Evaluating the effectiveness of dyslipidemia control strategies

ATHEROSCLEROSIS Atherosclerosis

108 (Suppl.) (1994) Sl27-5135

Evaluating the effectiveness of dyslipidemia control strategies Thomas E. Kottke *a*b,Hiroyuki Daida”,’ “Division of Cardiovmcular

Diseases and Internal Fomdation.

Medicine,

“Department

Rochester. Minnesota.

of Health Sciences Research, Mayo MN

55905,

Clinic and Mayo

USA

Abstract

While cost-electiveness analyses of anti-hyperlipidemia programs featuring drug treatment suggest that the best use of public dollars is to delay treatment until an individual develops coronary heart disease, a comprehensive hyperlipidemia treatment policy must take a broader perspective. The high case-fatality rates of patients exhibiting first manifestations of coronary heart disease, the limited population impact of interventions aimed solely at high risk groups, the cost of testing to identify the high risk segment cf the population, the social origins of the behavioral risk factors for coronary heart disease, and the perspective of the individual must also be considered. Available data suggest that the best public policy to control the burden of heart disease is one with two components: On the one hand, all individuals without clinically manifest heart disease would be encouraged to adopt healthy behaviors without an attempt to sort the population into ‘high’ and ‘not high’ risk groups. On the other hand, the risk factors of individuals who already have coronary heart disease would be treated aggressively with a case-management system of follow-up. The data that support this conclusion are presented in this paper. Keywords:

Hyperlipidemia;

Populations; Treatment; Evaluation strategies

1. Introduction There is consensus that lowering serum cholesterol levels both lowers the risk of developing coronary heart disease for those without clinically manifest disease and lowers the risk of recurrent events for individuals who already have disease [ 11.The relationship of serum cholesterol to coronary heart disease also satisfies the criteria that justify preventive intervention [ 21. Exactly what

* Corresponding author, Tel.: 5071284-4898; Fax: 507/2841516. ‘Present address: Juntendo University, Tokyo, Japan. Supported in part by NIH Grants He24326 and AR30582.

should be done to manage serum cholesterol in populations, however, is widely disputed [ 3,4]. When designing prevention programs, limiting the intervention to individuals at highest risk can appear to be the most cost-effective [S] and efficient strategy because it iimits the size of the task [6] and focuses resources on the individuals who are most likely to have an event in the near future [7]. On the other hand, there is evidence that it is the goals that communities share that make coronary heart disease rates high in some populations and low in other populations [b,‘ij. These data suggest that hyperlipidemia is a common source epidemic that can only be controlled by addressing the goal behaviors of entire populations [lo- 121.

0021-9150/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0021-9150(94)05298-W

S128

T.E. Kottke. H. Duidu

1 Atherosclerosis

108 (Suppl.)

(1994)

S127-S135

Costperyear of lie saved($10.000s)

Secondaryprevention, TSC z-250,age 55-64

Primaryprevention. DBP>105.smoker, obese,TSC-300. age 55-64

Primarypreventbn. DBP&. nonsmoker, non-obese,TSC - 300, age 35-44

Fig. 1. The cost-effectiveness of drug treatment for hyperlipidemia can vary by over one thousand-fold depending on the characteristics of the patient. Secondary prevention is far more cost effective than primary prevention because the individuals who are treated are more likely to have an event in the near future. Adapted from Goldman et al. [S]. with permission.

A comprehensive public policy towards hyperlipidemia can be developed only after at least four phenomena are considered: (i), if the policy is to wait until coronary heart disease is clinically manifest, 25% to 300/uof those who de&op coronary heart disease will die before lipid treatment can have an effect [ 131; (ii), if an intervention is aimed solely at a small high risk group, even the most effective intervention will have a limited impact on disease rates for the population as a whole [ 141; (iii), if the intervention strategy requires identification of the high risk, the cost of testing to identify this segment of the population may be greater than the financial benefits that accrue from limiting the size of the intervention pool [ 151; (iv). limiting the scope of the intervention pool rather than addressing the goals of the population may actually reduce the effectiveness of an intervention because the behavioral risk factors for coronary heart disease are usually products of a population’s social goals and are not simply attributes of individuals [lo- 121. A fifth factor is important from the perspective of the individual: Even though screening to identify modifiable risk factors may llot be cost effective from the public policy perspective, it may be cost-effective from the perspective of the individual who is trying to protect future livelihood and

well-being by minimizing personal risk of developing coronary heart disease. Available data suggest that the best public policy to control the burden of heart disease is one that has two components: For individuals without clinically manifest heart disease, resources would be directed towards creating opportunities to adopt and maintain healthy behaviors; minimal resources would be devoted to sorting the population into ‘high’ and ‘not high’ risk groups. For individuals who already have coronary heart disease, a case-manager system would be developed to aggressively treat all identifiable risk factor deviations. The rationale for this conclusion is discussed in the following paragraphs. 2. Secondary prevention: cost-effective, but a lost opportunity for many has been observed that serum cholesterol discriminates risk for future events far better for individuals with coronary heart disease than for individuals who have yet to experience a clinical event [16]. It has also been calculated that, on the one hand, drug treatment of hyperlipidemia among patients who have suffered a non-fatal coronary event can both increase life expectancy and reduce future medical costs while, on the It

T.E. Kottke, H. Daida 1 Atherosclerosis 108 (Suppl.) (1994) S127-S135

-

0

1

2

3

4

5

6

s129

men

7

6

9

10

years

Fig. 2. Over50%of women andover 40% of men are dead within two years of experiencing a definite coronary event (myocardial infarction or sudden unexpected death). If public poky were to focus exclusively on secondary prevention, this segment of the population could not benefit from hyperlipidemia t&tment.

other hand, treating otherwise low risk hyperlipidemic individuals may cost hundreds of thousands of dollars per life-year gained [ 51 (Fig. 1). The fact that the event to be prevented for primary prevention occurs far in the future makes the cost of drug treatment and the efficacy of drug treatment the two most important factors in the cost-effectiveness calculation. Future health care costs, the survival rate after the appearance of coronary heart disease, and similar factors have almost no impact on the cost-etrectiveness estimations [7]. Even though secondary prevention is the most cost-effective use of drugs, 45% of men and 50% of women who experience a definite coronary heart disease event (myocardial infarction or sudden unexpected death) will be dead within two years [lo] (Fig. 2). Because two years is the time that is required for lipid interventions to take effect [ 17,181, these individuals will not have an opportunity to benefit from a policy that focuses on secondary prevention. 3. The clustering of risk: weak within populations Serum cholesterol was first observed to be a risk factor because it discriminates between populations with high and populations with low rates of heart disease. For example, a total serum cholesterol of 200 mg/dl is abnormal in both

Japan and Finland - it is abnormally high in Japan and abnormally low in Finland [ 191(Fig. 3, left panel). However, total serum cholesterol values discriminate quite poorly between individuals who will become diseased and those who will remain disease free at the end of a period of time (Fig. 3, right panel) [lo]. Thus it has been correctly concluded that for individuals, serum cholesterol is a poor predictor of coronary heart disease risk [20]. An additional difficulty in trying to predict the appearance of coronary heart disease for Americans is that over a short period of time practically no one will develop coronary heart disease [21]. However, over a lifetime, the risk of developing coronary heart disease is widely disseminated and is the leading cause of death for both men and women. This wide dissemination of risk in western populations results in an inability to address the majority of preventable disease by focusing on high risk groups alone [22]. This can be demonstrated by comparing the achieved and potential impact of the Multiple Risk Factor Intervention Trial (MRFIT) to the achieved and potential impact of the North Karelia Project (Fig. 4) [ 141. MRFIT screened for high risk men with the goal of reducing the burden of heart disease in the population by focusing an intensive intervention on the top 10% of the population at risk. Rather

s130

T.E. Kottke, H. Dad

/ Atherosclerosis 108 (Suppl.) (1994) S127-S135

r

a

Ent?umd

200

300

400

400 150 180 220 260 200 240 230 420

SerumCholntsrol(mp/dll

Fig. 3. Although serum cholesterol distributions differ markedly between populations with low and populations with high coronary heart disease rates (left panel), within a population serum cholesterol discriminates risk poorly. In the Framingham population, there is no point that discriminates between men who did and did not develop coronary heart disease in the follow-up period (right panel). Left panel from Blackburn [ 191 and right panel from Rose [IO], with permission

mum of 95 mmHg and the North Karelia Project was able to achieve a 5% reduction in the average diastolic blood pressure in the population. The achieved risk factor changes of MRFIT would be expected to result in a 16% reduction in events in the population from which the high risk men were selected; the achieved effect of the North Karelia Project was a 30% reduction in events in the population (Fig. 4). Even if MRFIT had been able to eliminate risk factor elevations in the top 10% of the population (reducing maximum cholesterol to 190 mg/dl and maximum diastolic blood pressure to 80 mmHg), the impact on the population from which the high risk men were

than emphasizing screening for high risk, the North Karelia Project sought to create opportunities for behavioral change for the entire population. The treatment go81 of MRFIT was to lower serum cholesterol by 20% and lower maximum diastolic blood pressure to 90 mmHg for the top 10% of the population. The goal of the North Karelia Project was to lower serum cholesterol by 20% and diastolic blood pressure by 10% for the entire population. Both MRFIT and the North Karelia Project were able to achieve a 10% reduction in total serum cholesterol. MRFIT was able to lower diastolic blood pressure levels to a maxi-

Pophtbn

...._.__..__. . Level

-0.

Ach!aved

Goal

Ideal

Achieved GaaI /

Ideal

% 40. decline

Fig. 4. Even if the Multiple Risk Factor Intervention Trial (MRFIT) had been able to eliminate all risk factor elevations among the men targeted by the intervention, the effect would have been little greater than that achieved by the North Karelia Project. Creating major changes in coronary heart disease death rates will require risk factor modification for the majority of the population. From Kottke et al. [14], with permission.

TX. Kot~ke. H. Drrih Table

/ Atl~~~rc~.s~l~~rc~.~i.s 108 (S~ppl.) (1994) Sl27~-Sl_Z.5

s131

I

Projected followed

effects and costs of fk!

interventions

in the United

States Railroad

Cohort

of the Seven Countries

Study (2571

men

for 5 years) Intervention

type

None

Targeted Number

Population of risk factors required

to trigger an intervention

Proportion 5-year

of population

total mortality

‘at risk’

for population

Program cost (SIOOO/iO 000 popln.) Deaths averted (/IO 000 popln.) Cost/death

averted ( $ I 000s)

I

3

1

0

0.016

0.154

0.566

I .oo

0.064

0.061

0.049

0.029

0.041

0 0

255 31

155 152

‘55 350

37.5 797 --_

0

8.73

I .6X

0.73

0.17

drawn would only have been as large as the changes actually achieved with the North Karelia Project. Eliminating hyperlipidemia and hypertension (an idea1 population-based intervention) could reduce coronary heart disease mortality by 70%. 4. Finding the ‘high risk’: a considerable cost Cost-effectiveness analyses of pharmacologic interventions usually don’t include the cost of finding the candidates for intervention. If the purpose of an analysis is to compare the costs of a public policy focusing on the high risk with one that intervenes in the entire population, however, these analyses must include the cost of sorting the population into those who would be treated with drugs (‘high risk’) and those who would not be treated (‘not at high risk’). The cost of testing the population to find the high risk may be more expensive and less effective than treating the entire population with an intervention that encourages behavior change [ 151 (Table 1). As defined for the purposes of this example of the 2571 men in the United States Railroad Cohort of the Seven Countries Study [9], the targeted intervention would eliminate smoking, lower total serum cholesterol to 190 mg/dl, and lower diastolic blood pressure to 85 mmHg for all individuals in the targeted group. A risk factor would be considered elevated if the level were above the 75th percentile for the popu-

lation. If an individual were in the targeted group, all risk factor levels would be lowered to those defined above. The population intervention would lower serum cholesterol by 10% and lower diastolic blood pressure by 5% for all individuals. It would also reduce the number of cigarette smokers by 20%. Screening and population intervention costs are based on the costs of the North Karelia Project [23]. The cost of screening the entire population to identify the high-risk subpopulation was $25.50 per person. The costs of delivering the 5-year program was $3.75 per person. For the purposes of this example, it is assumed that the costs of treatment of the high risk are borne by the individual. While ail costs would be higher in the United States and the true costs of drug treatment of hyperlipidemia or hypertension have not been included in this analysis, comparing the costs of Table 2 Serum cholesterol levels. prevalence. and incidence of coronary heart disease

in Japanese men living in Nagasaki. Honolulu.

and San Francisco

Total strum cholesterol

Nagasaki N=2127

Honolulu N=7998

San Francisco N=1795

1x1

218.

228

3

12

16

25

35

45

(mean. mg/dl) ‘XI > $60 mg/dl Coronary hcdrt disease prevalence (/lOOO) lncidcncc

(/ lOOO/5 years)

1.3

2.2

3.7

T.E. Kottke, H. Daida 1 Atherosclerosis 108 (Suppi.) (1994) S127-SI35

S132

Nomdlwbled Ma&d

$14,305

I

Women

Men

Dlrbbd Marlied

women

57.732

$13523

56.720

I

Men

Women

Unmatried

., 15% ;.;.~.ij.&, 24% g$yf 61%

c!3 s7,433

m

15,470

Responde~Ws earnings ~pouse’s

earnings

’

=Public

52.663 lncon’~~Maintenance

$2,387 m

Other

Fig. 5. Disablement or death of an adult causes severe financial distress for a household. Households in which an adult is disabled or has died have an income that is only about 50% as large as income of intact households. Household incomes of severely disabled, unmarried individuals are only about one-sixth as large as household incomes of their married, non-disabled counterparts. From Burdette and Frohlich [29].

screening the entire population to the cost of a population-based intervention are adequately iilustrative. Only when the targeted intervention included all individuals with one or more risk factor levels in the top quarter of the distribution (57% of the population) is it expected to have a greater effect than the population intervention. Even without including the costs of drug treatment, the cost of screening for the targeted intervention would be seven times the cost of the population intervention. If we were to add the costs of drug treatment of hyperlipidemia and hypertension, approximately $4500 per person over a five year period [7], the cost effectiveness of any targeted intervention would be even less favorable. 5. The origins of behavioral risk factors: social In the Seven Countries study, Keys found that behaviors relating to risk of coronary heart disease differed widely among the cohorts [9]. Men from Japan only received 3% of their calories from saturated fat while men from eastern Fin-

land received more than 20% of their calories from saturated fat. While more than 90% of Japanese and Finnish men were physically active, more than 90% of the men in the Belgrade cohort were sedentary. Only 400/u of the Belgrade men smoked while almost 900/o of the men from Zutphen were smokers. Thus, the social environment molds the behavioral risk factors of individuals. It has also been demonstrated that changing the social environment changes the risk of developing coronary heart disease. Japanese men living in Nagasaki, Honolulu, and San Francisco were followed in the Ni-Hon-San study to determine the impact of social environment on risk of coronary heart disease [24] (Table 2). The average serum cholesterol was almost 50 mg/dl higher for men living in San Francisco in comparison to men living in Nagasaki, and the prevalence of severe hyperlipidemia (serum cholesterol > 260 mg/dl) was over five times as high. As a result, the prevalence of coronary heart disease was almost twice as high, and the incidence of coronary heart disease was three times as high. Both the risk factors and the disease rates for men living in

T.E. Kortke, H. Daida 1 Atherosclerosis 108 (Suppl.) (1994) Sl27-Si35

Honolulu groups.

were intermediate

to the other

two

6. The perspective of the client If a public health perspective is assumed, treatment of hyperlipidemia reduces medical costs only for a subset of individuals who already have coronary heart disease [5,25]. However, health care costs are only a minor portion of the total costs generated by ischemic heart disease. For example, it has been calculated that the indirect costs (loss of earnings) of preventable mortality from ischemic heart disease among Canadians is eight times the direct (medical care) costs [26]. In the United States, Cooper and Rice calculated that medical care costs are only 27% of the total cost of coronary heart disease [27]. In North Karelia, the earnings lost because of coronary heart disease were estimated to be 1.45 times the medical care costs of treating the disease [23]. The North Karelia Project was associated with a four dollar reduction in disability pension awards for every dollar invested in the project intervention

WI. It is customary not to count lost earnings in cost-effectiveness analyses because it is assumed that the production from a worker who can no longer work will be replaced by that from a currently unemployed worker. Small social units like families, however, can rarely make up the lost earnings of a member who becomes severely disabled [29]. In 1972, the household income of married disabled men was only 54% of the household income of married non-disabled men (Fig. 5). Household income of married disabled women was 64Oh of household income of married non-disabled women [29]. Unmarried women had an average household income that was only 41% as large as the average income of married women. The average household income of severely disabled unmarried men or women was less than 20% of the household income of their married, non-disabled counterparts. (Fig. 5) In addition to an unfavorable economic impact, disability tends to disrupt the family structure. Although the disabled are about as likely to have

s133

married as the non-disabled, their marriages are more likely to end in divorce or separation [30]. Most disabled receive no more help from relatives living outside of the household than would nondisabled, and rather than a pattern of role reversal when an individual becomes disabled - that is, the disabled person stays home and does the household chores while the spouse enters the labor force - the usual pattern is one of contraction of participation in employment and in social activities in the community. Chronic poor health impoverishes not only those it afflicts, it impoverishes those living with the afflicted. The impact of death and disability on earnings and family structure makes it possible to conclude that periodic risk factor assessment is cost-effective for individuals who want to keep their risk factors at minimal levels. If, on the other hand, an individual seeks to use screening for biological risk factors (e.g., lipid levels, blood pressure levels, or exercise tolerance) to justify behavioral indiscretions such as smoking, sedentary lifestyle, or a diet high in saturated fat, there is no screening test that can assure the individual that he or she is not at increased risk of coronary heart disease because of these behaviors. 7. Conclusion Coronary heart disease is widely disseminated in Western populations, and for most people, it is a product of social goals. Waiting for disease to appear before any intervention is undertaken reduces consumption of health care resources, but the strategy denies preventive technology to 15’3~ 20% of all individuals who develop coronary heart disease. Although currently available screening tools do not discriminate well between individuals who will and those who will not develop coronary heart disease during their lifetime, screening can identify opportunities for intervention to minimize risk. While primary prevention is only cost-effective from the perspective of an individual who wishes to minimize loss of livelihood and disruption of family structure, aggressive Jecondary prevention programs (prescription of beta-blockers and angiotensin converting inhibitors; correction of dyslipidemia, hypertension, and obesity; absti-

T.E. Kottke, H. Daida / Atherosclerosis 108 (Suppl.) (1994) S127-Sl35

nence from tobacco; and performance of adequate physical activity) reduce mortality, reduce morbidity, and reduce costs to individuals and to society. These data suggest that a comprehensive public policy for the treatment of dyslipidemia must contain two components. For those not known to be at high risk the intervention would emphasize a community-wide general awareness and behavior change campaign that creates opportunities and incentives for behavior change; there would be minimal emphasis on screening for biological markers of risk. Those who have coronary heart disease or who are known to be at high risk for another reason should be followed closely to ensure abstinence from tobacco, maintenance of ideal weight, aggressive blood pressure control, adequate exercise, maintenance of low density lipoprotein levels at less than 100 mg/dl and high density lipoprotein levels at greater than 40 mg/dl. For patients with coronary heart disease, aspirin, beta blockers, and angiotensin converting enzyme inhibitor should be prescribed prophylactically unless contraindicated. 8. References 111 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), J. Am. Med. Assoc., 269 (1993) 3015. PI Frame, P.S. and Carlson, S.J., A critical review of periodic health screening using specific screening criteria. Part I: Selected diseases of respiratory, cardiovascular, and central nervous systems, J. Fam. Pratt., 2 ( 1975) 29. 131 Smith, G.D. and Pekkanen, J.. Should there be a moratorium on the use of cholesterol lowering drugs?, Br. Med. J., 304 (1992) 431. I41 Hulley, S.B., Walsh, J.M.B. and Newman, T.B., Health policy on blood cholesterol. Time to change directions. Circulation, 86 (1992) 1026. [51 Goldman, L., Weinstein, M.C., Goldman, P.A. and Williams, L.W.. Cost-effectiveness of HMG-CoA reductase inhibition for primary and secondary prevention of coronary heart disease, J. Am. Med. Assoc., 265 (1991) 1145. [61 Rothenberg, R., Ford, E.S. and Vartiainen. E., ischemic heart disease prevention: estimating the impact of interventions, J. Clin. Epidemiol., 45 ( 1992) 21.

[71 Hay. J.W., Wittels. E.H. and Gotto. A.M., An economic evaluation of lovastatin for cholesterol lowering in coronary artery disease reduction, Am. J. Cardiol.. 67 (1991) 789. PI Beaglehole, R., International trends in coronary heart disease mortality, morbidity, and risk factors, Epidemiol. Rev., I2 (1990) I. [91 Keys, A., Seven Countries, Harvard University Press, Cambridge, MA, 1980. [lOI Rose, G.. Sick individuals and sick populations, Int. J. Epidemiol., 14 ( 1985) 32. Rose, G. and Day, S.. The population mean predicts the [Ill number of deviant individuals, Br. Med. J.. 301 (1990) 1031. iI21 Rose, G., Ancel Keys Lecture, Circulation, 84 (1991) 1405. [I31 Orencia, A.. Bailey, K.. Yawn, B.P. and Kottke, T.E.. El%ct of gender on long-term outcome of angina pectoris and myocardial infarction/sudden unexpected death, J. Am. Med. Assoc., 269 (1993) 2392. [I41 Kottke, T.E., Puska, P., Salonen, J., Tuomilehto, J. and Nissinen A., Projected effects of high-risk versus population-based prevention strategies in coronary heart disease, Am. J. Epidemiol., I21 (1985) 6974. 1151 Disease and risk factor clustering in the United States: the implications for public health policy. In: Integration of Risk Factor Interventions. Two Reports to the Office of Disease Prevention and Health Promotion. Washington, DC: US Department of Health and Human Services. Public Health Service. Office of Disease Prevention and Health Promotion. 1986, p. 1. 1161 Pekkanen, J., Linn, S., Heiss, G., Suchindran, C.M., Leon, A., Ritlcind. B.M. and Tyroler. H.A., Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease, N. Engl. J. Med., 322 ( 1990) 1700. 1171 Lipid Research Clinics Program. The lipid research clinics primary prevention trial results: 1. Reduction in the incidence of coronary heart disease, J. Am. Med. Assoc., 251 (1984) 351. 1181 Frick, M.H., Elo, 0.. Haapa, K., Heinonen. O.P., Heinsalmi, P. and Helo, P.. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease, N. Engl. J. Med., 317 11987) 1237. iI91 Blackburn, H., Diet and mass hyperlipidemia: a public health view. In: Levy. R.I., Rifkind, B.M., Dennis B.H., et al. (Eds.). Nutrition. Lipids and Coronary Heart Disease, Raven Press, New York, 1979. p. 309. PO1 Heller, R.F., Chinn, S., Tunstall Pedoe, H.D. and Rose, G.. How well can we predict coronary heart disease? Findings in the United Kingdom Heart Disease Prevention Project, Br. Med. J., 288 (1984) 1409. 1211 Kottke, T.E., Gatewood, L.C. and Park, H.A., Using serum cholesterol to identify high risk and stimulate

T.E. Kottke, H. Dada 1 Atherosclerosis 108 (Suppl.) (1994) S127-S135 behavior change: will it work?. Ann. Med.. 21 (1989) 181. Goldman, L.. Weinstein, M.C. and Williams, L.W.. P21 Relative impact of targeted versus population wide cholesterol interventions on the incidence of coronary heart disease, Circulation, 80 (1989) 254. 1231 Puska, P., Tuomilehto. J.. Salonen, J. et al.. The North Karelia Project. Evaluation of a Comprehensive Community Programme for Control of Cardiovascular Discases from 1972-1977 in North Karelia, Finland. Copenhagen: World Health Organization, WHO Monograph Series, 198 I, pp. 254-256. r241 Marmot, M.G., Syme, S.L., Kagan, A., et al., Epidemiologic studies of CHD and stroke in Japanese men living in Japan, Hawaii and California. Prevalence of coronary and hypertensive heart disease and associated risk factors, Am. J. Epidemiol., 102 (1975) 514. WI Goldman, L., Gordon, D.J., Ritkind, B.M.. Hulley,

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S.B., Detsky. A.S., Goodman, D.W.. Kinosian, B. and Weinstein, MC., Cost and health implications of cholesterol lowering, Circulation, 85 (1992) 1960. 1261 Smith. E.S.O.. The economic impact of preventable ischemic heart disease, Can. Med. Assoc. J., I17 (1977) 507,508,512. v71 Cooper, B.S. and Rice, D.P., The economic cost of illness revisited, Sot. Sec. Bull., ( 1976) 21. Kottke, T.E., Puska, P., Feldman, R.D., Salonen, J.T. PI and Tuomilehto, J., A decline in earnings losses associated with a community-based cardiovascular disease prevention project, Med. Care, 20 (1982) 663. ~91 Burdette, M.E. and Frohlich, P., The effect of disability on unit income - 1972 survey of disabled and nondisabled adults, HEW Publication No. (SSA) 78-l 1717, 1978. I301 Franklin, P.A., Impact of disability on the family structure, HEW Publication No. (SSA) 77.