Statins The HMG-CoA Reductase Inhibitors in Perspective Second edition
Statins The HMG-CoA Reductase Inhibitors in Perspective Second edition Edited by
ALLAN GAW MD PhD Director Clinical Trials Unit Glasgow Royal Infirmary Glasgow, UK
CHRISTOPHER J PACKARD FRCPath DSc Professor of Pathological Biochemistry University of Glasgow, and Top Grade Biochemist, Department of Pathological Biochemistry Royal Infirmary, Glasgow, UK
JAMES SHEPHERD PhD FRCPath FRCP(Glasg) FRSE Professor of Pathological Biochemistry University of Glasgow, and Honorary Consultant Biochemist Department of Pathological Biochemistry Royal Infirmary Glasgow, UK
LONDON AND NEW YORK
© 2000, 2004 Martin Dunitz, an imprint of the Taylor & Francis Group plc First published in the United Kingdom in 2000 by Martin Dunitz Ltd This edition published in the Taylor & Francis e-Library, 2005. To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/. Second edition published in 2004 by Martin Dunitz, an imprint of the Taylor & Francis Group plc, 11 New Fetter Lane, London EC4P 4EE Tel.: +44 (0) 20 7583 9855 Fax.: +44 (0) 20 7842 2298 E-mail:
[email protected] Website: http://www.dunitz.co.uk/ All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. ISBN 0-203-42729-7 Master e-book ISBN
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[email protected] Contents Contributors
ix
Preface to the first edition
xiii
Preface to the second edition
xiv
1. Hyperlipidaemia as a risk factor for vascular heart disease Allan Gaw 2. Lipid control in the pre-statin era William B Kannel and Peter WF Wilson 3. The discovery and development of the statins Akira Endo 4. Comparative chemistry, pharmacology and mechanism of action of the statins Allan Gaw and Christopher J Packard 5. Ancillary benefits of the statins Brendan M Buckley 6. Angiographic and IVUS techniques evaluating progression and regression of coronary atherosclerosis: statin intervention trials in perspective Philippine Kiès, Albert VG Bruschke and J Wouter Jukema 7. The Scandinavian Simvastatin Survival Study (4S) Ole Faergeman 8. Primary prevention of coronary heart disease with statins James Shepherd 9. The CARE trial: the effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels J Wayne Warnica 10. The LIPID study: results and implications for clinical practice Andrew M Tonkin, on behalf of the LIPID Study Group 11. Mega-trials: the Prospective Pravastatin Pooling Project (PPP) and the Heart Protection Study (HPS) Robert P Byington and Curt D Furberg 12. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) James Shepherd, Gerard Jan Blauw, Michael B Murphy and Allan Gaw 13. Combination therapy with statins Gilbert R Thompson 14. Guidelines for clinical use of the statins Christopher J Packard 15. The cost-effectiveness of statin use J Jaime Caro and Krista F Huybrechts
1 27 44 61
78 96
125 142 158
187 197
225 243 257 273
16. Unanswered questions about the use of statins Mehmet Cilingiroglu and Christie M Ballantyne 17. Statin therapy for the 21st century James Shepherd Index
290 308
323
Contributors Christie M Ballantyne Associate Professor and Clinical Director Section of Atherosclerosis Department of Medicine Baylor College of Medicine 6565 Fannin Street, MS A-601 Houston, TX 77030 USA Gerard Jan Blauw Leiden University Medical Centre Albinusdreef 2 2333 ZA Leiden The Netherlands Albert VG Bruschke Professor of Cardiology Leiden University Medical Center Albinusdreef 2 2333 ZA Leiden The Netherlands Brendan M Buckley Department of Pharmacology and Therapeutics University College Cork 2200 Cork Airport Business Park Cork Ireland Robert P Byington Professor, Section on Epidemiology Department of Public Health Sciences Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem, NC 27157–1063 USA J Jaime Caro Caro Research Institute 336 Baker Avenue
Concord, MA 01742 USA Mehmet Cilingiroglu Cardiology Fellow Section of Cardiology Department of Medicine Baylor College of Medicine 6550 Fannin Street, MS A-601 Houston, TX 77030 USA Akira Endo Department of Applied Biological Science Faculty of Agriculture Tokyo Noko University Fuchu-Shi, Tokyo 183 Japan Ole Faergeman Department of Medicine and Cardiology Aarhus Amtssygehus University Hospital Tage-Hansens Gade 2 DK-8000 Aarhus Denmark Curt D Furberg Professor, Department of Public Health Sciences Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem, NC 27157–1063 USA Allan Gaw Director, Clinical Trials Unit 4th Floor, Walton Building Glasgow Royal Infirmary Glasgow G4 0SF UK Krista F Huybrechts Caro Research Institute 336 Baker Avenue Concord MA 01742 USA
J Wouter Jukema Associate Professor of Cardiology Head, Cardiac Catheterization Laboratory/Interventional Cardiology Department of Cardiology, C5-P Leiden University Medical Center PO Box 9600 2300 RC Leiden The Netherlands William B Kannel Professor of Medicine and Public Health Boston University School of Medicine Framingham Heart Study 73 Mt Wayte Avenue Framingham, MA 01702 USA Philippine Kiès Department of Cardiology Leiden University Medical Center Albinusdreef 2 2333 ZA Leiden The Netherlands Michael B Murphy Department of Pharmacology and Therapeutics University College Cork Clinical Sciences Building Cork University Hospital Wilton Cork Ireland Christopher J Packard Department of Pathological Biochemistry Glasgow Royal Infirmary 4th Floor, Queen Elizabeth Building 10 Alexandra Parade Glasgow G31 2ER UK James Shepherd Head, University Department of Pathological Biochemistry Glasgow Royal Infirmary
Castle Street Glasgow G4 0SF UK Gilbert R Thompson Emeritus Professor Division of Investigative Science Imperial College, Faculty of Medicine Hammersmith Hospital Du Cane Road London W12 0NN UK Andrew M Tonkin National Heart Foundation of Australia 411 King Street West Melbourne Victoria 3003 Australia J Wayne Warnica Professor of Medicine University of Calgary Department of Cardiology Director, Cardiac ICU Foothills Provincial General Hospital 140329 Street NW Calgary, Alberta Canada T2N 2T9 Peter WF Wilson Framingham Heart Study 73 Mt Wayte Avenue Framingham, MA 01702 USA
Preface to the first edition The first studies using lipid-lowering drugs, such as the early fibrates or the bile acid sequestrant resins, provided, at best, equivocal results, which fuelled the arguments for inaction or procrastination among physicians. When the statins were introduced into clinical practice and, more importantly, when they were tested in the fire of the randomized controlled clinical trial, these arguments disappeared. The statins were proven to provide clinical benefits in terms of reduction in all-cause mortality and coronary morbidity in a wide spectrum of patients. Now that the question of whether we can reduce the risk of atherosclerotic disease in our patients has been answered, we face new challenges. What targets, if any, should we strive for in cholesterol lowering? What is the significance of the non-lipid effects of the statins? Which statins should we use? Can we afford to use any? The clinical trials that have taught us so much about the statins were not designed to answer these new questions. How could they have been? When the trials were set up, a moratorium was being called for on all lipid-lowering drug prescribing. Therefore, it was essential to answer the fundamental questions of safety and efficacy before we could allow ourselves the relative luxury of considering the detail. And, it is the continued study of this detail that makes the story of the statins alive and, as yet, incomplete. This book tells the story of the statins, for the most part in the words of those who lived this story. The background, describing the lipid world before the statins, is told by the Framingham investigators. Akira Endo, working with his team in Japan, discovered the early statins and describes his breakthrough. The major clinical trials from Scandinavia, North America, Australia and New Zealand and, of course, Scotland are detailed by those who conducted them. The book is completed by other chapters on the pharmacology and mechanisms of action of the statins, the statin angiographic trials, the use of statins after vascular surgery, guidelines for the use of the statins in clinical practice and the cost-effectiveness of statin therapy. The concluding chapters detail the future statin trials, of which there are many, and we take a look into the future of lipidlowering therapy beyond statins. We would like to thank Alan Burgess, Rebecca Hamilton and the team of Martin Dunitz Publishers without whose encouragement this book would not have been completed. We also acknowledge the hundreds of investigators, the tens of thousands of trial subjects, and the millions of patients receiving statin therapy throughout the world today, for without them there would have been no story to tell. Allan Gaw, Christopher J Packard and James Shepherd
Preface to the second edition Statins have become a global phenomenon in terms of both the market value of prescribed drugs and the spectrum of attributed clinical benefit. They are at the core of coronary prevention programmes, and are also under investigation for their impact on other diseases such as osteoporosis and rheumatoid disease. The evidence base underpinning their use in a wide range of patients has expanded year on year. Trial experience continues to show that the drugs are safe and effective in all patients tested. Yet further studies are planned to explore new aspects of statin pharmacology, pleiotropic effects and the limits of clinical effectiveness. Against this background of ever-expanding knowledge of this class of drugs, we felt it appropriate to update the previous edition of this book. The success of the first edition of this book—its breadth of coverage and appropriate depth of information—prompted us only to make changes where necessary. That said, major advances in this field required substantial rewrites of several chapters and the introduction of new ones. What we have produced represents an up-to-date and in-depth review of statins from both a scientific and a clinical perspective. We are indebted to our authors who have produced excellent reviews of their subjects and have presented these in a format that can be easily read by specialist and generalist alike. We would also like to thank Drs Jane Kent, Eleanor Dinnett and Moira Mungall for their valuable help and comments on the manuscripts. Lastly, we would like to acknowledge our editorial and production team at Martin Dunitz, principally Pete Stevenson and Giovanna Ceroni. Sticks and carrots were used in equal and appropriate measure and they have allowed us to produce what we believe is a very valuable addition to the literature in this increasingly important field. Allan Gaw Christopher J Packard James Shepherd
1 Hyperlipidaemia as a risk factor for vascular disease Allan Gaw INTRODUCTION Enormous resources are put into the study of human lipid and lipoprotein metabolism. Similarly, great efforts are made to develop and test drugs that alter the lipid profile. The reason for these endeavours is a simply stated hypothesis: that a raised blood cholesterol concentration causes atherosclerotic vascular disease and by lowering the blood cholesterol level we can prevent this disease. Coronary heart disease (CHD) is the main clinical manifestation of atherosclerosis and is the major cause of death in modern, industrialized countries and an increasing cause in developing countries.1 Atherosclerosis may also affect the peripheral arteries and the cerebral circulation, leading to other debilitating or life-threatening conditions. It is not surprising therefore that given the possibility that such a prevalent disease may be preventable, we have seized upon the opportunity. In recent years, the hypothesis outlined above has been proven and we now enter a new era in medicine where we are armed with an unsurpassed portfolio of evidence upon which to base our clinical practice. This book focuses specifically on the statins, a group of drugs that indisputably have had the most important impact in this field. However, before these drugs are discussed in detail it is important to understand the background to this subject. In this introductory chapter we shall examine the evidence for hyperlipidaemia as a risk factor, review the pathogenesis of atherosclerosis, look at lipid and lipoprotein metabolism in detail, and discuss the classification of the dyslipidaemias. RISK FACTORS FOR CHD A risk factor is a characteristic that predisposes an individual to the development or progression of the condition in question. Risk factors are defined on the basis of epidemiological studies, but a distinction must be made between characteristics that are simply associated with CHD and those that actually cause it. For causation to be established the following criteria must be fulfilled: • There must be a strong, temporal correlation between the existence of the characteristic and the incidence of CHD. • This correlation must be consistent, dose-responsive and predictive.
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• There must be a possible mechanism of action by means of which the risk factor can exert its influence. • The association must be reversible. There have been many studies undertaken to identify CHD risk factors. One of the best known and earliest is the Framingham Study, which started in 1948 as a long-term epidemiological analysis of CHD and continues today. This study clearly identified the link between raised blood cholesterol and increased CHD risk.2 A second important study—the Multiple
Table 1.1 Risk factors for CHD Modifiable
Non-modifiable
Smoking
Age
Raised blood pressure
Male sex
Raised LDL cholesterol
Family history of CHD
Low HDL cholesterol Raised triglyceride
Personal history of CHD
Diabetes mellitus Obesity Diet Thrombogenic factors Lack of exercise Excessive alcohol consumption
Risk Factor Intervention Trial (MRFIT), which screened a total of 356662 men and followed them up for six years—supported these findings.3 There are now a large number of characteristics or traits that have been identified as risk factors for CHD. A small number of these function as independent risk factors; that is, they exert their influence independently of the presence of any other risk factor. There are many others that are secondary; that is, they have a positive correlation with CHD but require the presence of other risk factors for this to be manifest. It is useful to consider risk factors in the clinical setting as those that can be modified, either by lifestyle changes or therapeutic intervention, and those that are not modifiable. A list of the major risk factors is shown in Table 1.1. It is important to realize that risk factors do not generally occur in isolation but tend to cluster in an individual. This is significant because, when risk factors coexist, they interact and their combined effect is much greater than would be expected from the sum of their individual effects. The concept of multiple CHD risk factors is of great practical importance because it means that the patient at greatest risk is not necessarily the individual with a single serious risk factor such as severe hypercholesterolaemia. Instead the individual with a
Hyperlipidaemia as a risk factor for vascular disease
3
poor profile of risk factors such as the male smoker with moderate hypertension and moderately elevated lipids is at relatively greater risk. This is illustrated in Fig. 1.1. While this chapter focuses on hyperlipidaemia as a risk factor for vascular disease, it is important to recognize that other risk factors are equally important. In clinical terms, any attempt to modify a patient’s vascular disease risk profile must attend to all the major correctable risk factors, especially hyperlipidaemia, smoking and hypertension. For balance, we shall briefly examine the roles of smoking and hypertension as CHD risk factors within the context of controlling hyperlipidaemia. Smoking Smoking is probably the greatest preventable cause of death in developed countries. It accounts for 50% of all avoidable deaths and, of these, one half are due to cardiovascular disease.4,5 The risk associated with smoking is related to the amount of tobacco smoked daily and the length of time over which the individual has smoked.6 The exact mechanism by which smoking exerts its influence is unclear. It is apparent, however, that it enhances the development of atherosclerosis in addition to increasing the occurrence of thrombotic events. The latter are thought to be the most important, as stopping smoking leads to a quicker reduction in CHD risk in patients with established disease than in those who are asymptomatic. In patients with established CHD, the risk in those who stop smoking approaches that of those who have never smoked in approximately two or three years.7 Asymptomatic individuals, however, require ten years or more before reaching the risk levels of those asymptomatic individuals who have never smoked.8,9 Hypertension CHD risk increases with increasing blood pressure but it is not possible to identify a threshold value below which a patient is safe from CHD. For this reason, the diagnosis of hypertension is somewhat arbitrary and there is not a universally agreed method of classification.
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Fig. 1.1 (a) CHD mortality for nonsmokers by plasma cholesterol and blood pressure, (b) CHD mortality for smokers by plasma cholesterol and blood pressure. (Adapted with permission from ref. 3.)
Hyperlipidaemia as a risk factor for vascular disease
5
Treatment of mild hypertension by lifestylemodification has been evaluated by a number of randomized controlled trials such as that carried out by Stamler et al.10 It has been demonstrated that changes such as a reduction in dietary salt intake, weight loss and reduced alcohol intake together with increased exercise can successfully reduce blood pressure. However, trials have been too short and too small to say, as yet, what these effects would be on CHD morbidity. Much evidence does exist concerning the reduction of CHD mortality and morbidity effected by the use of anti-hypertensive drugs. The meta-analysis by Collins et al.11 showed a reduction in CHD risk of 14%. This is smaller than predicted from epidemiological data and contrasts with the reduction in stroke risk of 42%, which was just as predicted from epidemiological studies. The reasons for this discrepancy are not yet clear but may be due to the very slow development of coronary atherosclerosis. For the full clinical benefit to become apparent, these trials may have to be much longer. The greatest benefit of blood pressure reduction is obtained by those with high overall risk.
Fig. 1.2 International relationship between CHD mortality and total serum cholesterol. (Adapted with permission from ref. 13.) Consequently, even modest reductions in blood pressure will be worthwhile in those with multiple risk factors and/or pre-existing vascular disease or severe hypertension. Once hypertension has caused target organ damage the CHD risk associated with a particular blood pressure level is much higher. Left ventricular hypertrophy carries a
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particularly poor prognosis. Management should therefore be aimed at preventing target organ damage and should be initiated without delay. While there is still debate about the choice of initial treatment for hypertensive patients, the recent Antihyperensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) supports the use of thiazide diuretics.12 DYSLIPIDAEMIA Cholesterol and LDL The identification of cholesterol as a possible risk factor for CHD was first made after the recognition that in countries with a high mean blood cholesterol the mortality from CHD was also high. Figure 1.2 gives the results from one such study, showing the relationship between mean total cholesterol and number of CHD deaths.13 The country with the highest cholesterol levels in this study, Finland, also experiences the highest CHD mortality. The position of Japan on this graph (Fig. 1.2) is significant, as it experiences a relatively low CHD mortality. This is in keeping with its generally low
Table 1.2 Ni-Hon-San study: CHD rates and risk factors in Japanese men in three societies Japan
Hawaii
California
Acute MI rate/1000
7.3
13.2
31.4
Hypertensive heart disease/1000
9.3
1.4
4.6
26.0
57.0
64.0
4.7
5.6
5.9
Non-smokers (%) Serum total cholesterol (mmol/l) Adapted with permission from ref. 11.
cholesterol levels but occurs in spite of high population rates of smoking and hypertension, two other important risk factors for CHD. This relationship has been studied further in the Ni-Hon-San study, which looked at CHD rates and risk factors in Japanese men in three societies.14 The results of this are summarized in Table 1.2. It is clear from this that serum cholesterol level is one of the most important factors in predicting CHD risk in the population. Cholesterol is directly involved in atherogenesis and it has been shown that the severity of atherosclerosis is directly proportional to the concentration of cholesterol in the blood.15 It is also clear that diet is important, as studies such as the Seven Countries study16 have shown that CHD is inversely related to the ratio of polyunsaturated to saturated fats in the diet. The above studies have identified the association between CHD and cholesterol, but in order to quantify the risk it was necessary to design prospective cohort studies. The results of three such studies are illustrated in Fig. 1.3.17 In these studies the relationship between CHD risk and cholesterol level is curvilinear. This was reinforced by the much
Hyperlipidaemia as a risk factor for vascular disease
7
larger MRFIT study, which was able to show that the relationship between cholesterol and CHD was not one of threshold, i.e. there is a graded and continuous risk and
Fig. 1.3 Relation between plasma cholesterol level and relative risk of CHD in three prospective studies. (Adapted with permission from ref. 17.) there is probably no cholesterol level which can be considered completely safe in terms of cardiovascular risk.3 There has been some concern over the risks of low cholesterol, as MRFIT demonstrated a J-shaped relationship between total cholesterol and total mortality. This increase in total mortality occurring at cholesterol levels below 4 mmol/l has been duplicated in other studies and it has been suggested that low cholesterol causes cancer. However, international comparative data do not support this hypothesis. For example, in Japan, where 90% of men have cholesterol levels below 4.4, the overall risk of cancer is no greater than that experienced by American or Northern European men.18 A more likely explanation is that a low plasma cholesterol concentration is an effect of cancer rather than a cause. Concerns have also arisen with regard to low plasma cholesterol levels and stroke resulting from intracranial haemorrhage. This risk is small and, as suggested by Iso et
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al.,19 is far outweighed by the cardiovascular risks (including thrombotic stroke) of raised plasma cholesterol levels. Our discussion so far has centred on total cholesterol as a risk factor, but since 60– 70% of plasma cholesterol is transported in the form of low-density lipoprotein (LDL), the effects of total cholesterol reflect the effects of LDL cholesterol. HDL cholesterol There is considerable evidence to support an inverse relationship between plasma highdensity lipoprotein (HDL) and CHD risk. The British Regional Heart Study is one such source of evidence and their results concerning HDL and CHD risk are shown in Fig. 1.4.20 This inverse relationship exists for both men and women and is equally strong in patients with established heart disease as well as those who are asymptomatic. Premenopausal women have levels of HDL cholesterol that are 0.2–0.3 mmol/l higher than those of their male counterparts. After the menopause this difference diminishes with increasing age and may partly explain the relative protection of women from CHD.
Fig. 1.4 Risk of CHD events according to concentration of HDL. (Adapted with permission from ref. 20.) Plasma HDL is lowered by: • smoking • obesity • physical inactivity.
Hyperlipidaemia as a risk factor for vascular disease
9
Modification of these factors may reverse this HDL lowering effect. Diets containing high polyunsaturated fat levels have been shown to decrease LDL cholesterol while simultaneously lowering HDL cholesterol. However, it is possible to lower LDL cholesterol while maintaining HDL cholesterol levels by reducing saturated fat and substituting moderate amounts of monounsaturated and polyunsaturated fats in the diet. The importance of HDL as a risk factor is related to LDL levels, and the ratio of total cholesterol to HDL cholesterol is a better predictor of CHD risk than either of the variables alone. A ratio of five or less appears to be desirable and is of particular importance when considering treatment options for patients whose cholesterol levels are in the 5–6.5 mmol/l range. Lp(a) This is an LDL-like lipoprotein whose plasma concentration is related to CHD risk.21 It may be of importance only when total cholesterol levels are high. Its plasma level is genetically determined and these levels are resistant to most conventional lipid-lowering strategies. As yet it does not have a clear role in the assessment of CHD risk. Triglyceride The plasma triglyceride level is related to the risk of CHD. This effect is more marked in patients with raised plasma cholesterol levels. A raised triglyceride is also commonly associated with low HDL and increased levels of small, dense LDL, which is regarded as particularly atherogenic. Many subjects with hypertriglyceridaemia also produce increased levels of a particularly atherogenic type of LDL (small, dense LDL). It has been noted by Assman et al.22 that the combination of: • hypertriglyceridaemia (plasma triglyceride >2.3 mmol/l) • total cholesterol/HDL cholesterol ratio >5 • low HDL (240 mg/dl) is about 30–45%. About half of the original
Fig. 2.1 LDL cholesterol distribution in cases of coronary heart disease and controls. (Adapted with permission from ref. 20.) Table 2.1 Prevalence of mild and definite hypercholesterolaemia in the general population by age and sex: Framingham Study Percent prevalence
Age (yrs)
Mild
Definite
(200–239 mg/dl)
(>240 mg/dl)
(5.2–6.2 mmol/l)
(>6.2 mmol/l)
Men
Women
Men
Women
35–44
37
37
38
24
45–54
39
35
44
50
55–64
39
29
44
50
Lipid control in the pre-statin era
29
65–74
40
29
34
61
75–84
41
35
19
47
85–94
32
41
11
21
cohort would be eligible for treatment based on their serum total cholesterol values alone or in combination with other risk factors. In the off-spring cohort, cholesterol levels were found to be substantially lower at all ages, with only 20% of men and women aged 30–69 years having cholesterol values >240 mg/dl (6.21 mmol/l).20 In this offspring sample LDL cholesterol >160 mg/dl (4.14 mmol/l) occurred in about 20% of men and 22% of women.
Table 2.2 Mean serum cholesterol of persons developing coronary heart disease in the Framingham Study by decade (1950s–1980s) Average cholesterol level Decade
Men
Women
1950s
246 mg/dl 6.4 mmol/l
281 mg/dl 7.3 mmol/l
1960s
243 mg/dl 6.3 mmol/l
246 mg/dl 6.4 mmol/l
1970s
229 mg/dl 5.9 mmol/l
244 mmol/l 6.3 mmol/l
1980s
228 mg/dl 5.9 mmol/l
248 mg/dl 6.4 mmol/l
The prevalence of such abnormal cholesterol values among persons who sustained myocardial infarctions was about 50% overall: 66% of women and 35–52% of men, in whom the prevalence of hypercholesterolaemia decreased in advanced age. Although the risk of coronary disease is distinctly greater in persons with such high cholesterol values, it is important to recognize that 20% of myocardial infarctions in the Framingham Study occurred in persons with cholesterol values
