 mg/dl (2.1 mmol/l) during the treatment phase of the study (20 patients received concomitant colestipol) with a mean LDL-C throughout the treatment period of 91 mg/dl (2.4 mmol/l). Therefore, in order to look at the effect of low LDL-C on the safety profile, the safety data for all atorvastatin-treated patients were compared with safety data for the atorvastatin-treated patients with at least one LDL-C value 80 mg/dl (2.1 mmol/l). In addition, safety data for the atorvastatin patients with LDL-C levels 80 mg/dl (2.1 mmol/l) were also compared to safety data for all patients treated with lovastatin, simvastatin or pravastatin. Since only 27 patients treated with these other statins achieved at least one LDL-C value 80 mg/dl (2.1 mmol/l), this group was not used as a comparator. Overall, baseline patient characteristics for the atorvastatin LDL-C 80 mg/dl (2.1 mmol/l) subgroup were similar to those of all atorvastatin-treated patients and to those of the patients treated with lovastatin, simvastatin or pravastatin (Table 1). Regarding lipid parameters, patients in the atorvastatin LDL-C 80 mg/dl (2.1 mmol/l) subgroup had a higher mean plasma TG level and a lower mean plasma LDL-C level at baseline than the total atorvastatin-treated population and patients treated with other statins. 2.8. Patient exposure Of the 2502 patients that received at least one dose of atorvastatin, 2453 (98%) received atorvastatin for at least 4 weeks, 2228 (89%) for at least 8 weeks, 1835

126 R.G. Bakker-Arkema et al. / Atherosclerosis 149 (2000) 123 129 (73%) for at least 16 weeks (4 months), 1721 (69%) for at least 6 months and 1253 (50%) for at least 1 year. The mean duration of treatment was 269 (atorvastatin), 334 (lovastatin), 314 (pravastatin), and 254 days (simvastatin). Patient exposure to the 10 80 mg/day dose range for all atorvastatin-treated patients as well as the patients with low LDL-C levels is summarized in Table 2. Each patient may have received several doses and, therefore, may have been counted more than once. It is evident that a greater proportion of patients in the all-patient group received the 10 mg starting dose of atorvastatin, with 67% of patients being exposed to atorvastatin 10 Table 1 Patient characteristics for each treatment group pooled dataset at baseline a Characteristic Atorvastatin Other statins b LDL-C 80 mg/dl (n=319) All patients (n=2502) All patients (n=742) Sex, n (%) Men 189 (59) 1386 (55) 374 (50) Women 130 (41) 1116 (45) 368 (50) Age (years) Mean 56 55 57 Median 58 57 58 Min max Race, n (%) 23 79 13 80 18 80 White 300 (94) 2346 (94) 698 (94) Black 10 (3) 86 (3) 21 (3) Other 9 (3) 70 (3) 23 (3) Mean plasma lipids, mg/dl (S.E.) LDL-C 178 (2) 208 (1) 210 (2) VLDL-C 50 (3) 39 ( 1) 38 ( 1) TC 269 (2) 293 (1) 295 (2) TG 225 (10) 192 (2) 185 (3) HDL-C 47 (1) 47 ( 1) 48 ( 1) a LDL-C, low density lipoprotein cholesterol; VLDL-C, very low density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride; HDL-C, high density lipoprotein cholesterol. b Lovastatin, n=260; simvastatin, n=310; pravastatin, n=172. Table 2 Patient exposure* by dose for the atorvastatin 10 80 mg dose range Dose (mg) Patients treated with atorvastatin, n (%) LDL-C 80 mg/dl (n=319) All patients (n=2502) 10 152 (48%) 1677 (67%) 20 71 (22%) 754 (30%) 40 78 (24%) 493 (20%) 80 86 (27%) 383 (15%) * Data reflects each dose that a patient may have received. Therefore, patients may have been counted more than once. mg at least once compared with 48% for the low LDL-C group. The proportion of patients in the low LDL-C group (27%) that was exposed to the atorvastatin 80 mg dose was almost twice that of the patients in the all-patient group (15%). 2.9. Safety Overall, the adverse event profile for the atorvastatin LDL-C 80 mg/dl (2.1 mmol/l) subgroup was similar to those for all atorvastatin-treated patients and for the patients that received lovastatin, simvastatin or pravastatin (Table 3). In each of the treatment group pooled datasets, the most common treatment-associated adverse events related to the gastrointestinal system. Constipation, dyspepsia and flatulence were reported in 4, 4 and 4%, respectively, of atorvastatin-treated patients with LDL-C 80 mg/dl (2.1 mmol/l). Comparative values for the total atorvastatin-treated population were 3, 2 and 2%, respectively, and for the patients receiving the other statins were 5, 2 and 3%, respectively. The frequency of drug-attributable adverse events in the atorvastatin LDL-C 80 mg/dl (2.1 mmol/l) subgroup (24%) was comparable to the frequencies observed for all atorvastatin-treated patients (20%) and for patients treated with lovastatin, simvastatin or pravastatin (24%) (Tables 3 and 4). Similarly, comparable frequencies were observed across all treatment group pooled datasets for serious adverse events. Values were 4% for the LDL-C 80 mg/dl (2.1 mmol/ l) subgroup, 5% for all atorvastatin-treated patients and 7% for the other statin-treated patients. Only two patients in the total atorvastatin group ( 1%), one of which was also in the atorvastatin LDL-C 80 mg/dl (2.1 mmol/l) group ( 1%), had serious adverse events which were considered by the investigators to be associated with treatment. No treatment-associated deaths occurred in any group. The number of patient withdrawals due to treatmentassociated adverse events was low and consistent across all treatment groups. The incidence of withdrawal was 3% for atorvastatin-treated patients with LDL-C values 80 mg/dl (2.1 mmol/l) and 2% for all atorvastatintreated patients. For patients receiving lovastatin, simvastatin or pravastatin, the incidence of withdrawal was 3%. A similar proportion of the atorvastatin LDL-C 80 mg/dl (2.1 mmol/l) subgroup (1.3%) experienced 3 times the upper limit of normal persistent liver transaminase elevations as in the entire atorvastatin and combined statin patient groups (0.9 and 0.7%, respectively) (Table 4). No atorvastatin-treated patients experienced clinically important elevations in CPK. One lovastatintreated patient (80 mg/day) unintentionally received concurrent erythromycin treatment and had persistent elevations in CPK levels greater than 10 times the

R.G. Bakker-Arkema et al. / Atherosclerosis 149 (2000) 123 129 127 Table 3 Frequent treatment-associated adverse events (AEs) ( 2% of patients in any treatment group pooled dataset) Adverse event Patients treated with atorvastatin (%) Patients treated with other statins a (%) LDL-C 80 mg/dl All patients All patients (n=319) (n=2502) (n=742) Constipation 4 3 5 Dyspepsia 4 2 2 Flatulence 4 2 3 Diarrhea 2 1 1 Abdominal pain 2 2 2 Headache 2 1 2 Myalgia 2 1 2 Insomnia 2 1 1 All treatment-associated AEs 24 20 24 a Lovastatin, n=260; simvastatin, n=310; pravastatin, n=172. Table 4 Overview of safety comparing each treatment group pooled dataset a Patients treated with atorvastatin (%) Patients treated with other statins b (%) LDL-C 80 mg/dl All patients All patients (n=319) (n=2502) (n=742) Treatment-associated AEs 24 20 24 Serious AEs 4 5 7 Withdrawals due to treatment-associated AEs 3 2 3 Persistent elevations in ALT or AST 3 ULN 1.3 0.9 0.7 Persistent elevations in CPK 10 ULN c 0 0 0.1 a AEs, adverse events; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CPK, creatine phosphokinase; ULN, upper limit of normal. b Lovastatin, n=260; simvastatin, n=310; pravastatin, n=172. c With concurrent muscle pain, tenderness or weakness. upper limit of normal with accompanying muscle soreness. The lovastatin treatment was interrupted and within 2 weeks CPK levels returned to normal. 2.10. Subgroup of patients whose LDL-C le els decreased below 50 mg/dl (1.3 mmol/l) Within the atorvastatin treatment group pooled dataset, a second subgroup of 21 patients was identified who each had at least one LDL-C level 50 mg/dl (1.3 mmol/l). One patient received concomitant colestipol. Baseline patient characteristics for this subgroup were generally similar to those for all atorvastatin-treated patients and patients treated with lovastatin, simvastatin or pravastatin, with the exception of the distribution of gender (81% male in the atorvastatin LDL-C 50 mg/dl [1.3 mmol/l] subgroup compared with 55 and 50% in the total atorvastatin and the other statin patient groups, respectively). The treatment-associated adverse event profile for atorvastatin-treated patients with LDL-C 50 mg/dl (1.3 mmol/l) was unremarkable and comparable with those for all patients treated with atorvastatin and for the patients treated with the other statins. The frequency of serious adverse events in the atorvastatin LDL-C 50 mg/dl (1.3 mmol/l) subgroup (5%) was the same as the frequency for all atorvastatin-treated patients (5%). No patient with an LDL-C value 50 mg/dl (1.3 mmol/l) withdrew from a study as a result of an adverse event or experienced persistent liver transaminase elevations greater than 3 times the upper limit of normal or persistent CPK elevations more than 10 times the upper limit of normal. 3. Discussion An aggressive lipid-lowering strategy features in most of the official guidelines for the secondary prevention of CHD. This includes current NCEP [10] and new Joint European Societies [11] guidelines, which have established aggressive targets that are considered minimum levels. In patients in whom these targets are not achievable by lifestyle changes and dietary modification alone, the use of lipid-lowering drugs is recommended.

128 R.G. Bakker-Arkema et al. / Atherosclerosis 149 (2000) 123 129 Previous analyses have shown that the overall safety profile of atorvastatin (i.e. associated adverse events, serious adverse events, deaths, and clinical laboratory values) was unaffected by dose, while transaminase elevations, as with other compounds in this class, were dose-dependent. In fact, it is well recognized that all statins when dosed at 80 mg have an incidence in transaminase elevations of approximately 2%. This current pooled studies database analysis was intended to determine whether aggressive LDL-C lowering to values below 80 mg/dl (2.1 mmol/l) was associated with any changes to the safety profile normally observed with atorvastatin therapy. Atorvastatin-treated patients having at least one LDL-C measurement 80 mg/dl (2.1 mmol/l) with a mean treatment LDL-C of 91 mg/dl (2.4 mmol/l) exhibited similar treatment-associated adverse event profiles compared with the entire atorvastatin-treated patient population and patients treated with lovastatin, simvastatin or pravastatin. The frequencies of serious adverse events and withdrawals were also similar across the three patient groups. Moreover, atorvastatin-treated patients with LDL-C levels 50 mg/dl (1.3 mmol/l) also had similar treatment-associated adverse event profiles and comparable rates of serious adverse events and withdrawals as the entire atorvastatin-treated patient population and patients treated with these other statins. Treatment with statins has been associated in some patients with increases in serum liver transaminases and with myositis. In this analysis, the number of patients experiencing persistent elevations in AST and ALT was low for all treatment groups ( 1.5%) and was not significantly increased by treating patients to lower LDL-C levels. The slight increase in transaminase elevations in the low LDL-C group is a reflection of a greater number of patients exposed to the higher doses. In conclusion, aggressive cholesterol-lowering therapy has been shown to significantly reduce cardiovascular risk. Clinical trials investigating the effects of atorvastatin on cardiovascular morbidity and mortality are underway. In one study, the Atorvastatin Versus Revascularization Treatments (AVERT) trial, aggressive lowering of LDL-C (mean on-treatment level was 77 mg/dl [2.0 mmol/l]) with atorvastatin in a population of stable CHD patients scheduled to undergo angioplasty, significantly delayed the time to the first ischemic event compared with those patients who received angioplasty plus usual care (a heterogeneous mix of therapies that could include lipid-lowering therapy) [18]. Furthermore, over a dose range of 10 40 mg atorvastatin has been shown to reduce LDL-C levels significantly more than other statins at milligram equivalent doses [19]. The data presented here demonstrate that despite this greater efficacy, patients on atorvastatin therapy whose LDL-C levels fall below 80 mg/dl (2.1 mmol/l), or even below 50 mg/dl (1.3 mmol/l), do not experience an increase in adverse events or reduced tolerability compared with patients whose LDL-C levels remain 80 mg/dl (2.1 mmol/l). These results indicate that previously reported concerns that low cholesterol levels may be hazardous to health are illfounded [20 23]. It should be recognized that the treatment of hypercholesterolemia in CHD patients requires chronic statin therapy and that the current data are short term all patients who received atorvastatin were treated for 1 year and approximately 30% were treated for 6 months. However, these preliminary findings are highly encouraging and suggest that the use of atorvastatin to lower lipids well beyond current NCEP or the Second Joint European Societies recommendations does not compromise safety. Acknowledgements The authors would like to acknowledge and thank Nancy Fish, BS, for her technical expertise and Matthew Smith, PhD, for his assistance in the preparation of the manuscript. This study was supported by Parke-Davis Pharmaceutical Research. 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