Cholesterol and coronary heart disease mortality
Peter Sleight Field Marshal Alexander Professor of Cardiovascular Medicine, lJniversir.v of Oxford, John Radclqfe Hospital, Headingron, Oxford, UK.
Abstract: The epidemiological relation between increased levels of blood cholesterol and increased risk of future heart disease is clear, both within and between countries. These strong relationships have led to the adoption of consensus statements in most countries which recommend measures such as the reduction of dietary saturated fat/an increase in the polyiinsaturated/saturated ratio and other dietary and sometimes drug methods to reduce serum cholesterol. There is controversy as to whether these measures should be rargeted at individuals with high levels of cholesterol or whether rhere should be a public health approach to the whole population. The public and medical debate has become more heated since the data from intervention trials are conflicting. Taken overall the trials do appear to show reduction in risk of coronary which is stronger for noti fatal, compared with fatal coronary events. Meta analysis suggests that increasing benefit accrues from larger reductions and also longer reductions in cholesterol by intervention. However, individual trials frequently show variable results and some, especially the recent 15 year follow up of a Finnish five year intervention (by diet, cholesterol lowering and blood pressure lowering drugs) was strikingly adverse - although the total number of events was not large. Total mortality is much harder to influence and the sum of the available trials is hopelessly inadequate in size to address these questions. As a result confusion abounds and is unlikely to be clarified by the present on going trials. The need for more data is clear. The pilot study for the Oxford Cholesterol Study will be presenred as a prelude for a proposed main study in about 20 000 high risk individuals. (Aust N Z 3 Med 1992; 22: 576-579.) Key words: Cholesreroi, coronury disease, morraliry
INTRODUCTION t present we have the curious paradox that, at the same time as the epidemiology of the very strong relationship between cholesterol level and coronary mortality becomes increasingly clear, the opposition to national dietary change is growing more vociferous. Senior cardiologists' on both sides of the Atlantic are questioning the wisdom of intervention except in subjects at higher risk because their cholesterol levels fall at the higher end of our so called normal range.
A
CONTROVERSY OVER LIPID LOWERING POLICIES These critics of national policies on diet present several arguments. They mostly readily accept the
relationship between cholesterol and coronary risk but argue that intervention should only be offered to those subjects with raised levels - the so called high risk strategy. They cite the evidence that on linear scales the relationship between cholesterol level and risk is curvelinear, so that there is less absolute benefit in intervention to lower cholesterol at levels below 6.5 mmol. They also point out that there is little or no information as to the value of cholesterol lowering in particular groups of subjects such as women, the elderly, diabetics etc.
DANGERS OF LOWERING CHOLESTEROL These critics also argue that there is not any significant benefit on total mortality in any individ-
Correspondence 10: I'erer Sleight, Professor of' Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, IJK.
576
Aust N Z J Med 1992; 22
CHOI.ES1EROL. AND CHI)
ual trial of cholesterol lowering, or when all the cholesterol trials are pooled. Finally, several authors have drawn attention to the risks of cholesterol lowering. These arguments take several lines. In some trials, for example the WHO Clofibrate trial: there was an excess of cancer deaths, particularly Gastrointestinal (GI) cancer. However, it should be pointed out that after the trial was completed the follow-up showed that the ratio reversed, with more cancer deaths in the former placebo arm of the trial. There is also an epidemiologicalassociation between very low cholesterol and excess risk of cancer. This excess largely disappears after the first few years, which suggests that it is latent cancer which is causing the low cholesterol rather than vice versa. Another argument draws attention to the excess of violent death (suicide, accident, murder) seen when selected trials are pooled.3 When this is done these non cardiac causes of death are in marginally significant excess in the treated group. Individually no single cause shows a statistically significant excess. Nevertheless a hypothesis has been erected, which postulates that lowering cholesterol in the cell membranes in the central nervous system (CNS) might interfere with the number of serotonin receptors in the nerve cells and thereby change behaviour. This theory by Engleberg4 has been vigorously criticised. Severs’ points out that the modest 8.5-13.6% falls in cholesterol in these trials is still well within the physiologic range and very unlikely to compromise the capacity of the cells regulatory system to control membrane cholesterol. Marmot and his colleagues‘ found no relation between cholesterol and behaviour in the large prospective study of Whitehall civil servants.
ARE TRIALS INCONCLUSIVE? All these arguments have been reinforced by the recent well publicised results of a very much underpowered Finnish trial of lifestyle change in 1222 healthy businessmen of high social class.’ They had one or more of a number of risk factors (glucose, blood pressure, cholesterol etc). Six hundred and twelve were randomised to a mixture of interventions, including, in some, lipid lowering by diet and/or drugs (probucollclofibrate). Cholesterol was lowered somewhat (7.1-6.7 mmollL after 5 years), but rose back to the pretrial levels when the trial stopped. T h e subjects were followed up a further ten years. At this 15 year point, of all the baseline risk factors, only smoking was independently predictive of death. T h e results of the 15 year follow-up were remarkable. During the trial period there were no significant effects on total or cardiac deaths. ThereCHOI.ESTEKO1. A K I ) CHL?
after, the groups diverged strikingly with a significant excess of total and coronary mortality in the intervention group. There were 13 violent deaths in this group versus only one in the control group. This seems hard to relate to any delayed effect of a modest reduction of cholesterol in cell membranes some five to ten years earlier! A Lancet editorial ‘Should trials carry a health warning? (unsigned)” states: ‘the most boring interpretation of these results is that by some quirk of selection the intervention group had a higher cardiovascular disease risk’. Boring or not the play of chance seems much the most likely reason for these results. The number of deaths was ludicrously small to justify the media delight - 67 versus 46 control for total death, and 34 versus 14 for cardiac death. T h e result for total death is marginally significant ( P - 0.048). My confidence in being dismissive of these arguments is reinforced by the POSCH trial’ of partial ileal bypass. This produced many side effects, as might have been expected and so, of all the cholesterol trials, might have led to the greatest increase in suicide or violent death. Furthermore, the cholesterol lowering achieved (23% reduction over ten years) was the largest and longest of any trial. The result? - absolutely no increase in cancer or violent deaths in intervention versus control. Nevertheless, we clearly need more data to reassure critics (and ourselves) on this point.
HAVE TRIALS BEEN UNDERPOWERED? None of the trials has shown a reduction in total, as opposed to cardiovascular, mortality, but this is a quite misleading statement. The truth is that a meta-analysis of all cholesterol lowering trials (R Peto et al. unpublished) shows a nonsignificant reduction of 3% in total mortality. This is not significantly different from the 6% which might have been expected, based on epidemiological data. The fact is that these trials were generally done on relatively low risk middle aged men, many of whom died of non cardiovascular causes such as accidents, or cancer. Keech (personal communication) has calculated that about 650 000 subjects would need to be randomised to have adequate power to detect change in total mortality in such a trial. Even with current agents, such as the statins which lower cholesterol by 20-300/, randomisation of 50 000 subjects would be needed. T h e sum of patients randomised in trials reported so far is about 25 000 - an order of magnitude too small to detect a change in total mortality. HIGH RISK vs A POPULATION STRATEGY Fierce arguments have raged over this question. I believe both approaches are needed. One should Aust NZ J Med 1992; 22 577
TABLE 1 'Expected' Numbers of Deaths and Power to Detect Effects on Total Mortaltty in Current HMG CoA Reductase Inhibitor Trials of over 1000 Patients's
Nos, to be HMG CoA Type of patients 8. randomlsed reductase study name inhibitor
Estimated 5-6yr Approx nos of av cholesterol CHD ( + non-CHD) reduction deaths planned
Post MI patients
ssss
4500
LIPID 8000 CARE 4200 All other patients Post-CABG 1500 AFCAPS 8000 WOSCOPS 6500 Overview of trial results All Post-MI 16700 All other 16000
I
+ 80)
'Expected' nos of all-cause deaths' Statin Control
Power for total
Sirnvastatin Pravastatin Pravastatin
23% 1 8% 1 8Vo
360 700 260
+ 180)
197 405 157
243 475 183
38% 46% 1 3%
Lovastatin Lovastatin Pravastatin
1 8% I 8%
150 + 25) 100 + 150) 100 + 80)
80 120 85
95 130 95
2% 3O/o
1320 + 340) 350 + 255)
759 285
901 320
85O/o 12010
Various Various
1 8%
19VO 18Vo
+ 80)
7%
"Expected' numbers of deaths are calculated by assuming no effect on non-CHD deaths and a 1.1 relationship between the estimated 5 6 year average cholesterol reduction and the percentage reduction in CHD deaths, 'power' to detect a total mortality dlfference IS calculated as the probability of achieving 2P < O 01
experienced a vascular event, such as MI, stroke, peripheral vascular disease or angina, or who were hypertensive or diabetic. After a run-in period to ensure compliance they were randomised to 20 or 40 mgs/day of simvastatin or placebo. Over this period 96% continued to attend the clinic and compliance with treatment was 90%. Side effects were minimal, and not significantly different between active and placebo treatment in over 600 randomised subjects. Baseline cholesterol in these high risk subjects ranged from 3.6 to an astonishing 11.4 (mean 7.0) mmol/L. (They were under no treatment!) We intend to extend this to a full study in 18 000 similar subjects in a multicentre trial. Such a study is needed to answer questions about the effect on total mortality, and in important groups such as women, the elderly, diabetics etc. Current studies, even when pooled, may well not answer this question (see Table l)."
not lose the opportunity to intervene when a high risk individual, for example, after a myocardial infarction (MI), is identified, or in families with premature vascular disease. Important as this may be for the individual such a strategy would have negligible public health impact, since the large majority of events occur in individuals with so called 'normal' serum cholesterol. A strategy of lowering cholesterol in the whole population by diet and lifestyle change is likely to be far more effective. Evidence for this can be. seen in population statistics. Tunstall-Pedoe'" has recently pointed out that mortality fell steeply in the US from the mid-late 1960s, but was much later in the UK, where the decline started in the 1980s. These declines, in each case, started simultaneously in all ages, strongly suggesting an environmental influence, such as cigarette smoking, and/or dietary change. I do not believe that it is at all likely that lowering cholesterol to 6 mmol will cause harm. Studies from China" have shown the same relation between cholesterol and coronary risk, albeit at much lower risk and much lower cholesterol values, which do not even overlap the so called normal range in Western or urbanised societies. Nevertheless we badly need better trials to convince an apathetic profession (at least in the UK).
THE OXFORD CHOLESTEROL STUDY Over the last three years we have conducted a pilot study in Oxford (coordinator A Keech)." We have invited subjects at high risk to attend a 'Healthy Heart Clinic'. These were patients, identified from the Oxford hospital records, who had previously Ausr N Z J Med 1992; 578
The Role of Antioxidants: Vitamin E In this trial we will also 'factor in' vitamin E. T h e rationale for this is the accumulating evidence that oxidised low density lipoprotein (LDL) is taken u p by macrophages and smooth muscle cells to form the atherosclerotic p l a q ~ e . ' ~ . 'Vitamin ' E is an important defense against oxidation of LDL. CONCLUSION I believe the overwhelming epidemiological evidence supports Ancel Keys's hypothesis. I 6 . I 7 There are also enough experimental and clinical data to justify present public health advice on dietary change, but we need better trial data to convince sceptics and also to identify possible harmful effects of cholesterol lowering, if any. 22
CHOI.ESTEROL AND CHD
References 1. Oliver M F . Might treatment of hypercholesterolaemia
increase non-cardiac mortality? Lancet 1991; i: 1529.31. 2. Committee of Principal Investigators. W H O cooperative trial on primary prevention of ischaemic heart disease wlth clofibrate to lower serum cholesterol: final mortality followup. Lancet 1984; ii: 600-4. 3. Muldoon MI:, hianuck SR, Matthews KA. 1,owcring cholesterol concentrations and mortality: a quantitative revlew of primary prevention trials. Hr hied J 1990; 301: 309-14. 4. Engelberg H. Low serum cholesterol and suicide. Lancet 1992; 339: 727-9. 5. Severs NJ. Low serum cholesterol and suicide. Lancet 1902; 339: 1001. 6. Brunner E. Low serum cholesterol and suicide. Lancet 1992; 339: 1001-2. 5. Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ, Micttinen T A . Long-term mortality after 5-year multifactorial primary prevention of cardiovascular diseases in middle-aged men. JAMA 1991; 268: 1225-9. 8. Editorial. Should trials carry a health warning? 1,ancet 190 1; 338: 1495-6. 9. Huchwald H , Varco KL, hlatts JP cr a/. Effect of partial ileal bypass surgery on mortalitv and morbidity from coronary heart disease in patients with hpI’ercholesterolemia: report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 1990; 323: 946-55. 10. Tunstall-Pedoe H. Is the child the father of the man? Br Med J 1992; 304: 1312.
CHOI.ESTEROL A S D Clil)
I I . Chen ZM, Peto R, Collins R er a/. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. Br Med J 1991; 303: 276 82. I?. Keech A, for the Oxford Cholesterol Study Group. Randomised trial of the effects of cholesterol lowering with simvastatin in patients at increased risk of coronary heart disease. Arherosclerosis 1990; 85-92, and personal communication. 13. Collins R, Peto R, Keech er a/. Effects of cholesterol lowering on total mortality, need for larger trials. Br Med J 1992; in press. 14. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modification of low density lipoprotein that increases its atherogenicity. N Engl J Med 1989; 320: 915-24. 15. Keech A, Collins R, Petor R C I 01. Vitamin E supplementation inhibits L D L oxidation in patients at risk ofcoronary disease taking simvastatin or placebo. XI Int Sympos I)rugs Lip Met 1992 (abstract submitted). 16. Keys A. Seven Countries: a multivariate analysis of health and coronary heart disease in population with low cholesterol concentrations. Rr Med J 1991; 303: 276-82. 17. Martin MJ, Hulley SB, Browner WS, Kuller L H , Wentworth D. Serum cholesterol, blood pressure and mortality: implications from a cohort of 36 1 662 men. Lancet 1986; ii: 933-6. 18. Collins R, Keech A, Peto R, Sleight P EI al. Cholesterol and total mortality: need for larger trials. Hr Med J 1992; 304: 1689.
Aust K Z J Med 1992; 22
579
Peter Sleight Field Marshal Alexander Professor of Cardiovascular Medicine, lJniversir.v of Oxford, John Radclqfe Hospital, Headingron, Oxford, UK.
Abstract: The epidemiological relation between increased levels of blood cholesterol and increased risk of future heart disease is clear, both within and between countries. These strong relationships have led to the adoption of consensus statements in most countries which recommend measures such as the reduction of dietary saturated fat/an increase in the polyiinsaturated/saturated ratio and other dietary and sometimes drug methods to reduce serum cholesterol. There is controversy as to whether these measures should be rargeted at individuals with high levels of cholesterol or whether rhere should be a public health approach to the whole population. The public and medical debate has become more heated since the data from intervention trials are conflicting. Taken overall the trials do appear to show reduction in risk of coronary which is stronger for noti fatal, compared with fatal coronary events. Meta analysis suggests that increasing benefit accrues from larger reductions and also longer reductions in cholesterol by intervention. However, individual trials frequently show variable results and some, especially the recent 15 year follow up of a Finnish five year intervention (by diet, cholesterol lowering and blood pressure lowering drugs) was strikingly adverse - although the total number of events was not large. Total mortality is much harder to influence and the sum of the available trials is hopelessly inadequate in size to address these questions. As a result confusion abounds and is unlikely to be clarified by the present on going trials. The need for more data is clear. The pilot study for the Oxford Cholesterol Study will be presenred as a prelude for a proposed main study in about 20 000 high risk individuals. (Aust N Z 3 Med 1992; 22: 576-579.) Key words: Cholesreroi, coronury disease, morraliry
INTRODUCTION t present we have the curious paradox that, at the same time as the epidemiology of the very strong relationship between cholesterol level and coronary mortality becomes increasingly clear, the opposition to national dietary change is growing more vociferous. Senior cardiologists' on both sides of the Atlantic are questioning the wisdom of intervention except in subjects at higher risk because their cholesterol levels fall at the higher end of our so called normal range.
A
CONTROVERSY OVER LIPID LOWERING POLICIES These critics of national policies on diet present several arguments. They mostly readily accept the
relationship between cholesterol and coronary risk but argue that intervention should only be offered to those subjects with raised levels - the so called high risk strategy. They cite the evidence that on linear scales the relationship between cholesterol level and risk is curvelinear, so that there is less absolute benefit in intervention to lower cholesterol at levels below 6.5 mmol. They also point out that there is little or no information as to the value of cholesterol lowering in particular groups of subjects such as women, the elderly, diabetics etc.
DANGERS OF LOWERING CHOLESTEROL These critics also argue that there is not any significant benefit on total mortality in any individ-
Correspondence 10: I'erer Sleight, Professor of' Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, IJK.
576
Aust N Z J Med 1992; 22
CHOI.ES1EROL. AND CHI)
ual trial of cholesterol lowering, or when all the cholesterol trials are pooled. Finally, several authors have drawn attention to the risks of cholesterol lowering. These arguments take several lines. In some trials, for example the WHO Clofibrate trial: there was an excess of cancer deaths, particularly Gastrointestinal (GI) cancer. However, it should be pointed out that after the trial was completed the follow-up showed that the ratio reversed, with more cancer deaths in the former placebo arm of the trial. There is also an epidemiologicalassociation between very low cholesterol and excess risk of cancer. This excess largely disappears after the first few years, which suggests that it is latent cancer which is causing the low cholesterol rather than vice versa. Another argument draws attention to the excess of violent death (suicide, accident, murder) seen when selected trials are pooled.3 When this is done these non cardiac causes of death are in marginally significant excess in the treated group. Individually no single cause shows a statistically significant excess. Nevertheless a hypothesis has been erected, which postulates that lowering cholesterol in the cell membranes in the central nervous system (CNS) might interfere with the number of serotonin receptors in the nerve cells and thereby change behaviour. This theory by Engleberg4 has been vigorously criticised. Severs’ points out that the modest 8.5-13.6% falls in cholesterol in these trials is still well within the physiologic range and very unlikely to compromise the capacity of the cells regulatory system to control membrane cholesterol. Marmot and his colleagues‘ found no relation between cholesterol and behaviour in the large prospective study of Whitehall civil servants.
ARE TRIALS INCONCLUSIVE? All these arguments have been reinforced by the recent well publicised results of a very much underpowered Finnish trial of lifestyle change in 1222 healthy businessmen of high social class.’ They had one or more of a number of risk factors (glucose, blood pressure, cholesterol etc). Six hundred and twelve were randomised to a mixture of interventions, including, in some, lipid lowering by diet and/or drugs (probucollclofibrate). Cholesterol was lowered somewhat (7.1-6.7 mmollL after 5 years), but rose back to the pretrial levels when the trial stopped. T h e subjects were followed up a further ten years. At this 15 year point, of all the baseline risk factors, only smoking was independently predictive of death. T h e results of the 15 year follow-up were remarkable. During the trial period there were no significant effects on total or cardiac deaths. ThereCHOI.ESTEKO1. A K I ) CHL?
after, the groups diverged strikingly with a significant excess of total and coronary mortality in the intervention group. There were 13 violent deaths in this group versus only one in the control group. This seems hard to relate to any delayed effect of a modest reduction of cholesterol in cell membranes some five to ten years earlier! A Lancet editorial ‘Should trials carry a health warning? (unsigned)” states: ‘the most boring interpretation of these results is that by some quirk of selection the intervention group had a higher cardiovascular disease risk’. Boring or not the play of chance seems much the most likely reason for these results. The number of deaths was ludicrously small to justify the media delight - 67 versus 46 control for total death, and 34 versus 14 for cardiac death. T h e result for total death is marginally significant ( P - 0.048). My confidence in being dismissive of these arguments is reinforced by the POSCH trial’ of partial ileal bypass. This produced many side effects, as might have been expected and so, of all the cholesterol trials, might have led to the greatest increase in suicide or violent death. Furthermore, the cholesterol lowering achieved (23% reduction over ten years) was the largest and longest of any trial. The result? - absolutely no increase in cancer or violent deaths in intervention versus control. Nevertheless, we clearly need more data to reassure critics (and ourselves) on this point.
HAVE TRIALS BEEN UNDERPOWERED? None of the trials has shown a reduction in total, as opposed to cardiovascular, mortality, but this is a quite misleading statement. The truth is that a meta-analysis of all cholesterol lowering trials (R Peto et al. unpublished) shows a nonsignificant reduction of 3% in total mortality. This is not significantly different from the 6% which might have been expected, based on epidemiological data. The fact is that these trials were generally done on relatively low risk middle aged men, many of whom died of non cardiovascular causes such as accidents, or cancer. Keech (personal communication) has calculated that about 650 000 subjects would need to be randomised to have adequate power to detect change in total mortality in such a trial. Even with current agents, such as the statins which lower cholesterol by 20-300/, randomisation of 50 000 subjects would be needed. T h e sum of patients randomised in trials reported so far is about 25 000 - an order of magnitude too small to detect a change in total mortality. HIGH RISK vs A POPULATION STRATEGY Fierce arguments have raged over this question. I believe both approaches are needed. One should Aust NZ J Med 1992; 22 577
TABLE 1 'Expected' Numbers of Deaths and Power to Detect Effects on Total Mortaltty in Current HMG CoA Reductase Inhibitor Trials of over 1000 Patients's
Nos, to be HMG CoA Type of patients 8. randomlsed reductase study name inhibitor
Estimated 5-6yr Approx nos of av cholesterol CHD ( + non-CHD) reduction deaths planned
Post MI patients
ssss
4500
LIPID 8000 CARE 4200 All other patients Post-CABG 1500 AFCAPS 8000 WOSCOPS 6500 Overview of trial results All Post-MI 16700 All other 16000
I
+ 80)
'Expected' nos of all-cause deaths' Statin Control
Power for total
Sirnvastatin Pravastatin Pravastatin
23% 1 8% 1 8Vo
360 700 260
+ 180)
197 405 157
243 475 183
38% 46% 1 3%
Lovastatin Lovastatin Pravastatin
1 8% I 8%
150 + 25) 100 + 150) 100 + 80)
80 120 85
95 130 95
2% 3O/o
1320 + 340) 350 + 255)
759 285
901 320
85O/o 12010
Various Various
1 8%
19VO 18Vo
+ 80)
7%
"Expected' numbers of deaths are calculated by assuming no effect on non-CHD deaths and a 1.1 relationship between the estimated 5 6 year average cholesterol reduction and the percentage reduction in CHD deaths, 'power' to detect a total mortality dlfference IS calculated as the probability of achieving 2P < O 01
experienced a vascular event, such as MI, stroke, peripheral vascular disease or angina, or who were hypertensive or diabetic. After a run-in period to ensure compliance they were randomised to 20 or 40 mgs/day of simvastatin or placebo. Over this period 96% continued to attend the clinic and compliance with treatment was 90%. Side effects were minimal, and not significantly different between active and placebo treatment in over 600 randomised subjects. Baseline cholesterol in these high risk subjects ranged from 3.6 to an astonishing 11.4 (mean 7.0) mmol/L. (They were under no treatment!) We intend to extend this to a full study in 18 000 similar subjects in a multicentre trial. Such a study is needed to answer questions about the effect on total mortality, and in important groups such as women, the elderly, diabetics etc. Current studies, even when pooled, may well not answer this question (see Table l)."
not lose the opportunity to intervene when a high risk individual, for example, after a myocardial infarction (MI), is identified, or in families with premature vascular disease. Important as this may be for the individual such a strategy would have negligible public health impact, since the large majority of events occur in individuals with so called 'normal' serum cholesterol. A strategy of lowering cholesterol in the whole population by diet and lifestyle change is likely to be far more effective. Evidence for this can be. seen in population statistics. Tunstall-Pedoe'" has recently pointed out that mortality fell steeply in the US from the mid-late 1960s, but was much later in the UK, where the decline started in the 1980s. These declines, in each case, started simultaneously in all ages, strongly suggesting an environmental influence, such as cigarette smoking, and/or dietary change. I do not believe that it is at all likely that lowering cholesterol to 6 mmol will cause harm. Studies from China" have shown the same relation between cholesterol and coronary risk, albeit at much lower risk and much lower cholesterol values, which do not even overlap the so called normal range in Western or urbanised societies. Nevertheless we badly need better trials to convince an apathetic profession (at least in the UK).
THE OXFORD CHOLESTEROL STUDY Over the last three years we have conducted a pilot study in Oxford (coordinator A Keech)." We have invited subjects at high risk to attend a 'Healthy Heart Clinic'. These were patients, identified from the Oxford hospital records, who had previously Ausr N Z J Med 1992; 578
The Role of Antioxidants: Vitamin E In this trial we will also 'factor in' vitamin E. T h e rationale for this is the accumulating evidence that oxidised low density lipoprotein (LDL) is taken u p by macrophages and smooth muscle cells to form the atherosclerotic p l a q ~ e . ' ~ . 'Vitamin ' E is an important defense against oxidation of LDL. CONCLUSION I believe the overwhelming epidemiological evidence supports Ancel Keys's hypothesis. I 6 . I 7 There are also enough experimental and clinical data to justify present public health advice on dietary change, but we need better trial data to convince sceptics and also to identify possible harmful effects of cholesterol lowering, if any. 22
CHOI.ESTEROL AND CHD
References 1. Oliver M F . Might treatment of hypercholesterolaemia
increase non-cardiac mortality? Lancet 1991; i: 1529.31. 2. Committee of Principal Investigators. W H O cooperative trial on primary prevention of ischaemic heart disease wlth clofibrate to lower serum cholesterol: final mortality followup. Lancet 1984; ii: 600-4. 3. Muldoon MI:, hianuck SR, Matthews KA. 1,owcring cholesterol concentrations and mortality: a quantitative revlew of primary prevention trials. Hr hied J 1990; 301: 309-14. 4. Engelberg H. Low serum cholesterol and suicide. Lancet 1992; 339: 727-9. 5. Severs NJ. Low serum cholesterol and suicide. Lancet 1902; 339: 1001. 6. Brunner E. Low serum cholesterol and suicide. Lancet 1992; 339: 1001-2. 5. Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ, Micttinen T A . Long-term mortality after 5-year multifactorial primary prevention of cardiovascular diseases in middle-aged men. JAMA 1991; 268: 1225-9. 8. Editorial. Should trials carry a health warning? 1,ancet 190 1; 338: 1495-6. 9. Huchwald H , Varco KL, hlatts JP cr a/. Effect of partial ileal bypass surgery on mortalitv and morbidity from coronary heart disease in patients with hpI’ercholesterolemia: report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 1990; 323: 946-55. 10. Tunstall-Pedoe H. Is the child the father of the man? Br Med J 1992; 304: 1312.
CHOI.ESTEROL A S D Clil)
I I . Chen ZM, Peto R, Collins R er a/. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. Br Med J 1991; 303: 276 82. I?. Keech A, for the Oxford Cholesterol Study Group. Randomised trial of the effects of cholesterol lowering with simvastatin in patients at increased risk of coronary heart disease. Arherosclerosis 1990; 85-92, and personal communication. 13. Collins R, Peto R, Keech er a/. Effects of cholesterol lowering on total mortality, need for larger trials. Br Med J 1992; in press. 14. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modification of low density lipoprotein that increases its atherogenicity. N Engl J Med 1989; 320: 915-24. 15. Keech A, Collins R, Petor R C I 01. Vitamin E supplementation inhibits L D L oxidation in patients at risk ofcoronary disease taking simvastatin or placebo. XI Int Sympos I)rugs Lip Met 1992 (abstract submitted). 16. Keys A. Seven Countries: a multivariate analysis of health and coronary heart disease in population with low cholesterol concentrations. Rr Med J 1991; 303: 276-82. 17. Martin MJ, Hulley SB, Browner WS, Kuller L H , Wentworth D. Serum cholesterol, blood pressure and mortality: implications from a cohort of 36 1 662 men. Lancet 1986; ii: 933-6. 18. Collins R, Keech A, Peto R, Sleight P EI al. Cholesterol and total mortality: need for larger trials. Hr Med J 1992; 304: 1689.
Aust K Z J Med 1992; 22
579
