Strategies for Preventing Coronary Heart Disease

Michael F. Oliver, M. D., F, R. C. P.

Strategy is simple, but not easy. - Clausewitz

ltering lifestyles through whole-population A intervention, and specific intervention with identified high-risk individuals are complemen- tary, not opposing strategies for reducing risk of coronary heart disease. They are valid alter- natives, presenting society with different choices and uses of its limited resources. Community health educators, and, evidently, epidemiologists, prefer mass intervention. To many physicians, the high-risk strategy is likely to be more attractive. In the best of all possible worlds, we should be able to afford both poli- cies if they truly benefit society.

So far, however, the results of investment in mass intervention trials have not been impres- sive - a very considerable outlay has pro- duced little or no yield. It is argued that such trials are unnecessary, because the cost of changing individual lifestyles on a mass-popu- lation basis is negligible, and it is not expensive to promote campaigns telling people to stop smoking, change their diets or exercise more. The argument assumes that such advice is bound to do more good than harm.

Improved health, however, is not the only public need. Simply to argue that cigarette smoking should be eliminated without consid- ering economic and employment repercus- sions is a narrow medical view. Similarly, rec- ommended changes in farm policy and economy leading to dairy farming reductions by one quarter or one third need much more thought than they usually receive from health education enthusiasts. Reducing milk produc- tion and requiring less carcass fat imply a sub-

Dr.Oliver is Duke of Edinburgh Professor of Cardio- logy, University of Edinburgh, Edinburgh, Scotland EH8 9XF.

stantial reduction in animal feed, of which bar- ley is the major component.1 Land would be released for other purposes, but perhaps more would be available than is needed for fruit and vegetables. The case for making large changes in agricultural strategy, with all its re- percussions on cereal, fruit, vegetable and edi- ble oil production and on the welfare of those working in these industries, should surely be based on clear evidence that such changes will consequently improve public health. This evi- dence is not yet apparent.

Mass Intervention for Individuals at Moderate Risk

One of the underlying problems with inter- vention to prevent coronary heart disease is the very low specificity with which we are able to identify individuals at risk. The strength of the concept relating risk factors to coronary heart disease lies in the factors’ relative or proportional risk, and not in their absolute risk or predictive power. While it is undeniable that those individuals with serum cholesterol or blood pressure in the top 10 or 20 percent of the population distribution have a higher risk than those with lower levels,2-4 the actual risk is low. Thus, two thirds of healthy adult males (40 to 55 years of age) found to have the highest risk (above the 80th percentile) as a result of elevated cholesterol (excluding famil- ial hypercholesterolemia) and blood pressure can be estimated to remain healthy over the next 25 years.2 It is hoped that this low specifi- city will improve when some of the emerging predictors of thrombogenic risk have been evaluated.

It should not be a surprise, therefore, or be particularly controversial, that intervention to

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control raised cholesterol and raised blood pressure in healthy adult men who are at mod- erate risk, even when conducted simultane- ously with reduction of cigarette smoking, has not been successful on a mass basis.5-7 What lessons does this failure teach us? One argu- ment, given in defense by enthusiasts, is that too little has been done too late. We will only know if this is true when more has been done earlier. But it is impractical to do much more. For example, in the Multiple Risk Factor Inter- vention Trial,5 attempts were made to pro- foundly alter consumption of dietary fat, along the lines recommended by the World Health Organization.8 It is quite clear, however, from the disappointing reduction in plasma choles- terol and the unchanged incidence of coronary heart disease, that compliance was indifferent despite advice received from teams of physi- cians, dietitians, sociologists and psycholo- gists. To do more to control blood pressure means lifelong use of potent drugs with their attendant side effects. More might be done, however, about cigarette smoking, although the chances of eliminating this habit are negli- gible. Another common argument from those committed to mass intervention is that 5 or 10 years is too short a period to appraise trial results, because coronary atherosclerosis takes many years to develop and an equal period may be necessary to prove the effec- tiveness of changes in lifestyle on coronary heart disease. This may be so. But coronary atherosclerosis and coronary heart disease do not equate, and even successful demonstra- tion of regression of coronary atherosclerosis does not necessarily mean less coronary heart disease. There are no large, randomized multi- ple-risk-factor intervention trials against coro- nary heart disease proceeding into a second decade of testing, and so how shall we know? Evidently, we will have to rely on the interpre- tation of national trends in coronary heart dis- ease mortality rates to guide prevention poli- cies. There are, however, so many con- founding influences that this information does not look promising.

Selective Intervention for Individuals at High Risk

The scientific evidence supporting interven-

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tion for those at high risk for coronary heart disease due to hypercholesterolemia is much stronger than for those at moderate risk. But intervention efficacy is still uncertain because the numbers of subjects in the two main trials -the Oslo trial9 and the Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT)lo in which very high (95th per- centile) serum cholesterol levels were reduced - are too small, and the margins of difference in coronary heart disease rates are too narrow to ascertain whether and how large a propor- tion of the public will benefit from treatment. In the Oslo Heart Study (comprising 1,232 men aged 40 to 49 years), there was a significant reduction (p<0.03) in the mixed endpoint of cardiac death and nonfatal myocardial infarc- tion. There was, however, one case of sudden “unexplained” death in the control group. If this case was not due to coronary heart disease, and if it had been randomized to the interven- tion group, total coronary heart disease and total cardiovascular events would not have been significant at the 5 percent level.11 The LRC-CPPT showed a 19 percent fall in heart disease incidence (a mixed endpoint of coro- nary deaths and nonfatal myocardial infarc- tion) in the experimental group, significant at the 4 percent level using a one-tail test of significance. The confidence limits of + 3 and +32 percent (or -0.1 percent and +3.5 per- cent, considering difference in riskll) sur- rounding the main endpoints do not provide a sound enough basis to argue, as the authors have done, that these results provide the basis for lowering moderately raised cholesterol and low density lipoproteins in lower-risk popula- tions. The consistency between the results of these two trials, however, is impressive. Addi- tionally, the LRC-CPPT showed nonsignifi- cant reductions in the incidence of angina, and abnormal exercise ECT referrals for coronary artery surgery. There was also a reduced rate of coronary heart disease incidence in three other trials of reducing high concentrations of serum cholesterol-the WHO clofibrate trial,12 and the Helsinki Mental Hospitals13 and Vet- erans’ Administration Studies,14 in which diets high in polyunsaturated fatty acids were used.

The frailty of the above case is enhanced by the fact that all these studies, including the

dietary intervention trials, showed an increase in noncardiovascular mortality. In several trials, the order of magnitude of this increase was comparable to that of the decrease in coronary heart disease.15 The increase in non- cardiovascular mortality in the WHO clofibrate trial has recently been shown to relate closely to the period of administration of the drug.16 The increase in the incidence of oral-gastroin- testinal cancers which occurred in the LRC- CPPT should not be dismissed as a random change in cancer prevalence, since a plausible explanation-a change in the pH of bowel con- tents due to the cholestyramine anion-ex- change resin-may be advanced.

It has been argued17 that the results of all trials, when lumped together, regardless of treatment, design, numbers and mixed end- points, show a mathematically convincing pre- ventive effect on nonfatal coronary heart dis- ease. By the same analysis, total non- cardiovascular mortality in the combined ex- perimental groups was not reduced,l7 which cannot be easily dismissed.

The basis for intervening with those at high risk due to marked hypertension is that the incidence of strokes is reduced. If this were not so, it might be hard to make a strong case for lowering moderately elevated blood pressure to reduce coronary heart disease, for the evi- dence of benefit is unconvincingl* and inter- vention may even be harmful in those with established signs of myocardial ischemia.5

Nevertheless, the case for intervention with individuals at very high risk for coronary heart disease is stronger than the case for doing nothing. We are justified in exposing these indi- viduals to the risks of drugs and the inconven- ience of stringent dietary changes. The Ameri- can Heart Association has recently made appropriate recommendations for the manage- ment of such people.19 How can we best iden- tify such individuals?

To Screen or Not To Screen Just as there are alternative conceptual ap-

proaches to intervention, there are alternatives for screening the population in order to identify people at greatest risk for coronary heart dis- ease.

Screening is considered an unnecessary

event by those health officials who propound a policy of mass prevention, since they wish to advise the whole population to change its life- style. But for those who have doubts about the value and practicality of mass intervention and who endorse the high-risk strategy, the difficult question of how to screen the population sim- ply, cheaply, effectively and without producing anxiety must be addressed. The alternatives are to screen the entire male adult population, or to try to identify, mostly through clinical ex- pertise, those at maximum risk. Individual and collective approaches to the latter (that is, case-finding) depend to an extent upon the medical specialties of the physicians involved.

At present, the best policy seems to be to identify those adults above the 80th percentile of the distribution of serum cholesterol or blood pressure, who are clearly in need of advice. There are three reasons for adopting this atti- tude. One is that the relationship of a given risk factor to the subsequent development of coro- nary heart disease is increasingly diluted by other known and unknown factors at lower de- ciles-in other words, specificity decreases. The relationship is relatively good at high levels. Recent figures for the Multiple Risk Factor Intervention Trial20 indicate that nearly 50 percent of cases of coronary heart disease “attributable” to serum cholesterol occur in those with serum concentrations above the 80th percentile, and 30 percent of cases occur in those above the 90th percentile. The United KingdomNVHO trial21 has also shown, taking four factors into account, that 32 percent of “attributable” cases occur in those above the 85th percentile of risk. A second reason is that successful treatment of very high serum cho- lesterol and blood pressure levels requires the use of drugs. Medication should only be ethi- cally acceptable to physicians when the risk of the disease is at least equal to the risk of giving drugs,*2 and to symptom-free people when there is a valid reason for making big changes in their lifestyle and committing themselves to drugs for the rest of their days. A third reason for a high “cutoff point is that the costbenefit ratio increasei when intervention is attempted below the 80th percentile, due to greater use, and therefore costs, of drugs in relation to a decreasing ultimate expected benefit.

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Screening of All Adult Males At least two considerations need to be

thought through by those who advocate screening the adult male population for subse- quent implementation of high-risk intervention against coronary heart disease. One is the practicality, cost and advantage to society of universal screening. The other is the possible disadvantage to those for whom specific inter- vention is not really indicated. Incidentally, data concerning the relation of risk factors to coronary heart disease in women is far less well assembled than for men and none of the clinical trials referred to above included women. The evidence is that the prevalence and significance of risk factors in women is lower and, until more formal evidence is avail- able, a case for screening the female adult population cannot be adequately supported. Additionally, most of the data relating risk fac- tors to coronary heart disease come from stud- ies of those under 60 years of age. There is really no case for screening, and expecting subsequent benefit, in those over 60. The em- phasis should be on the young and the middle- aged.

While blood pressure measurement is easy and acceptable to most, a venipuncture for measuring serum cholesterol is less so. Spe- cial facilities and improved laboratory services might be required. There are about 12.5 million men aged 15 to 55 in the United Kingdom. The cost of estimating serum cholesterol is in the range of f 3 ($4) per person, or f37.5 million ($50 million) for this population. In order to focus on the top 20 percent at highest risk, a repeat estimate would be necessary together with measurement of HDL cholesterol (at about f 3 [$4]) per person and this might add f12.5 million ($16 million) to the total. Thus, identification of the top quintile might cost f50 million ($65 million). This calculation is only for biochemical analyses, and does not include costs of staff and facilities necessary to do venipunctures.

Screening the adult male population will identify many individuals with raised choles- terol and raised blood pressure between the 50th and 80th percentiles. What should we tell these people? We know that their risk of coro- nary heart disease is only slightly higher than

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that of those in the three deciles below the median. We know that prediction of coronary heart disease is weak and that it cannot be individualized. Finally, we know that mass in- tervention has, so far, been singularly disap- pointing. Even in a health-conscious commun- ity, informing these men about their serum cholesterol or blood pressure will probably not be conducive to reassurance, so long as the medical profession lacks a strong basis for advice or action. Indeed, it is likely to increase anxiety. Physicians who support male adult population screening programs should, there- fore, first ask themselves what they will advise when screening identifies an otherwise fit, nonobese 35-year-old man with serum choles- terol or blood pressure in the sixth to eighth deciles. Should he be told? If so, what should he be told about his individual risk and how to reduce it? Should the test be repeated in 1 or 5 years’ time, or should the mildly abnormal re- sult be completely ignored? Each of these questions must be identified and answered by policy makers.

Selective Screening There are problems of comparable difficulty

for those who advocate selective screening on the basis of clinical acumen, or case-finding. The biggest of these-and there is no informa- tion available at present-is the proportion of high-risk individuals (above the 80th percen- tile) that would be missed by even the most assiduous clinical screening programs. If this proportion was large, then the strategy of se- lective screening would probably have to be abandoned in favor of mass screening.

Selective screening may identify currently symptom-free individuals with marked hyper- cholesterolemia. It is less suitable for finding those with marked hypertension, except through hypertensive families. The finding of tendon xanthomata, for which a routine search should be made, points to monogenic familial hypercholesterolemia, but this only comprises about 15 percent of those with severe hyper- cholesterolemia, with most being polygenic. Identification of a premature corneal arcus or xanthelasma should spread the net a little wider; it is interesting that ophthalmologists do not seem to look for these features routinely.

The recent American Heart Association rec- ommendations19 emphasize that family screening can be the key to diagnosis. A big yield might come from the first-degree rela- tions of patients who have developed any clini- cal features of coronary heart disease under the age of about 50.23 It apparently is rare for physicians dealing with large numbers of hos- pitalized coronary heart disease patients to routinely screen first-degree relations for serum cholesterol and blood pressure levels. This is a matter of improving education. Family doctors, especially, should be able to add con- siderably to the yield by identifying families with aggregation of vascular disease, and screening the apparently healthy relatives.

One advantage of case-finding is that pa- tients’ motivation to identify their high-risk rela- tives, and their doctors’ motivation to inter- vene, will be far higher than that of the general population. It is up to physicians to join epide- miologists and to demonstrate via population surveys whether or not the majority of those at high risk are identified by selective screening on the basis of case-finding.

Improving Prediction Whichever screening strategy is favored,

coronary heart disease will occur in many peo- ple in whom it was not predicted or was, in fact, predictable. This phenomenon is the inevitable consequence of its multiple etiology. The strengths and weaknesses of the classic risk factors of cigarette smoking, raised serum cholesterol level and raised blood pressure in predicting coronary heart disease are now well established. Nonetheless, little new in terms of measurements for screening the population for coronary heart disease has become available during the last 10 years.

Sharpening the methods for identifying those at very high risk is overdue. Perhaps the most obvious and urgent area in need of im- provement is prediction of incipient arthero- genesis and thrombogenesis. Identification of new DNA polymorphisms-such as athero- genic apoprotein gene clusters-that might be applicable to some readily available tissue such as skin is one hope. Knowledge of the factors that make people intrinsically resistant to coronary heart disease is another important

research area. More studies are needed of the characteristics of families and individuals who do not get coronary heart disease; this is an area of almost complete ignorance.

One of the greatest priorities, then, for the control of coronary heart disease is to improve both the sensitivity and the specificity with which we are able to predict its development.

Summary Intervention in whole populations, and spe-

cific intervention in high-risk groups, are com- plementary rather than opposing strategies for reducing the risk of coronary heart disease. So far, however, the efficacy of mass intervention efforts via drugs and/or diets is unimpressive. The scientific evidence for intervention with those at high risk is much stronger than for those at moderate risk. Screening of adult males is thus a reasonable strategy, although whether such screening should be general or selective is debatable. Current methods of pre- dicting coronary heart disease must be im- proved in order to facilitate long-term interven- tion with diet and/or drugs.

Despite the importance of coronary heart disease as a public health problem, it is point- less to attempt to control the disease by imple- menting ineffective preventive strategies. 0

The Editor thanks Dr. Oliver and Dennis Krikler, Editor of British Heart Journal, for theirpermission to reprint this article. Strategies for Preventing Coro- nary Heart Disease originally appeared, in slightly different form, in British Heart Journal 54: 1-5, 1985.

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