This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pedersen, T. R. Articles by Schwartz, J. S. Search for Related Content PubMed PubMed Citation Articles by Pedersen, T. R. Articles by Schwartz, J. S.

(Circulation. 1996;93:1796-1802.)
© 1996 American Heart Association, Inc.

Articles

Cholesterol Lowering and the Use of Healthcare Resources

Results of the Scandinavian Simvastatin Survival Study

Terje R. Pedersen, MD; John Kjekshus, MD; Kåre Berg, MD; Anders G. Olsson, MD; Lars Wilhelmsen, MD; Hans Wedel, PhD; Kalevi Pyörälä, MD; Tatu Miettinen, MD; Torben Haghfelt, MD; Ole Færgeman, MD; Gudmundur Thorgeirsson, MD; Bengt Jönsson, PhD; J. Sanford Schwartz, MD; for the Scandinavian Simvastatin Survival Study Group¹

Correspondence to Dr Terje R. Pedersen, Cardiology Section, Medical Department, Aker Hospital, N 0514 Oslo, Norway.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background Advances in the treatment of cardiovascular disease have increased costs; annual cardiovascular healthcare expenditure in the United States currently exceeds $100 billion. Physicians and third-party payers need to assess the economic impact of treatments that reduce cardiovascular morbidity and mortality.

Methods and Results The Scandinavian Simvastatin Survival Study is a randomized, double-blind, placebo-controlled trial in which simvastatin reduced the risk of death by 30% (P=.0003) over the median follow-up period of 5.4 years in patients with previous myocardial infarction or stable angina pectoris as a result of a 42% reduction in the risk of coronary deaths (P=.00001). In the present report, data prospectively collected from hospital admissions were analyzed to evaluate the impact of simvastatin on healthcare resource use and perform a cost-minimization analysis. In the placebo group (n=2223), there were 1905 hospitalizations (average duration, 7.9 days) for acute cardiovascular events or coronary revascularization procedures among 937 patients, whereas in the simvastatin group (n=2221), there were 1403 such hospitalizations (average duration, 7.1 days) among 720 patients (all differences, P<.0001). The corresponding number of hospital days was 15 089 and 9951 in the two groups, respectively (34% reduction, P<.0001). In the United States, the resulting reduction in hospitalization costs over the 5.4 years of the trial would be $3872 per patient, reducing the effective cost of simvastatin by 88% to $0.28 per day.

Conclusions In addition to reducing mortality and morbidity in coronary heart disease patients, simvastatin markedly reduces use of hospital services, thus offsetting most of its cost.

Key Words: cholesterol • prevention • coronary disease • drugs

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Despite advances in diagnosis and treatment, in industrialized countries cardiovascular disease still accounts for approximately half of all deaths and large expenditures of healthcare resources. In the United States, the direct medical expenditures for cardiovascular disease exceed $100 billion,¹ mainly for hospitalizations and revascularization procedures.

Simvastatin is an inhibitor of HMG coenzyme A reductase that produces a substantial reduction of LDL cholesterol accompanied by a modest increase in HDL cholesterol. It is prescribed to slow the progression of coronary atherosclerosis and to reduce coronary mortality and morbidity in patients with coronary heart disease (CHD). In the Scandinavian Simvastatin Survival Study (4S),² simvastatin 20 to 40 mg once daily produced a long-term 35% mean reduction in LDL cholesterol, accompanied by a mean increase in HDL cholesterol of 8%. Simvastatin therapy resulted in a 30% reduction in the risk of death (P=.0003) over a median follow-up period of 5.4 years, resulting from a 42% reduction in coronary deaths. The risk of major coronary events was reduced by 34%, and a subsequent report³ demonstrated that this risk reduction was independent of baseline total, LDL, and HDL cholesterol. The results of 4S support the recommendations of expert panels in Europe and the United States on lowering serum cholesterol substantially in patients with established CHD.^{4 5}

Healthcare payers are increasingly interested in health economic analyses to guide the allocation of limited resources. Previous health economic studies of cholesterol reduction have been limited by the lack of prospective data from randomized clinical trials and have therefore been modeled on observational data and simulated cohorts,^{6 7 8 9 10} a process that requires assumptions about the effect of therapy on cardiovascular events. Using data collected prospectively in 4S, we now report on the effect of treatment of CHD patients with simvastatin 20 to 40 mg daily on the use of healthcare resources for acute cardiovascular disease hospitalizations and myocardial revascularization procedures. US costs were applied to these data to perform a cost-minimization analysis, which quantifies the direct economic impact of simvastatin without converting its clinical benefits into financial terms (as in a cost-benefit analysis) or into life-years saved–quality-adjusted life-years saved (as in a cost-effectiveness analysis).

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The methods were described previously.² In brief, 4444 men and women 35 to 70 years of age who had CHD, serum total cholesterol levels of 5.5 to 8.0 mmol/L (212 to 309 mg/dL), and triglycerides of 2.5 mmol/L (221 mg/dL) while on a lipid-lowering diet were randomly allocated to treatment with placebo or simvastatin 20 to 40 mg daily. Dosage was adjusted at week 12 and month 6 if the treatment goal of total cholesterol between 3.0 and 5.2 mmol/L (116 and 200 mg/dL) was not achieved. Patients visited the clinic at weeks 6, 12, and 18; at month 6; and every 6 months thereafter for the remainder of the study. The median length of follow-up was 5.4 years (range, 4.9 to 6.3 years), and vital status was confirmed in all patients at the completion of the study. The primary study end point was total mortality. In addition to data on clinical events and mortality as classified by an independent end point classification committee according to a modification of the World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease method,^{11 12} data also were prospectively collected on hospital admissions and length of stays for acute cardiovascular events, revascularization procedures, and concomitant medication usage.

The plan for the resource use analysis included two primary hypotheses: a between-group difference in the rate of CHD hospitalizations and revascularization procedures. Secondary hypotheses included between-group differences in all acute cardiovascular hospitalizations, total number of days spent in hospital, average length of stay, frequency of coronary artery bypass grafting and percutaneous transluminal coronary angioplasty, and times to first hospitalization and first revascularization procedure. For the purposes of this analysis, cardiovascular hospitalizations were grouped into the following categories: acute myocardial infarction, cardiac arrest, angina pectoris (unstable angina and prolonged chest pain), left ventricular failure, cardiac arrhythmia, stroke (nonembolic cerebral infarction, embolic infarction, intracerebral hemorrhage, unclassified stroke, and subarachnoid hemorrhage), transient ischemic cerebral attack, revascularization procedures, and other cardiovascular events. In cases in which multiple diagnoses were reported for a single hospitalization, a primary event for classifying the hospitalization was determined by applying a hierarchy based on relative cost as follows: revascularization procedures, stroke, acute myocardial infarction, left ventricular failure, angina pectoris, transient ischemic cerebral attack, arrhythmia, and other cardiovascular events.

To perform the cost-minimization analysis, only prospectively collected healthcare resource data were used. This was done to provide a conservative estimate of the economic impact of simvastatin that avoids many of the assumptions required by economic modeling. Therefore, the focus of this analysis was on the cost of hospitalizations and revascularization procedures, which represents a substantial portion of the economic cost of cardiovascular disease. The impact of simvastatin on these costs was then evaluated compared with the cost of the therapy itself.

The costs of acute cardiovascular hospitalizations were estimated by use of diagnosis-related group (DRG)–based cost per case in the United States from MEDSTAT.¹³ These costs are from a sample of actual payments made by payers to hospitals and physicians for each hospitalization. They represent the incremental cost incurred with each hospitalization from a payer's perspective. For each hospitalization, a DRG code was assigned on the basis of the definition of clinical events as determined by the end point classification committee. Complications and comorbidities that occurred during the hospitalization were identified from the clinical adverse experience database and incorporated into the DRG codes given to each hospitalization. Some DRG codes are a function of the use of cardiac catheterization. Because this procedure was not consistently captured in the trial, US data on the proportion of relevant hospitalizations that included catheterization were used.¹³ Costs for DRG codes with and without cardiac catheterization were applied to each hospitalization on the basis of these proportions. The same rates were applied to both treatment groups. A 5% annual discount rate was applied to future costs to obtain the net present value of the total cost for cardiovascular hospitalizations. For patients randomized to simvastatin (Zocor, Merck), the current average discounted cost of the drug per patient was obtained by use of the daily prescribed dosages over the study period and current US wholesale acquisition costs for Zocor (April 1995¹⁴ ), which represent an upper bound on the price of Zocor to institutions such as managed-care companies and hospitals. The actual price varies, depending on financial arrangements with Merck or group purchasing organizations.

Statistical Analysis
Treatment differences in the rate of CHD hospitalizations, revascularization procedures, and total acute cardiovascular hospitalizations were assessed with Cox's regression method for recurrent events.¹⁵ Times to first hospitalization and first revascularization were determined with the Kaplan-Meier procedure. Treatment differences were assessed with a stratified log-rank test. ANOVA was used to test treatment differences in the average length of stay per hospitalization and total bed days per patient. Because two primary hypotheses were specified, significance testing for these was based on Hochberg's procedure for adjusting for multiplicity at the 5% level.¹⁶ For all other hypotheses a 5% level of significance was used with no adjustment for multiplicity.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The two treatment groups were well matched at baseline for demographics, cardiovascular risk factors, qualifying diagnosis, and lipid levels.² Mean serum total cholesterol was 6.75 mmol/L (261 mg/dL). During the first 6 months of the study, 37% of the 2221 patients randomized to simvastatin had their dose increased to 40 mg daily according to the study protocol, while the remaining study participants continued on 20 mg, except for 2 patients whose dose was reduced to 10 mg. Study medication was discontinued (for reasons previously reported² ) in 13% in the placebo group and 10% in the simvastatin group. There were 4 252 381 total days of follow-up (mean, 1915 days per patient) in the simvastatin group. Dose titration and discontinuation resulted in the following use of simvastatin during follow-up: 61.6% of days for patients given 20 mg daily, 31.6% of days for those given 40 mg daily, 0.1% of days for patients given 10 mg daily, and 6.7% of days for participants given no study drug.

Simvastatin therapy reduced hospitalizations for acute cardiovascular disease, including revascularization procedures (Table 1), by 26% (P<.0001). Coronary artery bypass grafting accounted for 81% of all revascularization procedures. Hospitalizations for acute CHD events (myocardial infarction, angina pectoris, left ventricular failure) were reduced 32% (P<.0001). These reductions in hospitalizations were consistent for all clinical events within the acute CHD category. There also were reductions in hospitalizations for other acute cardiovascular disease events, except for supraventricular arrhythmias. (The data on the latter were strongly influenced by two patients in the simvastatin group who accounted for 25 of 113 admissions for supraventricular arrhythmias.) The average length of stay for all acute cardiovascular disease hospitalizations and revascularization procedures was 7.1 days in the simvastatin group compared with 7.9 days in the placebo group (P=.006). There was no significant difference in length of stay between the two treatment groups for any single hospitalization category. Rather, simvastatin preponderantly reduced the hospitalization categories associated with the longest stays, thus shortening the average length of stay. The combination of fewer hospitalizations and shorter hospital stays led to fewer hospital days over the course of the study for total cardiovascular disease in the simvastatin group (9951 days), a reduction of 5138 days (34%, P<.0001) compared with the placebo group (15 089 days). Acute CHD and revascularization procedures (34% and 31% reductions in hospital days, respectively) accounted for 78% of all hospital days in the placebo group.

View this table: [in this window] [in a new window]   Table 1. Number of Patients, Hospitalizations, and Length of Stay by Hospitalization Categories

The Kaplan-Meier probability of avoiding hospitalization for acute cardiovascular disease or a revascularization procedure over the course of the trial was 55% in the placebo group and 66% in the simvastatin group (Fig 1). The relative risk in the simvastatin group was 0.73 (95% CI, 0.66 to 0.80; P<.0001). Divergence of the two curves is observed after 10 months, becoming statistically significant (based on 95% CIs for the difference between the two curves) after 22 months. The probability of avoiding hospitalization for an acute CHD event (excluding revascularization procedures) was 67% in the placebo group and 78% in the simvastatin group (Fig 2). The relative risk was 0.70 (95% CI, 0.62 to 0.78; P<.0001).

View larger version (14K): [in this window] [in a new window]   Figure 1. Kaplan-Meier curves for the probability of avoiding hospitalization for acute cardiovascular (CV) disease and coronary revascularization procedures.

View larger version (13K): [in this window] [in a new window]   Figure 2. Kaplan-Meier curves for the probability of avoiding hospitalization for acute coronary heart disease (CHD).

The average number of concomitant medications used during the trial differed little between the treatment groups. The mean number of antianginal drugs per day was 1.58±1.18 (±SD) in the placebo group and 1.54±1.14 in the simvastatin group; for other cardiovascular drugs, 0.77±0.74 and 0.71±0.70; and for noncardiovascular drugs, 0.59±1.15 and 0.59±1.16. Average daily use of antianginal and other cardiovascular drugs did not differ significantly between the two groups.

Extrapolation of the results of the study to the United States (Table 2) shows that the cost associated with hospitalizations for total cardiovascular disease over the 5.4-year median follow-up period would be reduced by 31% or $3872 per randomized patient, primarily because of the reduction in hospitalizations for acute CHD events and revascularization procedures. The current wholesale acquisition costs of simvastatin in the United States as of May 1995 are $45.10, $81.75, and $82.50 for a 30-day supply of the 10-, 20-, and 40-mg tablets, respectively.¹⁴ The cost of simvastatin (similarly discounted) would be $4400 per patient ($4879 undiscounted) over the mean 1915 days of follow-up. The effective cost of simvastatin would be reduced by 88% to $528 per patient ($4400-$3872), or $0.28 per day. The use of simvastatin entails laboratory measurement of lipids and transaminases, typically three to four times in the first year of therapy and annually thereafter. With the assumption of nine measurements of both over 5.4 years (four times in the first year and once annually over the next 5 years) and with both measurements together costing $30, a discounted cost of $250 per patient, or an additional $0.13 per day, is added to the cost of treatment.

View this table: [in this window] [in a new window]   Table 2. Extrapolated Costs, Total and Averaged Over All Randomized Patients, Based on DRG Costs Associated With Cardiovascular Disease Hospitalizations

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
In addition to the previously described² effects on CHD morbidity and mortality, 4S demonstrated that simvastatin therapy in patients with CHD reduced hospital admissions for total cardiovascular disease by 26%, the average length of stay by 10%, and thus the number of days spent in hospital by 34%. Addition of simvastatin 20 to 40 mg daily to the treatment regimens of 100 CHD patients, with characteristics similar to those of the 4S patients, can be expected to yield the following approximate benefits over the first 5.4 years: avoidance of 23 of the 86 expected hospitalizations, including the prevention of 6 of 19 expected revascularization procedures, and the consequent elimination of 231 of the expected 679 days in hospital for cardiovascular events. With US DRG-based cost estimates applied, of the $1.23 million anticipated expenditure for acute cardiovascular hospitalizations and procedures in these 100 patients, $387 000 could be saved through the use of simvastatin. This represents 88% of the cost of simvastatin in the 100 patients during the same period.

Although hospitalizations and procedures represent a substantial portion of the economic costs of cardiovascular disease, a number of cost components are not included in this cost-minimization analysis: concomitant medications, outpatient visits, nursing home stays, and indirect costs. Simvastatin did not significantly reduce the use of other cardiovascular medications, which therefore were not included in the cost calculations. (Much of this concomitant therapy such as aspirin and ß-blockers was also intended to reduce the risk of recurrent coronary events and was not expected to be reduced through the use of simvastatin.)

Outpatient visits were specified in the study protocol and therefore could not differ by treatment group. The treatment of CHD generally requires regularly scheduled physician appointments; it is not likely that the need to monitor lipids and transaminases after the addition of simvastatin therapy would increase them. Inasmuch as simvastatin reduces the risk of CHD events, outpatient visits might be reduced; however, data were not collected on unscheduled outpatient visits. Admissions to nursing homes would probably be reduced for the same reason, but these data also were not collected during the trial. In addition to the direct savings arising from the reduction in days in hospital and in revascularization procedures, smaller savings would be expected in indirect costs such as disability benefits and lost earnings. Because these costs that we cannot assess are probably reduced by simvastatin, the true US drug cost offset may well exceed our estimation of 88%.

In the placebo group, CHD hospitalizations and revascularization procedures accounted for 78% of the days in hospital (Table 1) and 89% of the extrapolated costs (Table 2). The cost extrapolation therefore depends on the assumption that the frequency of recurrent CHD events, the proportion of such events that lead to hospitalization, and the rate of revascularization procedures are similar in Scandinavia and the United States. Comparative data on recurrent events in CHD patients are not readily available but are not likely to differ greatly because, according to government figures, CHD mortality and morbidity rates in the two regions are similar^{17 18} and the Scandinavian CHD hospitalization rate is only slightly higher (population-weighted average, 9.2 per 1000 compared with 7.5 per 1000 in the United States¹⁹ ). Average serum cholesterol is slightly higher in Scandinavia than in the United States,¹⁷ but the relative risk reductions produced by simvastatin in 4S were independent of baseline serum cholesterol.³ Revascularization procedures are performed much more frequently in the United States. The population-weighted average rates per 100 000 in 1991 were 55 and 29 for coronary artery bypass grafting and percutaneous transluminal coronary angioplasty in Scandinavia versus 161 and 120 in the United States.²⁰ However, the difference is smaller when rates in trials are compared. The average annual revascularization procedure rate per 1000 patients in the 4S placebo group was 36 compared with 50 in the control arm of a recent secondary prevention study performed in the United States, the Stanford Coronary Risk Intervention Project.²¹ Because revascularization procedures account for more than half the extrapolated expenditures, we have probably underestimated total costs in the United States. Cardiac catheterization rates in hospitalized patients are higher in the United States than in Scandinavia. Our method of using DRG-based hospitalization costs based on US use rates might have overestimated the cost in the simvastatin group because these patients had generally less severe CHD when hospitalized compared with the placebo group.

Governments and other healthcare payers face difficult decisions on how best to allocate limited funds. In Australia and Canada, health economic data are a prerequisite for the reimbursement of new medications.^{22 23} In other countries and in managed-care organizations in the United States, the demand for justification of the value of treatment is less explicit but equally strong. In some countries, such as the United Kingdom, physicians have been given the responsibility of managing their allocated funds. Previous economic analysis of cholesterol lowering required numerous assumptions about the effect of therapy on clinical events, generated mostly from limited data on the reduction of CHD morbidity produced by less effective cholesterol-lowering therapies combined with epidemiological studies on the prevalence of cardiovascular disease. The present report is the first analysis of resource use based on data collected prospectively within a large, randomized, controlled clinical trial of an effective cholesterol-lowering intervention that uses such data to assess the cost implications. This study makes no attempt to balance the net cost of therapy with the clinical benefits that were demonstrated previously. Instead, it represents a cost-minimization analysis that provides an accounting of the actual cost-generating events observed in a randomized controlled trial and places these events into context using US costs.

The rates and costs of acute hospitalizations for cardiovascular disease and revascularization procedures and (to a lesser extent) the cost of simvastatin vary from country to country. The offset for any given healthcare provider can be approximated by applying local costs to the data presented. Meta-analyses of previous intervention trials with lipid-lowering agents indicate that the reductions in coronary mortality and morbidity are dependent on the degree of cholesterol lowering achieved during the trial.^{24 25} Extrapolation of our results to other lipid-lowering therapy would therefore be appropriate only for regimens with long-term effects on LDL cholesterol similar to that observed with simvastatin 20 to 40 mg.

Conclusions
In this report, we have shown that treating CHD patients with simvastatin reduces the major costs of cardiovascular disease, thus offsetting a large part of the drug cost in the United States. These resource use analyses provide data that are fundamental for any further health economic analysis of lipid lowering with simvastatin.

	Acknowledgments

 
The Scandinavian Simvastatin Survival Study was made possible by a grant from Merck Research Laboratories, Rahway, NJ.

	Footnotes

 
¹ Collaborators and participating centers are listed in the "Appendix."

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Collaborators and Participating Centers
Denmark (713 patients randomized): Dr Alexandrines Sygehus, Faeroe Islands (H. Thomsen, E. Nordenø, and B. Thomsen); Fredriksberg Hospital, Copenhagen (K. Lyngborg, G. Steen Andersen, F. Nielsen, U. Talleruphuus, and M. Mogensen); Haderslev Sygehus (K. Egstrup, E. Hertel Simonsen, and I. Simonsen); Herning Sygehus (H. Vejby-Christensen, L. Sommer, P.O. Eidner, E. Klarholt, and A. Henriksen); Hillerød Sygehus (K. Mellemgaard, J. Launberg, P. Fruergaard, and L. Nielsen); Holbæk Syghus (E. Birk Madsen, H. Ibsen, U. Andersen, L. Thyrring, and K. Thomassen); Hvidovre Hospital, Copenhagen (G. Jensen, S. Lind Rasmussen, and N. Skov); Odense Sygehus (T. Haghfelt, K. Nørgård Hansen, M. Lytken Larsen, B. Haastrup, I. Hjære, A. Thurø, and K. Sørensen); K.A.S. Glostrup, Copenhagen (A. Leth, M. Munch, R. Worck, B. Nielsen, and A.G. Thorn); Nyborg Sygehus (O. Pedersen-Bjerregaard and B. Fournaise); Nykøbing Falster Sygehus (B. Sigurd, B. Enk, H. Nielsen, and L. Jacobsen); Næstved Sygehus (T. Lysebo Svendsen, A. Høegholm, and H. Münter); Rigshospitalet, Copenhagen (S. Haunsø, P. Grande, C. Eriksen, and H. Høegh Nielsen); Svendborg Sygehus (T. Pindborg, J. Pindborg, and H. Tost); Varde Sygehus (B. Dorff Christiansen and M. Oppenhagen); Vejle Sygehus (F. Egede, S. Hvidt, and T. Kjærby); and Århus Amtssygehus (O. Færgeman, L. Flemming, and I. Klausen).

Finland (868 randomized patients): Helsinki University Hosptial (T. Miettinen, H. Vanhanen, T. Strandberg, and K. Hölttä); Tampere University Hospital (A. Pasternak, H. Oksa, L. Siitonen, and R. Rimpi); Oulu University Hospital (A. Kesäniemi, H. Juustila, A. Nissilä, M. Savolainen, M. Lilja, A. Rantala, M. Rantala, L. Laine, L. Mäntymaa, A. Nissilä, and L. Virkkala); and Kuopio University Hospital (Kalevi Pyörälä, T. Ebeling, M. Helin, S. Lehto, P. Palomäki, A. Rantala, E. Voutilainen, H. Miettinen, R. Räisänen, A. Salokannel, and A. Jantunen).

Iceland (157 randomized patients): Landspitalinn University Hospital, Reykjavik (G. Thorgeirsson, J. Högnason, and G. Thorsteinsdottir); Reykjavik City Hospital (G. Sigurdsson); and Sjukrahusio Akureyri (J.T. Sverrisson).

Norway (1025 randomized patients): Aker Sykehus, Oslo (T.R. Pedersen, V. Hansteen, F. Kjelsberg, K. Berget, R. Pettersen, E. Randi, and T. Holm); Aust-Agder Sentralsykehus, Arendal (T. Gundersen, B. Aslaksen, and E. Hauge Andresen); Bærum Sykehus, Sandvika (H. Torsvik, R. Pettersen, J. Kjekshus, and A. Faber); Gjøvik Fylkessykehus (T. Indrebø, A. Ose, and T. Roterud); Fylkessjukehuset i Haugesund (L. Holst-Larsen, K. Waage, and E. Holst-Larsen); Hamar Sykehus (J.W. Hærem, P. Aukrust, R. Torp, and K. Mauseth); Haukeland Sykehus, Bergen (A. Hallaråker, E. Gerdts, G. Gradek, O. Nygård, and E. Moberg Vangen); Hedmark Sentralsykehus, Elverum (H. Schartum Hansen, A.M. Resfsum, S. Listerud, B. Gundersrud, and A.M. Stene); Innherred Sykehus, Levanger (O. Aakervik, B. Klykken, A. Loraas, P.O. Foss, A. Haga, and L. Thoresen); Moss Sykehus (A. Drivenes, P. Lem, F. Gabrielsen, and S. Hestad); Nordland Sentralsykehus, Bodø (R. Røde, B. Kvamme Haug, G. Skjelvan, and E. Eldorsen); Regionsykehuset i Tromsø (K. Ytre-Arne, K. Rasmussen, I. Nermoen, F.T. Gjestvang, L. Christiansen, and K. Walberg); Regionssykehuset i Trondheim (H.A. Tjønndal, B. Kulseng, R. Rokseth, T. Vigeland Nergård, and M. Olstad Røe); Ringerike Sykehus, Hønefoss (O. Tenstad, I.L. Løfsnes, and U. Bergsrud); Rogaland Sentralsjukehus, Stavanger (T.H. Melberg, C. von Brandis, L. Hegrenes, S. Barvik, L. Woie, A.M. Abrahamsen, T. Aarsland, and H. Svanes); Sandefjord Sykehus (G. Noer, K.E. Nordlie, and A.E. Hanedalen); Sarpsborg Sykehus (K. Overskeid, P. Sandvei, and Å. Johansen); Sentralsykehuset for õstfold, Fredrikstad (T. Johansen, T. Holm, C.B. Larsen, and E. tholm); Sogn og Fjordane Sentralsjukehus, Førde (S. Hegrestad, Å. Reikvam, E. Søgnen, E. Stilianoy, and L. Hawkes); Spesialistsenteret, Kristiansand (S. Hoff, R. Nordvik, and C. Jørgensen); Ullevål Sykehus, Oslo (I. Hjermann, P. Leren, and A. Narvestad); and Paul Leren Vest Agder Sentralsykehus, Kristiansand (D. Fausa, F.T. Gjestvang, K. Berget, and B. Nordland).

Sweden (1681 randomized patients): Arvika Sjukhus (P. Brunmark, H. Biörklund, and H. Biörklund); Boden/Luleå Lasarett (H. Forsberg, J. Nilsson, B. Bergström, I. Laaksonen, and M.B. Vestermark); Bollnäs Sjukhus (G. Mascher, E. Hammarström, and K. Trosell); Enköping Lasarett (L. Karlsson, L. Hallström); Eskilstuna Sjukhus (A. Stjerna, M.K. Slette, and K.-P Berglund); Falun Lasarett (B. Linde, G. Ahlmark, H. Sætre, G. Ahlberg, and K. Sundkvist); Gävle Sjukhus (R. Löfmark, P.E. Gustafsson, E.W. Michaeli, and E. Gustafsson); Halmstad Länssjukhus (E. Skarfors, G. Rüter, and L. Åkesson); Helsingborg Lasarett (F. Wagner, L. Ljungdahl, and V. Wagner); Huddinge Sjukhus (O. Edhag, D. Vourisalo, and H. Hjelmsell); Hudiksvall Lasarett (L. Lundkvist, K. Ångman, and A. Olsson); Jönköping Länssjukhus (O. Svensson, J. Kuylenstierna, K. Frisenette-Fich, and E. Bergman); Karlshamn Länslasarett (H. Strömblad, S. Jensen, E. Jönsson, and C. Levin); Karlskrona (H. Odeberg, P.O. Bengtsson, and E. Holmesson); Karlstad Centralsjukhus (H. Hedstand, L. Bojö, and S. Öberg); Kristianstad Sjukhus (S. Persson, C. Cline, H. Leksell, and U.B. Wirenstam); Kristinehamn Sjukhus (B. Moberg and A.B. Ekstrand); Köping Lasarett (P. Nicol, B. Malmros, J. Saaw, N. Arcini, J. Kobosko, and I.G. Ånevik); Landskrona Lasarett (F. Gyland, B. Lundh, M. Wennerholm, and C. Olsson); Lidköping Bassjukhus (J. Kjellberg and K. Fabianson); Lindesberg Lasarett (T. Fraser and I. Bergkvist); Linkåoping Universitätssjukhus (A.G. Olsson, B. Bergdahl, K. Fluur, and S. Wärjestam); Ljungby Lasarett (K.A. Svensson, L. Ekholm, E. Torebo, and A. Ryberg); Ludvika Lasarett (J. Frisell, A. Hedman, L. Vallrup, G. Andersen, M. Sundström, and K. Albery); Lund Lasarett (B. Fagher, T. Thulin, and I. Svenstam); Lundby Sjukhus, Göteborg (A. Norrby, B. Jaup, and L. Svensson); Lycksele Lasarett (A. Bjurman, E. Skoglund, and G. Dahl); Malmö Lasarett (T. Kjellström, P. Juhlin, and M. Sjöö-Boquist); Nacka Sjukhus (A. Sjögren, E. Loogna, and T. Jansson); Norrköping Lasarett (J. Friden, O. Nilsson, P.O. Andersson, and C. Henriksson); Sandviken Lasarett (J. Ellström, H. Brodersson, L. Lundquist, and M. Åslund); Skellefteå Lasarett (K. Boman, J.H. Jansson, and B. Norrfors); Stockholm Heart Center (C. Höglund and M. Lundblad); Skövde Kärnsjukhus (J. Ejdebäck, K. Malmberg, S. Hogström, and L. Ståhl); St Göran Sjukhus, Stockholm (B. Leijd, C. Falkenberg, L. Bergsten, S. Ström, A.C. Engström, and I. Petz); Sabbatsberg Sjukhus, Stockholm (I. Liljefors, L. Wennerström, and I. Petz); Sahlgrenska Sjukhuset, Göteborg (O. Wiklund, T. Linden, C.H. Bergh, K. Jonsted, B. Bonnier, and Y. Lundin); Sundsvall Lasarett (B.H. Möller, M. Lycksell, and M. Söderström); Säffle Sjukhus (E. Hansson, L. Gillgren, and C. Hallén); Trollhättan Lasarett (H. Stakeberg, J. Börretzen, B. Hedén, and K. Andersson); Umeå Universitätssjukhus (O. Johnson, L. Slunga, S. Jensen, and B. Elander); Uppsala Akademiska Sjukhus (C. Lidell, P.E. Andersson, and E. Marklund); Visby Lasarett (M. Dahlen, F. Rücker, M. Löfqvist, and B. Wannberg); Växjö Lasarett (B.H. Lim, O. Larsson, G. Andersson, A. Hansson, M. Gowenius, and I. Uggeldahl); Ängelholm Sjukhus (D. Ursing, P. Hammarlund, and E. Tsuppuka); Örebro Regionsjukhus (L. Malmberg, K. Göransson, P. Hasselgren, K.M. Inberg, S. Petterson, and A. Årlin); Östra Sjukhuset, Götebrog (G. Ulvenstam, S. Johansson, I. Wallin, K. Dudas, M. Andreasson, and G. Torelund); and Önsköldsvik Sjukhus (O. Lövheim, L.O. Hemmingson, and I. Grundström).

Steering Committee: J. Kjekshus (chairman, Norway), K. Berg (Norway), T.R. Pedersen (Norway), T. Haghfelt (Denmark), O. Færgeman (Denmark), G. Thorgeirsson (Iceland), K. Pyörälä (Finland), T. Miettinen (Finland), L. Wilhelmsen (Sweden), A.G. Olsson (cochairman, Sweden), H. Wedel (Sweden), and K. Kristianson (nonvoting; Merck Research Laboratories Scandinavia, Sweden).

Study coordinator: T.R. Pedersen (Norway).

Data and Safety Monitoring Committee: D.G. Julian (chairman, England), C. Furberg (United States), S. Thompson (England), J. Lubsen (retired, the Netherlands), W. McFate Smith (United States), and J. Huttunen (Finland).

Endpoint Classification Committee: M. Romo (Finland) and K. Thygesen (Denmark).

ECG Major Events Coding Centre: S. Lehto and H. Miettinen (Finland).

ECG Annual Visits Coding Centre: R. Crow (United States).

Central Lipid Laboratory: B. Christophersen, M. Buchman, and T. Gran (Norway).

Data Analysis: J. Cook, D. Gomes, S. Boccuzzi, and T. Cook (Merck & Co, Inc, United States).

Central Monitoring Office: K. Kristianson (Merck Research Laboratories Scandinavia, Sweden).

Received September 13, 1995; revision received December 12, 1995; accepted December 19, 1995.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 

1. American Heart Association. Heart and Stroke Facts: 1994 Statistical Supplement. Dallas, Tex: American Heart Association; 1994.
   
2. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389. [Medline] [Order article via Infotrieve]
   
3. Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet. 1995;345:1274-1275. [Medline] [Order article via Infotrieve]
   
4. 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). JAMA. 1993;269:3015-3023. [Medline] [Order article via Infotrieve]
   
5. Pyörälä K, De Backer G, Graham I, Poole-Wilson P, Wood D, for the Task Force. Prevention of coronary heart disease in clinical practice: recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J. 1994;15:1300-1331.[Free Full Text]
   
6. Oster G, Epstein AM. Cost-effectiveness of antihyperlipemic therapy in the prevention of coronary heart disease. JAMA. 1987;258:2381-2387. [Abstract]
   
7. Kinosian BP, Eisenberg JM. Cutting into cholesterol: cost-effective alternatives for treating hypercholesterolemia. JAMA. 1988;259:2249-2254. [Abstract]
   
8. Goldman L, Weinstein MC, Goldman PA, Williams LW. Cost-effectiveness of HMG-CoA reductase inhibition for primary and secondary prevention of coronary heart disease. JAMA. 1991;265:1145-1151. [Abstract]
   
9. Sønbø Kristiansen I, Eggen AL, Thelle DS. Cost-effectiveness of incremental programmes for lowering serum cholesterol concentration: is individual intervention worth while? Br Med J. 1991;302:1119-1122.
   
10. Martens LL, Rutten FFH, Erkelens DW, Ascoop CAPL. Clinical benefits and cost-effectiveness of lowering serum cholesterol levels: the case of simvastatin and cholestyramine in the Netherlands. Am J Cardiol. 1990;65:27F-32F. [Medline] [Order article via Infotrieve]
    
11. WHO MONICA Project. MONICA Manual, Revised Edition. Geneva, Switzerland: Cardiovascular Diseases Unit, WHO: 1990.
    
12. Tuomilehto J, Arstila M, Kaarsalo E, Kankaanpää J, Ketonen M, Kuulasmaa, K, Lehto S, Miettinen H, Mustaniemi H, Palomäki P, Puska P, Pyörälä K, Salomaa V, Torppa J, Vuorenmaa T. Acute myocardial infarction in Finland: baseline data from the FINMONICA AMI register in 1983-85. Eur Heart J. 1992;13.577-587.
    
13. The MEDSAT Groups Inc. DRG Guide: Descriptions and Normative Values. Ann Arbor, Mich; 1994.
    
14. First Data Bank/Hearst Corp. Wholesale Acquisition Costs of Inhibitors of HMG-CoA Reductase. San Bruno, Calif: Price Probe (4.2); April 24, 1995.
    
15. Andersen PK, Gill RD. Cox's regression model for counting processes: a large sample study. Ann Stat. 1982;10:1100-1120.
    
16. Hochberg Y. A sharper Bonferroni procedure for multiple test of significance. Biometrika. 1988;75:800-802. [Abstract/Free Full Text]
    
17. Law MR, Wald NJ. An ecological study of serum cholesterol and ischaemic heart disease between 1950 and 1990. Eur J Clin Nutr. 1994;48:305-325. [Medline] [Order article via Infotrieve]
    
18. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A. Myocardial infarction and coronary deaths in the World Health Organization MONICA project: registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation. 1994;90:583-612. [Abstract/Free Full Text]
    
19. US Department of Health and Human Services. National Hospital Discharge Survey: Annual Summary, 1991. Vital Health Stat. 1993; series 13.
    
20. Unger F. European survey on open heart surgery, PTCA and cardiac catheterisation in 1992. Ann Eur Acad Sci Arts. 1993;6:12-66.
    
21. Haskell WL, Alderman, EL, Fair JM, Maron DJ, Mackey SF, Superko HR, Williams PT, Johnstone IM, Champagne MA, Krauss RM, Farquhar JW. Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease: the Stanford Coronary Risk Intervention Project (SCRIP). Circulation. 1994;89:975-990. [Abstract/Free Full Text]
    
22. Canadian Coordinating Office for Health Technology Assessment. Guidelines for Economic Evaluation of Pharmaceuticals. 1st ed. Ottawa, Ontario, Canada: November 1994.
    
23. Pharmaceutical Benefits Advisory Committee, Commonwealth Department of Health, Housing and Community Service. Guidelines for the Pharmaceutical Industry on Preparation of Submissions to the Pharmaceutical Benefits Advisory Committee. Canberra, Australia: Australian Government Publishing Service; 1992.
    
24. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? Br Med J. 1994;308:367-372. [Abstract/Free Full Text]
    
25. Gould AL, Rossouw JE, Santanello NC, Heyse J, Furberg CD. Cholesterol reduction yields clinical benefit: a new look at old data. Circulation. 1995;91:2274-2282.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				N F Murphy, S Stewart, C L Hart, K MacIntyre, D Hole, and J J V McMurray A population study of the long-term consequences of Rose angina: 20-year follow-up of the Renfrew-Paisley study Heart, December 1, 2006; 92(12): 1739 - 1746. [Abstract] [Full Text] [PDF]

				W. S. Weintraub, E. M. Mahoney, A. Lamy, S. Culler, Y. Yuan, J. Caro, S. Gabriel, S. Yusuf, and CURE Study Investigators Long-term cost-effectiveness of clopidogrel given for up to one year in patients with acute coronary syndromes without ST-segment elevation J. Am. Coll. Cardiol., March 15, 2005; 45(6): 838 - 845. [Abstract] [Full Text] [PDF]

				References Circulation, December 17, 2002; 106(25): 3373 - 3421. [Full Text]

				T. Marshall and A. Rouse Resource implications and health benefits of primary prevention strategies for cardiovascular disease in people aged 30 to 74: mathematical modelling study BMJ, July 27, 2002; 325(7357): 197 - 197. [Abstract] [Full Text] [PDF]

				L. Goldman, K. A. Phillips, P. Coxson, P. A. Goldman, L. Williams, M. G. M. Hunink, and M. C. Weinstein The effect of risk factor reductions between 1981 and 1990 on coronary heart disease incidence, prevalence, mortality and cost J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1012 - 1017. [Abstract] [Full Text] [PDF]

				J. Yarzebski, F. Spencer, R. J. Goldberg, D. Lessard, and J. M. Gore Temporal Trends (1986-1997) in Cholesterol Level Assessment and Management Practices in Patients With Acute Myocardial Infarction: A Population-Based Perspective Arch Intern Med, June 25, 2001; 161(12): 1521 - 1528. [Abstract] [Full Text] [PDF]

				S. A. Grover, M. Dorais, G. Paradis, J. G. Fodor, J. J. Frohlich, R. McPherson, L. Coupal, and H. Zowall Lipid screening to prevent coronary artery disease: a quantitative evaluation of evolving guidelines Can. Med. Assoc. J., November 1, 2000; 163(10): 1263 - 1269. [Abstract] [Full Text] [PDF]

				R. M. Vicari, G. J. Wan, A. M. Aura, C. M. Alexander, L. E. Markson, S. M. Teutsch, and for the Simvastatin Combined Hyperlipidemia Regist Use of Simvastatin Treatment in Patients With Combined Hyperlipidemia in Clinical Practice Arch Fam Med, September 1, 2000; 9(9): 898 - 905. [Abstract] [Full Text] [PDF]

				S. A. Grover, L. Coupal, H. Zowall, and M. Dorais Cost-Effectiveness of Treating Hyperlipidemia in the Presence of Diabetes : Who Should Be Treated? Circulation, August 15, 2000; 102(7): 722 - 727. [Abstract] [Full Text] [PDF]

				S. Frankel, S. Ebrahim, G. Davey Smith, and B. New The limits to demand for health care Commentary: An open debate is not an admission of failure BMJ, July 1, 2000; 321(7252): 40 - 45. [Full Text]

				S. M. Haffner Is All Coronary Heart Disease Prevention in Type 2 Diabetes Mellitus Secondary Prevention? J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2108 - 2110. [Full Text]

				L. Goldman, P. Coxson, M. G. M. Hunink, P. A. Goldman, A. N. A. Tosteson, M. Mittleman, L. Williams, and M. C. Weinstein The relative influence of secondary versus primary prevention using the National Cholesterol Education Program Adult Treatment Panel II guidelines J. Am. Coll. Cardiol., September 1, 1999; 34(3): 768 - 776. [Abstract] [Full Text] [PDF]

				D M Pickin, C J McCabe, L E Ramsay, N Payne, I U Haq, W W Yeo, and P R Jackson Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment Heart, September 1, 1999; 82(3): 325 - 332. [Abstract] [Full Text] [PDF]

				S. M. Grundy, J. I. Cleeman, B. M. Rifkind, L. H. Kuller, and for the Coordinating Committee of the National Cho Cholesterol Lowering in the Elderly Population Arch Intern Med, August 9, 1999; 159(15): 1670 - 1678. [Abstract] [Full Text] [PDF]

				A. M. Gotto Jr Lipid-lowering therapy for the primary prevention of coronary heart disease J. Am. Coll. Cardiol., June 1, 1999; 33(7): 2078 - 2082. [Full Text] [PDF]

				S. A. Grover, L. Coupal, S. Paquet, and H. Zowall Cost-effectiveness of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors in the Secondary Prevention of Cardiovascular Disease: Forecasting the Incremental Benefits of Preventing Coronary and Cerebrovascular Events Arch Intern Med, March 22, 1999; 159(6): 593 - 600. [Abstract] [Full Text] [PDF]

				West of Scotland Coronary Prevention Study Group The effects of pravastatin on hospital admission in hypercholesterolemic middle-aged men: West of Scotland Coronary Prevention Study J. Am. Coll. Cardiol., March 15, 1999; 33(4): 909 - 915. [Abstract] [Full Text] [PDF]

				S. B. Soumerai and D. Ross-Degnan Inadequate Prescription-Drug Coverage for Medicare Enrollees -- A Call to Action N. Engl. J. Med., March 4, 1999; 340(9): 722 - 728. [Full Text]

				A. M. Gotto Jr and S. M. Grundy Lowering LDL Cholesterol : Questions From Recent Meta-Analyses and Subset Analyses of Clinical Trial DataIssues From the Interdisciplinary Council on Reducing the Risk for Coronary Heart Disease, Ninth Council Meeting Circulation, March 2, 1999; 99 (8): e1 - e7. [Abstract] [Full Text] [PDF]

				D. E. Gutstein and V. Fuster Pathophysiology and clinical significance of atherosclerotic plaque rupture Cardiovasc Res, February 1, 1999; 41(2): 323 - 333. [Abstract] [Full Text] [PDF]

				T. A. Jacobson, J. R. Schein, A. Williamson, and C. M. Ballantyne Maximizing the Cost-effectiveness of Lipid-Lowering Therapy Arch Intern Med, October 12, 1998; 158(18): 1977 - 1989. [Abstract] [Full Text] [PDF]

				P. McBride, H. G. Schrott, M. B. Plane, G. Underbakke, and R. L. Brown Primary Care Practice Adherence to National Cholesterol Education Program Guidelines for Patients With Coronary Heart Disease Arch Intern Med, June 8, 1998; 158(11): 1238 - 1244. [Abstract] [Full Text] [PDF]

				M. Gheorghiade and R. O. Bonow Chronic Heart Failure in the United States : A Manifestation of Coronary Artery Disease Circulation, January 27, 1998; 97(3): 282 - 289. [Full Text] [PDF]