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Background: People with peripheral artery disease are at a high risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Randomized controlled trials suggest that intensive lowering of low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors is an effective strategy to prevent these events. This study estimated the potential benefit and cost-effectiveness of administrating PCSK9 inhibitors to a cohort of participants with peripheral artery disease., Methods: A total of 783 participants with intermittent claudication (IC; n = 582) or chronic limb-threatening ischemia (CLTI; n = 201) were prospectively recruited from three hospitals in Australia. Serum LDL-C was measured at recruitment, and the occurrence of MACE and MALE was recorded over a median (interquartile range) follow-up of 2.2 years (0.3-5.7 years). The potential benefit of administering a PCSK9 inhibitor was estimated by calculating the absolute risk reduction and numbers needed to treat (NNT) based on relative risk reductions reported in published randomized trials. The incremental cost-effectiveness ratio per quality-adjusted life year gained was estimated., Results: Intensive LDL-C lowering was estimated to lead to an absolute risk reduction in MACE of 6.1% (95% confidence interval [CI], 2.0-9.3; NNT, 16) and MALE of 13.7% (95% CI, 4.3-21.5; NNT, 7) in people with CLTI compared with 3.2% (95% CI, 1.1-4.8; NNT, 32) and 5.3% (95% CI, 1.7-8.3; NNT, 19) in people with IC. The estimated incremental cost-effectiveness ratios over a 10-year period were $55,270 USD and $32,800 USD for participants with IC and CLTI, respectively., Conclusions: This analysis suggests that treatment with a PCSK9 inhibitor is likely to be cost-effective in people with CLTI., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: PCSK9 inhibitors were approved by the Food and Drug Administration in 2015 to lower low-density lipoprotein cholesterol (LDL-C) levels. In the years following, additional research findings, changes in national guideline recommendations, and price reductions have occurred., Objective: The goal of the study is to describe the characteristics and trends in PCSK9 inhibitor prescription fills and price, from initial FDA approval in Quarter 3 2015 through Quarter 4 2019, at the national and state levels., Methods: Cross-sectional study of fills obtained using the IQVIA National Prescription Audit®, Extended Insights, New to Brand, and Regional databases. Prescription fills included injections that provided cholesterol-lowering therapy from 14 to 90 days for the two PCSK9 inhibitors: alirocumab (75 mg/mL and 150 mg/mL) or evolocumab (140 mg/mL and 420 mg/3.5 mL). Quarterly prescription fills obtained nationally for Quarter 3 2015 through Quarter 4 2019, by sex, age, and state during 2019., Results: Over the time period examined, 2.75 million PCSK9 inhibitor prescriptions were filled nationally (alirocumab: 38%; evolocumab: 62%), and the average retail price per fill (unadjusted $US) from retail pharmacies decreased by 40% from $1502 to $896 per fill. Year-over-year percent change in new PCSK9 inhibitor users increased throughout the observation period, with 9611 new alirocumab users and 25,381 new evolocumab users in Q4 2019. PCSK9 inhibitor fill rates ranged from 5.6 per 1000 in the Northeast to 3.4 per 1000 in the West in 2019, with the highest rate per 1000 in Louisiana (9.1), and lowest in Wyoming (1.3)., Conclusions: PCSK9 inhibitor prescriptions have increased nationally since 2015, coinciding with additional evidence supporting their use for LDL-C lowering and cardiovascular event reduction. Although the retail price has decreased since introduction, cost and delivery mode likely continue as barriers., (Copyright © 2021 National Lipid Association. All rights reserved.)

Objectives: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is)-innovative yet costly cholesterol-lowering agents-have been subject to substantial prior authorization (PA) requirements and low approval rates. We aimed to investigate trends in insurer approval and reasons for rejection for PCSK9i prescriptions as well as associations between patients' demographic, clinical, pharmacy, payer, and PCSK9i-specific plan/coverage factors and approval., Methods: We examined trends in PCSK9i approval rates and reasons for rejection using medical and prescription claims from 2015 to 2017 for individuals who received a PCSK9i prescription. We used multinomial logistic regression to estimate quarterly risk-adjusted approval rates for initial PCSK9i prescriptions and approval for any PCSK9i prescription within 30, 90, and 180 days of the initial PCSK9i prescription. For a 2016 subsample for whom we had PCSK9i-specific plan policy data, we examined factors associated with approval including PCSK9i-specific plan formulary coverage, step therapy requirements, and number of PA criteria., Results: The main sample included 12 309 patients (mean age 64.8 years [SD = 10.8], 52.1% female, 51.5% receiving Medicare) and was similar in characteristics to the 2016 subsample (n = 6091). Approval rates varied across quarters but remained low (initial prescription, 13%-23%; within 90 days, 28%-44%). Over time, rejections owing to a lack of formulary coverage decreased and rejections owing to PA requirements increased. Lack of formulary coverage and having ≥11 PA criteria in the plan policy were associated with lower odds of PCSK9i prescription approval., Conclusions: These findings confirm ongoing PCSK9i access issues and offer a baseline for comparison in future studies examining the impact of recent efforts to improve PCSK9i access., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Understanding the molecular defects underlying cardiovascular disease is necessary for the development of therapeutics. The most common method to lower circulating lipids, which reduces the incidence of cardiovascular disease, is statins, but other drugs are now entering the clinic, some of which have been approved. Nevertheless, patients cannot tolerate some of these therapeutics, the drugs are costly, and/or the treatments are approved for only rare forms of disease. Efforts to find alternative treatments have focused on other factors, such as apolipoproteinB (apoB), which transports cholesterol in the blood stream. The levels of apoB are regulated by endoplasmic reticulum (ER) associated degradation as well as by a post ER degradation pathway in model systems, and we suggest that these events provide novel therapeutic targets. We discuss first how cardiovascular disease arises and how cholesterol is regulated, and then summarize the mechanisms of action of existing treatments for cardiovascular disease. We then review the apoB biosynthetic pathway, focusing on steps that might be amenable to therapeutic interventions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Considerable interest exists among health care payers and pharmaceutical manufacturers in designing outcomes-based agreements (OBAs) for medications for which evidence on real-world effectiveness is limited at product launch., Objectives: To build hypothetical OBA models in which both payer and manufacturer can benefit., Methods: Models were developed for a hypothetical hypercholesterolemia OBA, in which the OBA was assumed to increase market access for a newly marketed medication. Fixed inputs were drug and outcome event costs from the literature over a 1-year OBA period. Model estimates were developed using a range of inputs for medication effectiveness, medical cost offsets, and the treated population size. Positive or negative feedback to the manufacturer was incorporated on the basis of expectations of drug performance through changes in the reimbursement level. Model simulations demonstrated that parameters had the greatest impact on payer cost and manufacturer reimbursement., Results: Models suggested that changes in the size of the population treated and drug effectiveness had the largest influence on reimbursement and costs. Despite sharing risk for potential product underperformance, manufacturer reimbursement increased relative to having no OBA, if the OBA improved market access for the new product. Although reduction in medical costs did not fully offset the cost of the medication, the payer could still save on net costs per patient relative to having no OBA by tying reimbursement to drug effectiveness., Conclusions: Pharmaceutical manufacturers and health care payers have demonstrated interest in OBAs, and under a certain set of assumptions both may benefit., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved by the US Food and Drug Administration (FDA) as cholesterol-lowering therapies for patients with familial hypercholesterolemia or atherosclerotic cardiovascular disease., Objectives: To estimate the long-term health and economic value of PCSK9 inhibitors for Americans (51 years and older)., Methods: We conducted simulations using the Future Elderly Model, an established dynamic microsimulation model to project the lifetime outcomes for the US population aged 51 years and older. Health effects estimates and confidence intervals from published meta-analysis studies were used to project changes in life expectancy, quality-adjusted life-years, and lifetime medical spending resulting from the use of PCSK9 inhibitors. We considered two treatment scenarios: 1) current FDA eligibility and 2) an extended eligibility scenario that includes patients with no pre-existing cardiovascular disease but at high risk. We assumed that the price of PCSK9 inhibitors was discounted by 35% in the first 12 years and by 57% thereafter, with gradual uptake of the drug in eligible populations., Results: Use of PCSK9 inhibitors by individuals covered by current FDA approval would extend life expectancy at the age of 51 years by an estimated 1.1 years and would yield a lifetime net value of $5800 per person. If use was extended to those at high risk for cardiovascular disease, PCSK9 inhibitors would generate a lifetime net benefit of $14,100 per person., Conclusions: Expanded access to PCSK9 inhibitors would offer positive long-term net value for patients and the US health care system at the current discounted prices., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

We used the Archimedes Model, a mathematical simulation model (Model) to estimate the clinical- and cost-effectiveness of using LDL particle concentration (LDL-P) as an adjunct or alternative to LDL cholesterol (LDL-C) to guide statin therapy. LDL-P by NMR has been shown to be a better measure of cardiovascular disease (CVD) risk than LDL-C, and may therefore be a better gauge of the need for and response to statin treatment. Using the Model, we conducted a virtual clinical trial comparing the use of LDL-C alone, LDL-P alone, and LDL-C and LDL-P together to guide treatment in the general adult population, and in high-risk, dyslipidemic subpopulations. In the general population, the 5-year major adverse cardiovascular event (MACE) relative risk reduction (RRR) of LDL-P alone compared to the control arm (LDL-C alone) was 5.0% (95% CI, 4.7-5.3; p < .0001); using both LDL-C and LDL-P (dual markers) led to 3.0% RRR compared to the control arm (95% CI, 2.8-3.3; p < .0001). For individuals with diabetes, the RRR was 7.3% (95% CI, 6.4-8.2; p < .0001) for LDL-P alone and 6.9% for dual markers (95% CI, 6.1-7.8; both, p < .0001). In the general population, the costs per quality-adjusted life year (QALY) associated with the use of LDL-P alone were $76,052 at 5 years and $8913 at 20 years and $142,825 at 5 years and $25,505 at 20 years with the use of both markers. In high-risk subpopulations, the use of LDL-P alone was cost-saving at 5 years; whereas the cost per QALY for the use of both markers was $14,250 at 5 years and $859 at 20 years for high-risk dyslipidemics, $19,192 at 5 years and $649 at 20 years for diabetics, and $9030 at 5 years and $7268 at 20 years for patients with prior CHD. In conclusion, the model estimates that using LDL-P to guide statin therapy may reduce the risk of CVD events to a greater extent than does the use of LDL-C alone and maybe cost-effective or cost-saving for high-risk patients., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Saskatchewan is the only Canadian province that lists ezetimibe for open formulary access even though it is a second-line agent for lowering cholesterol., Methods: A retrospective analysis of ezetimibe use in Saskatchewan between 2002 and 2011 was carried out using provincial health administrative databases. Overall use and costs of ezetimibe were described over time. Among new users of ezetimibe, the percentage who received the drug as first-line monotherapy was estimated. First-line monotherapy was defined as no statin dispensations in the 365 days before and the 60 days after the first ezetimibe dispensation. Potential predictors of first-line monotherapy were assessed using generalized linear mixed-effect models., Results: In 2004, ezetimibe represented 2.5% of cholesterol-lowering dispensations. In 2011, its use increased to 8.8% of cholesterol-lowering dispensations and 13.2% of the total cost of cholesterol-lowering agents. Overall, ezetimibe was used as first-line monotherapy in 23% of all new users (4024 of 17,475 patients). Approximately half of all cases of first-line monotherapy were prescribed by 10.4% (112 of 1074) of prescribers in the cohort. Patients who had experienced previous acute coronary syndrome or who had undergone coronary revascularization procedures were significantly less likely to receive first-line monotherapy., Conclusions: A high proportion of ezetimibe's use is not in accordance with evidence-based recommendations. Suboptimal prescribing could partially explain current patterns of use; however, other factors such as medication nonadherence may have played an important role. Restricting ezetimibe use in the provincial formulary in addition to improving prescribers' awareness through academic detailing should be considered., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the incremental cost-effectiveness ratio (ICER) of switching to ezetimibe/simvastatin (Eze/Simva) compared with doubling the submaximal statin doses, in patients with acute coronary syndrome (ACS) events in the INFORCE study., Methods: Lifetime treatment costs and benefits were computed using a Markov model. Model inputs included each patient's cardiovascular risk factor profile and actual lipid values at baseline and 12 weeks (endpoint). Cardiovascular event and drug costs were discounted at 3.5%. Age-specific utilities were based on UK literature values and non-coronary heart disease mortality rates on the Office of National Statistics data. In the INFORCE study, 384 patients taking statins at stable doses for ≥6 weeks before hospital admission were stratified by statin dose/potency (low, medium, and high) and then randomized to doubling the statin dose or switching to Eze/Simva 10/40mg for 12 weeks., Results: The Eze/Simva group (n=195) had a higher mean baseline total cholesterol than the double-statin group (n=189). Analyses were adjusted for baseline characteristics. In the INFORCE study, Eze/Simva reduced low-density lipoprotein cholesterol (LDL-C) by ∼30% (vs. 4% with doubling statin doses) and significantly enhanced LDL-C goal attainment. In the cost-effectiveness analysis, Eze/Simva conferred 0.218 incremental discounted quality-adjusted life year (QALY) at a discounted incremental cost of £2524, for an ICER of £11,571/QALY (95% confidence interval=£8181-£18,600/QALY). The ICER was £13,552/QALY, £11,930/QALY, and £10,148/QALY in the low-, medium-, and high-potency strata, respectively., Conclusions: Switching to Eze/Simva 10/40 mg is projected to be a cost-effective treatment (vs. double-statin) in UK patients with ACS., (© 2010, International Society for Pharmacoeconomics and Outcomes Research (ISPOR).)

Objectives: This study evaluated the economic implications of results obtained by the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial., Methods: To enable long-term projection of the trial results, a discrete event simulation of the course of clinical care after a recent stroke or transient ischemic attack (TIA) was developed. It generates pairs of identical patients; both receive usual care, one receives atorvastatin in addition. Their clinical course is simulated based on their risk of stroke, cardiovascular events, and case fatality rates taken from SPARCL, life expectancy from Saskatchewan Health data, and utility weights from literature. Costs, from a US health-care payer perspective in 2005 US dollars, were estimated for a within-trial 5-year period; survival and quality-adjusted life-years (QALYs) were extrapolated over a patient's lifetime; all discounted at 3%/year., Results: The prevention of stroke, coronary, and other cardiovascular events expected with atorvastatin translates to mean gains of 0.155 life-years gained and 0.172 QALYs per patient over their lifetime. Reducing associated medical costs ($8405 vs. $11,237) but increasing drug costs ($13,984 vs. $8752) results in net $2400/patient, or $13,916/QALY gained. Probabilistic sensitivity analysis indicates no simulations yield ratios above $50,000/QALY., Conclusion: Prescribing atorvastatin for patients with prior stroke or TIA is expected to provide health benefits at an acceptable cost in the United States.

Objective: We sought to determine lifetime costs, morbidity, and mortality associated with varying adherence to antihypertensive and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statin) therapy in a hypertensive population., Methods: A model was constructed to compare costs and outcomes under three adherence scenarios: no treatment, ideal adherence, and real-world adherence. Simulated patients' characteristics matched those of participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm and event probabilities were calculated with Framingham Heart Study risk equations. The real-world adherence scenario employed adherence data from an observational study of a US population; risk reductions at each level of adherence were based on linear extrapolations from clinical trials. Outputs included life expectancy, frequencies of primary and secondary coronary heart disease and stroke, and direct medical costs in 2006 US$. The incremental cost per life-year gained and incremental cost per event avoided were calculated comparing the three adherence scenarios., Results: Mean life expectancy was 14.73 years (no-treatment scenario), 15.07 (real-world adherence), and 15.49 (ideal adherence). The average number of cardiovascular events per patients was 0.738 (no treatment), 0.610 (real-world adherence), and 0.441 (ideal adherence). The incremental cost of real-world adherence versus no treatment is $30,585 per life-year gained, and ideal adherence versus real-world adherence is $22,121 per life-year gained., Conclusions: Hypertensive patients taking antihypertensive and statin therapy at real-world adherence levels can be expected to receive approximately 50% of the potential benefit seen in clinical trials. Depending on its cost, the incremental benefits of an effective adherence intervention program could make it an attractive value.

Background: Lowering low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of coronary heart disease. The introduction of a highly efficacious new statin, rosuvastatin, may enable more patients to be treated to LDL-C goal within a fixed budget., Objectives: To compare the cost-effectiveness of rosuvastatin 10 mg and atorvastatin 10 mg in lowering LDL-C and achieving guideline goals after 12 weeks of treatment. The LDL-C goals were those recommended by the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III and the Third Joint European Task Force., Methods: The analysis was performed on pooled data from three clinical trials. Efficacy was measured as the percent reduction in LDL-C and the proportion of patients who reached guideline LDL-C goals following the first 12 weeks of treatment, prior to dose titration. Costs comprised drug acquisition costs only. The cost-effectiveness measures were cost per 1% reduction in LDL-C and cost per patient treated to their LDL-C goal., Results: Treatment with rosuvastatin 10 mg costs 1.85 per 1% reduction in LDL-C, compared with 2.37 per 1% reduction with atorvastatin 10 mg. The average costs per patient treated to the European LDL-C goals were 130.18 for rosuvastatin 10 mg and 242.44 for atorvastatin 10 mg. Treating to NCEP ATP III goals costs 115 per patient treated with rosuvastatin 10 mg vs. 163 per patient treated with atorvastatin 10 mg., Conclusions: Rosuvastatin has the same acquisition costs as and is more efficacious than atorvastatin in lowering LDL-C and treating patients to target LDL-C levels.

Objective: This analysis was designed to estimate the cost-effectiveness of pravastatin for the primary prevention of coronary heart disease in Japan., Methods: A state-transition model was used to compare the cost-effectiveness of pravastatin therapy with no intervention. Hypothetical cohorts were assumed according to patients' age, sex, initial serum total cholesterol (TC) levels, and other cardiac risk factors. For the baseline analysis, 20 mg/day of pravastatin was used for people aged 60 years who had an initial TC level of 240 mg/dl. Epidemiological, clinical, and economic data were collected from published articles. Incremental cost-effectiveness ratios (ICERs) in yen per quality-adjusted life year (QALY) were calculated. To confirm the effects of different variables, a sensitivity analysis was performed. The assumptions of our model were in accordance with the Japan Atherosclerosis Society Guidelines for the Diagnosis and Treatment of Atherosclerotic Cardiovascular disease., Results: ICERs were respectively 44 million and 76 million yen/QALY for men and women at low cardiac risk (i.e., the risks of hypercholesterolemia and old age) and 7.5 million and 4.3 million yen/QALY for those at high cardiac risk (i.e., the risks of hypercholesterolemia, old age, cigarette smoking, hypertension, and hyperglycemia)., Conclusions: The cost-effectiveness of pravastatin therapy differs substantially according to the level of cardiac risk. At present, pravastatin therapy is not cost-effective for persons at low cardiac risk.

Background: Statin therapy reduces the rates of heart attack, stroke, and revascularisation among a wide range of individuals. Reliable assessment of its cost-effectiveness in different circumstances is needed., Methods: 20,536 adults (aged 40-80 years) with vascular disease or diabetes were randomly allocated 40 mg simvastatin daily (10,269) or placebo (10,267) for an average of 5 years. Comparisons were made of hospitalisation and statin costs (2001 UK prices) during the scheduled treatment period between all simvastatin-allocated versus all placebo-allocated participants. Cost-effectiveness was estimated among different categories of participant., Findings: Allocation to simvastatin was associated with a highly significant 22% (95% CI 16-27; p<0.0001) proportional reduction in hospitalisation costs for all vascular events, with similar proportional reductions in every subcategory of participant studied. During an average of 5 years, estimated absolute reductions in vascular event costs per person allocated 40 mg simvastatin daily ranged from UK 847 pounds sterling (SE 137) in the highest risk quintile studied to 264 pounds sterling (48) in the lowest. Mean excess cost of statin therapy among participants allocated simvastatin was 1497 pounds sterling (8), with similar absolute increases in every subcategory. Costs of preventing a major vascular event with 40 mg simvastatin daily ranged from 4500 pounds sterling (95% CI 2300-7400) among participants with a 42% 5-year major vascular event rate to 31,100 pounds sterling (22,900-42,500) among those with a 12% rate (corresponding to 5-year major coronary event rates of 22% and 4%, respectively)., Interpretation: Statin therapy is cost effective for a wider range of individuals with vascular disease or diabetes than previously recognised (particularly with lower-priced generics). It would be appropriate to consider reducing the estimated level of vascular event risk at which statin therapy is recommended.

Objective: To estimate the short-term healthcare costs and incremental cost per event avoided, associated with aggressive atorvastatin treatment in patients with acute coronary syndrome in Sweden., Methods: The total expected 16-week healthcare costs per patient on atorvastatin 80 mg per day and placebo were compared using clinical outcomes data from The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study and Swedish cost data sources. The incremental cost per event avoided was also assessed for. The clinical outcomes measured in this pharmacoeconomic analysis included: death, cardiac arrest, non-fatal myocardial infarction, fatal myocardial infarction, angina pectoris, non-fatal stroke, congestive heart failure, and surgical or percutaneous coronary revascularizations. All direct medical costs were taken into account., Results: The probability of the occurrence of an event was 40.4% per patient in the placebo cohort and 36.6% per patient in the atorvastatin cohort. The total expected cost per patient was SEK 17,887 (1950.21 euro) in the placebo group and SEK 18,465 (2013.06 euro) in the atorvastatin group, resulting in an incremental cost of SEK 578 (63.0137 euro) per patient. The cost per event avoided was SEK 15,076 (1643.64 euro). Sixty six percent of the cost of atorvastatin treatment was offset by the cost savings obtained through the reduction in the number of events in the atorvastatin group compared to the placebo group., Conclusions: In Sweden, the clinical benefits of aggressive short-term atorvastatin treatment administered within a few days after acute coronary syndrome is associated with a substantial hospitalization cost offset secondary to the clinical benefits of atorvastatin.

Little information exists to quantify the functional status and economic consequences of lipid-lowering therapy in elderly patients. We describe the design of the cost-effectiveness component of the first large, randomized, placebo-controlled trial of lipid-lowering therapy in subjects aged 70 years or older. The PROspective Study of Pravastatin in the Elderly at Risk has randomized 5804 men and women 70-82 years old, with existing vascular disease or related risk factors, to receive 40 mg/d of pravastatin or placebo. The cost-effectiveness study will be based on within-trial observations of differences between the two study arms in rates of myocardial infarction, stroke and related vascular disease outcomes (including vascular dementia). In addition to comparing within-trial clinical outcomes, we will model the projected changes in life expectancy and cardiovascular outcome rates that would be seen with lifelong use of the drug, based on the risk reduction rates seen in the trial as well as baseline observational data from the three countries where the trial is being conducted (Scotland, Ireland and the Netherlands). A state transition (Markov) model will be constructed to estimate the likely states of health, functional status and health care resource utilization (including lipid-lowering drug costs) in a cohort of elderly patients with versus without pravastatin therapy over a series of 1-year cycles until death. In addition, a standard measure of utility (the Health Utilities Index) will be administered to all study subjects to permit calculation of quality-adjusted life-years gained with this regimen. This approach will make it possible to go beyond the calculation of a single endpoint for each subject, and to translate the trial findings into definitions of effectiveness and outcomes that will be relevant to the ongoing debate concerning how best to relate the benefits of such medications to their costs.

Today's society places a great emphasis on value for money, so medical interventions must not only be shown to be effective but also be proved to be costeffective. Drug treatment is no exception. In health economics, costeffectiveness is calculated differently depending on the indication and the perspective. For cholesterol-lowering drugs (as an example) there is a difference between primary and secondary intervention. In primary prevention, the cut off value for absolute risk when treatment is costeffective varies with age and sex, but in secondary prevention, although treatment is costeffective for all groups of patients, costeffectiveness varies with age, sex, cholesterol concentration, and other risk factors. There are three complementary approaches to economic assessment of secondary prevention-analysis of the whole population, subgroup analysis, and modelling.

Objective: To compare the results and cost-effectiveness of a cholesterol lowering protocol implemented by registered dietitians with cholesterol lowering advice by physicians., Design: Six month randomized controlled trial, cost-effectiveness analysis. Subjects included 90 ambulatory care patients (60 men, 30 women), age range 21 to 65 years, with hypercholesterolemia and not taking hypolipidemic drugs. Patients were randomly assigned to receive medical nutrition therapy (MNT) from dietitians using a NCEP based lowering protocol or usual care (UC) from physicians. Outcome measures were plasma lipid profiles, dietary intake, weight, activity, patient satisfaction, and costs of MNT. Changes from baseline for each variable of interest were compared between treatment groups using analysis of covariance controlling for baseline value of the variable and gender., Results: MNT achieved a 6% decrease in total and LDL cholesterol levels at 3 and 6 months compared with a 1% increase and a 2% decrease in both values at 3 and 6 months with UC (P<.001 and P<.05, respectively). Weight loss (1.9 vs 0 kg, P<.001) and dietary intake of saturated fat (7% of energy vs 10%, P<.001) were better in the MNT than the UC group. The additional costs of MNT were $217 per patient to achieve a 6% reduction in cholesterol and $98 per patient to sustain the reduction. The cost-effectiveness ratio for MNT was $36 per 1% decrease in cholesterol and LDL level., Applications/conclusions: MNT from registered dietitians is a reasonable investment of resources because it results in significantly better lipid, diet, activity, weight, and patient satisfaction outcomes than UC.

We asked if medical nutrition therapy (MNT) administered by registered dietitians could lead to beneficial clinical and financial outcomes in men with combined hyperlipidemia (hypercholesterolemia and hypertriglyceridemia). A retrospective chart review was conducted on 73 men with combined hyperlipidemia who were being considered for statin therapy because of a previous history of noncompliance with niacin therapy. Subjects participated in an 8-week dietitian intervention program as a qualifying requirement, before statin therapy. Patient records were reviewed to determine the beginning and ending serum lipid concentrations and the number and length of dietitian sessions. Complete information was available on 43 subjects, aged 60.7 +/- 10.1 years (mean +/- standard deviation). Total dietitian intervention time was 169 +/- 19 minutes in 2.7 +/- 0.6 sessions (range = 2 to 4 sessions) during 6.5 +/- 2.2 weeks of MNT (range = 4 to 8 weeks). MNT lowered levels of total cholesterol 11% (P < .001), low-density lipoprotein cholesterol 9% (P < .001), and triglycerides 22% (P < .0001) and body mass index 2% (P < .0001); MNT raised high-density lipoprotein cholesterol levels 4%. After dietitian intervention, only 15 of 30 eligible patients required antihyperlipidemic medications, which led to an annual cost savings of $27,449.10 or $638.35 per patient. A cost saving of $3.03 in statin therapy was realized for each dollar spent on MNT. We conclude that an average of 3 individualized dietitian visits of 1 hour each over an 8-week period has a beneficial effect in treating patients with combined hyperlipidemia and recommend consideration of MNT as a cost-effective intervention.

This study was designed to evaluate whether medical nutrition therapy administered by registered dietitians could lead to a beneficial clinical and cost outcome in men with hypercholesterolemia. Ninety-five subjects participating in a cholesterol-lowering drug study took part in an 8-week nutrition intervention program before initiating treatment with a cholesterol-lowering medication, Patient records were reviewed via a retrospective chart review to determine plasma lipid levels at the beginning and end of the program and the number and length of sessions with a dietitian. Complete information was available for 74 subjects aged 60.8 n+/- 9.8 years (mean +/- SD). Medical nutrition therapy lowered total serum cholesterol levels 13% (P < .001), low-density lipoprotein cholesterol (LDL-C) 15% (P < .0001), triglyceride 11% (P < .05), and high-density lipoprotein-cholesterol (HDL-C) 4% (P < .05). Total dietitian intervention time was 144 +/- 21 minutes (range = 120 to 180 minutes) in 2.8 +/- 0.7 sessions (range = 2 to 4) during 6.81 +/- 0.7 weeks of medical nutrition therapy (range = 6 to 8 weeks). Analysis of covariance was conducted to examine whether mean change in LDL-C differed by number of dietitian visits. Results showed a marginal difference between the number of dietitian visits and change in LDL-C (f = 2.6, P < .084). However, the magnitude of LDL-C reduction was significantly higher with 4 dietitian visits (180 minutes) than with 2 visits (120 minutes) (21.9% vs 12.1%; P = .027). Lipid drug eligibility was obviated in 34 of 67 (51%) subjects per the National Cholesterol Treatment Program guidelines algorithm. The estimated annualized cost savings from the avoidance of lipid medications was $60,561.68. Therefore, we conclude that 3 or 4 individualized dietitian visits of 50 minutes each over 7 weeks are associated with a significant serum cholesterol reduction and a savings of health care dollars.

Recent literature on the cost effectiveness of hepatic hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the treatment of hypercholesterolemia is reviewed with a twofold objective. First, the relative cost effectiveness of treatment with HMG-CoA reductase inhibitors is compared with that of other interventions based on recent long term morbidity and mortality trials; and second, drugs within this therapeutic class are identified that produce the desired effect at minimum cost. Given the limited resources available to treat hypercholesterolemia, the question of establishing which subgroup of the population is most likely to benefit from treatment with statins is legitimate. The latest economic evidence is used to demonstrate that the most cost effective public health strategy is to identify the patient population that needs to be treated and to select the most cost effective treatment.

Methodological differences and variations in health care regulations among countries often preclude direct comparisons of cost-effectiveness studies. A projected risk model was applied, designed to determine the economic value in the United States of pravastatin in the secondary prevention of coronary heart disease (CHD), to Belgium using local health care costs. A Markov process was used to model the effectiveness of treatment for 3 years with pravastatin versus placebo in 1000 male CHD patients aged 60 years and clinically similar to those in the pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I) and pravastatin, lipids and atherosclerosis in the carotid arteries (PLAC II) studies. The PLAC I and II trials have shown that pravastatin treatment for 3 years at a weighted mean dose of 36.64 mg daily significantly reduced the incidence of non-fatal myocardial infarction in patients with CHD. Framingham data were used to project the risk of mortality 10 years post-myocardial infarction. The incremental cost per life year gained (LYG), after discounting costs and benefits by 5% annually, in the setting of Belgian health care regulations, was Belgian francs (BEF) 720794 (US$ 24359) for CHD patients with one additional risk factor; BEF 526464 (US$ 17792) for those with two additional risk factors; and BEF 392765 (US$ 13274) for those with three or more additional risk factors. The cost per LYG in Belgium appeared to be more sensitive to drug acquisition cost than to costs of medical interventions. The cost-effectiveness ratios of pravastatin monotherapy for 3 years in secondary prevention of CHD, obtained with the same projected risk model, are from 86 to 92% higher in Belgium than in the United States, due to differences in medical patterns of practice and in intervention costs.

The Long-term Intervention with Pravastatin in Ischemic Heart Disease (LIPID) trial is a double-blind, randomized, placebo-controlled trial evaluating the long-term effect of pravastatin on coronary mortality in patients with a previous myocardial infarction or unstable angina-ischemic heart disease (IHD). It is planned to run for at least five years with 9014 patients from 85 centers in Australia and New Zealand. The trial will monitor cause-specific mortality and major clinical events associated with each treatment. Running in parallel with the main study is a prospective economic analysis, the objectives of which are (1) to estimate the effectiveness of pravastatin compared with placebo in terms of survival, quality of life (QOL), and quality-adjusted life-years (QALY); (2) to estimate the resource usage associated with pravastatin compared with placebo-in particular, to study whether it alters resource usage through prevention of disease progression; and (3) to use this information for a cost-utility analysis with cost per quality-adjusted life-year as the unit of analysis. A novel aspect of the design is the use of a preliminary cost-effectiveness analysis, based on "best-guess" values, and a sensitivity analysis over plausible ranges to guide the choice of subsample size. Some data, such a mortality, days spent in hospital, major clinical events, and drug use, are being collected within the main LIPID trial. However, additional subsamples for the cost-effectiveness study will include information on quality of life, time off work, and resources used, such as time in hospital, procedures, and medications taken. The methods and sample sizes for these substudies have been a crucial issue in validity and feasibility.