US cost-effectiveness of simvastatin in 20,536 people at different levels of vascular disease risk: randomised placebo-controlled trial UK Medical Research Council ($14M); British Heart Foundation ($2M); Merck ($8M); Roche Vitamins ($8M) Designed, conducted & analysed independently of all sources of support The funding for the study is shown. The study was designed, conducted and analysed independently of all sources of support.

HPS: Eligibility criteria Increased risk of CHD death due to prior disease Myocardial infarction or other CHD Occlusive disease of non-coronary arteries Diabetes mellitus or treated hypertension UK adults aged 40-80 years Total cholesterol  135mg/dl ( 3.5 mmol/l) Statin or vitamins not considered clearly indicated or contraindicated by patient’s own doctors This slide shows the sorts of people that took part in the Heart Protection Study. About 20 000 UK adults at an increased risk of CHD due to prior disease and with total cholesterol levels above 135mg/dl were randomized to 40mg simvastatin daily or placebo and were followed for an average of 5 years.

Two questions addressed for people at different vascular disease risk What is the US cost-effectiveness of allocation to simvastatin 40mg daily over the 5-year timescale of the trial? What is the US cost-effectiveness of simvastatin 40mg daily continued for life? In this presentation we address two questions for people at different vascular disease risk. The first question is “What is the US cost effectiveness of allocation to simvastatin 40mg daily during the 5-year trial?”. These intention-to-treat analyses are based on within trial data on events and resource use, and use US unit costs for these resources. The second question is “What is the US cost-effectiveness of simvastatin 40mg daily continued for life” uses trial data and extrapolates beyond the 5-year trial duration.

Vascular disease risk subgroups in HPS Risk Group Number of patients 5-yr risk MVE 5-yr risk MCE 5-yr risk vascular death 1 2 3 4 5 4107 4108 12% 18% 23% 28% 42% 4% 7% 10% 13% 22% 3% 5% A standard Cox proportional hazards model with age, sex, treatment allocation, prior disease, lipids, blood pressure, smoking and other risk factors at baseline as explanatory variables was used to estimate the 5 year risk of major vascular events, defined as non-fatal MI or coronary death, non-fatal or fatal stroke, or arterial revascularisation, for every trial participant. We then stratified the trial participants into five equal-sized risk groups. The average 5-year risk of MVE for each group is shown in the table, together with the 5-year risk of two endpoints: major coronary event, defined as nonfatal MI or coronary death, and vascular death. This approach yields almost four-fold difference in the risk of MVE between the low and high risk groups, ranging from about 12% 5-year MVE risk in the lowest risk group to about 42% 5-year MVE risk in the highest risk group. Cox model on baseline characteristics used to create five similar sizes multivariate risk groups

Economic analyses using US costs Study simvastatin (40mg at $3.83 daily) & any non-study statin (2003 Wholesale Acquisition Costs) Hospitalisations for vascular events mapped into CMS DRGs; 2003 average Medicare payments Costs and outcomes discounted at 3% per annum This economic analysis is based on US costs for two main resources: Firstly, the 2003 Wholesale Acquisition Costs were used to evaluate the costs for different statins that HPS participants took (for example the cost of simvastatin 40mg is $3 and 83 cents daily), and Secondly, the within trial hospitalisations related to vascular events were mapped into CMS DRGs and their costs were evaluated based on the 2003 average Medicare payments. In the cost-effectiveness results both future costs and future outcomes were discounted at US recommended rate of 3% per annum.

Within trial cost-effectiveness in vascular disease risk subgroups Analyses in different subgroups indicate: Similar relative reductions in major vascular events (MVEs) of ~ 25% Similar relative reductions in costs of vascular event hospitalisations of ~19% Similar additional statin treatment costs of ~ $5,500 Hence, US cost effectiveness of statin per MVE and per vascular death avoided was estimated for subgroups by applying overall treatment effects to placebo event rates and costs observed in each subgroup Previous HPS analyses have shown about 25% similar relative reductions in vascular events in both univariate and multivariate risk subgroups, including the 5 risk subgroups presented in a previous slide. Further analyses showed similar relative reductions of about 19% in the estimated US cost of vascular events across these risk subgroups. BY contrast, we found similar absolute differences in statin cost of about $5,500 per participant between simvastatin and placebo allocated groups in each of the risk subgroups. Therefore, we estimated cost-effectiveness by applying the overall effects estimated from the whole study to the placebo event rates and costs observed in each risk subgroup. For within trial cost-effectiveness analyses, we report: Cost per major vascular event avoided, and Cost per vascular death avoided.

Within trial cost per MVE avoided by risk group This figure shows the cost per MVE avoided overall and for each of the 5 risk groups along with the associated 95% confidence interval. Note the large differences between risk-group cost-effectiveness ratios compared to the overall estimate, with about a 4-fold difference in cost-effectiveness ratio between the lowest ($130 000) and highest ($30 000) risk groups.

Within trial cost per VASCULAR DEATH avoided by risk group A similar pattern is seen for the cost per vascular death avoided (note that the scale is different from the previous graph), here there is about a ten-fold difference between the lowest ($1.2 million) and highest ($140 000) risk groups.

Methods for lifetime extrapolation model Predicts future non-fatal vascular events, vascular deaths and vascular hospitalisation costs from HPS within trial data Uses US life-table to predict non-vascular deaths Adjusts survival for US age and sex specific quality of life Estimated outcomes: Life year gained (LY) Cost per quality adjusted life year gained (QALY) In order to address the question of cost per life year (LY) or quality adjusted LY (QALY) gained we have developed a model to extrapolate beyond the 5-year of HPS and to predict the cost-effectiveness of lifetime treatment with 40mg simvastatin daily. The model is based on the prediction of future non-fatal vascular events, vascular deaths and vascular hospitalisation costs based on the HPS within trial data. The model uses US life-table data to predict non-vascular deaths and adjusts survival for US age and sex specific quality of life. We present the estimated Life years gained and Cost per Quality adjusted Life year gained (QALY).

Within trial validation of the model for major vascular events Firstly, we have validated our model against the 5-year trial data. The annual rates of vascular events predicted using the model were comparable with those observed during the study. The figure on this slide shows the agreement between predicted and observed differences in the annual rates (per 1000 participants) of first and subsequent nonfatal MVEs or vascular deaths during the scheduled 5-year treatment period of the study. Using an 18-month average LDL cholesterol difference in the model provided a good fit to the observed event rate difference.

Age at initiation of statin Lifetime statin treatment: Life years gained as estimated from the model Age at initiation of statin 40-49 50-59 60-69 ≥70 12% 1.7 1.4 1.1 0.7 18% 2.0 1.6 0.8 22% 2.2 1.2 0.9 28% 2.4 1.9 1.3 1.0 42% 5-year major vascular event risk Using this model, we estimate that life years gained with lifetime simvastatin 40 mg daily ranged between 0.7 years for people aged over 70 at low vascular risk and 2.4 years for those aged 40-49 years at high vascular risk.

Lifetime treatment: Cost per Quality Adjusted Life Year gained The cost per quality adjusted life year gained estimated from the model ranged from about $42 000 in those at 12% 5-year MVE risk to about $15 000 in those at 42% 5-year MVE risk. Within each risk subgroups we have looked at the age of initiation of statin which showed little effect on the results.

Lifetime treatment: Cost per QALY beyond the HPS population Finally, we further extrapolated our analyses to include slightly younger and slightly older individuals than took part in HPS, and to lower 5-year MVE risk (down to about 5%). The figure shows that the cost per quality adjusted life-year gained is relatively stable across this wider age range, but increases substantially as the 5-year MVE risk decreases. The estimated cost per QALY was above $70 000 for those at 5% 5-year MVE risk.

CONCLUSIONS: US cost-effectiveness of simvastatin 40mg daily At current US prices, statin cost-effectiveness is chiefly determined by an individual’s overall risk of vascular events (rather than age or single risk factors, such as LDL) In the US, statin treatment is cost-effective (i.e. less than $50,000 per QALY) for a wide range of individuals at major vascular event risk as low as 2-3% per annum At lower prices of generic statins cost-effectiveness of statins would improve In conclusion: At current US statin prices, the statin cost-effectiveness is chiefly determined by an individual’s overall risk of vascular events (rather than age or single risk factors, such as LDL) Our analyses suggest that in the US statin treatment is cost-effective (i.e. costs less than $50,000 per QALY) for a wide range of individuals at major vascular event risks as low as about 2-3% per annum. Finally, at lower prices of generic statins cost-effectiveness of statins would improve..

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