Pain relief produces negative reinforcement throughactivation of mesolimbic reward–valuation circuitryEdita Navratilovaa,1, Jennifer Y. Xiea,1, Alec Okuna, Chaoling Qua, Nathan Eydea, Shuang Cia, Michael H. Ossipova,Tamara Kingb, Howard L. Fieldsc, and Frank Porrecaa,2 aDepartment of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ 85724; bDepartment of Physiology, University of NewEngland, Biddeford, ME 04005; and cErnest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, CA 94608
Grover.fmCosts of dyslipidemia
Hanna Zowall and Steven A Grover†
Dyslipidemia has been recognized as an important risk-factor for the development of
cardiovascular disease. The current, available therapies of dyslipidemia, their
effectiveness, costs, cost-effectiveness and healthcare implications are discussed. At the
present time, the lipid-lowering therapies are dominated by statins. Despite a variety of
assumptions regarding modeling cardiovascular disease risks and costs, statin therapy is
generally cost-effective for secondary prevention and for primary prevention in individuals
with additional risk-factors. The costs of drug therapy and the absolute risk of developing
future cardiovasular events are the dominant factors determining the cost-effectiveness.
When developing clinical guidelines, the cost-effectiveness and proportion of the
therapies for dyslipidemia
population to be treated must be considered as well as the total population costs
Costs of dyslipidemia
Results of recent
Expert Rev. Pharmacoeconomics Outcomes Res. 3(3), 273–281 (2003) Public health implications of
As the leading cause of death in developed The current available therapies of dyslipi- countries, cardiovascular disease (CVD) is demia, their effectiveness, costs and cost-effec- associated with substantial healthcare costs.
tiveness among different CVD risk popula- For example, in the USA alone, the total tions, and healthcare implications based on costs of CVD have been estimated at results of economic evaluations are discussed. Key issues
US$329 billion, in the year 2002 . The direct health costs related to CVD treatment Available pharmacological therapies
were US$199 billion (or 61% of the totalcosts). They included hospital, physician Currently, there are four major classes of drugs and related professional services, medica- available to lower cholesterol. They include 3- tions and other healthcare costs. The indi- Hydroxy-3-Methylglutaryl (HMG) Coenzyme rect costs relating to lost productivity from A (CoA) reductase inhibitors (statins), bile morbidity and premature mortality were acid sequestrants (resins), nicotinic acid and US$130 billion.
fibric acid derivatives (fibrates).
Dyslipidemia has long been recognized as an important risk-factor for the future development HMG CoA reductase inhibitors
of CVD (coronary heart disease [CHD] and Statins include drugs, such as lovastatin (Meva- stroke). It is also a modifiable risk-factor as cor®, Ranbaxy Laboratories Ltd, New Delhi, †Author for correpondence increasingly demonstrated by the number of India), pravastatin (Pravachol®, Bristol-Meyers Departments of Medicine and successful randomized clinical trials [2–9]. The Squibb, NY, USA), simvastatin (Zocor®, Merck Epidemiology & Biostatistics,McGill University, Montreal, results of these trials have recently lowered the & Co, NY, USA), fluvastatin (Lescol®, Novartis Quebec, Canada threshold for initiating lipid therapy and also Pharmaceuticals Corp., NJ, USA) and atorvas- Tel.: +1 514 934 1934 reduced the targets for lipid control. The tatin (Liptor®, Pfizer Inc., NY, USA). They are Fax: +1 514 934 8293, number of individuals eligible for lipid therapy the most effective class of drugs to reduce total will grow in the coming years. There is there- cholesterol especially low-density lipoproteins fore, increasing interest in identifying those indi- (LDL). Recent clinical trial results have demon- cost-effectiveness, costs, viduals at high-risk of future CVD, events such strated that they can significantly reduce CHD dyslipidemia, economic evaluation, lipid-lowering drugs, that the benefits of lipid therapy can be targeted events and stroke, total mortality and the need towards those who will benefit the most.
for revascularization procedures .
Future Drugs Ltd. All rights reserved. ISSN 1473-7167 Zowall & Grover
A meta-analysis of five major randomized, placebo-control- Nicotinic acid therapy can be accompanied by a number of led, double-blind trials of 30,817 participants followed up on side effects including gastrointestinal symptoms, flushing of the average for 5.4 years, revealed that statins reduced total choles- skin and other complications, such as hepatotoxicity, hyperuri- terol, LDL and triglyceride levels by 20, 28 and 13%, respec- cemia and hyperglycemia, especially at higher doses. Since many tively, while high-density lipoprotein (HDL) was increased by patients cannot tolerate higher doses, nicotinic acid is typically an average of 5% . Overall, statin therapies reduced the risk not used to lower LDL level alone. Instead, it is usually used in of major coronary events by 31% and all-cause mortality by combination with other drugs such as statins.
21%. In the three trials: the Scandinavian Simvastatin Survival Crystalline preparations of nicotinic acid are available with- Study (4S), the Cholesterol and Recurrent Events Trial out a prescription and are relatively inexpensive. The time- (CARE) and the Long-term Intervention with Pravastatin in release preparations are designed to minimize cutaneous flush- Ischemic Disease (LIPID) conducted among 17,617 patients ing. Niaspan is a proprietary extended-release formulation of with a history of CHD (secondary prevention) statin therapies nicotinic acid that also reduces skin flushing. It also appears to were associated with a 34% risk-reduction in major coronary reduce the risk of hepatotoxicity.
events [2,4,5,11]. In two trials: the West of Scotland CoronaryPrevention Study (WOSCOPS) and the Air Force Texas Coro- Fibric acid derivatives
nary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) Fibric acid derivatives include drugs, such as gemfibrozil among 13,200 healthy participants (primary prevention) a (Lopid®, Pfizer Inc., NY, USA), fenofibrate (Tricor®, Allergan, 30% risk-reduction was observed [3,6,11].
MA, USA) and clofibrate (Atromid-S®, AstraZeneca, London, A more recently published trial among 20,536 UK adults, UK). The fibrates are often used for lowering triglycerides, typ- the Medical Research Council (MRC)/British Heart Founda- ically by 25–50% . They also lower LDL and raise HDL. In tion (BHF) Heart Protection Study, demonstrated a 24% the past there has been some concern about the safety of reduction in major vascular events, including coronary events, fibrates due to increased rates of nonCHD death . In the ischemic strokes, coronary and peripheral revascularizations Helsinki Heart Study of a primary prevention, gemfibrozil among a wide range of high-risk individuals irrespective of reduced 37% fatal and nonfatal myocardial infarction (MI) their initial cholesterol levels . Moreover, the study results with no change in total mortality .
suggest cholesterol lowering may be beneficial at much lower In the recent Veterans Administration HDL Intervention thresholds than previously thought.
Trial (VA-HIT), a secondary prevention trial, gemfibrozilsignificantly reduced the risk of CHD and stroke with no Bile acid sequestrants
increased risk of nonCHD mortality . In the Diabetes Resins include drugs such as cholestyramine (Prevalite®, Atherosclerosis Intervention Study (DAIS), micronized Bristol-Myers Squibb, NY, USA), colestipol (Colestid®, fenofibrate significantly reduced the cholesterol concentra- Pharmacia & Upjohn, NJ, USA) and colesevelam (Wel- tions and the angiographic progression of CVD among Type chol®, GelTex Pharmaceuticals, MA, USA). They reduce 2 diabetic patients . However, the trial was not powered to LDL by 15–30% and increase HDL by 3–5% . In the examine clinical end-points.
Lipid Research Clinics Coronary Primary Prevention Trial, Overall, the results of clinical trials of fibrate therapy showed therapy with cholestyramine reduced the risk of CHD by substantial reductions in CVD risk. There are no major side 19% [12,13]. Resins are often used in combination with statins effects associated with fibrates other than various gastrointesti- to further reduce the LDL. They remain unabsorbed in their nal complaints and increased risk of cholesterol gallstones and passage through the gastrointestinal track and lack systemic myopathy. In combination with statins, there is an important toxicity. These drugs are relatively inexpensive compared risk of myositis and rhabdomyolisis. There is no consistent data with statins but are not popular with patients and their phy- to suggest that fibrates constitute a cost-effective therapy.
sicians despite their proven safety records. Their major disad-vantages are their bulk as they lack convenience of adminis- tration and are believed to frequently cause various Currently the lipid-lowering market is dominated by statins. In a recent USA survey of over 48,000 patients with establishedCVD, most patients (84%) who received dyslipidemia treat- ment were prescribed statins . Approximately 13% received Nicotinic acid includes crystalline and time-release preparations fibrates, 8% niacin and 3% resins, some of them in combina- and long-acting Niaspan® (Kos Pharmaceuticals, Inc., FL, tion with statins. Consequently, in the USA alone, over 8 mil- USA) . This class of lipid-lowering drug favorably modifies lip- lion people are currently being treated with statins (4.5 million ids and lipoproteins and is especially effective in raising HDL people on atorvastatin, two million on simvastatin, one million levels by 15–35% . Several clinical trials demonstrated the on pravastatin, 0.5 million on fluvastatin and negligible effectiveness of nicotinic acid in reducing the risk of CHD and number on lovastatin) . In a UK survey of 3689 patients in progression of atherosclerosis. In combination with statins, the primary care practices, 88% of patients who were prescribed results have been particularly impressive .
lipid-lowering drugs were on statins .
Expert Rev. Pharmacoeconomics Outcomes Res. 3(3), (2003) Costs of dyslipidemia
Cholesterol lowering drugs, especially statins, constitute one costs of 40 mg pravastatin at US$925 . They also calculated of the most dynamic segments of the total prescription drug the costs of other cardiac medications for patients in secondary market in the world. In terms of retail expenditure by therapeu- prevention at US$1295.
tic category, cholesterol-lowering drugs rank second after anti- Johannesson and colleagues in their cost-effectiveness analy- ulcer agents and accounted for 5% of the worlds US$364 bil- sis of the 4S trial estimated (1995) the annual costs of simvas- lion drug market in 2001 . Cholesterol-lowering drugs have tatin using data from Sweden at US$604 . In Canada, the experienced a 22% increase in world sales since the year 2000, annual cost of simvastatin was estimated at US$667 in 1996 compared with 14% for antiulcer drugs. In the USA, dyslipi- . In a seven-country comparison of cost-effectiveness, demia drugs account for 6.4% (US$10 billion) of the US$155 annual simvastatin costs were highest in the USA and Ger- billion drug market in 2001 . In Europe, cholesterol-lower- many, US$1027 and 882 . The costs for Canada, France ing drugs constitute the second largest drug expenditures after and the UK were in the range of US$600–700 with the lowest antiulcer agents, with US$3.8 billion in sales or 4.6% of the costs of US$367 in Spain.
total European market . In the UK alone, US$0.7 billion isspent, representing 5.8% of total UK drug market. Since the Costs of treating CVD
year 2000, sales of dyslipidemia drugs have increased 22% in Hospital costs of treating MI range from US$9000–13,000 the USA, 19% in Europe and 28% in the UK [21,22].
[23,28]. The costs of surgical intervention, such as PercutaneousTransluminal Coronary Angioplasty (PTCA) and Coronary Costs of dyslipidemia
Artery Bypass Graft (CABG) vary from US$18,000–36,000.
The costs included in a cost-effectiveness analysis of dyslipi- Ganz and colleagues estimated the hospital cost for MI demia can be divided into two major components: direct and between US$3000–7000 and the costs of stroke at US$4500 indirect costs. Direct medical costs included all medical costs . Institutional care costs after stroke have been estimated related to a disease (hospitalization, outpatient services, medi- between US$20,000 and over 60,000. In one cost-effective- cation, rehabilitation). Dyslipidemia therapy postpones the ness analysis, Tsevat and colleagues estimated the hospital onset of CVD and in some cases reduces the need for surgical costs of MI between US$5087–6521, and stroke between interventions. A calculation of the direct costs in a cost-effec- tiveness analysis of cholesterol reduction includes the costs of Based on Swedish data, Johanesson and colleagues esti- therapy and any CVD-related costs that may be avoided mated the hospital costs of MI between US$1800–3800, and because of lipid therapy. The latter constitutes a cost–saving of CABG between US$12,100–16,000, in 1995 . In Canada, the hospital costs of MI and CABG were estimated at In primary prevention, the costs of therapy usually include US$5272–12,315 in 1996 .
the costs of medications, outpatient physician visits, and labo-ratory tests. In secondary prevention the costs of therapy are Results of recent cost-effectiveness studies
only the incremental (additional) costs in terms of additional Cost-effectiveness analysis is a widely used method for estimat- visits, tests and medication after the usual expenditures related ing the value of a health care intervention in clinical decision- to CVD management are subtracted.
making. The goal is to determine the cost-effectiveness ratio The indirect costs of the CVD include productivity loses due to (CER), or the dollar cost per unit improvement in health premature mortality and morbidity costs. In most cases they are obtained by a specific intervention in comparison with a well- calculated using the human capital approach based on the patient's defined alternative. The CER is defined as the difference in work status and average wage rate provided by labor statistics.
costs between two interventions, divided by the difference ineffectiveness, usually defined as years of life saved (YOLS) or Annual treatment costs of dyslipidemia
quality-adjusted life years (QALY). The QALY gives less Patients receiving diet therapy alone or niacin incur much weight to years of life that are spent in pain, impaired health or lower treatment costs than those on statin therapies. For exam- diminished function even if there is no effect on the duration ple, Prosser and colleagues estimated (1997) that the costs of of survival itself.
step one diet therapy in primary prevention at US$108 per Johanesson and colleagues estimated the short-term cost- patient per year as opposed to statin therapy (including outpa- effectiveness of simvastatin treatment based directly on the tient physician visits and laboratory tests) of US$1318 in pri- results of 4S trial . In the 4S trial patients with pre-existing mary prevention, and US$1329 in secondary prevention per heart disease had a 30% reduction of overall mortality. Costs patient per year . Costs of statin medications alone were cal- were defined as net costs of the intervention minus reduced culated at US$1189 per patient per year and constituted 90% treatment costs due to the decrease in morbidity from coro- of total annual treatment costs. The annual costs of niacin were nary causes. The benefits were reported in YOLS. Their anal- calculated at US$163 per patient. Patients taking niacin were ysis also included the indirect costs related to lost productiv- assumed to have an annual discontinuation rate of 27% ity due to coronary events. Both costs and benefits were whereas patients receiving statins had only a 6% discontinua- discounted at 5% per year to account for different timing of tion rate. Tsevat and colleagues calculated (1996) the annual Zowall & Grover
Table 1. Summary of the recent cost-effectiveness analyses in dyslipidemia.
Costs characteristics (US$)
Secondary prevention 4S and Swedish resource use Simvastatin US$604 Age 35–70 years Chol. 5.5–8.0 mmol/l Secondary prevention Canadian resource use Simvastatin US$667 Age 40–70 years LDL/HDL ratio 3.5–5.0 Secondary prevention Simvastatin US$1189 Age 35–84 years Chol. ≥ 4.1mmol/l Secondary prevention Pravastatin US$1237 Elderly age 75–85 years Chol. < 6.2 mmol/l LDL 3.0–4.5 mmol/l Secondary prevention CARE and USA resource use Pravastatin US$925 Chol. < 6.2 mmol/l LDL 3.0–4.5 mmol/l Primary prevention Simvastatin US$1189 Aged 35–84 years Chol. ≥ 4.1 mmol/l Primary prevention among diabetics Canadian resource use Simvastatin US$667 Age 40–70 years LDL/HDL ratio 3.5–5.0 4S: Scandinavian Simvastatin Survival Study; CARE: Cholesterol and Recurrent Events Trial; CHD: Coronary heart disease; Chol.: Cholesterol; HDL: High-density lipoprotein; LDL: Low-denisty lipoprotein.
Overall, the costs per YOLS ranged from US$3800–27,400 prevention the accuracy of the model was tested against stud- when only direct costs were included. When indirect costs asso- ies including the Program on the Surgical Control of Hyperli- ciated with morbidity were also incorporated, treatment led to a pidemias, the 4S and the CARE trials and hypertension trials cost-savings as the reduction in morbidity costs from coronary including Systolic Hypertension in the Elderly Program, the causes exceeded the costs of the intervention among men and Metoprolol Atherosclerosis Prevention in Hypertensives and women aged 35 years of age. The costs per YOLS dropped, the Multiple Risk Factor Intervention Trial [2,4,33–36].
ranging from US$1200–13,300 in the older groups of patients.
The authors concluded that simvastatin therapy in the second- These results were conservative because the authors did not ary prevention of CHD and stroke with a LDL/HDL ratio include the impact of simvastatin on the incidence of stroke greater than 3.5 for patients with and without additional risk-fac- which was reduced by 30% [2,30].
tors, was cost-effective with the estimates ranging from US$4419 Grover and colleagues forecast the long-term benefits and to 21,719 per YOLS . Among individuals with no additional cost-effectiveness of statins in the secondary prevention of risk-factors, the costs per year of life gained were estimated to be CVD based on the results of the 4S trial [2,26]. This study between US$5424 and 21,719 and among high-risk patients included the impact of statins on the incidence of stroke. It below US$10,000 per YOLS. If the effects of lipid modification also provided life-long estimates beyond the results of 4S trial on the risk of stroke were ignored, the costs per YOLS increase using the Cardiovascular Life Expectancy Model . This substantially, by as much as 100%.
study was notable as the model forecasts were also validated The Cardiovascular Life Expectancy Model has also been against the observed results of clinical trials including the used to estimate the cost-effectiveness of treating dyslipidemia results of primary prevention lipid trials, such as the Lipid in diabetic patients in primary prevention . The CER Research Clinics Coronary Primary Prevention Trial, the Hel- among diabetic patients with CVD were consistently lower sinki Heart Study and the WOSCOPS [3,13,31,32]. In secondary than those among nondiabetic CVD individuals, in the range Expert Rev. Pharmacoeconomics Outcomes Res. 3(3), (2003) Costs of dyslipidemia
Table 1. Summary of the recent cost-effectiveness analyses in dyslipidemia.
Cost-effectiveness (US$/YOLS or US$/QALY)
27% reduction in CHD Direct costs only based on 4S trial Direct and indirect costsAge = 35 years Saves money and lives Age > 35 years 35% decrease in LDL Direct costs only 8% increase in HDL Low-risk age 40–70 years based on 4S trial High-risk age 40–70 years 25% decrease in total chol Direct costs only 35% decrease in LDL Low-risk age 35–84 years 8% increase in HDL High-risk age 35–84 years based on 4S trial 33% reduction in CHD Direct costs only 40% reduction in stroke Age 75–84 years based on CARE trial Mortality and recurrent event models based on Direct costs only LDL < 3.2 mmol/l More expensive and less effective LDL 3.2–3.9 mmol/l LDL > 3.9 mmol/l 25% decrease in total chol Direct costs only 35% decrease in LDL LDL 4.2–4.9 mmol/ 8% increase in HDL LDL > 4.9 mmol/l based on 4S trial 35% decrease in LDL Direct costs among diabetics 8% increase in HDL based on 4S trial CHD: Coronary heart disease; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; QALYs: Quality-adjusted life years; YOLS: Years of life saved.
of US$4000 to 8000, indicating that the presence of diabetes any of the 240 risk subgroups and only a quarter of the risk identifies a subgroup among whom the secondary prevention is subgroups reached the threshold of US$100,000 per QALY.
particularly cost-effective. The CERs associated with primary Niacin for primary prevention had an estimated CE ratio of less prevention among diabetic patients were also substantially than US$100,000 per QALY for most risk subgroups.
lower than among nondiabetic patients and ranged from CERs for secondary prevention with statins were less than US$4000 to 40,000 across wide pretreatment lipid levels and US$50,000 per QALY for all subgroups and approximately other risk-factors.
US$10,000 per QALY or less for most high-risk subgroups. As Prosser and colleagues conducted a cost-effectiveness analysis expected, CERs became more favorable with increasing of primary and secondary prevention with cholesterol-lowering number of risk-factors and with advancing age. They were also therapies based on calculations of CHD risk from the Framing- more favorable among men than women. The authors con- ham Heart Study . Men and women aged between 35 and cluded that statins are generally cost-effective when used for 84 years with LDL-cholesterol levels of 4.1 mmol/l or greater secondary prevention but only sometimes when used for pri- were divided into 240 risk subgroups according to age, sex, mary prevention . Thus, in a low-risk population, a preven- diastolic blood pressure, smoking, LDL- and HDL-cholesterol tive intervention would be cost-effective only if it is clinically levels. The effectiveness of statins in primary prevention was effective, but very inexpensive . Consequently, at current based on results from studies of pravastatin, the effectiveness of drug costs, treatment with cholesterol-lowering drugs should be secondary prevention was taken from the 4S trial.
targeted to patients who have an elevated risk for CVD on the CERs for primary prevention with statins varied widely basis of both the lipid profile and other risk-factors.
according to the presence of other risk-factors, from Ganz and colleagues evaluated the cost-effectiveness of statin US$54,000–420,000 per QALY for men and from therapy among elderly patients (75–84 years of age) with a his- US$62,000–1,400,000 per QALY for women. Primary therapy tory of MI by extrapolating results from the CARE trial with with statins did not reach a CER of US$50,000 per QALY in pravastatin treatment (40 mg daily) and available epidemiologic Zowall & Grover
data [4,29]. In this analysis not only CHD but also stroke were Some current guidelines for cholesterol-lowering treatment explicitly modeled. They found that if the risk reductions found base their recommendations on the absolute risk of coronary in published trials prevail in older patients, statin therapy would disease [39–41]. In the Sheffield table for primary prevention, increase mean life expectancy by 4 months . The base case lipid-lowering treatment was recommended if the 1-year risk CER compared with usual care was estimated at US$18,800 of CHD exceeded 3% [39,40]. In the recommendations by the (1998) per QALY. Since costs of statins represent the majority of European Society of Cardiology, treatment was recommended the treatment costs, sensitivity analysis showed that a given if the 10-year risk of CHD exceeded 20% . In the USA, the decrease in drug costs resulted in a proportional decrease in CER.
recent ATP III recommendations were based predominantly Similar results were reported by Prossner and colleagues .
on LDL levels and on global risk assessment complemented by Higher rates of stroke and reinfarctions led to more favorable 10-year risk calculations using the Framingham risk scoring CERs because a greater absolute number of events would be system .
prevented by statin therapy. Overall, statin therapy at its cur- Researchers in the UK evaluated the healthcare policy impli- rent price appears to be cost-effective among older patients in cations of targeting statin treatment for populations at different secondary prevention. Moreover, inclusion of stroke costs, espe- CHD risk levels . Given a CHD risk of 4.5% per year (the cially expensive poststroke institutional care made the costs per risk observed among the participants of 4S trial), 5.1% of the QALY more favorable.
total UK adult population (4.8% in secondary prevention and Tsevat and colleagues assessed the cost-effectiveness of pravasta- 0.3% in high-risk primary prevention) would need to be tin therapy (40 mg daily) in survivors of MI with average choles- treated with statin. With the estimated costs at this risk level, of terol levels (the mean cholesterol level of 5.4 mmol/l and mean only US$9000 per YOLS, this translates into 16% of total UK LDL of 3.6 mmol/l) by extrapolating effectiveness data from the expenditures on prescription drugs to be spent on statins.
CARE trial [4,24]. The eligibility criteria for the CARE trial Full implementation of statin treatment at an annual CHD included a total cholesterol level of less than 6.2 mmol/l and a event risk of 1.5% (equivalent to the WOSCOPS risk level) LDL between 3.0 and 4.5 mmol/l. The survival model was based would result in 25% of the UK adult population receiving stat- directly on the data from the CARE trial and extrapolated beyond ins. This would consume almost 90% of the current UK the trial end-points using USA life tables and the Framingham expenditure on drugs. Despite a favorable CER (US$21,000 risk equations. The life expectancies were adjusted by health- per YOLS), the full implementation of this policy seems to be related quality of life data from the CARE study. The overall unlikely. If the costs of statins would fall from the current adherence rate of pravastatin therapy was calculated at 91.2% US$900 to less than 500, statin treatment of those with a based directly on the data from the CARE trial. All costs includ- CHD event risk of 1.5% would become cost-effective (below ing CHD events, stroke and revascularization procedures (PTCA US$7000) and viable from a health policy perspective.
and CABG) were calculated over the entire life of the patient.
Similarly, in the USA according to the new National Choles- Assuming a persistent survival benefit of 9% with pravastatin terol Education Program [NCEP] ATP III guidelines, 36 mil- therapy, costs per QALY were estimated between US$13,000 lion Americans requiring primary prevention alone would be and 32,000. In a sensitivity analysis with survival benefit eligible for lipid-lowering drug treatment, a 140% increase extended to 22% (taken from the LIPID study of pravastatin), since the ATP II . The economic implications of these new the incremental CER dropped to US$14,000 per QALY from guidelines primarily remain to be addressed. Given the annual the base case of US$31,000 .
costs of statins estimated at US$1000, one could imagine addi-tional drug expenditures of US$36 billion required of the US Public health implications of economic analyses
Despite a variety of assumptions regarding modeling CVD risks Goldman and colleagues estimated the population wide and costs, the findings of all the recent cost-effectiveness studies effect of full implementation of the ATP II guidelines. In their are consistent. Statin therapy is generally cost-effective for sec- results they concluded that primary prevention would only ondary prevention and for primary prevention in individuals yield about half of the benefits of secondary prevention with additional risk-factors.
despite requiring nearly twice as many person-years of treat- From the population perspective, prevention of CVD through ment . The projected increase in QALY per year of treat- diet modification, exercise, weight and smoking reduction ment for secondary prevention was 3- to 12-fold higher than might be most attractive [23,38]. These approaches are safe, incur for primary prevention.
few direct medical costs and offer benefits beyond CVD reduc- When developing guidelines, one must consider not only tion. By comparison, pharmacological interventions because of cost-effectiveness but also the proportion of the population their costs, are cost-effective only for high-risk individuals. The to be treated, as well as the total population costs of treat- introduction of relatively safe and efficacious statins makes clini- ment. Primary prevention is therefore, constrained by total cal interventions relatively attractive. However, the costs of drug drug costs. As patents on initial statins expire and competi- therapy and the absolute risk of developing future CVD events tion intensifies, it is likely that costs of cholesterol-lowering are the dominant factors determining the cost-effectiveness of drugs will decline substantially and statin therapy will the clinical approach to cholesterol reduction.
become more affordable for primary prevention. At the same Expert Rev. Pharmacoeconomics Outcomes Res. 3(3), (2003) Costs of dyslipidemia
• At the present time there are four major classes of drugs available to lower cholesterol. They include 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG CoA) reductase inhibitors (statins), bile acid sequestrants (resins), nicotinic acid and fibric acid derivatives (fibrates). Currently, the lipid-lowering therapies are dominated by statins.
• Dyslipidemia therapy postpones the onset of cardiovascular disease (CVD) and in some cases reduces the need for surgical interventions. A calculation of the direct costs in a cost-effectiveness analysis of cholesterol reduction includes the costs of therapy and any CVD related costs that may be avoided because of lipid therapy. The latter constitutes a cost–saving of a therapy.
• In the cost-effectiveness analyses, the costs of statin therapy range from US$600 to over 1000 per patient per year and appear to constitute 90% of total annual outpatient management costs, including physician visits and laboratory tests. Hospital costs of treating a myocardial infarction (MI) range from US$2000 to over 13,000. The costs of surgical intervention, such as coronary ar tery bypass graft (CABG) can vary from US$12,000 to over 36,000.
• Despite a variety of assumptions regarding modeling CVD risks and costs, statin therapy is generally cost-effective for secondary prevention, with the cost-effectiveness ratios (CER) generally below US$50,000. Among high-risk patients with CVD, the CERs are usually below US$20,000. In primary prevention, statin therapy appears to be cost-effective only among individuals with additional risk factors.
• In a low-risk population, a preventive intervention would be cost-effective only if it is clinically effective but very inexpensive. Consequently, at current drug costs, treatment with cholesterol-lowering drugs in primary prevention should be targeted to patients who have an elevated risk for CVD on the basis of both the lipid profile and other risk-factors.
• The introduction of relatively safe and efficacious statins makes clinical interventions relatively attractive. However, the costs of drug therapy and the absolute risk of developing CVD events are the dominant factors determining the cost-effectiveness of the clinical approach to cholesterol reduction.
• When developing guidelines, one must consider not only cost-effectiveness but also the proportion of the population to be treated as well as the total population costs of treatment. As competition intensifies, it is likely that costs of the cholesterol lowering drugs will decline substantially and statin therapy will become more affordable for primary prevention.
time, more accurate identification of high-risk individuals, based on global cardiovascular risk assessment will be When developing public health policy, one must consider needed to select individuals who are most likely to benefit.
not only cost-effectiveness but also the proportion of thepopulation to be treated as well as the total population costs of treatment. As competition intensifies, it is likely that At the present time, lipid-lowering therapies are dominated by costs of statins will decline, so that lipid-lowering therapy in statins. Given the current costs of statins, lipid-lowering therapy primary prevention will generally become more affordable.
is generally cost-effective for secondary prevention. In primary At the same time, more accurate identification of high-risk prevention, lipid-lowering therapy appears to be cost-effective individuals, based on global cardiovascular risk assessment only among individuals with additional risk factors.
will be adopted in treatment guidelines to select individualswho are most likely to benefit from therapy.
pravastatin in men with Downs JR, Clearfield M, Weis S et al. Primary Papers of special note have been highlighted as: hypercholesterolemia. N. Engl. J. Med. prevention of acute coronary events with 333, 1301–1307 (1995).
lovastatin in men and women with average •• of considerable interest Sacks FM, Pfeffer MA, Moye LA et al. The cholesterol levels: results of AFCAPS/ American Heart Association, Anonymous, effect of pravastatin on coronary events TexCAPS. JAMA 279, 1615–1622 (1998).
2002 Heart and Stroke Statistical Update. after myocardial infarction in patients with MRC/BHF Heart Protection Study of American Heart Association, TX, USA average cholesterol levels. N. Engl. J. Med. cholesterol lowering with simvastatin in 335, 1001–1009 (1996).
20536 high-risk individuals: a randomised Pedersen TR, Kjekshus J, Berg K. Lipid Study Group, Prevention of placebo-controlled trial. Lancet 360, 7–22 Randomised trial of cholesterol lowering in cardiovascular events and death with 4444 patients with coronary heart disease: pravastatin in patients with coronary heart Boden WE, High-density lipoprotein the Scandinavian Simvastatin Survival disease and a broad range of initial cholesterol as an independent risk-factor in Study (4S). Lancet 344, 1383–1389 cholesterol levels. The Long-term cardiovascular disease: assessing the data from intervention with pravastatin in ischaemic Framingham to the Veterans Affairs High- Shepherd J, Cobbe SM, Ford I et al. disease (LIPID) study group. N. Engl. J. Density Lipoprotein Intervention Trial. Am. J. Prevention of coronary heart disease with Med. 339, 1349–1357 (1998).
Cardiol. 86(Suppl), L19–L22 (2000).
Zowall & Grover
Effect of fenofibrate on progression of 18 Sueta CA, Chowdhury M, Boccuzzi SJ 29 Ganz DA, Kuntz KM, Jacobson GA, Avorn coronary-artery disease in Type 2 et al. Analysis of the degree of J. Cost-effectiveness of 3-Hydroxy-3- diabetes: the Diabetes Atherosclerosis undertreatment of hyperlipidemia and methylglutaryl coenzyme a reductase Intervention Study, a randomised study. congestive heart failure secondary to inhibitor therapy in older patients with Diabetes Atherosclerosis Intervention coronary artery disease. Am. J. Cardiol. 83, myocardial infarction. Ann. Intern. Med. Study Investigators. Lancet 357, 905– 1303–1307 (1999).
132, 780–787 (2000).
19 NDC Health. PharmaTrendsSM 2001 Year 30 Pedersen TR, Kjekshus J, Berg K et al. 10 Expert panel on detection, in Review. NDC Health, (2002).
Cholesterol lowering and the use of evaluation,and treatment of high blood 20 Whincup PH, Emberson JR, Lennon L healthcare resources. Results of the cholesterol in adults. Third Report of the et al. Low prevalence of lipid lowering Scandinavian Simvastatin Survival Expert Panel on Detection, Evaluation drug use in older men with established Study. Circulation 93, 1796–1802 and Treatment of High Blood Cholesterol coronary heart disease. Heart 88, 25–29 in Adults (Adult Treatment Panel III). 31 Grover SA, Paquet S, Levinton C, Full Report. National Cholesterol 21 IMS World Review 2002. Pointe-Claire, Coupal L, Zowall H. Estimating the Eduction Program (2001).
Quebec, Canada (2002).
benefits of modifying risk factors of Highlights the effectiveness and cost-
cardiovascular disease. A comparison of effectiveness of lipid-lowering therapies
22 The National Institute for Healthcare primary versus secondary prevention. and their public health implications.
Management, Research and Educational Arch. Intern. Med. 158, 655–662 11 LaRosa JC, He J, Vupputuri S. Effect of Foundation. Anonymous. Prescription drug statins on risk of coronary disease. A meta- expenditures in 2001: another year of 32 Manninen V, Elo O, Frick H et al. Lipid analysis of randomized controlled trials. escalating costs. NIHCM Foundation, alterations and decline in the incidence JAMA 282, 2340–2346 (1999).
Washington DC, USA (2002).
of coronary heart disease in the Helsinki 12 Lipid Research Clinics Program, The Lipid 23 Prosser LA, Stinnett AA, Goldman PA et al. Heart Study. JAMA 260, 641–651 Research Clinics Coronary Primary Cost-effectiveness of cholesterol-lowering Prevention Trial results. I. Reduction in therapies according to selected patient 33 Buchwald H, Varco RL, Matts JP and the incidence of coronary heart disease. JAMA characteristics. Ann. Intern. Med. 132, 769– POSCH Group. Effect of partial ileal 251, 351–364 (1984).
bypass surgery on mortality and morbidity 13 Lipid Research Clinics Program, The Lipid 24 Tsevat J, Kuntz KM, Orav EJ et al. Cost- from coronary heart disease in patients with Research Clinics Coronary Primary effectiveness of pravastatin therapy for hypercholesterolemia. N. Engl. J. Med. 323, Prevention Trial results. II. The relationship survivors of myocardial infarction with 946–955 (1990).
of reduction in incidence of coronary heart average cholesterol levels. Am. Heart J. 141, 34 SHEP Co-operative Research Group. disease to cholesterol lowering. JAMA 251, 727–734 (2001).
Prevention of stroke antihypertensive drug 365–374 (1984).
25 Johannesson M, Jönsson B, Kjekshus J for the treatment in older persons with isolated 14 Brown BG, Zhao X-Q, Chait A et al. Scandinavian Simvastatin Survival Study systolic hypertension. JAMA 265, 255–264 Simvastatin and niacin, antioxidant Group. Cost effectiveness of simvastatin vitamins, or the combination for the treatment to lower cholesterol levels in patients 35 Wikstrand J, Warnold I, Olsson G et al. prevention of coronary disease. N. Engl. J. with coronary heart disease. N. Engl. J. Med. Primary prevention with metoprolol in Med. 345, 1583–1592 (2001).
336, 332–336 (1997).
patients with hypertension. JAMA 259, 15 Committee of Principal Investigators, A 26 Grover SA, Coupal L, Paquet S, Zowall 1976–1982 (1988).
co-operative trial in the primary H. Cost-effectiveness of 3-hydroxy-3- 36 The Multiple Risk Factor Intervention Trial prevention of ischemic heart disease methylglutaryl-coenzyme A reductase Research Group. Mortality rates after using clofibrate. Brit. Heart 40, 1069– inhibitors in the secondary prevention 10.5 years for participants in the Multipile 1118 (1978).
of cardiovascular disease: forecasting the incremental benefits of preventing Risk Factor Intervention Trial: findings 16 Frick MH, Elo O, Haapa K et al. coronary and cerebrovascular events. related to a priori hypothesis of the trial. Helsinki Heart Study: primary- Arch. Intern. Med. 159, 593–600 JAMA 263, 1795–1801 (1990).
prevention trial with gemfibrozil in 37 Grover SA, Coupal L, Zowall H, Dorais M. middle-aged men with dyslipidemia. Cost-effectiveness of treating Safety of treatment, changes in risk 27 Grover SA, Coupal L, Zowall H et al. How hyperlipidemia in the presence of diabetes: factors and incidence of coronary heart cost-effective is the treatment of who should be treated? Circulation 102, disease. N. Engl. J. Med. 317, 1237– dyslipidemia in patients with diabetes but 722–727 (2000).
without cardiovascular disease? Diabetes Care 24, 45–50 (2001).
38 Lowensteyn I, Coupal L, Zowall H, Grover 17 Rubins HB, Robins SJ, Collins D et al. SA. The cost-effectiveness of exercise Gemfibrozil for the secondary prevention 28 Stinnett AA, Mittleman MA, Weinstein training for the primary and secondary of coronary heart disease in men with low MC et al. Cost-Effectiveness in Health prevention of cardiovascular disease. J. Levels of high-density lipoprotein and Medicine. Gold MR, Siegel JE, Cardiopulmonary Rehabil. 20, 147–155 cholesterol. N. Engl. J. Med. 341, 410–418 Russel LB, Weinstein V. (Eds). Oxford University Press, NY, USA (1996).
Expert Rev. Pharmacoeconomics Outcomes Res. 3(3), (2003) Costs of dyslipidemia
39 Ramsay LE, Haq IU, Jackson PR et al. risk of coronary heart disease and cost of Targeting lipid-lowering drug therapy for drug treatment. Heart 82, 325–332 (1999).
primary prevention of coronary heart •• Highlights the effectiveness and cost-
disease: an updated Sheffield table. Lancet effectiveness of lipid-lowering therapies
Hanna Zowall, MA, Centre for the Analysis of 348, 387–388 (1996).
and their public health implications.
Cost-Effective Care and the Divisions of General 40 Ramsay LE, Haq IU, Jackson PR, Yeo WW. 43 Fedder DO, Koro CE, L'Italien GJ. New Internal Medicine and Clinical Epidemiology, The Sheffield table for primary prevention National Cholesterol Education Program The Montreal General Hospital, Departments of of coronary heart disease: corrected. Lancet III Guidelines for primary prevention lipid- Medicine and Epidemiology & Biostatistics, 348, 1251–1252 (1996).
McGill University, Montreal, Quebec, Canada, lowering drug therapy: project impact on Tel.: +1 514 934 1934 ext. 44725, Fax: +1 Wood D, De Backer G, Faergeman O et al. the size, sex and age distribution of the 514 934 8293, [email protected] Prevention of coronary heart disease in treatment-eligible population. Circulation ver, MD, Centre for the Analysis of clinical practice: summary of 105, 152–156 (2002).
Cost-Effective Care and the Divisions of General recommendations of the Second Joint Task Internal Medicine and Clinical Epidemiology, Force of European and other Societies on 44 Goldman L, Coxson P, Hunink MGM The Montreal General Hospital, Departments of Coronary Prevention (Task Force Report). et al. The relative influence of secondary Medicine and Epidemiology & Biostatistics, Atherosclerosis 140, 199–270 (1998).
versus primary prevention using the McGill University, Montreal, Quebec, Canada, 42 Pickin DM, McCabe CJ, Ramsay LE et al. National Cholesterol Education Program Tel.: +1 514 934 1934 ext. 44644, Fax: +1 Cost effectiveness of HMG-CoA reductase Adult Treatment Panel II Guidelines. J. Am. 514 934 8293, [email protected] inhibitor (statin) treatment related to the Coll. Cardiol. 34, 768–776 (1999).
Nuance Healthcare Solutions Data Sheet Dragon Medical Practice Edition Speech-enable the practice's EPR for faster, more efficient, and profitable History of Present Il ness, Review How can clinicians efficiently of Systems, Physical Examination, Key benefits document patient care in their own