The West of Scotland Coronary Prevention Studys A Trial of Cholesterol Reduction in ScotMsh Men James Shepherd, MD, PhD, for The West of Scotland Coronary Prevention Study Group The West of Scotland Coronary Prevention Study is a men at entry had evidence of previous myocardial primary prevention trial designed to test the hypoth- infarction. All were given smoking and dietary ad- esis that reduction of serum cholesterol with pravas- vice throughout the study, which will terminate in tatin (a 3-hydrozy-3-methylglutaryl coenzyme A 1995. The principal endpoints are: (1) death due to reductase inhibitor) over an average of 5 years will coronary artery disease (CAD) plus nonfatal myocar- reduce the incidence of fatal and nonfatal myocar- dial infarction; (2) death due to CAD; and (3) nonfa- dial infarction. At entry, 6,595 men aged 45-64 tal myocardial infarction. years were randomized to treatment with either (Am J Cardioll995; 76:113C-117C) pravastatin (40 mg/day) or placebo. None of the T hree major primary prevention trials de- signed to test the potential of lipid-lowering agents for preventing coronary artery dis- ease (CAD) have been reported. The first, the World Health Organization (WHO) clofibrate trial,‘,2 demonstrated a reduction in the rate of nonfatal myocardial infarction in the drug-treated group but also indicated that clofibrate therapy was associated with a rise in total mortality. This finding raised doubts over the benefits of wide- spread use of lipid-lowering agents. The publica- tion of the Lipid Research Clinic’s Coronary Pri- mary Prevention Trial (LRC-CPPT) in 19843-5 and the Helsinki Heart Study (HHS) in 19876~7 reversed this attitude to some extent, but many still remain skeptical because of the inability of these later trials to show a significant effect on coronary or total mortality. In the LRC-CCPT, an 11% de- crease in level of low density lipoprotein (LDL) cholesterol was associated with a significant de- crease of (19%) in oardiac events (fatal plus nonfatal myocardial infarction). The performance of this study was less than predicted due to compli- ance problems. In HHS, gemfibrozil was less po- tent but was palatable and compliance among subjects at trial visits was high. The drug reduced LDL cholesterol and triglyceride levels by 8% and 35%, respectively, and increased levels of high density lipoprotein (HDL) cholesterol by about 10%. These lipid changes were associated with a significant reduction (34%) in the incidence of CAD as measured by the combined fatal plus nonfatal myocardial infarction endpoint. From the Institute of Biochemistry, Royal Infirmary, Glasgow, United Kingdom. See Appendix for list of Committee Members. Address for reprints: James Shepherd, MD, PhD, Institute of Biochemistry, Royal Infirmary, Glasgow G4 OSF, United Kingdom. Neither the LRC-CPPT nor HHS had the statis- tical power to address the question of the benefits of lipid-lowering agents in preventing coronary death. To do this, it is necessary to: (1) study a population with a higher event rate; (2) increase the sample size; and (3) use a more effective lipid-lowering agent. The West of Scotland Coro- nary Prevention Study (WOSCOPS), using pravas- tatin, attempts to address each of these issues. Pravastatin, one of the newly developed 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reduc- tase inhibitors, is a powerful cholesterol-reducing agent that is easily tolerated and uniformly effec- tive.%i4 The increase in sample size and the recruit- ment of older men in a high-risk area (Scotland has the world’s highest incidence of CAD mortality) with associated higher event rates will increase the power of the study to assess the impact of an improved lipid profile on CAD events. METHODS Design: The WOSCOPS trial compares the effect of pravastatin (40 mg taken at night) versus placebo in men aged 45-64 years. The aim is to accrue approximately 30,000 patient-years of fol- low-up based on a target population of 6,000 men, randomized in equal numbers to pravastatin or placebo. The average follow-up period for these men will be 5 years. The recruits for this study were identified by population screening. The men who met the age criterion were screened for CAD risk factors and were invited for a second visit if their total choles- terol levels were 2 251 mg/dl ( 2 6.5 mmol/liter) as measured by a Reflotron bench-top analyzer (Boeh- A SYMPOSIUM: CHOLESTEROL-LOWERING TRIALS 11%
Transcript
The West of Scotland Coronary Prevention Studys A Trial of Cholesterol Reduction in
ScotMsh Men James Shepherd, MD, PhD, for The West of Scotland Coronary Prevention Study Group
The West of Scotland Coronary Prevention Study is a men at entry had evidence of previous myocardial primary prevention trial designed to test the hypoth- infarction. All were given smoking and dietary ad- esis that reduction of serum cholesterol with pravas- vice throughout the study, which will terminate in tatin (a 3-hydrozy-3-methylglutaryl coenzyme A 1995. The principal endpoints are: (1) death due to reductase inhibitor) over an average of 5 years will coronary artery disease (CAD) plus nonfatal myocar- reduce the incidence of fatal and nonfatal myocar- dial infarction; (2) death due to CAD; and (3) nonfa- dial infarction. At entry, 6,595 men aged 45-64 tal myocardial infarction. years were randomized to treatment with either (Am J Cardioll995; 76:113C-117C) pravastatin (40 mg/day) or placebo. None of the
T hree major primary prevention trials de- signed to test the potential of lipid-lowering agents for preventing coronary artery dis-
ease (CAD) have been reported. The first, the World Health Organization (WHO) clofibrate trial,‘,2 demonstrated a reduction in the rate of nonfatal myocardial infarction in the drug-treated group but also indicated that clofibrate therapy was associated with a rise in total mortality. This finding raised doubts over the benefits of wide- spread use of lipid-lowering agents. The publica- tion of the Lipid Research Clinic’s Coronary Pri- mary Prevention Trial (LRC-CPPT) in 19843-5 and the Helsinki Heart Study (HHS) in 19876~7 reversed this attitude to some extent, but many still remain skeptical because of the inability of these later trials to show a significant effect on coronary or total mortality. In the LRC-CCPT, an 11% de- crease in level of low density lipoprotein (LDL) cholesterol was associated with a significant de- crease of (19%) in oardiac events (fatal plus nonfatal myocardial infarction). The performance of this study was less than predicted due to compli- ance problems. In HHS, gemfibrozil was less po- tent but was palatable and compliance among subjects at trial visits was high. The drug reduced LDL cholesterol and triglyceride levels by 8% and 35%, respectively, and increased levels of high density lipoprotein (HDL) cholesterol by about 10%. These lipid changes were associated with a significant reduction (34%) in the incidence of CAD as measured by the combined fatal plus nonfatal myocardial infarction endpoint.
From the Institute of Biochemistry, Royal Infirmary, Glasgow, United Kingdom. See Appendix for list of Committee Members.
Address for reprints: James Shepherd, MD, PhD, Institute of Biochemistry, Royal Infirmary, Glasgow G4 OSF, United Kingdom.
Neither the LRC-CPPT nor HHS had the statis- tical power to address the question of the benefits of lipid-lowering agents in preventing coronary death. To do this, it is necessary to: (1) study a population with a higher event rate; (2) increase the sample size; and (3) use a more effective lipid-lowering agent. The West of Scotland Coro- nary Prevention Study (WOSCOPS), using pravas- tatin, attempts to address each of these issues. Pravastatin, one of the newly developed 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reduc- tase inhibitors, is a powerful cholesterol-reducing agent that is easily tolerated and uniformly effec- tive.%i4 The increase in sample size and the recruit- ment of older men in a high-risk area (Scotland has the world’s highest incidence of CAD mortality) with associated higher event rates will increase the power of the study to assess the impact of an improved lipid profile on CAD events.
METHODS Design: The WOSCOPS trial compares the
effect of pravastatin (40 mg taken at night) versus placebo in men aged 45-64 years. The aim is to accrue approximately 30,000 patient-years of fol- low-up based on a target population of 6,000 men, randomized in equal numbers to pravastatin or placebo. The average follow-up period for these men will be 5 years.
The recruits for this study were identified by population screening. The men who met the age criterion were screened for CAD risk factors and were invited for a second visit if their total choles- terol levels were 2 251 mg/dl ( 2 6.5 mmol/liter) as measured by a Reflotron bench-top analyzer (Boeh-
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TABLE I Assumptions Mode in Calculating the Number of
Subjects Required
1. A meon ischemic heart disease mortality rate of 4.6/ 1,000 per cmnum
I” the base population of men aged 45-64 years over the period of the
study
2. The event rates in the study population will be 50% higher than in the
base population because of raised cholesterol levels, giving an
assumed mean mortality rate of 6.9/ 1,000 per annum
3. Nonfatal events will be twice CIS frequent CIS fatal events over the study
period, giving on event rate of 20.7/ 1,000 per annum for the
combined endpoint
4. The effect of treatment will be to reduce coronary orfery disease
morbidity and mortality by 30%
ringer Mannheim, Lewes, Kent). Subjects fasted during the second visit, which took place after a minimum of 4 weeks on a standard cholesterol- lowering diet. A full lipoprotein profile was ob- tained on this visit (plasma, LDL, HDL, very low density lipoprotein cholesterol, and plasma triglyc- eride). Progress to the third visit, on which a fasting lipoprotein profile was also obtained after a further 4 weeks of diet, required a fasting LDL cholesterol level 2 1.55 mg/dl (24.0 mmol/liter) at visit 2. Invitation to the randomization visit (visit 4) re- quired fasting LDL cholesterol to be 2 155 mg/dl (2 4.0 mmol/liter) at visits 2 and 3, at least 1 of them to be 2 174 mg/dl ( 2 4.5 mmol/liter), and at least 1 of them to be 5232 mg/dl (I 6.0 mmol/ liter). Subjects were required to be free of signifi- cant evidence of CAD, although subjects with angina (identified as those with a positive Rose questionnaire at baseline, who had not been hospi- talized in the previous 12 months) were eligible for entry. Further details of inclusion and exclusion criteria are given in the study design article.15
The study is designed to have adequate power to address the endpoint of CAD death plus nonfatal myocardial infarction. In addition, the incidence of important events-CAD death only (whether pre- ceded by a nonfatal myocardial infarction or not) and nonfatal myocardial infarction only-will be reported as indicated in the study design article.15 In addition, a report on all-cause mortality will be provided. Although not originally specified, results for all cardiovascular deaths will be published to permit comparison with other studies.
Sample size: The trial population is 6,595 men randomized to treatment with placebo or pravas- tatin. The target sample size was 6,000. The assump- tions made in deriving the trial sample size are listed in Table I.
On the basis of these assumptions, it can be shown that a comparison between the treatment groups, based on the log rank test with a 2-sided significance level of 0.05, has 99% power for
attaining the combined endpoint (fatal coronary events plus nonfatal myocardial infarction) and 66% power for attaining the single endpoint of fatal coronary events. If the reduction in events due to treatment is 35%, then the power for fatal coronary events is 80%. This study does not have adequate power to address the endpoint of total mortality.
MANAGEMENT Administrative and functional units: TRIAL CEN-
TERS/SCREENING CENTERS: Subjects identified by screening undergo follow-up evaluations by health centers in the health board districts of Lana&shire, Argyll and Clyde, Greater Glasgow, and Dumfries and Galloway. Trial center teams consist of a physician, a nurse, and an administrator and are responsible for an average of 400 subjects.
ADMINISTRATIVE CENTER: The Administrative Center is based in Glasgow Royal Infirmary and is responsible for general study coordination, manage- ment of drug dispensing, and the servicing of committees. During recruitment, the Administra- tive Center is responsible for approving all random- ization and for accumulating all prerandomization data prior to transmission to the Data Center.
DATA CENTER: All data entry and the validation of case report forms is carried out centrally at the study Data Center, which is housed in the Data- bases Unit of the Department of Statistics, Glasgow University. The Data Center is responsible for providing blinded reports to the Executive Commit- tee and unblinded reports to the Data and Safety Monitoring Committee.
CENTRALANALYSISOFBLOODANDELECTROCAR- DIOGRAMS: All biochemical and hematologic analy- ses of blood samples are carried out centrally in the Departments of Pathological Biochemistry and Hematology, respectively, Glasgow Royal Infir- mary. Electrocardiograms are recorded at the trial centers and transmitted in digital form to a Siemens Mingocare II ECG management system in the Department of Medical Cardiology, Glasgow Royal Infirmary. l6 Automated electrocardiographic analysis is undertaken using the Glasgow pro- gram17 modified to generate Minnesota codes.
Committee structure: The memberships of all key committees are given in Appendix I. The roles of these committees will be outlined. The Data and Safety Monitoring Committee is the only commit- tee to receive unblinded reports during the study period.
EXECUTIVE COMMITTEE: This committee forms the primary management group for the study and is
114c THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 76 SEPTEMBER 28. 1995
responsible for formulating policy and also direct- ing the activities of the various participating units.
DATA AND SAFETY MONITORING COMMITTEE: This group, which serves as an external advisory committee to the Executive Committee, reviews unblinded &month reports on safety and other data and advises the Executive Committee accord- ingly.
CARDIOVASCULAR ENDPOINTS COMMITTEE: The Cardiovascular Endpoints Committee is respon- sible for classifying all possible study endpoints. It receives reports of (1) all annual study electrocar- diographic results showing serial changes; (2) domi- ciliary visits or hospitalizations associated with possible myocardial infarction; and (3) all deaths (including death certificates and, if available, post- mortem results).
ADVERSE EVENTS COMMITTEE: This committee reviews all possible adverse events and hospitaliza- tions occurring in study participants and provides summary reports with International Classification of Disease coding to the Data Center. The group provides advice to trial physicians on the need for withdrawal of subjects from trial therapy and authorizes, when necessary, the unblinding of trial therapy.
RESULTS Baseline characteristics: Intervention in the
6,595 men recruited to the program is still continu- ing. Consequently, only baseline information can be presented on the population at this stage (Table II). Because a random allocation of treatments has been carried out, statistically testing the equality of the distributions is unnecessary. Any imbalances must be chance events, unless the randomization process has been compromised. As would be ex- pected in a study of this size, the balance between the 2 groups is very good.
TABLE II Biochemical and Hematologic Indices of Randomized Subjects*
trw~sammose; CK = creatlne kinase; HDL = high density lipoproiein; LDL = low density lipoprotem; MCV = mean corpurculor volume, SD = standard deviotmn; VLDL = very low density Ilpoprotein.
Comparison with previous primary prevention studies: Table III compares the baseline character- istics of randomized subjects in previous primary prevention studies involving cholesterol-lowering drugs. As can be seen, the WOSCOPS recruits are on average 7.5 years older than the recruits of the study with the nearest mean age. Mean plasma cholesterol levels in WOSCOPS are on average 19 mg/dl (0.5 mmol/liter) less than in the HHS and LRC-CPPT. Mean HDL cholesterol and plasma triglyceride levels are similar in all 3 studies where these levels are reported. Mean blood pressures are similar in WOSCOPS and the WHO study and lie between those for the HHS and LRC-CPPT.
TABLE Ill Comparison of Baseline Data from This Study with Previous Primary Prevention Trials of Lipid-Lowering Drugs
Randomized subjects
Age (vd Meon
Range Total cholesterol (mean, mg/dl)
HDL cholesterol (mean, mg/dl)
Triglyceride (mean, mg/dl)
Meon SBP/mean DBP (mm Hg)
Current smokers (%)t
HHS
4,081
47
(40-55) 290
46
177
141/90
36
WHO LRC-CPPT woscoPs
10,577 3,806 6,595
(30-z:) (35-g) (452)
247 290 271
NA 46 46
NA 168 73 135fB7 121/80 136184
56 37 44
tThe dais for current smokers includes alI smokers with the exception of LRC-CPPT, for which only ci orelte smokers were reported, Values for total and hi h density lipoprotein (HDL) for values in mmol/liter, multiply by converston factor 0.0258 8 for cholesterol levels and b 0.01 129 for triglyceride evels. P = Helsinki Head Study; HDL = high denstty lipoprotem; LRC-CPPT = Lipid R ereorch 2, lime’s Coronoly Primay Prevention Trial; NA = not
WHO = World Health Orgamrotion; WOSCOPS = West of Scotland Coronary Prevention Study.
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The number of current smokers was highest in the WHO study and was higher in WOSCOPS than in the HHS. When comparing the number of current cigarette smokers, numbers in WOSCOPS and LRC-CPPT were similar.
DISCUSSION The WOSCOPS trial has achieved its basic aim
to recruit a cohort of > 6,000 men aged 45-64 years with elevated levels of LDL cholesterol (mean level of approximately 193 mg/dl [5 mmol/liter]). The randomized participants possess other risk factors for CAD (44% are current smokers, 15.8% are hypertensive, 5.2% have positive Rose question- naires for angina, 1.2% are diabetic). A total of 30,000 patient-years of follow-up had accrued at the beginning of 1995. Subjects normally attended trial monitoring visits at 3-month intervals. The subjects were allocated a target visit date with an attendance window of -2 weeks and +4 weeks. The final follow-up evaluation was completed at those visits scheduled between January 31 and May 3, 1995. At this evaluation, subjects will have a final study electrocardiogram recorded in addition to the completion of routine case report forms. The actual date of attendance will be taken as the censoring date for each individual’s follow-up evalu- ation. Subjects not attending the final visit within the visit window will be allocated the final day of their visit window as their follow-up censoring date and their status at that time will be obtained by personal contact, contact with general practitio- ners, and by reference to national registries of deaths and hospitalizations. The results of the study will be reported in November 1995 at a major international conference and published in tandem in the medical literature. At the same time, each subject and his general practitioner will be un- blinded to the subject’s trial medication and will receive a summary of the lipid results before and during the trial so that appropriate ongoing treat- ment can be assessed.
The characteristics summarized in this article indicate that WOSCOPS, both individually and in combination with other ongoing trials involving statins, will make a significant contribution to the debate on the appropriate policy for the use of cholesterol-lowering agents in the prevention of CAD.
Acknowledgments: The Executive Committee members are indebted to the following for their technical support and substantial commitment to the design and implementation of the study: Clini-
cal administration, trial monitoring: Dr. E. Pom- phrey, Dr. A Whitehouse, E. T. Weston; computer- ized electrocardiographic analysis: D. Shoat, S. Latif, J. Kennedy; laboratory operations: A. Bell, B. Birrell; rheological measurements: Professor G. Lowe (Department of Medicine, Glasgow Royal Infirmary); Data Centre: D. Duncan, Dr. V. Mont- gomery, E. Anderson, A. G. McCormack; field operations: M. Percy (Minerva Medical Projects, Glasgow); and sponsor liaison and drug supply: Dr. M. Mellies, Dr. J. Meyer, W. Campbell (Bristol- Myers Squibb, Princeton, NJ).
1. Committee of Principal Investigators. WHO Clofibrate Trial. A cooperative. trial in the primary prevention of ischaemic heart disease using clofibrate, report. BrHeun J 197~40:106~1118. 2. Committee of Principal Investigators. WHO Clofibrate Trial. Cooperative Trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up report. Lancer 1988o;i:379-385. 3. The Lipid Research Clinics Program. The Coronary Primary Prevention Trial: design and implementation. J Chmn DiF 1979;32:6Ll%31. 4. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, I. Reduction in incidence of coronary heart disease. JAu/ 1984;251-3&1. 5. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, II. The relationship of reduction in incidence of coronary heart disease to cholesterol-lowering. JW 1984;251:365-374. 6. MBntlrri 0, Elo 0, Frick MH, Haapa K, Heinonen OP, Heinsahni P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, et al. The Helsinki Heart Study: basic design and randomisation precedure. Eur Heart J 1987;8:(suppl I):l-29. 7. Frick MH, Elo 0, Frick MH, Haapa K, Heinonen OP, Heinsahni P, Helo P, Huttnen JK, Maitaniemi P, Koskinen P, et al. The Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipide- mia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. NEnglJMed 1987;317:1237-1245. 8. Pan HY. HMG-CoA reductase inhibitors: clinical pharmacology. In: Gotto AM Jr, Mancini M, Richter WO, Schwandt P, eds. Treatment of severe hypercholesterolemia in the prevention of coronary heart disease. Proceedings of the 2nd International Symposium, Munich 1989, Basel: Karger, 1990:66-70. 9. Tsujita Y, Juroda M, Shimada Y, Tanzawa K, Arai M, Kaneko I, Tanaka M, Masuda H, Tarumi C, Watanabe Y, et al. CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaql coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species. Biochim Biqhys Acta 1986$77:5I360. 10. Tsujita Y, Watanabe Y. Pravastatin sodium: novel cholesterol-lowering agent that inhibits HMG-CoA reductase. Cardiovasc Drug Rev 1989;7:11&126. 11. Reihner E, Rudling M, Stahlberg D, Berglund L, Ewerth S, Bjorkhem I, Einarsson K, Angelin B. Influence of pravastatin, a specific inhibitor of HMG- CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med 1’)90,323: 224228. 12. Singhvi SM, Pan HY, Morrison RA, Willard DA. Disposition of pravas- tatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy sub- jects. Br J Clin Phannacol 1990,29:239-243. 13. Vega GL Krauss RM, Grundy SM. Pravastatin therapy in primary moder- ate hypercholesterolaemia: changes in metabolism of apolipoprotein B- containing lipoproteins. J fntem Med 1990,227:81-94. 14. Mosely ST, Kalinowski SS, Schafer BL, Tanaka RD. Tissue-selective acute effects of inhibitors of 3-hydroy-3-methylglutaryl coenzyme A reductase on cholesterol biosynthesis in the lens. J Lipid Res 1989;30:1411-1420. 15. The West of Scotland Coronary Prevention Study Group. A coronary primary prevention study of Scottish men aged 45-74 years: trial design. J C&I Epidemiol1992;45:84%8860. 16. Macfarlane PW, Detie B, Latif S, McLaughlin S, Shoat DB, Watts MP. Methodology of ECG interpretation in the Glasgow program. Methods Inf Med 1990;29:354361. 17. Macfarlane PW, Latif S, Shoat DB, Cobbe SM. Automated serial ECG comparison using the Minnesota code. Ew Heart J 199U;ll (XII European Society of Cardiology Congress Congress Abstract Supplement):411.
116C THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 76 SEPTEMBER 28, 1995
APPENDIX I Membership of Committees EXECUTIVE C~MMITTIZE (VOTING MEMBERS) AND
PUBLICATION COMMITTEE: Professor James Shep- herd, MD, PhD (Chairman, Co-Principal Investiga- tor), Institute of Biochemistry, Glasgow Royal Infirmary; Professor Stuart M. Cobbe (Chairman, Cardiovascular Endpoints Committee, Co-Princi- pal Investigator), Department of Medical Cardiol- ogy, Glasgow Royal Infirmary; Professor A. Ross Lorimer (Chairman, Adverse Events Committee), Department of Medical Cardiology, Glasgow Royal Infirmary; Professor James McKillop (General Medicine and Cardiology Liaison), Department of Medicine, Glasgow Royal Infirmary; Professor Ian Ford (Trial Statistician, Director of Data Centre), Department of Statistics, Glasgow University; Pro- fessor Peter Macfarlane (ECG Laboratory Co- ordinator), Department of Medical Cardiology, Glasgow Royal Infirmary; Dr. Chris Isles (Dum- fries & Galloway Co-ordinator) Department of
Medicine, Dumfries & Galloway District General Hospital
DATA AND SAFETY MONITORING COMMITTEE:
Professor Michael Oliver (Chairman), Wynn Insti- tute for Metabolic Research, London, England; Professor Anthony F. Lever, Medical Research Council Blood Pressure Unit, Glasgow, Scotland; Professor Byron W. Brown, Stanford University, Stanford, CA; Professor Stuart Pocock, London School of Hygiene & Tropical Medicine, London, England; Dr. Basil Rifkind, National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, MD
CARDIOVASCULAR ENDPOINTS COMMITTEE: Pro-
fessor Stuart M. Cobbe (Chairman); Dr. Barry Valiance, Department of Cardiology, Hairmyres Hospital, East Kilbride, Scotland; Professor Peter Macfarlane
ADVERSE EVENTS REVIEW BOARD: Professor A. Ross Lorimer (Chairman); Professor James Mc- Killop; Dr. David Ballantyne, Department of Car- diology, Victoria Infirmary, Glasgow, Scotland
