Screening experience and baseline characteristics in the West of Scotland coronary prevention study

Screening Experience and Baseline Characteristics in the West of Scotland Coronary Prevention Study The WOSCOPS

Study Group*

The West of Scotland Coronary Prevention Study (WOSCOPS) is a randomized, double-blind, placebocontrolled trial of pravastatin in a primary prevention context. The primary end point of the trial is definite coronary arte disease (CAD) death and/or nonfatal acute myocar 7 ial infarction. This study describes the baseline characteristics of the trial recruits and of the subjects who were screened during the recruitment process; 6,595 men, aged 45 to 64 years, with raised cholesterol levels, were randomized in equal numbers to placebo or pravastatin after initial screening of approximately 8 1,000 subjects in the West of Scotland. With the exception of cholesterol levels and history of CAD, the recruits had a similar risk factor profile and

demographic distribution to the group of screenees from which they were selected. Compared with previous primary prevention studies of cholesterol-lowering drugs, the WOSCOPS recruits are, on average, 7 to 9 years older than subjects in other trials and have average total cholesterol levels 0.5 mmol/L (19.4 m /dl) lower than those in the Helsinki Heart Study an 8 the Li id Research ClinicsXoronary Primary Prevention Tria.P The study has achieved its initial goal of accumulating r30,OOO patient-years of randomized follow-up. Recruits had their final trial visits in the first half of 1995 and the main results will be available in the fourth quarter of 1995. (Am J Cardiol 1995;76:485-49 1)

he West of Scotland Coronary Prevention Study (WOSCOPS) is a placebo-controlled, preT vention trial of pravastatin. ‘,2 It is designed, like its pre-

are given in the study design paper.9 The study is designed to have adequate power to address the primary end point of CAD death and/or nonfatal myocardial infarction. In addition, the incidence of other important categories of events-CAD death only (whether preceded by a nonfatal myocardial infarction or not), nonfatal myocardial infarction only, and total mortalitywill be reported as secondary end points as indicated in the study design paper. Although not originally specified, results for all cardiovascular deaths and CAD death plus nonfatal myocardial infarction excluding silent myocardial infarction will be published to permit comparison with other studies. “Diagnostic enzymes and equivocal electrocardiogram” and “angiographic evidence, not previously recorded, of occlusion of a major artery with appropriate ventriculographic wall motion abnormality” have been added to the list of sufficient criteria in the definition of a definite nonfatal myocardial infarction. All subjects who provided informed consent and were allocated to randomized treatment will be included in the final analysis. The study was approved by the ethics committee of the University of Glasgow and by the ethics committees of all of the Health Board regions in which it was conducted. Data acquisition at screening visits: Data collected at the first visit included standard risk factors, such as age, systolic and diastolic blood pressures, plasma cholesterol, smoking status, alcohol, height, weight, and personal history of hypertension, hyperlipidemia, or coronary heart disease as volunteered by the patient. At the second and third screening visits, more detailed information was recorded covering smoking status, alcohol consumption, history of diabetes or hypertension, evidence of angina or intermittent claudication (as measured by the Rose questionnaire), educational attainment, and marital and employment status. At the randomization visit (visit 4), data were recorded on age, systolic and

primary

decessors,3-8 to test the primary end point of coronary artery disease (CAD) death and/or nonfatal myocardial infarction. This study describes the population of screenees and the subjects who have been randomized into the trial, and compares the randomized subjects with those who were recruited into previous coronary primary prevention studies. METHODS Overview of study design: The study design has been described elsewhere.9 Briefly, WOSCOPS is a trial of pravastatin (40 mg taken each night) versus placebo treatment in moderately hypercholesterolemic men aged 45 to 64 years. Men in this age range were invited to attend a coronary screening clinic. Invitation to a second visit was conditional on finding a total cholesterol level 26.5 mmol/L (252 mg/dl). Invitation to the randomization visit (visit 4) required a fasting low-density lipoprotein (LDL) cholesterol of 24.0 mmol/L (155 mgldl) at visits 2 and 3, and each of the conditionsLDL 24.5 mmol/L (174 mg/dl) and LDL 16.0 mmol/L (232 mg/dl)-had to be satisfied for 21 of these visits. Subjects were required to be free of significant evidence of CAD, although those with angina, who had not been hospitalized in the previous 12 months, were eligible for entry. Further details of inclusion and exclusion criteria From the University of Glasgow, Glasgow, Scoiland. This study was supported in part by the Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, Newjersey Manuscript received May 25, 1995; revised manuscript received and accepted June 13, 199.5. Address for reprints: Ian Ford, PhD, Robertson Centre for Biostatistics, Boyd Orr Butldlng, Unlverslty of Glasgow, Glasgow Gl 2 BQQ, Scotland *See

Appendix

for membershlp

committees

of the study,

PREVENTIVE

CARDIOlOGY/WOSCOPS

STUDY

485

TABLE I Comparison (n = 81 ,161) at Screening

of Data and Randomized Visit 1

Recorded Patients

for All Age-Eligible Men (n = 6,595) Measured

All Screenees Continuous variables Age ot visit 1 (yr) Systolic blood pressure (mm %I Diastolic blood

pressure

(mm Hd Weight (kg) Body mass index (kg/m21 Total cholesterol (mmol/L) bd4 Categorical variables Medical status and personal history History of hypertension History of hyperlipidemia History of angina and/or myocardial infarction Smoking status Current cigarette smoker Alcohol ~21 units 221 units

Randomized Patients

54.8 137.4

f 5.7 * 19.2

54.8 138.2

+ 5.5 * 18.5

84.9

* 10.8

85.4

* 10.5

77.5 25.8

* 12.4 * 3.7

78.5 26.1

i 11 .O zt 3.2

5.9 228

* 1.2 * 46

7.3 283

f 0.7 zt 27

16.1 2.6 11.6

14.7 4.0 4.6

36.5

36.7

80.4 19.6

82.0 18.0

Values are expressed as mean * SD or CIS percentages.

diastolic blood pressures, heart rate, height, and weight as well as current medication. Current medication was coded into general classes of drugs. All study data were processed at the study data center (Robertson Centre for Biostatistics, University of Glasgow). All laboratory samples, including the full lipoprotein profiles at visits 2 and 3, and biochemistry and hematologic screens at the third screening visit, were analyzed at a Centre for Disease Control-Certified Central Laboratory at Glasgow Royal Infirmary. At visit 3, a 1Zlead electrocardiogram was recorded on a Siemens Sicard 440 electrocardiograph (Mortara Instrument, Inc., Milwaukee, Wisconsin). This provided an immediate interpretation and the electrocardiographic data were subsequently transmitted to the electrocardiogram laboratory in Glas100 /

Plasma Cholesterol

I

(mmdl)

FIGURE 1. Sample cumulative distribution function for plasma cholesterol as measured at screening visit 1 for 81,161 screenees. Ve&u/ axis shows the percentage of subjects with plasma cholesterol levels less than or equal to values on the horizontal axis.

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gow Royal Inlirmary for storage and automated Minnesota coding.‘O*li All results were verified manually. Further details of data acquisition and laboratory methods are given in the study design paper.9 Statistical methods: Most of the analyses in this study are descriptive in nature. Continuous variables are summarized as mean + SD. Data for categorical variables are presented as percentages of the total group of randomized study subjects or screenees as appropriate. Mean + SD for plasma triglyceride levels are presented in terms of the raw data. However, all statistical tests involving this variable are based on the logarithm of the triglyceride levels to reduce the effect of its positively skewed distribution. All statistical tests involving the comparison of mean lipid levels across subgroups are based on 2 sample t tests (for 2 groups) or on l-way analysis of variance (for >2 groups). These tests were repeated after adjustment for the following baseline covariates not including the factor being tested: age, systolic blood pressure, diastolic blood pressure, body mass index, smoking status, and alcohol consumption. Unless otherwise stated, the p values quoted are for tests after adjustment for the covariates. If a test yielded a significant result (p <0.05), all pairwise comparisons of the levels of the factor were tested. Only comparisons that were statistically significant after adjustment for covariates and for multiple comparisons (using the Bonferroni correction to give an overall significance level of 0.05) are discussed in the text. In addition to mean f SD, lipid levels are presented graphically in the form of sample cumulative distribution functions. The graphs present, for each lipid measurement, the percentage of subjects, on the vertical axis, with a value less than or equal to the value on the horizontal axis.

RESULTS Recruitment and baseline characteristics of the 6,595 randomized subjech: During the screening program,

81,161 age-eligible men attended screening visit 1, and from these, approximately 21,000 and 13,000 returned to screening visits 2 and 3, respectively. Approximately 9,000 men were invited to visit 4, having satisfied the entry criteria, and of these, 6,595 attended, provided informed consent, and were randomized. The baseline characteristics of the randomized patients, as measured at screening visit 1, are presented in Table I, together with the corresponding descriptors of the whole screened population of men in the same age range. With the exception of total cholesterol and variables that were associated with trial entry or exclusion criteria, randomized participants had a very similar profile to that of the screened population from which they were selected. Age, systolic and diastolic blood pressures, smoking history, and alcohol consumption had the same distributions in the 2 cohorts of subjects, whereas body weight was slightly higher (1 kg) in the randomized participants. The randomized group contained fewer hypertensive patients, more men with a history of hyperlipidemia, but fewer with a history of angina and/or myocardial infarction. As expected, plasma mean cholesterol level was higher in the randomized group than in the entire population of screenees. These data suggest SEPTEMBER

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TABLE III Results of Biochemical and Hematologic Tests in Randomized Patients In = 6,595) as Recorded at Screening

TABLE II Baseline Characteristics of Randomized Patients Measured at Screening Visits 2 and 3, and at the Randomization Visit (n = 6,595) Patient

Calcium (mmol/t) Adjusted calcium (mmol/t) Albumin (g/L) Creatinine (~mol/i) Glucose (mmol/L) Potassium (mmol/t) Sodium (mmol/L) Protein (g/l) Alkaline phosphatase (U/L) Alanine transaminase (U/t) Aspartate transaminase (U/t) Bilirubin (~mol/L) Creatine kinase [U/t) Hemoglobin (g/L) Mean corpuscular volume (fl) Platelet (1 O9 cells/L) Red blood cell count (lOI cells/l) Leukocytes (1 O9 cells/t)

Characteristics

Age at randomization visit {yr] Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rote (beats/min) Height (cm] Weight {kg) Body mass index (kg/m21 Medical status and history Positive Rose questionnaire Angina intermittent claudication Diabetic % ever having taken insulin % ever having taken oral hypoglycemics Hypertensive % currently on medication Smoking history Never smoked Currently smoking cigarettes, pipe, or cigars % currently smoking cigarettes Current smokers Current consumption (cig/day) Previous consumption (cig/day) Duration of smoking (yr) % former cigarette smokers Former smokers Previous consumption (cig/day) Duration of smoking (yr) Duration of abstention (yr) Current alcohol consumption Consume 520 units/week ~2 1 units/week Current medication Beta blockers ACE inhibitors Non-ACE inhibitor arterial vasodiiators Diuretics Calcium channel blockers Other antihypertensives Nitrates Aspir~n/antiplatelet agents Insulin Oral hypoglycemics Education Secondary, no certificate School-leaving certificate Further education, diploma University Marital status Married Never married Divorced Separated Widowed Employment status Employed Unemployed Retired invalid Values ore expressed 05 mec~n * SD or cts percentages. ACE = anSiotensin~onverting enzyme.

55.2 135.5 83.9 72.8 172.3 77.1 26.0

* f i r zt * rt

5.5 17.3 10.3 9.3 6.8 10.9 3.2

5.1 2.9 1.2 0.1 0.6 15.7 11 .o

Data ore presenied

21.6 44.1 35.2 18.2 * 9.5 20.1 f 9.1 35.1 + 8.4 39.2 23.6 23.5 12.5

zt 14.7 2 11.5 * 9.9

82.7 17.4 7.2 1.2 0.6 5.4 4.1 0.5 2.1 2.9 0.1 0.5 56.2 22.7 14.7 6.4 88.4 5.0 3.1 1.1 2.5 70.6 13.5 10.1 5.8

I

that the recruitment process, from attendance at screening visit 1 until randomization at visit 4, did not result in the selection of a subgroup that differed from the screened population other than as expected. The cumulative distribution function of plasma cholesterol, for all

2.4 2.4 45.3 96.0 4.8 4.4 140.6 69.5 182.3 23.4 21.9 11.7 110.9 15.1 90.8 284.1 4.9 6.6

Visit 3 zt 0.1 f 0.1 * 2.6 + 13.4 zt 0.7 * 0.4 ZIZ 1.9 * 3.9 * 48.7 f 9.2 f 5.9 f 4.5 * 54.1 * 1.0 * 4.1 + 65.4 + 0.3 + 1.9

OS mean e SD.

screenees, is shown in Figure I. Although the levels of plasma cholesterol observed in this Scottish population are high compared with what might be expected in many other parts of the world, they are nonetheless lower than those recorded in the Scottish Heart Health Study,12 where the mean serum cholesterol level in a sample of 3,860 men aged 45 to 59 years was 6.4 mmol/L (248 mgfdl). It should be noted that the Scottish Heart Health Study plasma cholesterol level was based on laboratory measured values, whereas the WOSCOPS results at screening visit 1 were nonfasting results obtained from a Reflotron bench-top analyzer (Boehringer Mannheim, Mannheim, Germany), which was potentially biased. To test this possibility, the relation between the Reflotron and laboratory measurements was assessed in a study in which blood samples were obtained from 326 screenees at visit 1. The mean 2 SD of the differences (Reflotron value minus laboratory value) was -0.29 rt 0.35 mmol/L (-11.2 f 13.5 mgldl), which does suggest an underestimation of plasma cholesterol level using the bench-top analyzer. Baseline data were recorded at screening visits 2, 3, and 4. Table II contains summary statistics for these data for all randomized patients. In Table II, age is given as at the randomization visit. Slight decreases in body weight and percentage of current cigarette smokers (compared with weight at screening visit 1) are consistent with the expected results of dietary and ~tismoking advice given at visit 1 and at subsequent visits. We surmise that the small increase in the number of hypertensive patients reflected new diagnoses of hypertension made during the screening process; screenees whose hypertension could be controlled before the randomization visit were allowed into the study. A small percentage of randomized patients had positive results for angina and intermittent claudication on the Rose questionnaires. Social variables such as marital status, educational attainment, and employment status are listed in Table II, as are the percentages of subjects taking medications commonly used for the prevention of CAD. The percentages of subjects taking p blockers, calcium an~gonists, diuretics, angiotensin-conve~ing enzyme inhibitors, and other antihypertensive agents PRFVENTIVE

CARDiOlOGY:‘WOSCOPS

STUDY

487

TABlE

IV

Lipid M~surements

for All Ra~domiz~ Number of Patients

Mean and difference Mean of ‘$2 and V3 Difference

(V3-V2]

Body mass index <27.5

6,595 6,595

4,788 1,803

~27.5 Smoking Current

status smoker

2,905

Former

smoker

2,265

Never

1,422

smoked

Alcohol consumption Nondrinker Drinker, Drinker,

<2 1 units/week ~21

units/week

1,086 4,361 1,144

Patients

(n = 6,595)

as Measured

at Screening mmol/t

Total

Choi.

101 Chol.

7.03 (272 0.00 (0

i zt f f

0.59 23) 0.67 26)

4.96 (192 0.03

7.02 (272 7.05 (273

zt i i i

0.58 22) 0.60 23)

4.97 (192 4.95 (192

f * A i

7.03 (272 7.05 (273 6.98 (270

f i * e zt i

0.59 23) 0.59 23) 0.58 22)

6.96 (269 7.01 (271 7.15 [277

f zt i f f zt

0.59 23) 0.58 22) 0.57 22)

EJZ0.45 i 17) * 0.59

0.86 (33 -0.03 (1

0.45 17) 0.45 17)

1.23 zt 0.26 (48 * 10)

0.83 (32 0.96 (37

zt jc 1, *

4.98 (193 4.95 (192 4.94 (191

5 0.46 ztz 18) f 0.45 i 17) * 0.43 f 17)

1.17 i 0.25 (45 f 10)

0.88 (34 0.06 (33 0.82 (32

5.00 (194 4.96 (192 4.93 [191

f f it I f f

0.84 (33 0.86 [33 0.91 (35

0.47 181 0.45 17) 0.44 17)

1 .I4

w

1.24

* i * +

VLDL Chol.

0.26 10) 0.17 71

(1 f. 23)

i 0.23

2 91

i 0.25

(47 f 10) 1.23

rt 0.27

(48 f 10) 1.12 (43 1.20 (46 1.31 (51

Visit 3 (V3)”

(mg/dl)

HDL Chol.

1.20 (46 0.00 to

Visit 2 (V2) and

f 0.22 f 9) e 0.25 ct 10) it 0.29 f 11)

i 0.39 2 15)

i 0.38 f 15) 0.37 14) 0.42 16)

Triglycerides

1.84 (163 -0.04 (4

A 0.78 ztz 69) f 0.68 1: 60)

1.75

* 0.73

(155

f 65)

2.07 (183

A 0.85 f 75)

i 0.38 f 15) L+ 0.40 f 15) i 0.38

1.91 (169 1.84 (163

f * zi I-

1.69

f 0.75

i

151

(150

k 66)

i 0.39

1.76 (156 1.82 (161 2.00 [177

* 0.77 f 68) +z 0.76 f 67) zt 0.84 f 74)

f

15)

zt f i *

0.38 15) 0.40 15}

*Measurements ore expressed os means and differences over the 2 visits, and as meclnS over the 2 visits broken down by cotegorier smoking status, alcohol consumption). Some counh may not add up fo 6,595 because of some missing data. Chol. = cholesterol; HDL = highdensity lipoprotein; LDL = low-density lipoprotein; VtDl = very-lowdensity lipoprotein.

0.79 70) 0.77 63)

(body moss index,

were consistent with the percentages of randomized patients who were hypertensive. Biochemistry and hematology results and the lipid Number (%) Codes results for all randomized patients are listed in Tables III 2-1 or 2-2 176 (2.7) and IV, respectively. The average of the lipid analyses 3-1, 3.2, or 33 475 (7.2) over screening visits 2 and 3 will be the value used to 4-2 or 4-3 147 (2.2) model the relation between baseline covariates and out5-2 or 5-3 499 (7.6) come in the analysis of the final trial data. Summary sta7-2-1 68 (1 .O) tistics for these data are given in the first row of Table WOSCOPS = The West of Scotland Coronary Prevention Study. IV. Mean plasma and LDL cholesterol levels are precisely the target values predicted by the design of the .- cholesterol ent~/ex~lusion criteria. Mean differences between levels at TABlE VI Comparison of Randomized Subjects with Previous Primary Prevention Trials o. screening visits 2 and 3 are also givLipi~Lowering Drugs* en. No significant difference was obHHS WHO LRC-CPPT WOSCOPS served between the 2 visits for any of (n = 4,081) (n i-: 10,577) (n = 3,806) (n = 6,595) these me~urements. A number of environmental and anAge tr) Mean 47.3 45.9 47.8 55.2 thropometric factors affect blood lipid (45-66) (40-55) (30-59) (35-59) (Raw1 and lipoprotein levels. When subjects Mean total chol. 7.5 1290) 6.4 (248) 7.5 (290) 7.0 (271) were classified on the basis of body (mmol/l [mg/dll) 1.2 (46) 1.2 (46) 1.2 (46) Mean t-ID1 chol. WA mass (~27.5 vs >27.5 kg/m2), no dif(mmol/L [mg/dll) ference was seen in plasma and LDL 1.8 (159) 1.8 (159) Meon triglycerides 2.0 (177) WA cholesterol, whereas high-density lipo(mmol/L Img/dll) protein (HDL) cholesterol was sign%135/87 121,‘80 136/84 Mean systolic/diastolic 141/90 cantly higher (p
488

Baseline

Minnesota

Codes

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Plasma

Plasma

VLDL

Choleeterol

Cholesteml

LDL

I9

(mmoltl)

Cholesterol

VLDL chdegterol

Cholesterol

Plasm8

(mmoI!l)

Triglyceride

, ?

oy_i_J 5

4.5

B

’

LDL chdestwoi

HDL

6

5.5 (~~

0=-

6.5

r

Cholesterol

100 so

---. Ir

c

1 HDL Cm

1.5 (mmoUI)

1

E

2

ferences among the smoking categories for plasma, LDL, HDL, and VLDL cholesterol levels, and plasma triglycerides (p = 0.023, p = 0.004, p
2 3 PIesma Triglyceriie

4

5

(mmotti)

FIGURE 2, The ots contain sample cumulative distribution randomized subiectsfor (XJ phr functions ba set on the 6,595 ma, [B] low-density lipoprotein (UN), (C) bi h-density lipoprolj cholesterol, tein (HDL), IDI very-low-density lipoprotein b and E] plasma triglycerides. Verficai axes show tie percentage of subiects witb levels less than or equal to the values given on the horizonfal axes.

tween the nond~~ng group and the other 2 groups achieved statistical signifi~nce, with a lower mean level in the dazing groups. HDL levels decreased across the 3 groups with decreasing levels of alcohol consumption. For both plasma triglyceride and VLDL cholesterol, levels decreased with a decrease in alcohol consumption, but comparisons between nondrinkers and those consuming 121 units/week were not statistically significant. Sample cumulative distribution functions for plasma, LDL,, HDL, and VLDL cholesterol, and plasma triglycerides are given in Figure 2. Table V shows the prevalence of selected electrocardiographic abnormalities according to the Minnesota code. Comparisons with previous studies: Table VI is an update of a table presented in the published results of the Helsinki Heart Study,8 comparing baseline characteristics of randomized subjects in previous primary prevention studies involving cholesterol-lowering drugs. The WOSCOPS recruits are, on average, 7 to 9 years older than the subjects of the other studies. Mean plasma cholesterol levels in the WOSCOPS are, on average, 0.5 mmol/L (19.4 mg/dl) less than in the Helsinki Heart Study and the Lipid Research Clinics-Coronary Primary Prevention Trial. Mean HDL cholesterol and plasma triglyceride levels are similar in all 3 studies in which these levels are reported. Mean blood pressures are similar in the WOSGOPS and the World Health

PREVENTIVE

CARDIOlOGY/WOSCOPS

SlUDY

489

Organization study and lie between those for the Helsinki Heart Study and the Lipid Research Clinics-Coronary Primary Prevention Trial. Current smokers were most frequent in the World Health Organization study, higher in the WOSCOPS than in the Helsinki Heart Study, and similar in the WOSCOPS and the Lipid Research Clinics~oron~ Primary Prevention Trial when compared on the basis of current cigarette smokers.

DISCUSSION The WOSCOPS has achieved its basic purpose of recruiting a cohort of >6,000 men aged 45 to 64 years with increased levels of LDL cholesterol. The randomized participants possess other risk factors for CAD (current smokers 44%, hypertensive patients 15.8%, positive results for angina on the Rose questionnaires 5.1%, diabetics 1.2%). The study has also met its objective in terms of follow-up: 30,000 patient-years of follow-up having been accrued at the beginning of 1995. Followup was completed at final visits scheduled between January 18 and May 28, 1995. At this time, subjects had a final study electr~~diogr~ recorded in addition to the completion of routine case report forms. The characteristics of the screened population are as would be expected in a West of Scotland population. Further, the baseiine profile of risk factors of the randomized p~icipants is consistent with the study design. Data in the World Health Organization clofibrate study, along with variable trends in the active treatment arms of other studies, suggesting increased mortality due to suicide, trauma, and cancer, have generated considerable controversy concerning the wisdom of pharmacologically inducing cholesterol reduction in persons asymptomatic for CAD. Individual and pooled analyses of trials and epidemiologic studiesi3-is have added to the controversy by establishing statistical assocjations between low cholesterol levels and raised rates of most causes of death other than CAD, although the causeeffect nature of this link has been questioned, and most commentators now recognize that a number of diseases and disorders can generate low blood cholesterol levels.i9,*0 In this atmosphere of uncertainty it is not surprising that the medical community finds it difficult to reach a consensus on future public health policy with respect to the use of lipid-lowering agents in CAD prevention. It is in the area of primary prevention that the dilemma is greatest. Any risk of increased non-CAD mortality associated with cholesterol reduction will affect the area of primary prevention, in which ~40% of deaths are due to CAD, more than secondary prevention in which ~80% of patients die of subsequent CAD-related events. Thus, the overall risk/benefit ratio will always be more favorable in secondary than in primary prevention However, in this era of treatment with throm~lysis, ~-bloc~ng drugs, aspirin, and ~giotensin-conve~ng enzyme inhibitors, it is likely that case fatality will decrease and the risk/benefit ratio for lipid-lowering treatment could theoretically worsen. The numbers of non-CAD events in individual trials have been low, and mew-~alyses often involve the pooling of trials with quite different cholesterol-lowering strategies. Drug and 490

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dietary trials, with varying periods of foflow-up and varying degrees of success in cholesterol reduction, are often studied together. From the data available, it is difficult to discern whether the trends observed are due to a generic cholesterol-lowering efl’ect, a general effect of drug treatment, an effect of a particular class of drugs, or a statistical artifact.‘9,20 There is no doubt that large randomized clinical trials, untainted by confounding factors that may affect epidemiologic studies, can play a critical role in clarifying this issue. Ideally, such trials should be of long duration and involve treatments capable of decreasing cholesterol levels significantly. A prime example of this strategy has been the Scandinavian Simvastatin Survival Study,21 which has provided conclusive evidence of the potential benefits of cholesterol reduction in the secondary prevention context. Acknowledgment: Company liaison and general support were provided by Margot Mellies, MD, Joseph Meyer, PhD, and Wendy Campbell.

APPENDIX Membership

of Commifteas: 1. EXECUTIVE COMMITTEE (VOTING MEMBERS): ~~~~er.si~ qf Glqqow. Glasgow Rqwl ~~~~~~; Professor James Shepherd (Chairman, Co-Principal Investigator), Institute of Biochemistry; Professor Stuart M. Cohbe (Chairman Cardiovascular Endpoints Committee, Co-Principal lnvestigator), Department of Medical Cardiology: Professor A. Rosa Lorimer (Chairman, Adverse Events Committee), Department of Medical Cardiology: Professor Jamec McKillop ((ieneral Medicine and Cardiology Liaison), Department of Medicine; Professor Ian Ford (Trial Statistician, Director of Data Centre), Department of Statistics; Professor Chris Packard (Study Director, Laboratory C~rdinator), Institute of Biochemistry; Professor Peter Macfarlane (ECG Laboratory Coordinator), Department of Medical Cardiology; Uw#‘ies & Galiowuy D&ricr Grnerai NLIFpit&: Chris Isles, MD (Dumfries & Galloway Coordinator), Department of Medicine.* 2. DATA AND SAFETY MONITORING COMMITTEE: Professor Michael Oliver (Chairman. National Heart and Lune Institute. London, U.K.), Professor Anthonv F. Lever (Medical Research Co~o~i~Bl~l Prwsure Unit, Glasgow, UK); Profeisor Byron W. Brown (Stanford University, Stanford, California); Professor John G.G. Lcdingham (Nuffield Department of Clinical Medicine. John Radcliffe Hospital. Oxford. U.K.): Professor Stuart Pocock (London School of Hygiene & Tropical Medicine, London, U.K); Basil Rifkind, MD, (National Institutes of Health, National Heart, Lung. and Blood Institute, Bethesda, Maryland). 3. CARDIOVASCULAR ENDPOINTS COMMIlTEE: Professor Stuart M. Cobbe (Chairman), Barry Valiance, MD (Department of Cardiology, Hairmyres Hospital, East Kilbride, U.K.), Professor Peter Macfarlane. 4. ADVERSE EVENTS REVIEW BOARD: Professor A. Ross Lorimer (Chairman). Professor James McKtllop. Dr. David Ballantyne (Department of Cardiology, Victoria Infirmary, Glasgow, U.K.). 5. DATA CENTER STAFF: Liz Anderson, David Duncan, Vivette ~lontgome~. PhD, John Norrie. 6. POPULATION SCREENING: Melvyn Percy (Minerva Medical pie). 7. CLINICAL COORDINATIONh‘RIAL MONITORING: Elspeth Pomphrey, MB ChB, Andrew Whitehouse. MB BS, Patricia Cameron, Pamela Parker. 8. CO~P~RIZED ECG ANALYSIS: David Shoat, Shahid Laatif. Julie Kennedy. 9. LABORATORY OPERATIONS: Margaret Anne Bell, Robert Birrell.

*The above IISI nlso

constitutes

Ihe Publicotlon Committee for ihe study

1. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin with serum total cholesterol levels from 5.2 to 7.8 mmol/l (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cdiol 1993:72: 1031-1037. 2. Mellies MI, De Vault AR, Kassler-Taub K, McGovern ME, Pan HY. Pravastatin experience in elderly and non-elderly patients. Aherosckrmis 1993: 101: 97-i 10. 3. Committee of Principal Investigators, W.H.O. Clofihrate Trial: a cooperative trial in the primary prevention of ischaemic heart disease using clotibrate, report. Br Hearr J 1978;40:1069-1118. 4. Committee of Principal Investigators, W.H.O. Clofihrate Trial: cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower semm cholesterol: mortality follow-up report. Lancer 1980;2:379-385. 5. The Lipid Research Clinics Program: The Coronary Primary Prevention Trial: design and implementation. I C/won Dis 1979;32:60943 I.

SEPTEMBER

1, 1995

6. Lipid Research Chntcs Program: The LipId Research Clinics Coronary Primary Prewntion Trial Resulrs, I. Reduction in incidence of coronary heart disease. &I%?/\ lY84;2S1:351--36% 7. Manttlri M, Elo 0, Frick MH, Haapa K. Heinonen OP, Heinsalmi P, Helo P, Hutiun~n JK, Kaitaniemi P, Koskmen P, Manninen V, M&q&d% H. M&lkixxn M, Nor& S, Pastemack A, Pikkarainen J, Romn M, SjBhlom T, Nikkili EA. The Helsinki Heart Study: basic destpu ant! rand(~mi~ti~~~ procedure. Er:rrr Ifmrr J IYX7;8:(suppl 1):I-29. 8. Frock MH, Elo 0. Haapa K, Heinonen OP, Heinsalm! P, Helo P, Huttunen JK, Kattaniemi P, Kwkinen P, Manninen V. MLnpBl H, Mzilkijnen M, MPnttiiri M, Norola S, Pastemack A. Pikkarainen J, Rome M. Sjiihlom T, NikkilZ EA. The Hclsinkt tiean Study: prirn~l~-pr~~,~nti~ln trial with gemfihrozil In middle-aged men with dyshpidemia: safety of treatment. changes m risk factor.\, and incidence of coronary heart disease. N Enj$ J Med 1987;317:1237-1245. 9. West ot Scotland Coronary Prevention Study Group. A coronary primary prevention study of Scottish men aged 45-M yeax trial design. J C&I Epidemiol 1992: 4f:X4Y.-xhO. 10. Prtnca.\ RI. Crow RS, Blackbum H. The Minnesota Code Manual of Electro~ardl[)~raphi~ Findtngs. Bristol: J.G Wright, I982. 1 I. Macfarlane PW. L;ltif S, Shoal DB, Cohhe SM. Automated serial ECG con,parison using the ~inncs~}t~~ code (abstr). Ezir Hem J l9~,(s~ppl 1 I I:4 I 1. 12. Smith WCS. Tunstall-Pedw H, Cromhle IK. Tavendale R. Concomitants of CXCL‘S\coronary deaths-major risk factor and lifestyle findings from IO.359 men and women in the Scottish Heart Health Study. Srorr h4rd J lYX9:34:551~S55

13. Jacobs D. Biackbum H, Higgins M, Reed D, Iso H, McMillan G. Neaton J, Nelson 1. Potter J, Rifkind B, Rossouw J, Shekelle R, Yusuf S. Report of the conference on low blood cholesterol: mortality aswciations. Circuinrr’on IoV2:86: I&& I 060. 14. Salmond CE: Beaglehole R, Prior IAM. Are low cholesterol values aswciated wtth excess mortality’? Br Med J iY85;290:422-424. 15. Sherwin RW, W~ntw[)~h DN, Cutler JA, Hulley SB, Kuller LH, Star&r J. Serum chole\tcrol levels and cancer mortality in 361,662 men screened for the Multiple Risk Factor Intervention Trial. JAMA 1987;?57:943mY4t4R. 16. Sorlie PD. Feinleib M. The serum cholestemi-cancer relationship: an analybi‘: of time trends in the Framingham Study. J Nutl Cancer- In.71 lY82:69:989-996. 17. Isles CC, Hole DJ. Gillis CR, Hawthorne VM. Lever AF. Plasma cholesterol, coronary heart disease. and cancer in the Renfrew and Paisley survey. Br Mrd J lYXY;ZYX:Y2~Y24. 18. Muldoon MF, Manuck SB. Matthew KA. Lowering cholesterol concentrations and mortality: a ~~ntitative w&w of primary pr~~enti~~a trials. Rr %&.I 19%); 101:309-3 I?. 19. Hulley SB, Walsh JMB, Newman TB. E&tonal. Health policy on blood cholesterol: time tu change dtrectlons. Crmkrfion 19Y2:Xh: 1026-1029. 20. Law MR. Thompson SC, Wald NJ. Assessing possible harards of reducing wum cholesterol. Br M& J 1994;308:.373-379. 21. The Scandmavian Simvastatin Survival Study Group. Rantlomised trial ofchoicsterol lowwing in 4444 p&nts with coronary heart disease: the S~andi~vian Simvastntm Surwal Study (4s). I&met lYY4;344:1381-1389.

PREVENTIVE

CARDIOlOGY/WOSCOPS

STUDY

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