Cost Effectiveness of Simvastatin Treatment to Lower Cholesterol Levels in Patients with Coronary Heart Disease
Magnus Johannesson, Ph.D., Bengt Jönsson, Ph.D., John Kjekshus, M.D., Ph.D., Anders G. Olsson, M.D, Ph.D., Terje R. Pedersen, M.D., Ph.D., Hans Wedel, M.D., Ph.D., for The Scandinavian Simvastatin Survival Study Group
Background The Scandinavian Simvastatin Survival Study (4S)showed that lowering cholesterol levels with simvastatin reducesmortality and morbidity in patients with angina pectoris orprevious acute myocardial infarction. Before the widespreaduse of cholesterol-lowering drugs in such patients is recommended,its cost effectiveness should be demonstrated. We estimatedthe cost effectiveness of simvastatin treatment to lower cholesterollevels in relation to the age, sex, and cholesterol level beforetreatment of patients with coronary heart disease.
Methods We estimated the cost per year of life gained with simvastatintherapy. To model the increased life expectancy, hazard functionsfrom 4S were used. The costs studied included those of the interventionand the direct and indirect costs associated with morbidityfrom coronary causes. We prepared separate estimates for menand women at various ages (from 35 to 70 years) and total cholesterollevels before treatment (213 to 309 mg per deciliter).
Results In the analysis limited to direct costs, the cost ofeach year of life gained ranged from $3,800 for 70-year-oldmen with 309 mg of cholesterol per deciliter to $27,400 for35-year-old women with 213 mg of cholesterol per deciliter.When we included indirect costs, the results ranged from a savingsin the youngest patients to a cost of $13,300 per year of lifegained in 70-year-old women with 213 mg of cholesterol per deciliter.
Conclusions In patients with coronary heart disease, simvastatintherapy is cost effective among both men and women at the agesand cholesterol levels studied.
Serum cholesterol is one of the main risk factors for coronaryheart disease, and in Western countries the prevalence of elevatedcholesterol levels is high.1 Recently, drugs have been developedthat lower these levels effectively.
In the Scandinavian Simvastatin Survival Study (4S), simvastatin(Zocor, Merck) was shown to reduce overall mortality.2,3 Patientswith preexisting coronary heart disease had a reduction in overallmortality of 30 percent, which was exclusively due to a reductionof 42 percent in mortality from coronary causes.2,3 For allcoronary events combined, there was a reduction of 27 percent.2Before the widespread use of cholesterol-lowering drugs is recommended,it is important to demonstrate that their use is cost effective.This is especially important because interventions to lowercholesterol levels with drugs involve large populations of patientsand potentially high costs.
The use of health care resources and the overall cost effectivenessof treatment to lower cholesterol levels in the 4S trial havepreviously been described.4,5 In the present study, we estimatedthe cost effectiveness of lowering cholesterol levels with simvastatinin relation to the age, sex, and pretreatment cholesterol levelof patients with coronary heart disease.
Methods
We analyzed the cost effectiveness of simvastatin treatmentto lower cholesterol levels on the basis of the 4S data.2 Thepatients in the present study were men and women 35 to 70 yearsof age with total cholesterol levels of 213 to 309 mg per deciliter(5.50 to 8.00 mmol per liter) who had a history of angina pectorisor acute myocardial infarction.2
Costs were defined as net costs (those of the intervention minusthe savings due to the reduction in morbidity from coronarycauses), and effects were defined as the number of years oflife gained.6 No adjustment was made for quality of life inorder to estimate the number of quality-adjusted years of lifegained, because of the lack of valid quality-of-life weightsto use for these patients. Our analysis also included costsoutside the health care system6 — namely, the indirectcosts (in lost production) attributable to morbidity from coronarycauses. Since the inclusion of such indirect costs is controversial,our results are presented both with and without them.6,7 Healthcare costs attributable to increases in the number of yearsof life were not included.8
Treatment lasting five years was used in estimating the cost-effectivenessratios. This period was based on the median follow-up of 5.4years in the 4S trial.2 Separate estimates of cost effectivenesswere prepared for men and women and for three ages (35, 59,and 70 years) and three pretreatment cholesterol levels (213,261, and 309 mg per deciliter [5.50, 6.75, and 8.00 mmol perliter]).
Both costs and numbers of years of life gained were discountedby 5 percent to account for the timing of costs and effects.9Costs were calculated on the basis of Swedish prices in 1995and were converted to U.S. dollars at the 1995 exchange rate($1 = 7.30 Kronor).
Estimates of Effects
To calculate the cost effectiveness of simvastatin treatment,we used a modification of a Markov model created to estimatethe cost effectiveness of efforts to prevent cardiovasculardisease.10 The starting point of the model was a cohort withpreexisting coronary heart disease for whom there were dataon the study variables (age, sex, and total cholesterol level).The members of the cohort were followed from their current agesto the age of 110 years, which we took to be the longest possiblesurvival. Each year the members of the cohort ran the risk ofhaving a coronary event or dying from a noncoronary cause. Coronaryevents were classified as either fatal or nonfatal. Personswho had nonfatal events were considered to be in a temporarystate of disease for one year after the event (during whichthey had an increased risk of death); if they survived thatyear, they were considered to enter a state of chronic disease(during which the risk of death declined but was still greaterthan that of the normal population). They then either died orcontinued in that state of chronic disease.
The probabilities of a transition from one of these predefinedstates to another in the Markov model were based on the hazardfunctions estimated for the placebo group in the 4S trial. Fourhazard functions were used to estimate the probabilities ofthe following four transitions: the annual risk of a coronaryevent (among the patients who had not yet had such an event),the annual risk of death from noncoronary causes (among thepatients who had not yet had an event), the risk of death duringthe first year after a coronary event, and the annual risk ofdeath during the second and subsequent years after such an event.A separate hazard function was estimated for the first yearafter an event because mortality during that year is higherthan in subsequent years. Poisson models were used to estimatethe hazard functions.11 Age, sex, and pretreatment total cholesterollevel were included as risk factors in the hazard functionsso that cost effectiveness in various groups of patients couldbe estimated. (The risk functions are available from the authorson request.)
Coronary events were defined, as in 4S (in which "any coronaryevent" was a tertiary end point 2), to include death from acoronary cause, a definite or probable hospital-verified nonfatalacute myocardial infarction, resuscitation after cardiac arrest,definite silent myocardial infarction, myocardial revascularization,and admission to the hospital for acute coronary heart diseasewhen there was no diagnosis of myocardial infarction. In themodel, the proportion of fatal coronary events among all coronaryevents in 4S was calculated. This proportion was estimated separatelyfor men and for women and in two age groups, persons 35 to 64years of age and persons 65 years old or older. Among patients35 to 64 years old, 7.7 percent of events in men and 2.2 percentof events in women were fatal; among patients 65 years old orolder, 14.4 and 5.7 percent of events, respectively, were fatal.
Using this model, we estimated the life expectancy of men andwomen with various ages and cholesterol levels before cholesterol-loweringtreatment (i.e., the life expectancy of the people in the placebogroup in 4S). Table 1 shows the estimated life expectancy ofvarious groups of patients.
Table 1. Estimated Life Expectancy of Patients with Coronary Heart Disease before Simvastatin Treatment, According to Age, Sex, and Pretreatment Cholesterol Level.
To estimate the increase in life expectancy attributable totreatment with simvastatin, we reduced the annual risk of coronaryevents during the five years of treatment in the model by 27percent, the reduction in risk observed in 4S.2 After five yearsof treatment, the annual risk was assumed to be equivalent tothe risk if there had been no treatment. We estimated the reductionin risk only for the first coronary event and not for subsequentevents, because we lacked sufficient data to permit a stableestimation of the risk of subsequent events. This assumptionis conservative, since the occurrence of an event increasesthe absolute risk of further events and the cost effectivenessof treatment would thus improve slightly if treatment afterthe first event was included in the calculation.
Estimates of Costs
In estimating the cost of treatment with simvastatin, we assumedthat the only added cost would be that of the drug itself. Simvastatintreatment was assumed not to lead to additional costs for physicianvisits and laboratory tests, since these are part of the standardtreatment after myocardial infarction or angina. The estimatedannual cost of the drug was based on the actual consumptionof simvastatin by the members of the treatment group in the4S trial and on the official retail price of the drug in Sweden.2,12By this method, the annual cost of the drug was estimated tobe $604. To be consistent with the manner in which the effectswere estimated, this annual cost was applied to patients onlybefore they had a coronary event.
To estimate the reduction in the cost of coronary events attributableto the simvastatin treatment, annual direct and indirect costsassociated with morbidity — those for health care andlost production, respectively — were included in the Markovmodel. These reductions in annual costs were divided into thoseoccurring during the first year after an event and those duringthe second and subsequent years (since the costs are substantiallyhigher in the first year). In 4S, data were recorded on allhospitalizations for cardiovascular causes.4 To estimate thedirect costs, we estimated the extra costs incurred throughhospitalizations for cardiovascular causes per patient-yearduring the first year after a coronary event and those duringthe second and subsequent years. These estimates were basedon the data for the patients in the 4S placebo group. To estimatethe costs of these hospitalizations, we used the costs of hospitalizationfor patients in various diagnosis-related groups at four hospitalsin Sweden that had patient-based cost-accounting systems13 (Table 2).(The costs of comparable procedures in the United Stateshave been presented by Mark et al.14) The prices we used indicatethe cost of treating the patient and are not charges or payments.On this basis, the annual direct costs were estimated to be$7,849 for the first year after an event and $1,041 for subsequentyears.
Table 2. Costs of Hospitalizations in Swedish Hospitals for Various Diagnoses.
Indirect costs were estimated similarly. The difference betweenlabor production per patient-year before a coronary event andafter the event was estimated for the patients in the 4S placebogroup who had nonfatal events. The estimates were based on thepatients' work status as assessed every six months. We estimatedindirect costs among patients 35 to 49 years old and among those50 to 64 years old, since the proportion of the population thatis working becomes smaller with increasing age.
Before the coronary event, the proportion of full-time workerswas 0.7500 among patients 35 to 49 years old and 0.4582 amongpatients 50 to 64 years old. According to our estimates, among35-to-49-year-olds the proportion of full-time workers decreasedby 0.2678 during the first year after an event and by 0.1300during subsequent years. Among 50-to-64-year-olds, the correspondingfigures were 0.1465 and 0.0888. The indirect costs were estimatedby applying these estimates to the average annual cost for thelabor of a full-time Swedish worker in 1995 ($35,300).15 Among35-to-49-year-olds this calculation gave annual indirect costsof $9,453 during the first year after an event and $4,589 duringsubsequent years. Among 50-to-64-year-olds, the correspondingindirect costs were $5,171 and $3,135.
Sensitivity Analysis
Various analyses of sensitivity were performed that involved59-year-old men and women with total cholesterol levels of 261mg per deciliter (the mean age and mean cholesterol level ofthe study patients at entry). In one analysis, the cost peryear of life gained was estimated on the basis of the lowerand upper bounds of the 95 percent confidence interval —0.66 and 0.80, respectively — around the relative risk(0.73) of coronary events in the 4S simvastatin group.2 Anotheranalysis used the average risk of death from noncoronary causesin Sweden at various ages instead of the risk of death obtainedby the hazard function.15 In one analysis we increased the annualrisk of death after a coronary event by 50 percent, and in anotheranalysis we decreased the risk by 50 percent.
In a separate analysis, we included the costs of health careduring the years of life gained, using estimates of the costof health care in Sweden at various ages.16 The costs associatedwith morbidity after a nonfatal coronary event were raised andlowered by 50 percent in one analysis. In additional analyses,various costs for the intervention were used. In one estimatethe cost of the follow-up was added to that of the intervention,to allow for the possibility that the patients were not alreadyvisiting their physicians regularly to have their coronary heartdisease treated. An annual cost of $356 ($317 in direct costsand $39 in indirect costs) was used in this analysis.17 In additionto the cost of follow-up, $808 ($630 in direct costs and $178in indirect costs), representing the cost of screening, wasadded in one analysis.18 A further analysis was based on theprice of simvastatin in the United States, which led to an annualcost of $930 for the drug.4
Quality of life was included in one sensitivity analysis, sincethe patients in the study were not in perfect health. We assumedthat in this population with preexisting coronary heart disease,1 year was worth only 0.88 of a year in the life of a personin perfect health19 but that there was no further reductionin the quality of life. Finally, in one sensitivity analysis,the discount rate applied to costs ranged from 0 to 10 percent.Since the discounting of years of life is controversial,20 oneanalysis was also performed in which there was no discountingof effects.
Results
The results of the cost-effectiveness analysis are shown inTable 3 for 59-year-old patients with pretreatment total cholesterollevels of 261 mg per deciliter.2 For men, the cost per yearof life gained was $5,400 when only direct costs were includedand $1,600 when indirect costs were also included. For women,these costs were $10,500 and $5,100, respectively.
Table 3. Cost Effectiveness of Simvastatin Treatment for Five Years in 59-Year-Old Patients with Coronary Heart Disease and a Pretreatment Total Cholesterol Level of 261 mg per Deciliter.
Table 4 shows the cost for each year of life gained in variousgroups of patients. When only direct costs were included, thecost per year of life gained was higher for women than for menand, as expected, decreased with increasing cholesterol levels.The cost per year of life gained also decreased with increasingage. Overall, the cost per year of life gained ranged from $3,800to $27,400 in the various groups of patients when only directcosts were included. When indirect costs associated with morbiditywere also included, the treatment led to a savings in the youngestpatients (those 35 years old) among both men and women (thatis, the reduction in the costs associated with morbidity fromcoronary causes exceeded the costs of the intervention). Inthe other groups, the cost per year of life gained ranged from$1,200 to $13,300.
Table 4. Cost per Year of Life Gained in Patients with Coronary Heart Disease Who Received Simvastatin Treatment for Five Years.
The results of the sensitivity analysis are shown in Table 5.When only direct costs were included, in the various analysesthe cost per year of life gained ranged from $3,000 to $12,100in men and from $4,500 to $21,800 in women. When indirect costswere included, the results in the various analyses ranged froma savings to a cost of $9,300 per year of life gained in men.In women, the cost per year of life gained ranged from $100to $18,500.
Table 5. Sensitivity Analyses of the Cost per Year of Life Gained with Simvastatin Treatment for Five Years in 59-Year-Old Patients with Coronary Heart Disease and a Total Cholesterol Level of 261 mg per Deciliter.
Discussion
We estimated the cost per year of life gained because of cholesterol-loweringtreatment with simvastatin in relation to the age, sex, andpretreatment cholesterol level of patients with preexistingcoronary heart disease. When only direct costs were studied,the cost ranged from $3,800 to $27,400 in the various groupsof patients. When the reduction in the indirect costs associatedwith morbidity was included, treatment led to a savings amongmen and women 35 years old, and the cost per year of life gainedranged from $1,200 to $13,300 in the older groups of patients.
The estimated cost-effectiveness ratios were well within therange that was considered cost effective in other studies.21,22,23,24We thus conclude that, according to the results of 4S, treatingpatients with coronary heart disease with simvastatin is costeffective in both men and women at the ages and cholesterollevels studied.
This conclusion should not be extrapolated to apply to primaryprevention, in which the absolute risks of coronary heart diseaseare substantially lower. The reason that the cost-effectivenessratios in this study were so favorable is that we analyzed thecost effectiveness of treating people with coronary heart disease,who are at high risk for coronary events. Even if the reductionin the relative risk were the same in primary prevention, thereduction in the absolute risk would be lower because of thelower absolute risk of coronary heart disease. Further studiesare thus needed that are based on reliable data from randomizedclinical trials of primary prevention.
The cost effectiveness of lowering cholesterol levels in secondaryprevention in the United States has also been studied by Goldmanet al.,24 who estimated the cost per year of life gained withlovastatin (another inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase) in secondary prevention, using extrapolationsfrom epidemiologic data. Their results are generally in linewith those reported here, except in the case of women less than55 years old with cholesterol levels below 250 mg per deciliter(6.47 mmol per liter), for whom the cost-effectiveness ratiosestimated by Goldman et al. were substantially higher than ours.Those authors concluded that secondary prevention with lovastatinwas cost effective in all groups of patients studied exceptwomen under 55 with cholesterol levels below 250 mg per deciliter.24
Although our conclusions generally agree with those of Goldmanet al.,24 we think that our study provides stronger and morereliable evidence of the cost effectiveness of lowering cholesterollevels in patients with coronary heart disease. This is becausewe used data on the costs and effects of treatment that wereobtained directly from a randomized clinical trial in whichstatistically significant reductions in both coronary eventsand overall mortality were demonstrated. Furthermore, we estimatedthe effects of simvastatin in 4S conservatively. In that study,the incidence of cerebrovascular events was reduced by 30 percent.2We chose not to include this potential additional effect ofsimvastatin in our analysis, however, since the comparison ofcerebrovascular events between study groups was performed ina post hoc manner.2 Prospective trials are needed to determinewhether a reduction in cerebrovascular events with simvastatinactually occurs.
Supported by a grant from Merck Research Laboratories, Rahway,N.J.
Source Information
From the Center for Health Economics, Stockholm School of Economics, Stockholm, Sweden (M.J., B.J.); the Section of Cardiology, University of Oslo, Rikshospitalet, Oslo, Norway (J.K.); the Department of Internal Medicine, Faculty of Health Sciences, Linköping, Sweden (A.G.O.); the Cardiology Section, Medical Department, Aker Hospital, Oslo, Norway (T.R.P.); and the Nordic School of Public Health, Gothenburg, Sweden (H.W.).
Address reprint requests to Dr. Johannesson at the Center for Health Economics, Stockholm School of Economics, Box 6501, S-113 83 Stockholm, Sweden.
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