Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being treated in general practice

Atherosclerosis 149 (2000) 199 205 www.elsevier.com/locate/atherosclerosis Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being treated in general practice P.J. Barter a, *, R.C. O Brien b a Cardio ascular In estigation Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia b Monash Medical Centre, Clayton, Vic., Australia Received 22 April 1999; received in revised form 6 September 1999; accepted 22 September 1999 Abstract A total of 1028 hypercholesterolaemic men and women aged 18 75 participated in an open label, randomised, parallel group, 6-month treatment-to-target study conducted in 240 general practices throughout Australia. The study compared atorvastatin monotherapy with simvastatin monotherapy or, if necessary, with the combination of simvastatin and cholestyramine in terms of their abilities to achieve a plasma total cholesterol target of 5.0 mmol/l. The initial daily dose of each drug was 10 mg. If the target was not achieved, the dose was doubled at 6 week intervals to a maximum daily dose of 80 mg atorvastatin or 40 mg simvastatin, with the simvastatin supplemented if necessary with 4 g cholestyramine. The percentage of patients achieving the target at 10 and 20 mg doses of atorvastatin were comparable to 20 and 40 mg of simvastatin, respectively. Despite relatively high baseline levels of plasma total cholesterol (mean levels of 7.41 and 7.31 mmol/l in the atorvastatin and simvastatin groups, respectively) the majority of patients in each group achieved the plasma total cholesterol target of 5.0 mmol/l. Treatment with atorvastatin achieved the target in 83% of patients, while simvastatin (or simvastatin plus cholestyramine) achieved the target in 66% of the patients (P 0.005). The target was achieved with 10 mg atorvastatin in 38% of patients and with 10 mg simvastatin in 26% of cases (P 0.005). In patients whose baseline cholesterol levels were between 5.6 and 6.5 mmol/l, 95% of the atorvastatin group and 86% of the simvastatin group reached the target. Even with baseline cholesterol levels between 7.6 and 8.5 mmol/l, the target was reached in 78% of the atorvastatin group and 61% of the simvastatin group. It is thus realistic for general practitioners to expect the majority of their at risk patients to achieve target plasma cholesterol levels that have been shown in population studies to be associated with relatively low rates of coronary heart disease. These targets are achieved in significantly more patients and at lower mg doses with atorvastatin than simvastatin. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atorvastatin; Simvastatin; Hypercholesterolaemia; General practice 1. Introduction The results of large scale drug intervention trials have demonstrated beyond all reasonable doubt that cholesterol lowering reduces the risk of coronary events in a wide range of subjects [1 4]. Benefit has been clearly shown in patients with [1,3] and without [2,4] prior coronary disease. A reduction in coronary events has been demonstrated not only in hypercholesterolaemic subjects but also in those with baseline LDL cholesterol levels as low as 3.2 mmol/l [4]. * Corresponding author. Tel.: +61-8-82240620; fax: +61-8- 82225608. E-mail address: pbarter.medicine.edu.au (P.J. Barter) A recent meta-analysis concluded that virtually all of the cardiovascular benefit derived from the use of cholesterol lowering drugs can be explained by their cholesterol lowering properties [5]. Since the magnitude of the reduction in coronary events is proportional to the amount of cholesterol lowering and the fact that coronary risk in treated and non-treated patients with equivalent cholesterol levels is comparable [6], there is a growing consensus that cholesterol levels in high risk patients should be reduced to target levels associated with low rates of coronary heart disease [7]. Despite this, a substantial proportion of patients at high coronary risk do not receive lipid-lowering therapy [8] and of those receiving therapy, many do not achieve recommended targets [8]. 0021-9150/00/$ - see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0021-9150(99)00402-5

200 P.J. Barter, R.C. O Brien / Atherosclerosis 149 (2000) 199 205 The present study was conducted to assess the feasibility of achieving a target plasma cholesterol level of 5.0 mmol/l in hypercholesterolaemic men and women treated in a primary care setting. The therapies used were atorvastatin over a dose range of 10 80 mg daily, simvastatin at a dose of 10 40 mg daily or simvastatin 40 mg/day plus cholestyramine 4 g/day. 2. Methods 2.1. Design The study was conducted throughout Australia in 240 general practices, each of which recruited at least three patients. The study was designed to compare atorvastatin monotherapy with simvastatin monotherapy or with the combination of simvastatin and cholestyramine. A total of 1028 hypercholesterolaemic men and women aged 18 75 participated in an open label, randomised, parallel group, optimal-titration and treatment-to-target study of 6 months duration. Enrolment commenced in November 1996, with the last patient completed in January 1998. The primary end point was the percentage of patients achieving a plasma total cholesterol target of 5.0 mmol/l as recommended (at the time of commencing the study) by the National Heart Foundation of Australia for subjects at increased coronary risk. Other end points included the percentage change from baseline in plasma total cholesterol, HDL cholesterol, LDL cholesterol and plasma triglyceride during treatment with these drugs. For inclusion, patients needed to meet the eligibility criteria for treatment with an HMG-CoA reductase inhibitor as defined by the Australian guidelines for the use of these agents at the time the study commenced. This meant that the baseline plasma total cholesterol was 5.5 mmol/l in the highest risk category of patient (those with existing coronary or peripheral vascular disease), 6.5 mmol/l in those with at least one major risk factor (hypertension, smoking, diabetes mellitus, positive family history of premature coronary disease, HDL cholesterol 1.0 mmol/l) or 7.5 mmol/l in those with no other risk factors. Patients were either not being treated with lipid regulating drugs or, if they were, they were inadequately controlled (plasma total cholesterol 5.0 mmol/l) on their existing medication. Those on prior lipid lowering medication had a one month washout period before entering the study. 48.3% of those randomised to take atorvastatin and 49.3% of those randomised to take simvastatin had been on prior lipid lowering therapy. There were no differences between the two groups in terms of the specific prior agents that had been taken. Eligible patients must have been adhering to the dietary recommendations of the National Heart Foundation of Australia for at least a month before randomisation. Patients were excluded if they had secondary causes of hypercholesterolaemia. They were also excluded if they had clinical symptoms of coronary heart disease in the previous three months, if the plasma triglyceride exceeded 4.0 mmol/l, if they had active liver disease (AST or ALT 1.5 time ULN), a CK 3 times the ULN, known hypersensitivities to HMGCoA reductase inhibitors or any other condition which, in the opinion of the investigators, may have compromised the patient s safety or successful participation of the study. Subjects were randomised 2:1 to atorvastatin or simvastatin treatment arms. The reason for the 2:1 randomisation was to increase the experience regarding safety and tolerance of atorvastatin which was not registered for use in Australia at the time of commencing the study. The initial dose of each drug was 10 mg. The dose was doubled at 6 week intervals if the target had not been reached. The maximum dose of atorvastatin was 80 mg. The maximum dose of simvastatin was 40 mg, supplemented if necessary with 4 g cholestyramine. Simvastatin 40 mg/day was the maximum dose recommended for use in Australia at the time of study commencement. The addition of 4 g cholestyramine (taken in the morning) to 40 mg simvastatin (taken in the evening) was the recommended best practice in Australia at the time of commencing the study. Once a patient achieved the plasma total cholesterol target of 5.0 mmol/l, the dose remained constant until the end of the study at week 24; in these patients there was no further upward dose titration even if the plasma cholesterol rose above 5.0 mmol/l at subsequent visits. The general practitioners in each region were supported by specialist advisers based in teaching hospitals. The protocol was approved by the ethics committees of these teaching hospitals. 2.2. Clinical and laboratory procedures Dietary compliance was monitored by the attending general practitioner. Drug compliance was assessed by tablet count at each titration and at the conclusion of the study. Plasma cholesterol and triglyceride were assayed enzymatically [9,10] and HDL cholesterol was assayed after polyanion precipitation of the other lipoproteins [11]; all samples were collected after an overnight fast. There was no cross standardisation between the measuring laboratories, although all five of the laboratories (a single central laboratory was used in each of the Australian states) met the performance standards of a national standardisation program. LDL cholesterol was calculated according to the Friedewald equation [12]. All patients were monitored for adverse events clinically and by routine blood biochemistry, liver function tests, creatine kinase and haematology.

P.J. Barter, R.C. O Brien / Atherosclerosis 149 (2000) 199 205 201 2.3. Statistical methods The primary efficacy analysis was the percentage of patients achieving the plasma total cholesterol target 5.0 mmol/l by 6 and 24 weeks and the mean percentage change in plasma total cholesterol at these time points. A linear regression model (for percentage change from baseline) or logistic regression model (for percentage of patients achieving target) was used to test for differences between the atorvastatin and simvastatin groups. Patients were included in the intention to treat analysis if they had an evaluable baseline and had received at least one dose of the study medication and a laboratory assessment after randomisation. When lipid data for any of the 6 week evaluations were missing, the last evaluable observation was carried forward for the analysis of percentage change from baseline. The secondary efficacy analysis was the mean percentage change in LDL cholesterol, HDL cholesterol and plasma triglyceride. 3. Results The baseline characteristics of the study populations are presented in Table 1. The subjects were well matched for gender, race, age, body mass index, alcohol usage, smoking and the presence of coronary heart disease. They were also well matched for lipid levels. The baseline plasma total cholesterol ranged from 5.2 to 13.1 mmol/l, with mean values of 7.41 and 7.31 mmol/l, respectively, in the atorvastatin and simvastatin groups (Table 2). Table 1 Baseline characteristics Atorvastatin (n=691) Simvastatin (n=337) Gender (%) Male/Female 49.9/50.1 53.8/46.2 Race (%) Caucasian 96.1 97.3 Other 3.9 2.7 Age (years) Median 57.7 56.5 Mean SD 57.1+10.9 56.2+10.4 Range 22 77 20 77 BMI (kg/m 2 ) Mean SD 27.9+4.4 28.4 4.5 Alcohol usage Yes 36.2 38.8 (%) Smoking (%) Never 47.7 53.7 Current 18.7 15.7 Past 33.7 30.5 Exhisting CHD (%) 19.1 22.8 3.1. Changes in plasma lipid concentrations The concentrations of plasma total cholesterol, LDL cholesterol, HDL cholesterol and plasma triglyceride at each visit are presented in Table 2. The mean doses of atorvastatin and simvastatin during the preceding 6 weeks are also shown. Both drugs were highly effective in reducing the concentrations of plasma total and LDL cholesterol, although the reductions achieved with atorvastatin were significantly greater than with equal mg doses of simvastatin. The reductions in total cholesterol, LDL cholesterol and triglyceride at week 6 were greater with 10 mg atorvastatin than 10 mg simvastatin. This superiority of atorvastatin was still apparent at week 24, although the difference in triglyceride levels at 24 weeks may have reflected a cholestyramine-induced increase in triglyceride in the simvastatin group. Each drug raised the level of HDL cholesterol to a similar extent. 3.2. Percentages of subjects achie ing a target plasma total cholesterol of 5.0 mmol/l A substantial proportion of patients in each group achieved the target plasma total cholesterol of 5.0 mmol/l (Fig. 1). Treatment with atorvastatin across the dose range of 10 80 mg per day achieved this target in 83.1% of patients, while 10 40 mg simvastatin (or simvastatin 40 mg plus cholestyramine) achieved the target in 65.9% of the patients (Fig. 1). At the 10 mg starting doses, significantly more patients achieved target with atorvastatin (38.0%) than with simvastatin (25.5%) (P 0.001). Throughout the study, when given in equal mg doses, atorvastatin was sign)ficantly more effective than simvastatin at treating patients to target (P 0.001). Predictably, the proportion of subjects achieving the target with either drug was influenced by the baseline plasma total cholesterol level (Table 3). In those with baseline cholesterol levels between 5.2 and 6.5 mmol/l, 95% of the atorvastatin group and 87% of the simvastatin group achieved the target plasma total cholesterol of 5.0 mmol/l. When the baseline cholesterol was between 6.5 mmol/l and 7.5 mmol/l, the target was achieved in 90% of the atorvastatin group and in 72% of those taking simvastatin (including those receiving simvastatin plus cholestyramine). Even with baseline levels between 7.6 mmol/l and 8.5 mmol/l and between 8.6 and 9.5 mmol/l, the percentage of patients achieving target was 78 and 68%, respectively, in the atorvastatin group and 61 and 19%, respectively, in the simvastatin group. With baseline levels 9.5 mmol/l, the target was achieved in 27% (9 of 33) of patients on atorvastatin and in 8% (one of 12) of patients in the simvastatin group. A substantial proportion of patients, including some with baseline levels up to 8.5 mmol/l, achieved the

202 P.J. Barter, R.C. O Brien / Atherosclerosis 149 (2000) 199 205 Table 2 Percent change in plasma lipids during treatment Baseline level (mmol/l) Week 6 Week 12 Week 18 Week 24 Percent change Total cholesterol Atorvastatin Mean 7.41 27.9 b 30.8 31.9 32.2 b 1.14 10.3 9.9 0.5 11.9 Median 7.30 28.8 31.6 33.3 33.8 Simvastatin Mean 7.31 23.4 25.8 28.1 27.1 1.09 9.3 10.1 10.1 11.6 Median 7.10 23.3 26.7 28.8 28.8 LDL cholesterol Atorvastatin Mean 5.22 37.0 b 40.8 42.3 42.8 b Group SD 1.10 13.2 12.3 13.1 15.2 Median 5.07 38.4 42.9 43.9 44.7 Simvastatin Mean 5.18 32.3 34.7 38.8 38.0 1.02 12.0 13.0 13.0 14.9 Median 5.04 32.5 35.5 40.3 39.5 HDL cholesterol Atorvastatin Mean 1.23 4.5 ns 5.4 6.7 8.4 ns 0.37 18.2 18.3 18.9 21.1 Median 1.20 0 0 6.3 7.6 Simvastatin Mean 1.21 4.3 6.6 9.7 10.2 0.35 15.6 17.6 19.0 18.1 Median 1.16 0 7.1 8.3 9.1 Triglyceride Atorvastatin Mean 2.10 13.7 b 16.6 18.8 19.5 b 0.84 36.2 24.8 34.7 35.8 Median 2.00 18.2 20.0 23.3 25.0 Simvastatin Mean 2.02 5.1 12.6 12.5 9.0 0.78 37.9 33.3 37.1 33.6 Median 1.90 11.1 17.6 20.0 14.3 Drug dose (mg per day) Atorvastatin Mean 10 16.0 24.1 32.5 4.9 13.2 26.6 Simvastatin Mean 10 17.4 28.7 28.6+C a Group SD 4.4 13.0 13.0 a C denotes cholestyramine which was added (in a dose of 4 g) to 40 mg simvastatin in 37% of the subjects. b P 0.001 for difference between atorvastatin and simvastatin groups. ns Difference between atorvastatin and simvastatin groups not statistically significant. target on the lowest 10 mg dose of both atorvastatin (38.0%) and simvastatin (25.5%). 3.3. Upward drift of plasma cholesterol in subjects maintained on 10 mg of each drug According to the study design, once the plasma total cholesterol reached the target of 5.0 mmol/l, the dose of drug was not further titrated for the duration of the 24 week study, even if the level of plasma total cholesterol rose above 5.0 mmol/l at subsequent visits. As is shown in Fig. 2, there was a progressive increase in plasma total cholesterol concentrations from weeks 6 to 24 in subjects who remained on the 10 mg dose of each drug. In some cases, patients who had reached the target plasma cholesterol level after 6 weeks on the 10 mg dose were no longer at target when assessed at later visits (Fig. 2). The plasma total cholesterol target of 5.0 mmol/l was achieved after 6 weeks on the 10 mg daily dose of atorvastatin in 262 subjects; this accounted for 38.0% of the total atorvastatin group. When these 262 subjects were tested at weeks 12, 18 and 24 the number of patients still at target were 186 (26.9% of the total group), 189 (27.4%) and 174 (25.2%) respectively (Fig. 2). After 6 weeks on 10 mg simvastatin the target was reached in 86 subjects (representing 25.5% of the total simvastatin group). Following these 86 subjects as a cohort, the numbers still at target at weeks 12, 18 and 24 fell to 54 (16.0% of the total simvastatin group), 52 (15.4%) and 39 (11.6%), respectively. This upward drift in plasma cholesterol while remaining on a constant dose of drug may reflect a regression towards the mean, although the fact that the upward drift was progressive when measured at weeks 12, 18 and 24 suggests that

P.J. Barter, R.C. O Brien / Atherosclerosis 149 (2000) 199 205 203 laboratory result at some time during the treatment period. In 31 of the atorvastatin group (4.4%) and eigth of the simvastatin group (2.3%), liver function tests (ALT, AST or GGT) were reported as an adverse event or a clinically significant elevation at some time during the treatment period. Differences between the frequency of adverse events in the two treatment groups were not statistically significant. 4. Discussion Fig. 1. Cumulative percentage of patients meeting the target plasma total cholesterol of 5.0 mmol/l with increasing doses of atorvastatin and simvastatin. The values are expressed as percentages of the total groups: n=691 for the atorvastatin group and 337 for the simvastatin group. The highest dose of atorvastatin was 80 mg, while the highest dose in the simvastatin group was 40 mg simvastatin plus 4 g cholestyramine (denoted C). *, Indicates P 0.001 for the difference between the two groups. other factors such as a declining compliance with either drug consumption or adherence to dietary recommendations may have contributed. 3.4. Safety data Both agents were well tolerated, with 92.6% of the atorvastatin group and 95.0% of the simvastatin group completing the 24 week study. Treatment-related adverse events (most commonly gastrointestinal and headache) were reported in 7% of the atorvastatin group and 7% of the simvastatin group. In 17 of the patients in the atorvastatin group (2.4%) and in eight of those in the simvastatin group (2.3%), the CK level was reported as an adverse event or a clinically significant This study demonstrates that it is quite realistic to aim at achieving a plasma total cholesterol target of 5.0 mmol/l in hypercholesterolaemic patients being treated in general practice. Atorvastatin-treated patients achieved the target at lower doses and in a greater proportion of patients than was achieved with simvastatin, although the target was realised in a majority of the patients in both the atorvastatin and simvastatin arms of the study. As predicted from previous reports [13 15], when the two agents were compared at equal mg doses, atorvastatin was significantly more effective than simvastatin at achieving the cholesterol target. The response to both atorvastatin and simvastatin varied widely from patient to patient. Some patients with baseline plasma cholesterol levels as high as 8.5 mmol/l achieved the target level of 5.0 mmol/l with the lowest 10 mg dose of each drug. Conversely, there were subjects with baseline levels below 6.5 mmol/l who failed to reach the target on the highest dose of either drug (Table 3). At least part of this variability may have been the consequence of differences in compliance, although there may also be individual differences in response to this class of drug. It will be of interest to determine whether responsiveness can be predicted by Table 3 Percentage of patients achieving the target plasma total cholesterol (TC) of 5.0 mmol/l with increasing drug doses: effects of baseline TC levels Baseline plasma TC (mmol/l) Treatment group Drug dose(mg/day) 10 10 20 10 40 10 80 10 40+C a Percentage of patients at target 5.2 6.5 Atorva (n=147) 71 86 90 95 Simva (n=78) 54 73 82 87 6.6 7.5 Atorva (n=269) 43 68 84 90 Simva (n=144) 27 47 67 72 7.6 8.5 Atorva (n=180) 21 43 63 78 Simva (n=72) 7 26 49 61 8.6 9.5 Atorva (n=62) 6 24 47 68 Simva (n=31) 0 6 13 19 9.5 Atorva (n=33) 3 3 12 27 Simva (n=12) 0 0 0 8 a C denotes cholestyramine which was added (in a dose of 4 g) to 40 mg simvastatin.

204 P.J. Barter, R.C. O Brien / Atherosclerosis 149 (2000) 199 205 Fig. 2. Patients achieving the plasma total cholesterol target of 5.0 mmol/l after 6 weeks on 10 mg of atorvastatin or simvastatin. The cohorts of subjects achieving the target after 6 weeks on the 10 mg dose of the two drugs (and who thus remained on this dose for the duration of the study) were tracked. The mean plasma total cholesterol (TC) levels at each visit in this cohort are shown in the upper sections of each panel. The lower sections of each panel show the percentages of patients at target after 6 weeks on the 10 mg doses of atorvastatin and simvastatin. The lower sections also show that despite continuing to take the drugs at the same dose, there is a decline in the percentages remaining at target. any of the parameters measured in the subjects in this study. It is clear that some patients are highly responsive to statins and that these drugs should always be initiated at their starting dose and only be titrated up if necessary to achieve the required target level. In addition, it is apparent that there is a need to retest after the target has been achieved. As shown in Fig. 2, of the 262 subjects who achieved the plasma total cholesterol target of 5.0 mmol/l by week 6 on the 10 mg dose of atorvastatin, only 174 were still at target by week 24. Similarly, of the 86 subjects at target by week 6 on 10 mg simvastatin, only 39 remained at target by week 24. Thus, having reduced the plasma cholesterol to below 5.0 mmol/l, it should not be assumed that the target will necessarily be maintained. The explanation for the upward drift in plasma cholesterol while remaining on a constant dose of drug is not known. In part, it may reflect a regression towards the mean, although the fact that the upward drift was progressive when measured at weeks 12, 18 and 24 indicates that other factors such as a declining compliance with either drug consumption or adherence to dietary recommendations may have contributed. However, regardless of the explanation, it is clear that the achievement of a target on one occasion does not necessarily indicate that the target will be sustained. Once a target is achieved, it is important that the cholesterol level be retested at 3 6 month intervals to ensure that the target level is maintained. Many guidelines for the use of lipid lowering drugs recommend target levels of LDL cholesterol in addition to plasma total cholesterol targets. In the present study, the changes in plasma total cholesterol were largely a reflection of changes in LDL cholesterol (Table 2). Furthermore, the percentages of patients whose LDL cholesterol fell below 3.0 mmol/l on the various doses of the two agents were similar to the percentages achieving the plasma total cholesterol target of 5.0 mmol/l (result not shown). Both atorvastatin and simvastatin decreased the plasma triglyceride to a limited extent (Table 2). As reported previously [13 15], the triglyceride reduction with atorvastatin was significantly greater than with simvastatin. Each drug also promoted a modest increase in HDL cholesterol, although the changes were not significantly different between the two groups. In conclusion, this study confirms both atorvastatin and simvastatin as highly effective cholesterol-lowering agents. Each is able to achieve a plasma total cholesterol target of 5.0 mmol/l in a large proportion of hypercholesterolaemic patients being treated in a primary care setting. The study also supports the superiority of atorvastatin in lowering total and LDL cholesterol over simvastatin when taken in equal mg doses. Thus, general practitioners can now treat their at risk patients in the realistic expectation that most will achieve target levels of plasma total (and LDL) cholesterol that have been shown in population studies to be associated with low rates of coronary events.

P.J. Barter, R.C. O Brien / Atherosclerosis 149 (2000) 199 205 205 Acknowledgements This study was sponsored by Parke Davis (Australia) and Pfizer (Australia). We are particularly grateful to the general practitioners who volunteered their time and their patients to the AAA Study (Australian Atorvastatin Assessment) and to the study nurse coordinators who made AAA possible. The specialist advisers are also gratefully acknowledged (see Appendix). Appendix A. Specialist advisers C. Aroney, Prince Charles Hospital, Qld; G. Aroney, Gold Coast Hospital, Qld; J. Best, St. Vincent s Hospital, Vic.; D. Colquhoun, Wesley Medical Centre, Qld; G. Conner, Liverpool Hospital, NSW; M. d Emden, Royal Brisbane Hospital, Qld; G. Fulcher, Royal North Shore, NSW; L. Howes, St. George Hospital, NSW; G. Jerums, Austin Hospital, VIC; H. Krum, Alfred Hospital, VIC; L. Simons, St. Vincent s Hospital, NSW; G. Tallis, Flinders Medical Centre, SA; G. Watts, Royal Perth Hospital, WA; T. Welborn, Sir Charles Gairdner Hospital, WA; G. Wittert and R. Yeend, Royal Adelaide Hospital, SA. References [1] The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet 1994;344:1383 89. [2] Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Eng J Med 1995;333:1301 7. [3] Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Eng J Med 1996;335:1001 9. [4] Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998;279:1615 22. [5] Gould AL, Rossouw JE, Santanello NC, et al. Cholesterol reduction yields clinical benefit impact of statin trials. Circulation 1998;97:946 52. [6] Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994;308:367 73. [7] Multiple Risk Factor Intervention Trial Research Group. Mortality rates after 10.5 years for participants in the Multiple Risk Factor Intervention Trial, JAMA 1990;263:1795 1801. [8] Hoerger TJ, Bala MV, Bray JW, et al. Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible US adults. Am J Cardiol 1998;82:61 5. [9] Allain CC, Poon LC, Chan CSG, et al. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470 5. [10] Bucolo G, David H. Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem 1973;19:476 82. [11] Burstein M, Scholnick HR, Morfin R. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res 1970;11:583 95. [12] Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without the use of the ultracentrifuge. Clin Chem 1972;18:499 502. [13] Jones P, Kafonek S, Laurora I, et al. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (The CURVES Study). Am J Cardiol 1998;81:582 7. [14] Dart A, Jerums G, Nicholson G, et al. A multicenter, doubleblind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol 1997;80:39 44. [15] Simons LA. Comparison of atorvastatin alone versus simvastatin+cholestyramine in the management of severe primary hypercholesterolaemia (The Six Cities Study). Aust NZ J Med 1998;28:327 33..