PHARMACOECONOMICS DRUG EVALUATION

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PharmacoEconomics I (2): 124-145, 1992 1170-7690(92(0002-0124($11.00(0 © Adis International Limited. All rights reserved. PEel

Simvastatin A Pharmacoeconomic Evaluation of its Cost-Effectiveness in Hypercholesterolaemia and Prevention of Coronary Heart Disease Paul Chrisp, I Nancy 1. W. Lewis 2 and Richard J, Milne I I Adis International Limited, Auckland, New Zealand 2 Institute for Pharmaceutical Economics, Philadelphia College of Pharmacy and Science, Philadelphia, Pennsylvania, USA

Various sections of the manuscript reviewed by: A.M. Dart, Alfred and Baker Medical Unit, Melbourne, Victoria, Australia; D. W. Erkelens, Department of Endocrinology, University Hospital Utrecht, Utrecht, The Netherlands; M.H. Frick, First Department of Medicine, University Central Hospital, Helsinki, Finland; Y. Goto, School of Medicine, Tokai University, Isehara, Japan; H. [kram, Cardiology Department, Princess Margaret Hospital, Christchurch, New Zealand; D.R. Illingworth, Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health Sciences University, Portland, Oregon, USA; W. B. Kannel, Boston University School of Medicine, Framingham, Massachusetts, USA; B. Kinosian, Section of General Internal Medicine, Ralston-Penn Center, Philadelphia, Pennsylvania, USA; J. Molgaard, Department of Internal Medicine, University Hospital Linkoping, Linkoping, Sweden; B. Murphy, Department of Marketing and International Business, University of Auckland, Auckland, New Zealand; M.J. Tikkanen, First Department of Medicine, University Central Hospital, Helsinki, Finland

Contents 125 126 126 127 127 128 129 131 131

131 135

135 136 136 138

142 142

142

Summary I, Serum Lipid Reduction and Coronary Heart Disease Prevention 1.1 Pathophysiology of Lipid Metabolism 1,2 An Overview of the Evidence 1.2.1 Epidemiological Studies 1,2,2 Primary Prevention Studies 1.2.3 Secondary Prevention Studies 2, Therapeutic Rationale for Simvastatin 2, I Efficacy 2,2 Tolerability 3, Pharmacoeconomic Considerations 3, I Costs of Coronary Heart Disease 3.2 Economic Impact of Simvastatin Intervention 3.2, I General Considerations 3.2.2 Cost-Effectiveness of Simvastatin 4, Pharmacoeconomic Positioning of Simvastatin 4, I General Prescribing Considerations 4,2 Formulary Considerations

Simvastatin in Hypercholesterolaemia

125

Summary Synopsis Epidemiological and intervention study results support reduction of coronary heart disease (CHD) risk, and hence direct and indirect costs, by lowering plasma lipids. Cost-effectiveness of a lipidlowering strategy thus depends significantly on the extent of plasma lipid decrease achieved. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin is a well tolerated and highly effective antihyperlipidaemic agent. Despite a current lack of direct evidence that simvastatin reduces CHD incidence, the cost-effectiveness of the drug [in terms of years of life saved (YOLS)} has been studied, based on findings of epidemiological trials. Simvastatin 20 mg/day is more cost-effective than cholestyramine 4g 3 times daily, particularly in men and in those with a higher pretreatment cholesterol level (> 8 mmol/L) and other risk factors. Cost-effectiveness is also enhanced if treatment is started at a younger age (35 to 45 years) and maintainedfor a defined period rather than lifelong. Thus, while additional direct comparative studies are needed to confirm this finding, present evidence suggests simvastatin is a cost-effective intervention in appropriately selected patients.

Disease Considerations Epidemiological studies support the relationship between increased risk of coronary heart disease (CHD) and elevated plasma cholesterol, particularly low density lipoprotein (LDL)-cholesterol. The Multiple Risk Factor Intervention Trial (MRFIT) revealed a 4-fold greater risk ofCHD mortality in middle-aged men with a serum cholesterol level > 4.68 mmol/L, and the Framingham Heart Study demonstrated a 2.5-fold increased CHD risk in men and 1.5-fold increased risk in women with levels> 6.89 mmol/L compared with those with a level of < 5.7 mmol/L. Primary prevention studies (i.e. reducing serum cholesterol in individuals without evidence of CHD) support the causal relationship. The Lipid Research Clinics Coronary Primary Prevention Trial reported a 19% reduction in CHD death and/or nonfatal myocardial infarction following cholestyramine-induced decreases of8.5 and 12.6%, respectively, in total and LDL-cholesterol after 7 years' follow-up. Similarly, a 34% lower frequency of cardiac events occurred in gemfibrozil recipients compared with those receiving placebo in the Helsinki Heart Study. In patients already with clinical evidence ofCHD, secondary prevention trials yield a 1.5 and 2% decrease in CHD incidence, respectively, for each diet- and drug-induced reduction of I % in serum cholesterol level.

Pharmacoeconomic Benefits and Costs The benefit of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase, resides in its ability to lower elevated cholesterol levels. Simvastatin reduces total and low density lipoprotein (LDL)-cholesterol by 30 to 45% in patients with heterozygous familial and nonfamilial hypercholesterolaemia, a magnitude of effect greater than that of probucol, the bile acid sequestrants cholestyramine and colestipol, and the fibrates gemfibrozil, bezafibrate, fenofibrate and clofibrate. Simvastatin is at least comparable to other HMG-CoA reductase inhibitors at conventional doses, and more potent on a weight for weight basis. The drug is very well tolerated, so that costs incurred treating adverse effects or providing additional therapy to account for poor efficacy related to noncompliance are likely to be negligible, although regular liver function tests are necessary.

Pharmacoeconomic Analysis The cost-effectiveness of simvastatin, and indeed other antihyperlipidaemic drugs, depends to a substantial degree on its ability to decrease plasma lipid levels and hence reduce costs associated with CHD. This latter factor must be extrapolated from the estimated effect on CHD incidence, based on findings of epidemiological and primary prevention studies, since direct evidence of reduced CHD mortality and morbidity during simvastatin therapy is not yet available. Cost-effectiveness analysis of the drug is generally expressed in terms of YOLS, based on

PharmacoEconomics 1 (2) 1992

126

epidemiological data. Cost of the drug itself (the most critical input factor), costs of medical care and costs of side effects, minus the cost savings associated with CHD reduction, are all accounted for and may vary greatly between studies and countries. In a cohort of 35- to 74-year old candidates for antihyperlipidaemic therapy from the Netherlands, without evidence of CHD, simvastatin 20 mg/day was more cost-effective than cholestyramine 4g 3 times daily [in men, cost per YOLS Fl (Netherlands guilders) 50000 to 110 000 vs Fl 220 000 to 510000]. The cost-effectiveness of both agents was greater in men, in those with higher pretreatment total serum cholesterol level, in those with other CHD risk factors (e.g. hypertension, diabetes), and if initiated at a younger age. However, simvastatin maintained its costeffectiveness advantage in all high and lower risk groups. An Australian study reported a higher monthly cost of simvastatin compared with standard (unspecified) therapy in high risk patients ($A6S.03 vs $AS.ll), but considerably better efficacy and tolerability. A congener of simvastatin, lovastatin, has been shown more cost-effective than probucol, colestipol, cholestyramine and gemfibrozil. Thus, simvastatin appears to be more cost-effective than other lipid-lowering agents (particularly in certain targeted subgroups), although more direct comparisons are required to confirm this.

The clinician faced with choosing an appropriate lipid-lowering agent to reduce coronary heart disease (CHD) risk is interested in the economic impact of simvastatin in comparison with other drugs suitable for a particular patient. The economic benefit of hypolipidaemic agents such as simvastatin resides in their potential to produce financial savings via avoidance of costs associated with CHD-related events, although this must be proven. Thus, these agents may decrease the need for hospitalisation, medical care services and other drug therapies associated with CHD. Lipid-lowering therapy may also result in savings in nonmedical direct costs and savings in medical and nonmedical indirect costs associated with CHD. The benefits of simvastatin must be viewed in light of the direct costs associated with its use, including the drug product costs, costs of monitoring cholesterol levels and liver function, and physician visits. Simvastatin therapy is also associated with medical indirect costs and nonmedical direct and indirect costs, all of which may have an impact on assessing its cost-effectiveness. The pharmacoeconomic place of simvastatin in the management of CHD is evaluated in this review, on the basis of the international published literature.

1. Serum Lipid Reduction and Coronary Heart Disease Prevention 1.1 Pathophysiology of Lipid Metabolism

The major serum lipids cholesterol and triglyceride are incorporated into hydrophilic lipoproteins which differ in their size, density and makeup. There are 5 main types of lipoproteins: chylomicrons, which transport dietary triglycerides from the small intestine via the lymph into plasma; very low density lipoprotein (VLDL), which carries endogenously synthesised cholesterol and triglyceride; low density lipoprotein (LDL), derived from VLDL remnants, which is the principal vehicle for cholesterol transport, and is taken up by LDL receptors on hepatocytes and peripheral cells thus releasing the cholesterol component for cellular use; high density lipoprotein (HDL), which mediates the reverse transport of cholesterol from peripheral tissues to the liver for elimination in bile and bile acids; and finally, remnant particles which result from lipoprotein lipase breakdown of chylomicrons and VLDL, and which may either be cleared by the liver or, in the case of VLDL, act as LDL precursors. An elevated level of any of these lipoproteins, other than HDL, is the basis of all hyperIipidaemia.

Simvastatin in Hypercholesterolaemia

Hyperlipidaemia usually arises through an interaction of genetic (primary) and environmental (secondary) factors, such as cigarette smoking, alcohol consumption and diet. Six pathological lipoprotein phenotypes have been described (table I), of which types IIa, lIb, III and possibly IV with their hypercholesterolaemia are most likely to be associated with coronary artery disease (Thompson 1988), although the role of triglyceride-rich particles may have been underestimated. It is clear that only some of the lipoprotein fractions, particularly LDL and remnant particles, are potential risk factors for atherogenesis and subsequent cardiovascular disease. Normally, chylomicron and VLDL remnants (intermediate density lipoprotein, IDL) are taken up by apo E receptors in the liver; variable amounts of the latter are converted to LDL. If cholesterol biosynthesis in the liver is partially disrupted, for example by an inhibitor of 3hydroxy-3-methylglutaryl-coenzyme A (HMO-CoA) reductase, the population of hepatic LDL receptors is elevated to increase the uptake of serum LDLcholesterol (Bilheimer 1988). Enhanced LDL receptor activity decreases serum levels of VLDL remnants and chylomicrons as well as LDL, thus reducing the risk of atherogenesis. Increasing serum HDL levels may also be beneficial through elevated reverse tra,nsport of cholesterol.

Table I. Lipoprotein phenotypes underlying hyperlipidaemia

Phenotype

Serum lipoprotein levels

Serum lipid levels

t chylomicrons

tt trigylcerides t cholesterol t cholesterol t cholesterol and

lia lib

t LDL t LDL and VLDL

iii

t chylomicrons and

IV

t VLDL

VLDL remnants - LDL V

t chylomicrons and

triglycerides t cholesterol and triglycerides t triglycerides and - or t cholesterol tt triglycerides

VLDL

t indicates mild to moderate increase; tt indicates marked increase; - indicates no change from normal.

Symbols:

127

1.2 An Overview of the Evidence The causal relationship between elevated serum cholesterol levels (particularly elevated LDL) and CHD is now widely accepted, supported as it is by a wealth of evidence, foremost of which are the epidemiological data which show an increased risk of CHD with elevated plasma cholesterol levels, and results obtained in intervention trials which demonstrate reduced CHD risk through lipid lowering. 1.2.1 Epidemiological Studies The Multiple Risk Factor Intervention Trial (MRFIT) screened 361 662 men aged between 35 and 57 years and clearly demonstrated an increased CHD mortality risk with increasing serum cholesterol levels (fig. 1). A level of 4.65 mmol/L (1 mmol/L = 38.67 mg/dl) or above was associated with 91 % of CHD deaths (Stamler et al. 1986); 48% of these were considered excess deaths attributable to a cholesterol level over 4.65 mmol/L, and of these excess deaths 54% occurred in men with a level between 4.65 and 6.54 mmol/L (Martin et al. 1986). This latter group, which consisted of 15% of the study population, were almost 4 times as likely to die from CHD as the baseline group (cholesterol level < 4.68 mmol/L). This risk associated with raised serum cholesterol was shown to be progressive and graded rather than stepped, and remained even when hypertension and smoking were accounted for (Stamler et al. 1986). A lower serum cholesterol « 5.72 ± 0.98 mmol/ L) also contributed to a 37 to 43% decline in cumulative cardiovascular disease mortality among cohorts of men participating in the Framingham Heart Study (Sytkowski et al. 1990). An earlier report from this study demonstrated a 2.5-fold greater CHD risk in men and 1.5-fold risk in women with a serum cholesterol of> 6.89 mmol/L compared with those with a level below 5.7 mmol/L (Kannel et al. 1971). Data from this study also reveal the beneficial effects of increased serum HDL-cholesterol levels; a total cholesterol : HDL-cholesterol ratio of < 3.5 indicates a reduced risk of CHD (Castelli 1990; Castelli et al.

PharmacoEconomics 1 (2) 1992

128

4

-* 3

..

~ 1: 0

E

0 J: U (;

-* 2

*

"'"

·c
r---

Q)

.~

OJ a;

*

a::

r---

~

4.68

4 .715 ,22

5.255,69

5.726.31

;;. 6.34

Serum cholesterol leve l (mmoljL)

Fig. 1. Relative risk of CHD death in 356222 men aged 35 to 57 years screened for MRFIT; • = p < 0.01 vs cholesterol level ~ 4.68 mmol/L (from Martin et al. 1986; Stamler et al. 1986).

1986). Stampfer et al. (1991) have also recently shown in a case-control study that myocardial infarction is less likely to occur as plasma levels of total HDL and the HDL2 and HDL3 subfractions increase. Serum cholesterol levels follow an essentially normal distribution pattern, but the range varies greatly between countries and populations (for a review of international hypercholesterolaemia epidemiology, see Wilson 1989). Approximately 40 to 50% of men and women aged 40 years or over in Europe and the United States have a serum cholesterol level of 5.1 to 6.5 mmol/L (Levy 1986; Theile 1990).

1.2.2 Primary Prevention Studies Pharmacological intervention is recommended in patients with primary hypercholesterolaemia if restriction of total fat, saturated fatty acids and cholesterol in the diet fail to reduce plasma total or LDL-cholesterol to the desirable limit or below after 6 months (table II). Physicians should also take into account other risk factors (e.g. smoking, diabetes, hypertension) to properly target therapy towards those who will benefit most, and to perhaps not treat patients with other risk factors who may not demonstrate reduced CHD risk. Drugs used to reduce plasma lipid levels include the HMG-CoA reductase inhibitors [e.g. simvastatin (for review see Todd & Goa 1990), lovastatin (Henwood & Heel 1988), pravastatin (McTavish & Sorkin 1991)]; fibric acid derivatives [e.g. gemfibrozil (Todd & Ward 1988), bezafibrate, clofibrate]; bile acid sequestrants (e.g. cholestyramine, colestipol); probucol; and nicotinic acid (niacin). In an early double-blind trial, a mean 9% reduction in plasma total cholesterol level in 5331 men receiving clofibrate 1.6 g/day was associated with a 20% lower incidence of ischaemic heart disease (nonfatal myocardial infarction only) compared with 5296 placebo-treated men (Committee of Principal Investigators 1978). These results have since been confirmed and elaborated upon in 2 major primary intervention studies. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) was a multicentre, randomised, double-blind study designed to investigate the efficacy of minimising CHD risk by reducing plasma cholesterol (Lipid Research Clinics Program 1984a). 3806 men aged 35 to 59 years without clinical evidence of CHD but with type lIa hyperlipidaemia (see table J) restricted dietary cholesterol and were randomised to receive cholestyramine resin 24 g/day (n = 1906) or placebo (n = 1900). After a mean follow-up of 7.4 years, mean plasma total and LDL-cholesterol, respectively, were 8.5% and 12.6% lower in cholestyramine compared with placebo recipients (p < 0.001). Primary end-points, defined as definite CHD death and/or nonfatal myocardial infarction, occurred in

129

Simvastatin in Hypercholesterolaemia

Table II. Classification of plasma cholesterol levels and treatment objectives in adults (after the National Cholesterol Education Program (1988)

Category

Desirable Borderline

a

treatment goal (mmoI/L) [gIL]

plasma level (mmoI/L) [gIL]

follow-up

plasma level (mmoI/L) [gIL]

follow-up

< 5.2 [2] 5.2-6.2 [2-2.39]

Repeat within 5y Dietary advice and repeat annually Base action on LDL level

< 2.3 [1.3] ;;. 2.3 [1.3]8

None Dietary advice

< 2.3 [1.3]

;;. 2.8 [1.59]

Dietary advice

< 2.8 [1.59]

;;. 2.8 [1.6]8 ;;. 2.4 [1.9]

Drug therapy Drug therapy

< 2.3 [1.3] < 2.8 [1.6]

5.2-6.28 [2-2.39] High

LDL-cholesterol

Total cholesterol

;;. 6.2 [2.4]

If the patient has definite coronary heart disease (CHD) or 2 of the fololowing risk factors: male sex, family history of premature CHD, cigarette smoking, hypertension, low HDL-cholesterol, diabetes mellitus, definite cerebrovascular or peripheral vascular disease or severe obesity.

155 of the cholestyramine group versus 187 in the placebo group (p < 0.05); the corresponding cumulative 7-year incidence rates were 7% and 8.6%, indicating a 19% reduction in patients receiving active drug treatment. Furthermore, the incidence of new positive exercise tests, angina, and coronary artery bypass surgery, respectively, were 25, 20 and 21 % lower in the cholestyramine recipients. For each 8% decrease in total cholesterol or 11 % decrease in LDL cholesterol observed in the latter group, CHD risk was reduced by 19% (Lipid Research Clinics Program 1984b). A small increase of 2.8% in mean plasma HDL-cholesterol induced by cholestyramine independently reduced risk by 2%, but this was not statistically significant. The second major randomised, double-blind primary prevention trial was the Helsinki Heart Study (Frick et al. 1987). 4081 asymptomatic men aged between 40 and 55 years with a non-HDL (i.e. LDL plus VLDL) cholesterol plasma level of> 5.2 mmol/L received gemfibrozil 600mg twice daily (n = 2051) or placebo (n = 2030) for 5 years in addition to a low cholesterol diet. Gemfibrozil caused reductions of 6, 8, 12 and 43%, respectively, in serum total-cholesterol, LDL-cholesterol, nonHDL-cholesterol and triglyceride levels, and an increase of 10% in HDL-cholesterol, whereas placebo was not associated with any consistent changes in lipid levels. Cardiac end-points (myocardial in-

farction and cardiac death) occurred in 56 gemfibrozil and 84 placebo recipients, representing a 34% reduction in frequency (p < 0.05; 95% confidence interval, 8.2 to 52.6). The beneficial effect of active drug treatment was noticeable within 2 years. The greater reduction in end-point incident in the Helsinki Heart Study compared with the LRC-CPPT (34 vs 19%) may have been partly due to the effect on triglycerides, and perhaps to the significant elevation in protective HDL- and reduction in harmful VLDL-cholesterol associated with gemfibrozil. Interestingly, LRC-CPPT revealed only a nonsignificant 7% reduction in aU-cause mortality in favour of active therapy (Lipid Research Clinics Program 1984a), and the Helsinki Study reported no differences (Frick et al. 1987). Moreover, Strandberg et al. (1991) reported increased total mortality in 612 men receiving lipid-lowering (clofibrate and/ or probucol) and antihypertensive therapy, compared with 610 untreated control subjects (67 vs 46; p = 0.048). The clinical significance of these findings has not yet been established. 1.2.3 Secondary Prevention Studies Secondary prevention describes methods aimed at reducing plasma cholesterol in patients with clinical manifestations of CHD. Early dietary intervention studies reveal a clear tendency toward decreased risk of further coronary events with

PharmacoEconomics 1 (2) 1992

130

cholesterol restrictIOn (table III) [Lipid Research Clinics Program 1984b; see review by Tyroler 1989]. Pharmacological intervention with clofibrate, nicotinic acid or dextrothyroxine also generally fits this pattern (table III); the 2 apparent anomalies of increased CHD incidence may have been caused by a small patient population (Research Committee to the Medical Research Council 1965) or druginduced cardiotoxicity (Coronary Drug Project Research Group 1972). Using regression analysis, Peto was able to demonstrate reductions of 1.5 and 2%, respectively, for each diet- and drug-induced decrease of I % in cholesterol level (Mann & Marr 1981). A recent metaanalysis revealed much greater absolute CHD risk reduction in secondary versus primary intervention studies (3.2 vs 0.1 %) [Silberberg & Henry 1991]. The results of early trials have been confirmed in subsequent secondary prevention studies (table III). The Program on the Surgical Control of the Hyperlipidemias (POSCH) revealed a 35% decrease in CHD incidence in survivors of myocard-

ial infarction who had undergone partial ileal bypass, an operation which increases faecal sterol excretion (Buchwald et al. 1990). Indeed, total and LDL-cholesterol were significantly lower in this group than in control patients. Clofibrate plus nicotinic acid were shown to lower CHD mortality by 36% in another group of279 previous infarction survivors (Carlson & Rosenhamer 1988), and the beneficial effects of nicotinic acid alone were still apparent with a 12% lower rate of CHD death 9 years after therapy had been stopped in a followup of the Coronary Drug Project (Canner et al. 1986). Total mortality was decreased II % in nicotinic acid recipients. Several studies have indicated that progression of established and new atherosclerotic lesions is significantly impeded by treatment with lipid-lowering agents including colestipol, nicotinic acid, cholestyramine and lovastatin (Blankenhorn et al. 1987; Brensike et al. 1984; Brown et al. 1990; Cashin-Hemphill et al. 1990; Kane et al. 1990), or by major modification of diet and other lifestyle

Table III. CHD incidence reduction in some secondary prevention studies Reference

Intervention

Buchwald et al. (1990) Canner et al. (1986) Carlson & Rosenhamer (1988) Coronary Drug Project Research Group (1972) Coronary Drug Project Research Group (1975) Group of Physicians of the Newcastleupon-Tyne Region (1971)

SurgeryC 838 Nicotinic acid (niacin) 3908 Clofibrate + nicotiniC acid 555 3798 Dextrothyroxine

Total number of patients studied 8

Follow-up (years)

CHD reduction (%)b

5 15 5 3

35 12d 36d -12 e

Clofibrate Nicotinic acid Clofibrate

3892 3908 497

5 5 5

9 20 44

Leren (1970) Research Committee to the Medical Research Council (1965)

Diet

412 252

5 3

35

Diet

Research Committee to the Medical Research Council (1968) Research Committee to the Scottish Society of Physicians (1971)

Diet

393

4

18

Clofibrate

717

6

26

a b

Including control group. Compared with control group.

c

Partial ileal bypass.

d e

Decrease in CHD mortality. CHD incidence increased during intervention.

-l e

Simvastatin in Hypercholesterolaemia

changes (Arntzenius et al. 1985; Blankenhorn et al. 1987; Ornish et al. 1990) although the clinical relevance of the effects of diet alone can be questioned.

2. Therapeutic Rationale of Simvastatin 2.1 Efficacy Cost-effectiveness of an antihyperlipidaemic drug depends upon the ability of the drug, in conjunction with diet and other lifestyle changes, to reduce the incidence and hence cost of CHD through decreased plasma cholesterol levels. In the case of simvastatin, studies published to date have assessed the efficacy of the drug in terms of intermediate end-points (i.e. effect on plasma lipids) rather than primary end-points (i.e. CHD incidence, morbidity and mortality). Thus, any assessment of cost-effectiveness in terms of reduced CHD risk must be extrapolated from the estimated effect of simvastatin-induced lipid reductions on CHD incidence. However, the ongoing Scandinavian Simvastatin Survival Study aims to directly investigate whether 4 years' simvastatin therapy in 4444 patients with CHD and hypercholesterolaemia will improve overall survival and reduce the incidence of myocardial infarction and sudden death (Jones 1990; data on file, Merck). The efficacy of simvastatin in lowering plasma cholesterol levels has been studied predominantly in individuals with primary hypercholesterolaemia, usually of heterozygous familial origin, with some studies in patients with polygenic nonfamilial disease (table IV). Familial hypercholesterolaemia has a prevalence of about 1 in 500 and is associated with an approximately 50% lower proportion of LDL receptors, and consequently a 2to 3-fold higher plasma cholesterol level. Nonfamilial hypercholesterolaemia is more common and results from a combination of genetic and environmental factors. Studies comparing the efficacy of simvastatin with other lipid-lowering drugs are shown in table IV. The drug decreased plasma levels of total and LDL-cholesterol to a greater extent than probucol. the bile acid sequestrants colestipol and cholestyr-

131

amine and conventional clinical doses of the fibrates gemfibrozil, bezafibrate, fenofibrate and clofibrate. The latter class of drugs, however, tended to raise plasma HDL-cholesterol and reduce triglycerides further than simvastatin, although the effects of simvastatin on these lipid fractions was often quite substantial. In contrast, probucol reduced HDL-cholesterol levels and cholestyramine increased plasma triglycerides. The ratio of LDL: HDL-cholesterol was decreased 30 to 50% by simvastatin 20 or 40 mg/day. The few comparisons of simvastatin with other HMG-CoA reductase inhibitors have revealed similar clinical efficacy between these agents (table IV). Simvastatin appears to produce reductions in LDLcholesterol that are equal to or greater than those with pravastatin or lovastatin (Ditschuneit et al. 1991; Malini et al. 1991; Yoshino et al. 1990). Although at least comparable using conventional clinical doses, simvastatin appears to be more potent on a weight for weight basis than lovastatin and pravastatin (Illingworth 1991; Tikkanen, personal communication), implying that smaller and/ or less frequent doses can be employed. Despite the significant reductions in total and LDL-cholesterol levels achieved with simvastatin monotherapy plus dietary control, some patients with severe hypercholesterolaemia may still have an unacceptably high plasma lipid profile. Combining simvastatin with a binding resin may therefore be indicated in these patients; this combination has decreased total and LDL-cholesterol by 40 to 50% and 50 to 60%, respectively (Da Col et al. 1990; Erkelens 1990; Geisel et al. 1990; Todd & Goa 1990). 2.2 Tolerability Good tolerability to drug therapy positively influences cost-effectiveness by avoiding treatment costs for unwanted drug effects, and may improve effectiveness through minimising noncompliance. For example, compliance with gemfibrozil therapy in the Helsinki Heart Study was linearly related to the serum cholesterol reduction (Maenpaa et al. 1991).

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132

Table IV. Summary of some studies comparing simvastatin (SIM) with other antihyperlipidaemic agents in patients with hypercholesterolaemia Reference

Patient type Design (no. entered) (duration of active treatment) [weeks)

Dosage [mg/day (no. of pts analysed)]

total C

LDL-C

HDL-C

total TG

LDL-C : HDL-C

-26·

-33· -43·

-12*···

-10*···

+11· +11· -27*·*·

-24· -23· -4*·

-33·

-33·

-SO· +30·'··

-40 -18·· -32

-4S -18·· -28·· -3S··

+9 -12·· 0 -32··

-40 -5*· -4*+2··

-Sl +23·· -29*· -5*·

-38· -36·

-46· -41·

+4 +14·

-12 -29·

-49· -48·

-37· SIM20 -13· GEM 120 1(30) PL -30· SIM 20 (8) -37 SIM 40 (S) -16· GEM 1200 (8) -28· SIM 10-20 (10) -10 GEM 1200 (8)

-16· -11·

+9 +19····

-S -20····

-37·

+S +11 +18

-22· -22 -2S·

Probucol (PRO) Pietro et al. (1989)

Familial Diet + pri SIM 20 (82) (134) or r, db, p SIM 40 (80) PRO 1000 (81) non-familial (12) (109) Probucol (PRO), colestlpol (COL) and their combination Diet Dujovne & Gcel Familial (8) 81M " LI'II'> .. } (1988) or co PRO 1000 .13 COL 20 g/day I( ) (12) nonfamilial PRO 600 + COL ! (S) Colestlpol (COL) plus tenotlbrate (FEN) SIM40 Weisweiler & Familial Diet Schwandt (1986) co COL lS g/day + 1(6) (8) FEN 2S0 Gemtlbrozll (GEM) Berioli et al. 'Primary' (1990) (40)

Diet r, nb, p (24) No protocol details (12)

Douste-Blazy et al. (1988)

Type lIa

Helve et al.

Nonfamilial type II a or b (I) LDL-C ~ 4.3 and < S mmol/L

(1988)

Tikkanen et al. (1989)

(II) LDL-C S mmol/L

(I) SIM S-10 (68) GEM 1200 (69) (II) SIM 10-20 (78) GEM 1200 (7S)

~

hzafibrete (BEZ) Klein & Kostener 'Primary' + (1988) coronary artery disease Lecart et al. Type lIa (1988) Schulzeck et al. (1988)

pri r, db, p (12) Diet r, db, p (12)

Familial (13) or nonfamilial (3)

Mean change (%) in plasma lipids versus baselinea

-22··

-21· -15*·*-27· -lS·

-44 -22·

-9

-38· -26· -18· -34· -17·

Diet r, db, p (12)

SIM" 40 (8) BEZ 400 (8)

-32· -lS·

-46· -23·

No protocol details (12)

SIM 20 (10) SIM 40 (S) BEZ 600 (8) SIM 20-40 (8) BEZ 600 (8)

-30· -37 -23· -32· -lS·

-37· -44 -28· -39· -20····

Diet + pri r, db, p (12)

+7· +17· +9· +16·

-10· -31· -7· -32·

+S +11 +22 +9 +lS·

-11· -22 -30 -6 -16·

-28 -2S -37· -22·

133

Simvastatin in Hypercholesterolaemia

Table IV. Contd Reference

Patient type Design (no. entered) (duration of active treatment) [weeks)

Dosage (no. of pts analysed) [mg/day)

total C

LDL-C

HDL-C

Smith et al. (1990)

'Primary' (28)

Diet + pri co (16)

Weisweiler (1988a)

Familial

pri r, p (12)

SIM 10 (14) SIM 20 (28) SIM 40 (14) BEZ 600 (28) SIM 20-40 (8) BEZ 600 (8)

-19· -23· -27· -13 -31· -18·

-24· -29· -38· -21· -38· -21·

+7 +20 +32 +26.5· +7 +7*

Diet + pri r. db, p (10) Diet + pri r, db, p

SIM 20 or 40 (92) FEN 400 (92) SIM 20-40 (8) FEN 400 (8)

-30· -19..·....

-35· -22*·**

-28· -16*·**

-36· -16*·*·

Diet + pri nb, p (4)

SIM 20 CLO 1.5 g/day

-30· -21·

Diet + pri r, nb, p (12)

SIM 20-40 (15) CHO 24 g/day (8)

-31 -20··

-36 -29

-2 +9

Diet r, p (6) Diet + pri r, nb, p (12) Diet +: pri r, nb, p (12)

SIM 10 (80) CHO 12 g/day (55) SIM 40 (40) CHO 8-16 g/day (20) SIM 20-40 (16) CHO 24 g/day (8)

-21· -16*·"

-30· -25·

+11· +7·

-36 -23

-43 -30

+16 +9

-21 +11

-38· -25·

-48·

-33·

+14 -12

-16 0

-60 -25

Diet + pri r, nb, p (12)

SIM 20-40 (24) CHO 16 g/day (10)

-30· -14*·**

-38· -28·

+21· +6

-24· +64*.**

-41 -31

Diet + pri r, p 12)

SIM 20-40 (40) CHO 12-24 g/day (20) SIM 20-40 (8) CHO 16-24 g/day (4)

-32· -20·

-41· -32····

+13· +6

-5 +38·

- 34*" .

Fenofibrate (FEN) Fricker et al. (1990); Ziegler et al. (1990) Stohler et al. (1989) Clofibrate (CLO) Gave"i et al. (1990)

'Primary' type IIa or lib (184) 'Primary'

Type lib (44)

Cholestyramine (CHO) Aubert et al. Familial (15) (1988) or nonfamilial (9) .Moderately Deslypers (1989) severe' Erkelens et al. (1988)

Familial

Lintott et al. (1989)

Familial (19) or nonfamilial (5) Familial (5) or nonfamilial (31) 'Primary'

Molgaard et al. (1989)

O'Brien et al. (1990) Riesen & Mordasini (1988)

Familial

Diet + pri r, nb, p (12)

Mean change (%) in plasma lipids versus baseline8 total TG

LDL-C : HDL-C

-22· -38· -52· -38·

-36·

-10 -28·

-27·

+7· +11·

-17·

-38·

-29····

-25*·*·

+14 +14·

-16· -51*·**

-44 -25··

-17 -55··

-6· +8··

-47·

-29· -13

Continued overleaf

PharmacoEconomics 1 (2) 1992

134

Table IV. Contd Reference

Patient type Design (no. entered) (duration of active treatment) [weeks]

Dosage (no. of pts analysed) [mg/day]

Stein et al. (1990)

Familial or nonfamilial

Diet + pri r, p (12)

Ytre-Arne & Nordoy (1989)

Type lIa (18) Type lib (2)

Diet + pri r, nb, p (12)

Pravastatln (PRA) or lovastatin (LOV) Ditschuneit et al. 'Primary' Diet nb, p (1991) type lIa or (26) lib (149) Malini et al. 'Primary' Diet (1991) (100) r, nb, p (6) Simons et al. 'Primary' nb, p (1990) (87) (78-104)

Yoshino et al. (1990)

Type lIa (26) Type lib (24)

Diet nb, p (12)

Mean change (%) in plasma lipids versus baseline a total C

LDL-C

HDL-C

total TG

LDL-C : HDL-C

SIM 20 (84) SIM 40 (81) CHO 24 g/day (85) SIM 40 (15) CHO 24 g/day (5)

-27 -33 -15

-32 -41 -21

+10 +10 +8

-13 -21 +15

-36 -45 -25

-35* -21"·*'*

-40* -33*

+9 +9

-20* -14

SIM 40 (84) PRA 40 (23) LOV 40 (42) SIM 10 (50) PRA 10 (50)

-30* -28* -25* -24* -15*,*-

-33* -22*·**

+2 +8 +10 +10* +7*·**

SIM 40 (21) SIM + CHD or CLO [no dosage details] (24) PRA 40 (12) PRA + CHO or CLO [no dosage details] (20) SIM 2.5 (25) PRA 10 (25)

-29 -41

-26* -28*

+7* +17*,**

-19 -6 -17 -12*

-6*·

-38* -25*,··

-24 -27

-20* -16*

Statistical analysis not performed in all studies. * and ** indicate statistically different from baseline and simvastatin, respectively (significant at least at the 95% level). b 6 patients received simvastatin and 7 lovastatin (only combined results provided), Abbreviations: r = randomised; p = parallel; co = crossover; nb = non-blind; db = double-blind; pri = placebo run-in (4 or 6 weeks); C = cholesterol; LDL = low density lipoprotein; HDL = high density lipoprotein; TG = triglycerides, a

Simvastatin has been administered to over 21 000 patients in clinical trials and compassionate-use programmes (data on file, Merck), Experience in 2361 patients involved in clinical trials indicates that simvastatin is well tolerated, the most frequent adverse effects being headache (in 1%), constipation (2.2%), nausea (1.1%), flatulence (2%), diarrhoea (2.9%), dyspepsia (2.9%), abdominal pain (2,5%) and fatigue (2.7%) [Boccuzzi et al. 1991; Walker 1989]. These effects are usually mild and

transient, and have led to treatment withdrawal in 0.3% of patients (Boccuzzi et al. 1991). In contrast, approximately 50% of patients receiving cholestyramine resin experience mild to moderate constipation, with anorexia, nausea, dyspepsia and abdominal cramps also occurring in many instances (Odegaard 1988). This relatively high incidence of unpleasant side effects, together with the often large doses (12 to 24g) of the powder formulation, limit the tolerability of cholestyramine (Grundy 1988;

Simvastatin in Hypercho1estero1aemia

Odegaard 1988; Stein 1989; Sweeney et al. 1991). Tikkanen and NikiHi (1987) reported that poor tolerability would be expected in 30 and 50%, respectively, of patients taking 12 and 16g of bile acid sequestrants daily; in 40 and 80% of those taking nicotinic acid 1.5 and 3 g/day; and in I % of patients receiving fibrates, although this may be overcome to some extent by careful patient counselling and lower doses. In the LRC-CPPT study, 49% of the cholestyramine group did not comply with the recommended regimen, compared with 33% of placebo recipients (Odegaard 1988). Another bile acid sequestrant, colestipol, is associated with a similar incidence of troublesome side effects as cholestyramine (Odegaard 1988; Stein 1989). These agents have, however, been used for many years with no evidence of serious long term toxicity. Slight transient elevations in serum transaminases(up to 3-times normal levels) may be associated with the commencement of simvastatin therapy in 1.5% of patients, and more pronounced persistent increases in a similar proportion of patients may require treatment withdrawal (Mauro & MacDonald 1991; Todd & Goa 1990). Regular liver function tests are therefore recommended. Regular ophthalmic examinations are not required with HMG-CoA reductase inhibitor therapy. Data regarding drug interactions with simvastatin are scarce. A class-specific myopathy which may occur with simvastatin appears to be enhanced by concurrent gemfibrozil, nicotinic acid, erythromycin or cyclosporin (Mauro & MacDonald 1991; Todd & Goa 1990), and a clinically insignificant increase of less than 2 seconds in prothrombin time in patients also receiving warfarin has been reported (Todd & Goa 1990; Walker 1989). Bile salt sequestrants on the other hand can potentiate the anticoagulant action of warfarin, and hinder the absorption of cardiac glycosides and thyroxine (Feely & O'Connor 1991; Odegaard 1988). Importantly, simvastatin can be coadministered with antihypertensive agents.

3. Pharmacoeconomic Considerations 3.1 Costs of Coronary Heart Disease CHD exacts a heavy toll on populations of industrialised societies, accounting for approxi-

135

Table V. Costs of cardiovascular disease during 1985 in SUS x 106 (from Teeling-Smith 1988) Country

Indirect costs8

Hospital costs

Co.st of medicines

Total costsb

Canada France Italy Japan Spain UK US West Germany Total

1365 5972 4816 4788 2304 6017 20537 8302 54101

1773 1995 1883 9576 483 2316 19452 2639 40117

180 850 500 1300 150 350 2700 1080 7110

3318 8817 7199 15664 2937 8683 42689 12021 101328

a b

Production lost due to morbidity and mortality. assuming 5 years lost per death. Outpatient and domiciliary costs excluded.

mately 25% of all deaths (McNeil & Sloman 1987). The age-adjusted death rate due to CHD varied between 40 per 100 000 in Japan to 261 per 100 000 in Ireland (mean 162.7 per 100,000) in the late 1980s (WHO 1989). Since the beginning of the I 970s, CHD mortality has steadily declined by roughly 2% per year in Western Europe, the United States and Australasia (Goldman & Cook 1984; McNeil & Sloman 1987). Despite the decrease in mortality, morbidityassociated with CHD is still highly significant and is the cause of massive economic expenditure. For example, Teeling-Smith (1988) estimated the total cost (in pounds sterling) of cardiovascular diseases in 8 industrialised countries in 1985 (table V). Indirect costs through lost productivity constituted 53%, hospital costs 40% and drug costs only 7% of the total cost of cardiovascular disease. If it is assumed that CHD represents approximately 50% of all cardiovascular disease, based on the proportion of cardiovascular deaths attributable to CHD, then this disease accounted for in the vicinity of £24 billion ($US46 billion) in direct costs and £27 billion ($US51 billion) in indirect costs. Other studies support the figures given in table V. Rice et al. (1985) estimated that during 1980 in the US cardiovascular disease incurred direct costs of $US32 billion and indirect costs of $US53 billion, values which tally well with the American

PharmacoEconomics 1 (2) 1992

136

Heart Association's calculation ofa total (i.e. direct plus indirect) cost of $US88 billion in 1988 (Stason 1990). On an individual case basis, direct cost of an uncomplicated myocardial infarction was calculated to be $US4254, with an indirect cost of $US25 500 in 1985 dollars; cost of care of a new angina case was $US2260; and the direct cost of a coronary artery bypass graft $USI2 748, with indirect cost due to loss of earnings of $US40 560 (Kinosian & Eisenberg 1988). It is therefore clear that the burden of CHD in direct healthcare costs and the cost of lost productivity in the workplace is considerable. Elevated serum cholesterol, which is a significant avoidable risk factor (together with smoking and high blood pressure) for CHD development, can be modified using dietary manipulation and/or drug therapy in appropriate patients. The effectiveness of these intervention strategies in preventing or delaying CHD and its associated costs must be weighed against the costs, both direct and indirect, of each of the strategies. 3.2 Economic Impact of Simvastatin Intervention 3.2.1 General Considerations As national standards for the screening and treatment of hypercholesterolaemia have been developed, economic costs of such programmes have been raised. This has led to the conduct of costeffectiveness analyses of cholesterol screening programmes, diet and lipid-lowering drug therapies. Controversy exists as to the benefit of allocating monies to such programmes and therapies due to the high costs per years of life gained from these interventions, although several broad trends are apparent. Mass screening for CHD risk factors is less cost effective than population-based strategies which attempt to modify behaviour (e.g. reduce dietary cholesterol intake, cease smoking), and than targeted screening of individuals with other risk factors (Berwick et al. 1981; Grover et al. 1991; Weinstein & Stason 1985). Pharmacological intervention

to lower serum cholesterol is more cost-effective in patients with high pretreatment levels and multiple risk factors, and if therapy is initiated earlier rather than later in life (Kinosian & Eisenberg 1988; Oster & Epstein 1986, 1987; Stason 1990; Weinstein & Stason 1985). For example, economic benefits of reducing total serum cholesterol by the same amount are approximately 2-fold greater in patients with coexisting hypertension or diabetes, or who smoke, than in age-matched low risk individuals (Oster & Epstein 1986). Direct benefits of lipidlowering therapy are less substantial than indirect benefits (Oster & Epstein 1986). Due to variations in efficacy and costs among the lipid lowering agents, therapeutic decisions regarding the use of these agents is complex. Clinical decision-makers are often faced with determining whether the additional efficacy and cost of a particular agent reflects a true increase in therapeutic value over a less costly but less efficacious product. Pharmacoeconomic analysis can assist with such decisions and provide an avenue for the rational selection of therapeutic agents. The most common and appropriate methodology utilised for determining the economic impact of lipid-lowering agents is cost-effectiveness analysis. Some investigators have defined effectiveness in terms of the intermediate outcome of lowered serum lipid concentrations, whereas others used the final end-point of years of life saved (YOLS). The latter analysis requires an estimation of the reduction in risk of CHD that can occur with drug therapy. In the light of any published direct evidence of reduced mortality with HMG-CoA reductase inhibitors, this estimation is typically based on the results of large epidemiological studies such as the Framingham Study or the LRC-CPPT (see sections 1.2.1 and 1.2.2). Cost-effectiveness analyses are frequently conducted from the perspective of society. Those models which look at YOLS as the study end-point generally are of the following form:

Cost-effectiveness

=

YOLS

Sirnvastatin in Hypercholesterolaernia

where: Cd = costs of drug product, Crne = costs of medical care, Cse = costs of side effects, CSCHD = cost savings from the reduction in CHD morbidity and mortality, and YOLS = years oflife saved, due to reduction in CHD incidence. The costs of therapy relate to the costs of the drug product based on a standard drug regimen. Physician visit and laboratory monitoring costs are included in medical care costs, with studies of HMG-CoA reductase inhibitors often including costs of liver function tests. Ophthalmic examinations are not necessary. Costs related to the treatment and sequelae of drug side effects are mentioned in most studies, although not all investigators actually incorporate estimated costs of managing adverse effects into the overall cost-effectiveness equation. Others believe that adverse effects are generally mild and rare, and thus, any costs incurred would be incidental when compared with the lifetime costs of drug therapy. Different compliance rates during treatment of variable duration were often not accounted for; Kinosian (personal communication) suggested adjusting all studies to 1 year using the I-year patient tolerance in long term trials. Cost savings from the reduction of CHD risk are uniformly included in studies which use YOLS as an end-point. None of the published studies included indirect costs, although some have argued that these values should be considered (Schulman et al. 1990). Investigators have used broadly similar methodological approaches when studying the economic impact of lipid-lowering agents. Most studies have utilised discount rates of 5% for both future costs and benefits and performed sensitivity analysis to test the strength of their conclusions (e.g. Martens et al. 1990; Schulman et al. 1990). In calculating the cost savings from the reduction of CHD risk, most workers assumed a 2-year lag-time before the cholesterol-lowering effects begin to alter the risk of CHD in primary prevention, although angiographic evidence indicates a halt in the development of regression of lesions in patients with established disease (Illingworth 1991). Although the methodological framework is similar in most studies, the method of determining the

137

quantity of input resources and their value varies considerably. These differences make comparisons between study results difficult and account for the wide variance in costs per life year gained reported for the same agent in different studies. Economic variables which tend to account for the variation in study results include drug and medical care costs related to therapy, and the estimated cost savings in medical care costs due to reduced CHD morbidityand mortality. The valuation of drug product costs is critical to study results since outcomes tend to be more sensitive to drug therapy costs than to other cost categories. Investigators use various sources of drug prices; some prices reflect market prices, others are prices unique to certain institutions, and others still represent published prices specified by pharmaceutical manufacturers. In studies where several dosage regimens of the same drug were evaluated, some state the methodology for determining drug costs for only a single dose. Information regarding the systematic determination of all drug regimen costs would be useful, since simple linear extrapolation of costs from one dose to another based on the difference in active drug may not be consistent with pharmaceutical manufacturers' pricing policies (e.g. a 20mg tablet is not twice the price of a lOmg tablet). The values assigned to medical care costs and side effect costs also differed among studies. In order to identify the quantity of each resource utilised in the treatment of hyperlipidaemia, researchers often used expert consensus panels which estimated the amount of resources used (e.g. Martens et al. 1990). Since treatment strategies for hyperlipidaemia tend to be fairly uniform, variation among estimated resource use was minor. Costs of these resources, however, varied depending on whether market prices, government payment amounts or cost values were used. Although it is important to note such differences, study results tend to be less sensitive to variations in these costs than to variations in drug product costs. The approach to assigning costs to the savings associated with the reduction in CHD also varied. The overall cost savings is dependent on 2 factors:

138

firstly, the estimated reduction in CHD and, secondly, the cost savings associated with this reduction. The greater the estimated effect of the drug, the higher are the estimated cost savings. When calculating cost savings, researchers assumed that the cost savings equalled the costs that would have occurred if CHD morbidity had not been lowered. Importantly, Oster and Epstein (1986) also estimated the additional costs incurred in managing noncardiovascular diseases that could arise during the life years gained from the lowered risk ofCHD. These costs were then added to overall costs of therapy. A variety of methods were used to determine the actual value of cost savings, similar to the methods used to determine medical care costs. Most estimated the occurrence of selected CHD events (e.g. myocardial infarction, coronary artery bypass graft) and assigned costs to each event. Costs were assigned via several mechanisms including: using actual market prices for various services adjusted by hospital cost-to-charge ratios; applying government payment amounts for specific diagnoses; or using a combination of payment and cost data applied to patterns of care determined by an expert consensus panel. Thus, all cost-effectiveness studies of lipid-lowering therapy, including simvastatin treatment, are highly sensitive to drug costs used in the analysis and to the patient characteristics. Lipid-lowering intervention is more cost-effective in males than in females, in those with high versus moderate cholesterol elevation, in those with other coronary risk factors, and in younger versus older individuals (Kinosian & Eisenberg 1988; Martens et al. 1991; Oster & Epstein 1986). Despite direct evidence for elevated cholesterol as a CHD risk factor being scarce in the elderly, extrapolation of results obtained in middle-aged individuals suggests that risk, although diminished, does persist into old age (Tikkanen & Tilvis 1991). It is also important to remember the rational differences in drug costs, CHD treatment costs, life expectancy and risk factor profiles.

PharmacoEconomics 1 (2) 1992

3.2.2 Cost-Effectiveness of Simvastatin Martens et al. (1989,1990,1991) have analysed and published cost-effectiveness data on simvastatin, comparing the drug with cholestyramine resin. Much of the available cost effectiveness data in lipid-lowering therapy concern cholestyramine resin, which is hardly surprising given the widespread and long clinical experience with this agent, often considered as a first-line option in managing hypercholesterolaemia. Schulman et al. (1990) compared the cost-effectiveness of cholestyramine with colestipol, nicotinic acid, gemfibrozil, probucol and lovastatin, an analogue of simvastatin with a broadly similar therapeutic profile (see section 2; Mauro & MacDonald 1991; Todd & Goa 1990). Results obtained for this drug have been used here to supplement the scarce published data on simvastatin itself. Martens' group in the Netherlands calculated the cost-effectiveness of simvastatin and cholestyramine in 1988 Netherlands guilders (Fl; Fl 1.0 is approximately $USO.50) from a health system rather than societal perspective. These investigators based their study on a cohort of men and women aged between 35 and 74 years, without symptoms of CHD but who were potential candidates for lipid-lowering therapy (Martens et al. 1989, 1990). Framingham Heart Study data were used to estimate annual CHD incidence, and eventspecific assumptions were based on Dutch national mortality statistics and German Prospective Cardiovascular Study and Minnesota Heart Survey results. A consensus panel estimated the costs of treating CHD, based on actual costs and reimbursement rates of inpatient and outpatient care, diagnostic procedures (e.g. angiography), surgical techniques (e.g. coronary artery bypass grafts) and drug treatment. Simvastatin 20 mg/day was shown to be more cost-effective than cholestyramine 4g 3 times daily (table VI). A sensitivity analysis which assumed a more pronounced decrease in cholesterol levels of 10% (vs 6.2%) during treatment with cholestyramine 12 g/day revealed a lower cost per YOLS ofFl 140000 ($US70 000) [vs Fl 220000 ($USIlO 000)], but this was still not as cost-effective as the corresponding value of Fl 50 000 ($US25 000) with simvastatin

Simvastatin in Hypercholesterolaemia

139

Table VI. Comparative cost-effectiveness of simvastatin (SIM) versus cholestyramine (CHO) in individuals aged 35 to 60 years with pretreatment serum total cholesterol levels of 8 mmol/L and no evidence of CHO Reference

Treatment

Total annual cost (FI) [SUS]

Cholesterol lowering efficacy (%)a

Cost-effectiveness (FI x 103 /YOLS) [SUS x 103/YOLS]b men

women

Martens et al. (1989)

SIM 20 mg/day CHO 4g tid

1526 [793.5]C 1767 [918.9]C

27 6.2

50-110 [25-55] 220-510 [110-255]

140-180 [70-90] 610-730 [305-365]

Martens et al. (1990)

SIM 20 mg/day CHO 4 g tid

1398.8 [727.4]d 1668.7 [867. 7]d

27 6.2

46-98 [23-49] 208-483 [104-241.5]

128-162 [64-81] 581-680 [290.5-340]

Value for simvastatin from data on file, Merck Sharp & Oohme; value for cholestyramine from LRC-CPPT (Lipid Research Clinics Program 1984a). b Cost-effectiveness = (cost of therapy - cost savings in CHO treatment)/net change in life expectancy, where: net change in CHO medical care costs = discounted sum (at 5%fyear) of changes in annual medical care costs in each future year of life, and net change in life expexctancy = discounted sum (at 5%/year) of changes in proportion of individuals alive in each future year due to treatment. c Includes cost of drug (marketed price in the Netherlands); plus 3 general practitioner visits and laboratory tests for cholestyramine; plus 'several additional physician visits' and an ophthalmiC examination for simvastatin. d Includes cost of drug; plus 4 physician visits and 2 serum cholesterol determinations and, for simvastatin, 2 additional physician visits plus liver function tests. Abbreviations: FI = Netherlands guilders in 1988 (1 FI = $USO.5); YOLS = years of life saved; tid = 3 times daily. a

in 40-year-o]d men with cholesterol levels of 8 mmoljL (Martens et al. 1989). Although sex, age when starting treatment (assessed in cohorts of a given age), pretreatment serum cholesterol level and presence of other risk factors all had a considerable influence, simvastatin remained more cost-effective than cholestyramine in all risk groups. The cost per YOLS of simvastatin and cholestyramine was Fl 50 000 to 110000 ($US25 000 to 55 000) and Fl 220000 to 510 000 ($USIIO 000 to 255000), respectively, in men with a cholesterol level of 8 mmoljL, compared with corresponding values of Fl 140000 to 180000 ($US70 000 to 90000) and Fl 610 000 to 730000 ($US305 000 to 365 000) in women (table VI). Treatment with both simvastatin and cholestyramine was approximately twice as cost-effective if initiated at 35 versus 60 years of age in men. This age difference was not as marked in women, with little variation in cost-effectiveness of either therapeutic option if started between the ages of 35 and 60 years, although beginning treatment at age 45 to 55 years tended to be more cost-effective. Cost-effectiveness of therapy was greater in in-

dividuals with a higher pretreatment serum total cholesterol level (fig. 2). For example, the cost of simvastatin per YOLS in a 40-year-old man with an initial cholesterol level of 7 mmoljL was Fl 70 000 ($US35 000) compared with Fl 30 000 ($USI5 000) in a man of the same age with a level of 9 mmoljL (Martens et al. 1990). Treatment with simvastatin 10 or 20 mg/day was also more cost-effective in men and women with 1 or more CHD risk factors (fig. 2). For example, the costs per YOLS were Fl 15 000 ($US7500), Fl 14000 ($US7000) and Fl 12000 ($US6000), respectively, in men aged between 40 and 44 years with a cholesterol level of 9 mmoljL and hypertension, diabetes or both compared with Fl 18000 ($US 9000) in men with no additional risk factors (Martens et al. 1991). Assuming decreases in total cholesterol of 21 and 27%, respectively, the cost per YOLS was Fl26 000 ($USI3000) with simvastatin 10 mg/day and Fl 29000 ($USI4 500) with 20 mg/day in 40- to 44year-old men with an initial cholesterol level of 8 mmoljL (Martens et al. 1991). Below this threshold, costs per YOLS in this group increased to Fl

Table VII. Relative cost-effectiveness of simvastatin (SIM) and Iovastatin (LOV) according to sex, pretreatment serum total cholesterol level and presence of additional risk factors Reference

Martens et al. (1991)C

Treatment

SIM 20 mg/day

Hay et al. (1991) LOV 20 mgjday

Cost-effectiveness b ($US x 1()3/yOLS)

Cholesterol lowering efficacya (%)

Sex (age)

Additional risk factors

27

Men (40-44y)

None Hyp Hyp + diab

14.5 12 9.5

11.5 9.5 7.5

Women (50-54y)

None Hyp Hyp + diab

44 39.5 14.5

37 33.5 12.5

Men (35y)

None Hypd

20

Women (55y)

TC 6.2-7.8 mmol/L

34

TC 7.0-8.8 mmol/L

TC 7.9-9.8 mmol/L

+ smoking

19 13

21 12 9

13 8 6

None Hypd Hypd + smoking

111 58 41

81 42 30

31

Hypd

"""

0

TC8 mmol/L

TC 8.5 mmol/L

TC 9 mmol{L 9 7.5 6 31 28 11

59 22

~

~

8 ~ Cl

;:, Cl

a b

Value for simvastatin from data on file, Merck, Sharp & Dohme; value for lovastatin from Lovastatin Study Group II (1986). For cost-effectiveness analysis, see footnote b, table VI.

=

$USO.50. c Cost-effectiveness originally presented in 1986 Netherlands guilders (FI); 1 FI d Systolic blood pressure 160mm Hg; average risk for left ventricular hypertrophy and diabetes. Abbreviations: YOLS '" years of life saved; hyp '" hypertension; diab '" diabetes mellitus; TC '" total serum cholesterol.

~

~.

... ~ ..... '0

;e

Simvastatin in Hypercholesterolaemia

54000 ($USn 000) with the lower dosage, indicating that this regimen should perhaps be reserved for individuals with multiple risk factors. The cost-effectiveness of cholestyramine reported by Martens and colleagues (1989, 1990, 1991) is consistent with values presented elsewhere; a narrow range of $ US 112 000 to 126 000 per YOLS has been reported for cholestyramine 16 g/day in men aged between 45 and 49 years with a moderately elevated cholesterol level of 6.85 mmoljL (Kinosian & Eisenberg 1988; Oster & Epstein 1987; Weinstein & Stason 1985). Cost-effectiveness was again increased in younger men with multiple risk factors, higher cholesterol levels or with less than lifelong therapy. Similarly, in 40-year-old men with cholesterol levels over 6.85 mmoljL plus I other risk factor, lovastatin 20 mg/day was more cost-effective than probucol 500mg twice daily ($US50 510 vs $US69 841/YOLS), colestipol 33 g/day (i.e. 4.4 x 7.5g packs per day) [$US73406], cholestyramine 20 gjday ($US92 603) and gemfibrozil 600mg twice daily ($USI08 826), although the cost per YOLS of the latter agent was more than halved if beneficial changes in LDL- and HDL-cholesterol were considered (Kelley 1990). Lepre and Lee (1991) reported that, although the monthly costs of treating a group of 77 patients at high CHD risk (ischaemic heart disease, n = 54; CABG, n = 21; angioplasty, n = 3) with simvastatin 10 to 40 mg/day were greater than prior 'conventional' (unspecified) therapy ($A68.03 vs $A58.11), efficacy and tolerability were substantially better. Only 7 of the group were well controlled (total cholesterol < 6 mmoljL) during previous treatment, compared with 51 on simvastatin; total and LDL-cholesterol were reduced by 22 and 29%, respectively. 39 patients experienced significant side effects with conventional treatment, compared with 6 minor reactions and I case of myalgia after switching to simvastatin. Thus, the slight acquisition cost advantage of the standard regimen would probably be offset by costs related to ineffective lipid-lowering and/or side effects. This would be even more true of the subgroup of 53 patients with nonfamilial hypercholesterolaemia,

141

50

en--'

0

>-

;0-

Men (40-44y) 40

~

x CIl ~

30

!!!. CI) CI)

Q)

c

20

Q)

.~

1:3 .2!

"¥

10

in 0

u

50

en

-

...J

0 ~

'"~'

~

~

f--

x (j)

Women (SO-54y)

40

30

-


f--

r-

CI) CI)

Q)

c

Q)

20

.~

(3

~

.2!

"¥in

10

--

..-- -

-

0

u TC

8 8.5 9

8 8.5 9

8 8.5 9

8 8.5 9

None

HypertenSion

Diabetes

Hypertension + diabetes

Fig. 2. Cost-effectiveness of simvastatin 20 mg/ day according to sex, pretreatment serum total cholesterol level (TC; mmol/L) and additional risk factors (adapted from Martens et al. 1991) [one 1988 Netherlands guilder = $USO.50).

where costs of therapy were not significantly different ($A58 for simvastatin vs $A56 for conventional treatment), possibly because the simvastatin doses were lower than in patients with familial disorder. In a meticulously conducted study lovastatin (a congener of simvastatin) 20 mg/day was estimated to be more cost-effective than cholestyramine 24 g/day in lowering LDL-cholesterol serum levels ($USI77 vs $US347 per 1% decrease), but slightly less effective than nicotinic acid 3 g/day ($US 139)

142

[Schulman et at. 1990]. However, lovastatin 20 mg! day and nicotinic acid were comparable in terms of cost effective reduction of the LDL: HDL ratio. Lovastatin compared favourably with gemfibrozil 1.2 g/day and colestipol 20 or 30 g/day. Although a direct comparison is presently lacking in the published literature, the cost-effectiveness of simvastatin 20 mg/day appears to be similar to that of lovastatin 20 mg/day (table VII), although simvastatin is more potent on a weightfor-weight basis indicating that a lower or less frequent dosage may be possible (see section 2.1). It should be borne in mind that the values shown in table VII do not reflect a direct comparison between simvastatin and lovastatin, and methods used in the 2 studies differed in some respects. Hay and colleagues (1991) included pharmacy mark-up when estimating cost of lovastatin, whereas Martens' group appeared to lise the market price of simvastatin (Martens et al. 1989). Unlike the simvastatin study, the data on lovastatin accounted for an ophthalmic examination and the cost of adverse drug effects, although the latter did not appear to be significant. A major reaction with an incidence of 1 in 10 000 and costing $US200 000 to treat would add an extra $US20 to the total lifetime cost of treatment (Hay et al. 1991). Similarly, a 20% reduction in full compliance with lovastatin therapy has no significant effect on cost-effectiveness. It is reasonable to assume that these sensitivity analyses would also generally apply to simvastatin.

4. Pharmacoeconomic Positioning of Sim,astatin 4.1 General Prescribing Considerations In patients with primary hypercholesterolaemia unresponsive to diet alone, simvastatin 10 to 20mg as a single dose in the evening usually effectively lowers plasma levels of total and LDL-cholesterol, and triglycerides. It should be noted that doses may vary between countries; for example lower doses (2.5 mg/day) are routinely employed in Japan. The hypocholesterolaemic efficacy of simvastatin is greater than that of the bile acid sequestrants, the fibrates, probucol and maybe other HMG-CoA re-

PharmacoEconomics 1 (2) 1992

ductase inhibitors, although this requires further validation. The convenient once-daily regimen and good tolerability of simvastatin may aid compliance. Simvastatin is contraindicated in patients with hepatic dysfunction; regular liver function tests are necessary during treatment in all other patients (England et al. 1991). The US Food and Drug Administration has recommended that annual ophthalmic examinations are unnecessary during treatment with lovastatin, an HMG-CoA reductase inhibitor closely related to simvastatin. 4.2 Formulary Considerations In the UK the recommended use of simvastatin is presently limited to a second-line role in patients with familial type IIa hypercholesterolaemia intolerant or unresponsive to other drugs (British National Formulary 1991; Laker & Edwards 1991). The bile acid sequestrants cholestyramine and colestipol are routinely cited as first-line drugs, on the basis of their efficacy and lack of serious side effects in 20 years of use as lipid-lowering agents (Grundy 1988; Laker & Edwards 1991; Stein 1989). Although experience with the HMG-CoA reductase inhibitors is less extensive, these agents do not appear to be associated with serious adverse effects and are much better tolerated than the bile acid sequestrant resins (see section 2.2). Simvastatin has been demonstrated to be more cost-effective than cholestyramine, particularly in younger men with higher initial serum total cholesterol levels and other CHD risk factors (see section 3.2.2). The effects of simvastatin, as well as its cost, contribute significantly to its favourable cost-effectiveness profile. Conversely, the relatively high cost of cholestyramine with its less pronounced effects on plasma lipids results in a poorer cost-effectiveness ratio; a lower acquisition cost for this agent would make it a more attractive option. With the exception of comparison with cholestyramine (section 3.2.2), direct cost-effectiveness comparisons between simvastatin and other lipidlowering drugs are currently lacking in the published literature but lovastatin, an analogue of sim-

Simvastatin in Hypercholesterolaemia

vastatin, is more cost-effective than colestipol but marginally less than nicotinic acid (section 3.2.2). The latter agent has been used as first-line treatment of hypercholesterolaemia (Grundy 1988) but its use is often limited due to frequent unwanted reactions, e.g. flushing (Dart 1990), although these may be less frequent with a newer controlled release formulation (Dart, personal communication). The cost per YOLS of lovastatin compares favourably with that of gemfibrozil, a second-line agent for hypercholesterolaemia and first-line drug for combined hyperlipidaemia (types lIb, III and IV) and hypertriglyceridaemia (type V) [Laker & Edwards 1991]. Simvastatin has a similar cost-effectiveness to lovastatin and hence may be expected to share the above cost comparisons. In conclusion, formulary committees must consider several factors when determining the status of simvastatin. Use of other agents, notably the bile acid sequestrants, may be recommended prior to the prescribing ofthis drug, although analysis demonstrates that simvastatin is more cost-effective than cholestyramine in all patients with hypercholesterolaemia. This benefit is particularly pronounced if therapy is started between the ages of 35 and 45 years in men with cholesterol levels of 8 mmol/L or above and with additional risk factors treated for a defined period of time rather than lifelong. Targeting treatment according to lipid profile will also aid cost-effectiveness. Government agencies and health maintenance organisations that care for these populations should perhaps therefore favour simvastatin over cholestyramine. Data generated for lovastatin also suggest that HMG-CoA reductase inhibitors should be considered over colestipol as first-line agents in hypercholesterolaemia, gemfibrozil in any hyperlipidaemia and possibly nicotinic acid in hyperlipidaemia and hypertriglyceridaemia. Direct cost-effectiveness comparisons between simvastatin and these agents are needed to support this view. Concrete evidence that HMG-CoA reductase inhibitors lower CHD morbidity and mortality through their effects on serum lipids is awaited with interest.

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