Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation

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Chapter 1 Introduction

A therosclerotic cardiovascular disease (CVD) is a disorder of the heart and blood vessels, which can lead to cardiovascular events such as heart attack [myocardial infarction (MI)] and stroke. The most common form of CVD is coronary heart disease (CHD), also known as coronary artery disease (CAD) and ischaemic heart disease. CHD is caused by the narrowing of the arteries that supply the heart as a result of the build-up of fatty material called atheroma. The narrowing can cause MI, angina (pain or discomfort in the chest or neighbouring parts of the body because of insufficient oxygen reaching the heart) and other forms of chronic heart disease. Angina is usually classified as stable or unstable disease. Other forms of CVD are stroke, transient ischaemic attack (TIA), vascular dementia and peripheral vascular disease (PVD). CVD is the most common cause of death in the UK, accounting for over 208,000 deaths in 2005. 1 Approximately 49% of these deaths were from CHD and 28% from stroke. CVD is also a significant cause of morbidity and can have a major effect on quality of life. 2

Cholesterol is a key component in the development of atherosclerosis (the accumulation of atheroma on the inner lining of the arteries). Mainly as a result of this, serum cholesterol increases the risk of CVD. 3,4 The lowering of cholesterol, whether by diet, drugs or other means, decreases CVD risk. 5 Statin therapy, associated principally with lowering concentrations of total cholesterol and low-density lipoprotein cholesterol (LDL-c), with smaller effects on raising high-density lipoprotein cholesterol (HDL-c) and decreasing triglyceride levels, can reduce the risk of cardiovascular events, morbidity and mortality. 6

Although blood cholesterol is an important risk factor for CVD, cholesterol lowering with drug therapy is only one of a number of methods of reducing the risk. 7 Dietary and lifestyle modifications (e.g. weight loss, smoking cessation, aerobic exercise) are an integral part of risk management. If these are unsuccessful and the patient is at high risk, more effective therapy, including lipid-regulating drug therapy, is initiated. 8 The decision to initiate therapy with a lipid-regulating drug is generally based on an assessment of overall CVD risk.

Long-term statin therapy reduces CVD events, and the early period following an acute coronary syndrome (ACS; i.e. MI or unstable angina) or coronary revascularisation [coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA)] represents a stage when the individual is at highest risk of recurrent cardiovascular events and mortality. 9 Meta-analyses of randomised controlled trials (RCTs) have shown that early, intensive (high) dose statin therapy is of benefit in reducing death and cardiovascular events when prescribed immediately after an ACS compared with standard (moderate) statin therapy. 10,11 Most, if not all, initial prescribing for ACS in the UK is undertaken at the hospital and the decision to continue specialist prescribing outside the hospital is governed by the NHS primary care trusts (PCTs). Of the 152 NHS PCTs in England, recommendations for the management (including prescribing practices) of patients with ACS vary widely. Initiation of the standard dose would be on the first day of the event and duration is, in theory, for life.

Although there are numerous publications describing economic evaluations comparing the cost-effectiveness of individual statins versus placebo, the literature describing the cost-effectiveness of more potent dose statins compared with moderate doses is more limited. Lindgren et al. 12 performed an evaluation based on the IDEAL study, comparing atorvastatin (40/80 mg/day) with simvastatin (20/40 mg/day) in individuals with stable CAD. The authors reported that atorvastatin is moderately cost-effective and when using a threshold of €50,000 (£40,000) per quality-adjusted life-year (QALY) would be considered cost-effective in Denmark, Norway and Sweden (but not in Finland). Chan13 compared the effectiveness of a higher-dose statin (assumed to be equivalent to atorvastatin 80 mg/day) with that of a conventional dose (assumed to be equivalent to simvastatin 20 mg/day) using a meta-analysis of effectiveness data from the Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE-IT]14 and the Aggrestat to Zocor [A to Z]15 RCTs. Chan reported a cost per QALY of US$12,900 (£6500) for a cohort with ACS in the USA. More recently, analysts in the UK16 reported results in the region of £4400 per QALY for a cohort with ACS using the same effectiveness data as Chan et al. 13

To our knowledge there are currently no published economic evaluations exploring the cost-effectiveness of atorvastatin 80 mg/day, rosuvastatin 40 mg/day or simvastatin 80 mg/day with that of simvastatin 40 mg/day in individuals with ACS.

Chapter 2 Aims and objectives

The aim of this research was to evaluate the cost-effectiveness of high-dose statins (atorvastatin 80 mg/day, rosuvastatin 40 mg/day and simvastatin 80 mg/day) versus simvastatin 40 mg/day in individuals with ACS. More specifically, the research aimed to:

1. evaluate the clinical effectiveness of higher-dose statins compared with simvastatin 40 mg/day in terms of mortality and cardiovascular morbidity

2. evaluate the adverse effect profile and toxicity associated with higher-dose statins compared with simvastatin 40 mg/day (the dose frequently prescribed for patients with ACS)

3. estimate the incremental cost-effectiveness of higher-dose statins in comparison with simvastatin 40 mg/day.

Chapter 3 Clinical evaluation

Chapter 4 Economic evaluation

Markov model

An existing CVD model initially constructed to explore the cost-effectiveness of statin therapy versus no treatment59 (Appendix 5), and subsequently modified to quantify treatment effects based on chemically induced changes in LDL-c,100 was adapted to explore the cost-effectiveness of high-dose versus standard-dose statin therapy. The evaluation follows the NICE guidelines for economic evaluations,101 thus a lifetime horizon was used with both costs and benefits discounted at 3.5%. The analysis was undertaken from the perspective of the UK NHS, hence only direct health-care costs were included.

Methods

The health states in the Markov model are shown in Figure 1. With all individuals starting in one of the three qualifying event health states, unstable angina, non-fatal MI or revascularisation, an annual cycle was used to model transitions to subsequent events. Where evidence was available, age-related transition probabilities were used to model the probabilities associated with the first year or subsequent year events. Individuals who did not experience an event in the current year moved to the corresponding ‘post’ health state, and subsequent year event rates were applied.

FIGURE 1.

Health states included in the Markov model. All health states have a ‘post health state’. ACS, acute coronary syndrome; CVD, cardiovascular disease; MI, myocardial infarction; QE, qualifying event; revascularisation, coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA).

Markov models are useful for conditions which involve events that can occur more than once, probabilities that change according to the time since a previous event, and risks that continue or increase over time. 102 The Markov process does not hold a memory of clinical history, and only the costs and health consequences associated with the current health state are applied. To ensure that individuals do not move to a health state with smaller costs and a greater quality of life, transition restrictions may be applied. However, this does not always reflect natural clinical history, particularly in CVD in which it is possible for an individual to experience a severe event followed by a less severe event (e.g. a stroke followed by an MI or rehospitalisation for unstable angina).

To enable the model to capture the costs and benefits associated with major events in the clinical pathway for individuals with ACS, a number of combined health states were included in which transitions to future events were assumed to be the maximum value associated with the history of events. For example, if an individual with a history of stroke experienced an MI, they moved to a combined health state ‘MI given history of stroke’. Transitions from the health state ‘MI given history of stroke’ would then be the maximum value of the transition from either the post stroke or the current year non-fatal MI health state. The costs and utilities were also adjusted to ensure that an individual experiencing a subsequent event did not have a lower ongoing cost or higher resultant utility than that associated with previous events.

Transitions between health states

The model was constructed with five alternative treatment arms: placebo, atorvastatin 80 mg/day, rosuvastatin 40 mg/day, simvastatin 40 mg/day and simvastatin 80 mg/day. Transitions for the placebo arm were obtained from individuals not receiving statin treatment. The RRs from the Bayesian mixed treatment meta-analysis (Table 8) were then applied to the baseline transitions to estimate the events in each arm of the model. The RRs for the different statins and events were sampled simultaneously from WinBUGS to preserve the properties of the joint posterior distribution.

TABLE 8 - Age-related transitions between health states

CHD, coronary heart disease; MI, myocardial infarction.

From	To	Age (years)				Source
		55	65	75	85
Unstable angina	Unstable angina hospitalisation	5.8%	5.8%	5.8%	5.8%	Fox et al., 2005103
	MI	5.0%	4.9%	4.7%	4.3%	Gray and Hapton, 2008106
	Stroke	0.2%	0.5%	1.0%	2.0%	Assumed same as MI to stroke
	Fatal CHD	3.9%	6.5%	10.5%	15.6%	Gray and Hapton, 2008106
	Fatal stroke	2.6%	4.3%	7.0%	10.3%	Gray and Hapton, 2008106
Post unstable angina	Unstable angina hospitalisation	2.0%	2.0%	2.0%	2.0%	Henderson et al., 2008104
	MI	3.5%	6.3%	11.2%	18.5%	Gray and Hapton, 2008106
	Stroke	0.1%	0.1%	0.3%	0.7%	Assumed same as post MI to stroke
	Fatal CHD	0.6%	0.7%	0.9%	1.0%	Gray and Hapton, 2008106
	Fatal stroke	0.4%	0.5%	0.6%	0.7%	Gray and Hapton, 2008106
Revascularisation	Unstable angina hospitalisation	3.2%	3.2%	3.2%	3.2%	Henderson et al., 2008104
	MI	3.8%	3.8%	3.8%	3.8%	Fox et al., 2005103
	Stroke	0.1%	0.1%	0.1%	0.1%	Henderson et al., 2008104
	Fatal CHD	3.1%	3.1%	3.1%	3.1%	Fox et al., 2005103
	Fatal stroke	0.1%	0.1%	0.1%	0.1%	Assumed same as non-fatal stroke
Post revascularisation	Unstable angina hospitalisation	2.1%	2.1%	2.1%	2.1%	Henderson et al., 2008104
	MI	1.0%	1.0%	1.0%	1.0%	Fox et al., 2005103
	Stroke	0.1%	0.1%	0.1%	0.1%	Assumed same as first year
	Fatal CHD	3.1%	3.1%	3.1%	3.1%	Fox et al., 2005103
	Fatal stroke	0.1%	0.1%	0.1%	0.1%	Assumed same as non-fatal stroke
MI	Unstable angina hospitalisation	5.8%	5.8%	5.8%	5.8%	Assumed same as unstable angina to unstable angina hospitalisation
	MI	11.5%	10.2%	8.7%	7.3%	Gray and Hapton, 2008106
	Stroke	0.3%	0.7%	1.4%	2.6%	Gray and Hapton, 2008106
	Fatal CHD	2.0%	3.8%	6.8%	11.2%	Gray and Hapton, 2008106
	Fatal stroke	1.3%	2.5%	4.5%	7.4%	Gray and Hapton, 2008106
Post MI	Unstable angina hospitalisation	2.0%	2.0%	2.0%	2.0%	Assumed same as post unstable angina to unstable angina hospitalisation
	MI	1.8%	2.0%	2.0%	1.9%	Gray and Hapton, 2008106
	Stroke	0.1%	0.2%	0.5%	0.9%	Gray and Hapton, 2008106
	Fatal CHD	0.6%	1.0%	1.5%	2.1%	Gray and Hapton, 2008106
	Fatal stroke	0.4%	0.6%	1.0%	1.4%	Gray and Hapton, 2008106
Stroke	Unstable angina hospitalisation	2.9%	2.9%	2.9%	2.9%	Assumed 50% of MI to unstable angina hospitalisation
	MI	5.8%	5.1%	4.4%	3.6%	Assumed 50% of MI to MI
	Stroke	4.6%	4.8%	4.8%	4.5%	Wolfe et al., 2002107
	Fatal CHD	1.1%	2.6%	5.9%	11.4%	Wolfe et al., 2002107
	Fatal stroke	1.1%	2.6%	5.9%	11.4%	Wolfe et al., 2002107
Post stroke	Unstable angina hospitalisation	1.0%	1.0%	1.0%	1.0%	Assumed 50% of post MI to unstable angina hospitalisation
	MI	0.9%	1.0%	1.0%	0.9%	Assumed 50% of post MI to MI
	Stroke	1.9%	2.2%	2.5%	2.5%	Wolfe et al., 2002107
	Fatal CHD	0.5%	1.0%	2.1%	3.5%	Wolfe et al., 2002107
	Fatal stroke	0.5%	1.0%	2.1%	3.5%	Wolfe et al., 2002107

UK-specific data were used where possible to ensure that event rates in the placebo arm matched the likely distribution in the UK. For individuals with a history of unstable angina or who had experienced an MI, the probabilities of further MIs, strokes and vascular deaths were derived from patients on the Nottingham Heart Attack Register (NHAR) and the Randomised Intervention Treatment for Angina (RITA-2) study. 59 The probabilities of subsequent strokes and vascular deaths for patients with a history of a stroke were derived from patients on the South London Stroke Register (SLSR). 59 Transitions from the qualifying revascularisation health state were taken from two large UK-based studies comparing coronary angioplasty with medical therapy, RITA-2 (n = 1018) and RITA-3 (n = 1810),103,104 as in a recent UK evaluation. 105 The individual transition rates by age are provided in Table 8.

Costs

Health state costs

The first year costs (£3880) for the unstable angina health state include secondary care costs (100% hospitalisation, 50% revascularisation procedure, three outpatient appointments), primary care costs (three GP visits) and medications (see Appendix 6). 18 First year costs (£3996) for the MI health state include secondary care costs (100% hospitalisation, 50% revascularisation procedure, three outpatient appointments), primary care costs (three GP visits) and medications. First year costs (£5857) for the revascularisation health state include secondary care costs (100% hospitalisation, three outpatient appointments), primary care costs (three GP visits) and medications. Subsequent year costs (£340) for all ACS patients include secondary care costs (one outpatient appointment), primary care costs (three GP visits) and medications. First year costs for non-fatal stroke (£8066) were obtained from the costs of acute events reported in Youman et al. 108 weighted by the distribution of severity of stroke. 59 The cost of non-fatal stroke for subsequent years (£2266) was based on the costs of ongoing care at home or in an institution weighted by the distribution of severity of stroke and discharge locations. The cost of fatal CHD events (£592) and the cost of non-cardiac fatal vascular events were obtained from Youman et al. 108 and Palmer et al. 109 respectively. It was assumed that only 50% of fatal cardiovascular events incur a cost.

A breakdown of the costs is provided in Appendix 6, and the mean health state values are provided in Table 9. Gamma distributions were used to explore uncertainty in the health state costs and costs were discounted at 3.5%. 101

TABLE 9 - Health state costs (price year 2007)

ACS, acute coronary syndrome; CHD, coronary heart disease; MI, myocardial infarction.

Health state	Base case, mean	Univariate sensitivity analyses		Source
		Minus 50%	Plus 50%
Unstable angina year 1	£3880	£1940	£5820	BNF, 200818
ACS year 2+	£340	£170	£510	BNF, 200818
MI year 1	£3996	£1998	£5994	BNF, 200818
Revascularisation year 1	£5857	£2928	£8785	BNF, 200818
Stroke year 1	£8066	£296	£887	Ward et al., 200759
Stroke year 2+	£2266	£1844	£5532	Ward et al., 200759
Fatal CHD event	£592	£4033	£12,099	Ward et al., 200759
Fatal non-coronary vascular event	£3688	£1133	£3399	Ward et al., 200759
Monitoring cost for high-dose statin	£76

Monitoring costs

The safety profile for statin therapy is good with adverse events predominantly consisting of myopathy or myalgia. However, evidence suggests that there is a relationship between statin potency and the frequency of adverse events, which could increase non-adherence to medication. It was assumed that individuals on high potency statins would incur additional monitoring costs in the form of two additional GP visits per year with full blood counts conducted by the practice nurse (£76.00). The cost of monitoring was reduced in proportion to adherence (see Scenarios).

Treatment costs

The costs of statin treatment were taken from the British National Formulary18 and are provided in Table 10. When generic alternatives for simvastatin became available there was a substantial decrease in the cost associated with this treatment. The cost for a pack of simvastatin 40 mg/day fell from £23.18 in 2004 to £1.31 in 2008. 59 When the patent for atorvastatin expires in 2011 the cost of this treatment is likely to fall considerably. We explored the effect on the results if it was assumed that the annual cost for atorvastatin 80 mg/day decreased to £90 per annum or if it decreased in line with that observed for simvastatin (i.e. to £20.78 per annum).

TABLE 10 - Annual treatment costs

Statin	Cost per pack of 2818	Annual cost
Atorvastatin 80 mg/day	£28.21	£367.74
Rosuvastatin 40 mg/day	£29.69	£387.03
Simvastatin 40 mg/day	£1.31	£17.08
Simvastatin 80 mg/day (assumed two times simvastatin 40 mg/day)		£34.15

Health state utility values

The health state utility values (Table 11) were taken from a cardiovascular model used in a recent Health Technology Assessment (HTA) report. 100 These data were obtained from a literature review of published evidence on preference-based utility measures for the different health states modelled. The studies identified were evaluated based on the following criteria:

• data collected using the EuroQol 5 dimensions (EQ-5D) instrument as recommended for the NICE reference case

• preference-based utility scores obtained from the UK EQ-5D preference weights

• UK studies preferred to non-UK studies.

TABLE 11 - Health state utility utilities

MI, myocardial infarction.

Assumed utility increases by 10% in subsequent years.

Health state	First year	Subsequent yearsa	Source
Unstable angina	0.77	0.847	Goodacre et al., 2008110
Revascularisation	0.78	0.858	Serruys et al., 2001111
MI	0.76	0.836	Goodacre et al., 2008110
Stroke	0.629	0.692	Pickard et al., 2005112

Unstable angina

The results from an RCT comparing care in a chest pain clinic observation unit (n = 676) with routine care in the emergency department of the Northern General Hospital in Sheffield suggested that the mean utility score measured using the EQ-5D at 6 months post diagnosis of unstable angina was 0.77. 59,110 It was assumed that 0.77 represents the HRQoL associated with the unstable angina health state. This was increased by 10% to 0.847 for the post event health state.

Revascularisation

The EQ-5D questionnaire was used to estimate utility values in 1205 patients randomly assigned to undergo either stent implantation or bypass surgery in the Arterial Revascularization Therapies Study (ARTS). 111 The mean utility value at baseline (3 months, 6 months and 12 months) was reported to be 0.68 (0.78, 0.86 and 0.87). 111 It has been assumed that 0.78 represents the HRQoL associated with the revascularisation health state. This was increased by 10% to 0.858 for the post event health state.

Myocardial infarction

The study by Goodacre et al. also collected EQ-5D data on individuals who had an MI (mean value was 0.76). 59,110 It was assumed that 0.76 represents the HRQoL associated with the MI health state. This was increased by 10% to 0.836 for the post event health state.

Stroke

A study (n = 98) by Pickard et al. 112 reported an increase in mean EQ-5D score from 0.31 (SD 0.38) at baseline to 0.629 (SD 0.33) at 6 months post stroke. These figures suggest that there is an initial large reduction in HRQoL and that the long-term HRQoL, although substantially lower than before the stroke, increases in the majority of individuals. It was assumed that 0.629 represents the HRQoL associated with the stroke health state. This was increased by 10% to 0.692 for the post event health state.

Subsequent major events

No evidence was found that could be used to model the effect on HRQoL for patients who have more than one cardiovascular event. An additional decrement of 10% was applied for subsequent major events such as MI or stroke. Uncertainty in the quality of life values was explored using beta distributions.

Health-related quality of life utility by age

A study by Kind et al. 113 using EQ-5D data collected from a sample (n = 3395) of the UK general population was used to inform changes in quality of life by age (Table 12). These data were used as the baseline HRQoL. It is acknowledged that by including a baseline utility adjusted for age there will be a small element of double counting as a proportion of individuals in the sample used in the Kind et al. study will have a history of ACS.

TABLE 12 - Utility values by age113

Utility = 1.060 – 0.004 × age.

Age (years)	Utility
50	0.848
55	0.826
60	0.805
65	0.784
70	0.763
75	0.741

Scenarios

Based on the limited evidence available we used three different scenarios to examine the effects of possible reductions in adherence rates in clinical practice. The RRs and treatment and monitoring costs were adjusted to account for the proportion of individuals who adhere to therapy.

Scenario 1

Adherence rates in statin clinical trials are reported to range between 80% and 90%. The effectiveness rates used in the current study are based on ITT analyses of changes in LDL-c values. It was assumed that adherence rates and discontinuation rates due to adverse events in clinical practice would be as observed in the clinical studies and no adjustments were made to the benefits or treatment or monitoring costs. The results generated for these analyses are applicable for individuals who tolerate the higher doses and adhere to treatment.

Scenario 2

It was assumed that adherence to statin therapy would be higher in individuals receiving simvastatin 40 mg/day than in those receiving the more potent doses (atorvastatin 80 mg/day, rosuvastatin 40 mg/day and simvastatin 80 mg/day). As in scenario 1 it was assumed that the ITT data for simvastatin 40 mg/day would reflect the benefits that would be achieved in clinical practice and that there would be an equal reduction in adherence rates for the three more potent statin doses. It was assumed that the proportion of individuals adhering to treatment decreased rapidly over the first 2 years (a reduction of 5% in each year), reducing more gradually over the next 3 years (a linear reduction of 5% over 3 years) until rates stabilised during the fifth year (Table 13). The benefits and treatment and monitoring costs were adjusted to reflect the proportions adhering to treatment.

TABLE 13 - Adherence rates used in scenarios 1, 2 and 3

Treatment	1 year	2 years	3 years	4 years	5 years
Scenario 1
Atorvastatin 80 mg/day	As per clinical trials
Rosuvastatin 40 mg/day	As per clinical trials
Simvastatin 40 mg/day	As per clinical trials
Simvastatin 80 mg/day	As per clinical trials
Scenario 2
Atorvastatin 80 mg/day	95%	90%	88%	87%	85%
Rosuvastatin 40 mg/day	95%	90%	88%	87%	85%
Simvastatin 40 mg/day	As per clinical trials
Simvastatin 80 mg/day	95%	90%	88%	87%	85%
Scenario 3
Atorvastatin 80 mg/day	75%	70%	68%	67%	65%
Rosuvastatin 40 mg/day	73%	68%	66%	64%	63%
Simvastatin 40 mg/day	80%	75%	73%	72%	70%
Simvastatin 80 mg/day	70%	65%	63%	62%	60%

Scenario 3

Based on the limited evidence base it was assumed that adherence rates are related to both brand of statin and dose. It was assumed that adherence rates were highest for the lower potency regimen of simvastatin 40 mg/day. Simvastatin 80 mg/day is not well tolerated in clinical practice and evidence suggests an 11-fold increase in rates of myopathy and myositis in patients receiving this dose compared with simvastatin 20 mg/day. 79 It was assumed that adherence rates would be lowest for this regimen. It has been hypothesised that rosuvastatin may be associated with low incidences rates of myopathy and myalgia, and recently published results show no significant difference in rates at any dose ratio when compared with atorvastatin (maximum doses being rosuvastatin 40 mg/day and atorvastatin 80 mg/day). 114,115 However, with no long-term data to support this it was assumed that adherence rates would be slightly lower for rosuvastatin 40 mg/day than for atorvastatin 80 mg/day. As in scenario 2, the proportion of individuals adhering to treatment decreased rapidly over the first 2 years, reducing more gradually over the next 3 years (a linear reduction of 5% over 3 years) until rates stabilised during the fifth year (Table 13). The benefits and treatment and monitoring costs were adjusted to reflect the proportions adhering to treatment.

Scenario 4

The adherence scenarios explored give an indication of the effects on the results if adherence is lower in clinical practice than observed in the RCTs, with the results generated for scenario 1 being a conservative estimate of the cost-effectiveness for individuals who adhere to treatment. To explore the effects of non-adherence, the RRs and treatment and monitoring costs were adjusted in proportion to the adherence rates modelled. This implies that individuals not adhering to treatment will not receive an alternative statin. However, it is likely that patients who do not tolerate the higher doses will be prescribed a lower-dose statin. Using the adherence rates for scenario 2 (Table 13), scenario 4 explores the cost-effectiveness of the treatments if it is assumed that individuals who do not adhere to the higher doses (atorvastatin 80 mg/day, rosuvastatin 40 mg/day and simvastatin 80 mg/day) switch to simvastatin 40 mg/day. The RRs and treatment costs were adjusted to reflect the proportions on each statin dose.

Sensitivity analyses

Sensitivity analyses were performed because there is always uncertainty in decision analysis. We used two methods to characterise this uncertainty: one-way sensitivity analyses and Monte Carlo simulations. One-way sensitivity analysis is a procedure in which the central estimates for key parameters in the model are varied one at a time. New results are generated from the model using the adjusted values and recorded. This process is repeated for key parameters in the model. One-way sensitivity analysis informs readers as to which variables drive the results generated by the model, but does not provide information on the overall uncertainty associated with the model. Monte Carlo simulations are used to create a probabilistic sensitivity analysis, which is a method of varying all variables simultaneously to assess the overall uncertainty in the model. 109 The individual simulations (5000) are generated using random numbers (0–1) to sample from the distributions. New results are generated by the model and each of the 5000 results stored. The recorded results are then used to illustrate the overall variability in the model. The 95% confidence intervals around the mean cost per QALY were estimated using jackknife techniques whereby the variance is estimated by sampling the residuals in the 5000 samples. 116

Incremental cost-effectiveness ratio

The results are presented in terms of the incremental cost-effectiveness of each higher-dose statin compared with simvastatin 40 mg/day. The primary outcome is the incremental cost-effectiveness ratio (ICER). The ICER demonstrates the additional cost per QALY gained from treatment A compared with treatment B where treatment A is one of the higher-dose statins and treatment B is simvastatin 40 mg/day:

ICER = (cost treatment A − cost treatment B)/(utility treatment A − utility treatment B)

Optimal treatment

Although the primary objective is to evaluate the cost-effectiveness of the higher-dose statins compared with simvastatin 40 mg/day, cost per QALY values may be difficult to interpret as the smallest value is not always associated with the optimal treatment. A hierarchy of interventions can be calculated by ranking all interventions in order of ascending health gain and initially comparing the two least effective treatments. If the resulting incremental cost per QALY is below a given cost per QALY threshold, the more effective treatment is selected as optimal. Similar comparisons are then iteratively conducted between the current optimal treatment and the next most efficacious treatment until the list is exhausted and the optimal treatment is found.

Net benefit

Results are also presented in terms of the ‘net benefit’ of the treatments. Because of the potential difficulties in interpreting cost per QALY values when more than two treatments are being compared, the use of net benefit is becoming more widespread. Although these results are analogous to those presented in the more traditional cost per QALY format, there is less scope for mistakes when interpreting the data as net benefit values can be directly compared across interventions. Net benefit is calculated using the formula NB = λ × QALY – cost, where λ denotes the maximum cost that society is prepared to pay. When net benefit is positive the treatment is cost-effective; when net benefit is negative the treatment is not cost-effective; and when net benefit is zero the cost per QALY is equal to the maximum cost per QALY that society is prepared to pay. The intervention with the highest net benefit is the most cost-effective at a given threshold.

Economic results

The following section describes the cost-effectiveness results for cohorts of 1000 individuals commencing treatment at the age of 60 years with ICERs generated using the costs and benefits accrued over a lifetime.

First, the results from the probabilistic sensitivity analyses (generated using 5000 Monte Carlo simulations) for each of the four different scenarios are presented. Results are compared in terms of the average numbers of events in each treatment arm. The cost-effectiveness of each of the individual higher-dose treatments is compared with that of simvastatin 40 mg/day and the results are described using ICERs and cost-effectiveness planes. The probabilistic sensitivity results are then used to identify a hierarchy in terms of the optimal treatment at a given cost per QALY threshold by ranking according to the benefits of the treatments. This is followed by a section describing the results in terms of the net benefit of the individual treatments using cost-effectiveness acceptability curves.

The penultimate set of analyses examines the potential differences in the ICERs and the net benefits of the treatments if the cost of atorvastatin 80 mg/day is reduced. Finally, a series of univariate sensitivity analyses are conducted to explore the effect of varying key parameters.

Probabilistic base-case analyses

For scenario 1 (Table 14), when assuming that the ITT results are representative of the benefits observed in clinical practice, simvastatin 80 mg/day is estimated to avoid on average 16 fatal CHD events, five fatal non-cardiac-related vascular events, 24 hospitalisations for unstable angina, 37 non-fatal MIs and three non-fatal strokes in comparison with simvastatin 40 mg/day. Atorvastatin 80 mg/day is estimated to avoid on average 33 fatal CHD events, 10 fatal non-cardiac-related vascular events, 51 hospitalisations for unstable angina, 78 non-fatal MIs and seven non-fatal strokes in comparison with simvastatin 40 mg/day. Rosuvastatin 40 mg/day is estimated to avoid on average 45 fatal CHD events, 14 fatal non-cardiac-related vascular events, 70 hospitalisations for unstable angina, 108 non-fatal MIs and nine non-fatal strokes in comparison with simvastatin 40 mg/day. The deaths from other causes are higher for the more potent statins because of the reduction in cardiovascular fatal events.

TABLE 14 - The average number of events over a lifetime (for a cohort commencing high-dose statin therapy at the age of 60 years)

CHD, coronary heart disease; CVD, coronary vascular disease; MI, myocardial infarction; UA, unstable angina.

	Simvastatin 40 mg/day	Simvastatin 80 mg/day	Atorvastatin 80 mg/day	Rosuvastatin 40 mg/day
Scenario 1
Total number of fatal events in each arm (number of events avoided compared with simvastatin 40 mg/day)
CHD	248	232 (16)	215 (33)	203 (45)
CVD	132	127 (5)	121 (10)	117 (14)
Other deaths	619	639 (–20)	662 (–43)	678 (–59)
Total number of non-fatal events in each arm (number of events avoided compared with simvastatin 40 mg/day)
UA	228	204 (24)	177 (51)	159 (70)
MI	398	361 (37)	320 (78)	290 (108)
Stroke	55	51 (3)	48 (7)	45 (9)
Scenario 2
Total number of fatal events in each arm (number of events avoided compared with simvastatin 40 mg/day)
CHD	247	245 (2)	231 (17)	221 (27)
CVD	131	131 (1)	126 (5)	123 (8)
Other deaths	620	623 (–2)	642 (–22)	655 (–35)
Total number of non fatal events in each arm (number of events avoided compared with simvastatin 40 mg/day)
UA	229	226 (4)	202 (27)	186 (43)
MI	398	392 (5)	357 (40)	333 (64)
Stroke	55	55 (0.3)	52 (3)	50 (6)
Scenario 3
Total number of fatal events in each arm (number of events avoided compared with simvastatin 40 mg/day)
CHD	271	269 (1)	254 (17)	249 (21)
CVD	139	138 (0.4)	134 (5)	132 (7)
Other deaths	589	591 (–2)	611 (–22)	617 (–28)
Total number of non fatal events in each arm (number of events avoided compared with simvastatin 40 mg/day)
UA	265	263 (2)	238 (27)	231 (34)
MI	451	448 (3)	412 (39)	401 (50)
Stroke	60	60 (0.2)	56 (4)	56 (5)
Scenario 4
Total number of fatal events in each arm (number of events avoided compared with simvastatin 40 mg/day)
CHD	247	234 (13)	219 (28)	209 (39)
CVD	132	128 (4)	123 (9)	119 (12)
Other deaths	619	637 (–18)	656 (–37)	670 (–51)
Total number of non fatal events in each arm (number of events avoided compared with simvastatin 40 mg/day)
UA	230	209 (21)	185 (45)	169 (61)
MI	398	366 (32)	330 (67)	305 (93)
Stroke	55	52 (3)	49 (6)	47 (8)

For scenario 2 (Table 14), when assuming that the ITT results are representative of the benefits associated with simvastatin 40 mg/day, but that the benefits associated with the more potent doses are reduced by equal amounts to take into account a potential reduction in adherence, simvastatin 80 mg/day is estimated to avoid on average two fatal CHD events, one fatal non-cardiac-related vascular event, four hospitalisations for unstable angina, five non-fatal MIs and less than one non-fatal stroke in comparison with simvastatin 40 mg/day. Atorvastatin 80 mg/day is estimated to avoid on average 17 fatal CHD events, five fatal non-cardiac-related vascular events, 27 hospitalisations for unstable angina, 40 non-fatal MIs and three non-fatal strokes in comparison with simvastatin 40 mg/day. Rosuvastatin 40 mg/day is estimated to avoid on average 27 fatal CHD events, eight fatal non-cardiac-related vascular events, 43 hospitalisations for unstable angina, 64 non-fatal MIs and six non-fatal strokes in comparison with simvastatin 40 mg/day.

For scenario 3 (Table 14), when assuming that adherence to therapy is reduced for all four treatment regimens with simvastatin 40 mg/day having the highest adherence rate and simvastatin 80 mg/day the lowest, simvastatin 80 mg/day is estimated to avoid on average one fatal CHD event, less than one fatal non-cardiac-related vascular event, two hospitalisations for unstable angina, three non-fatal MIs and less than one non-fatal stroke in comparison with simvastatin 40 mg/day. Atorvastatin 80 mg/day is estimated to avoid on average 17 fatal CHD events, five fatal non-cardiac-related vascular events, 27 hospitalisations for unstable angina, 39 non-fatal MIs and four non-fatal strokes in comparison with simvastatin 40 mg/day. Rosuvastatin 40 mg/day is estimated to avoid on average 21 fatal CHD events, seven fatal non-cardiac-related vascular events, 34 hospitalisations for unstable angina, 50 non-fatal MIs and five non-fatal strokes in comparison with simvastatin 40 mg/day.

For scenario 4 (Table 14), using the adherence levels as in scenario 2 (i.e. assuming that the ITT results are representative of the benefits associated with simvastatin 40 mg/day, but that the benefits associated with the more potent doses are reduced by equal amounts to take into account a potential reduction in adherence) and assuming that all individuals who do not adhere to the higher-dose treatment receive simvastatin 40 mg/day, simvastatin 80 mg/day is estimated to avoid on average 13 fatal CHD events, four fatal non-cardiac-related vascular events, 21 hospitalisations for unstable angina, 32 non-fatal MIs and three non-fatal strokes in comparison with simvastatin 40 mg/day. Atorvastatin 80 mg/day is estimated to avoid on average 28 fatal CHD events, nine fatal non-cardiac-related vascular events, 45 hospitalisations for unstable angina, 67 non-fatal MIs and six non-fatal strokes in comparison with simvastatin 40 mg/day. Rosuvastatin 40 mg/day is estimated to avoid on average 39 fatal CHD events, 12 fatal non-cardiac-related vascular events, 61 hospitalisations for unstable angina, 93 non-fatal MIs and eight non-fatal strokes in comparison with simvastatin 40 mg/day.

For scenario 1, when comparing simvastatin 80 mg/day with simvastatin 40 mg/day, the avoided events provide an average 111 more QALYs (Table 15) over a lifetime of treatment. The total incremental costs are estimated to be £588,000, giving a cost per QALY of £5319. When comparing atorvastatin 80 mg/day with simvastatin 40 mg/day, the avoided events provide an average 232 more QALYs. The total incremental costs are estimated to be £4,050,000, giving a cost per QALY of £17,469. When comparing rosuvastatin 40 mg/day with simvastatin 40 mg/day, the avoided events provide an average 316 more QALYs. The total incremental costs are estimated to be £3,942,000, giving a cost per QALY of £12,484.

TABLE 15 - Probabilistic base-case results (for a cohort of 1000 men aged 60 years, generated using 5000 simulations)

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

The incremental values are high dose compared with simvastatin 40 mg/day.

	Simvastatin 40 mg/day	Simvastatin 80 mg/day	Atorvastatin 80 mg/day	Rosuvastatin 40 mg/day
Scenario 1
Discounted benefits
Life-years	11,686	11,851	12,033	12,158
QALYs	7546	7657	7778	7862
Incremental discounted QALYs		111	232	316
Discounted costs
Total	£14,522,049	£15,110,134	£18,572,208	£18,463,934
Incremental total discounted costs		£588,085	£4,050,159	£3,941,885
Incremental cost-effectiveness ratio
ICER		£5319	£17,469	£12,484
Confidence interval		£5229 to £5408	£17,330 to £17,604	£12,372 to £12,595
Scenario 2
Discounted benefits
Life-years	11,693	11,727	11,886	11,993
QALYs	7543	7566	7672	7744
Incremental discounted QALYs		23	129	201
Discounted costs
Total	£14,511,140	£15,338,411	£18,306,366	£18,206,201
Incremental total discounted costs		£827,271	£3,795,226	£3,695,061
Incremental cost-effectiveness ratio
ICER		£35,445	£29,422	£18,372
Confidence interval		£34,022 to £36,842	£29,136 to £29,706	£18,200 to £18,557
Scenario 3
Discounted benefits
Life-years	11,448	11,463	11,635	11,685
QALYs	7383	7393	7507	7540
Incremental discounted QALYs		10	125	158
Discounted costs
Total	£15,232,422	£15,829,566	£17,971,442	£17,851,218
Incremental total discounted costs		£597,144	£2,739,020	£2,618,796
Incremental cost-effectiveness ratio
ICER		£59,200	£21,938	£16,592
Confidence interval		£53,300 to £64,826	£21,699 to £22,186	£16,407 to £16,776
Scenario 4
Discounted benefits
Life-years	11,688	11,833	11,991	12,101
QALYs	7545	7642	7748	7821
Incremental discounted QALYs		97	203	276
Discounted costs
Total	£14,547,316	£15,053,288	£18,042,271	£17,940,003
Incremental total discounted costs		£505,972	£3,494,954	£3,392,687
Incremental cost-effectiveness ratio
ICER		£5226	£17,217	£12,277
Confidence interval		£5138 to £5315	£17,081 to £17,353	£12,167 to £12,387

For scenario 2, when comparing simvastatin 80 mg/day with simvastatin 40 mg/day, the avoided events provide an average 23 more QALYs (Table 15) over a lifetime of treatment. The total incremental costs are estimated to be £827,000, giving a cost per QALY of £35,445. When comparing atorvastatin 80 mg/day with simvastatin 40 mg/day, the avoided events provide an average 129 more QALYs. The total incremental costs are estimated to be £3,795,000, giving a cost per QALY of £29,422. When comparing rosuvastatin 40 mg/day with simvastatin 40 mg/day, the avoided events provide an average 201 more QALYs. The total incremental costs are estimated to be £3,695,000, giving a cost per QALY of £18,372.

For scenario 3, when comparing simvastatin 80 mg/day with simvastatin 40 mg/day, the avoided events provide an average 10 more QALYs (Table 15) over a lifetime of treatment. The total incremental costs are estimated to be £597,000, giving a cost per QALY of £59,200. When comparing atorvastatin 80 mg/day with simvastatin 40 mg/day, the avoided events provide an average 125 more QALYs. The total incremental costs are estimated to be £2,739,000, giving a cost per QALY of £21,938. When comparing rosuvastatin 40 mg/day with simvastatin 40 mg/day, the avoided events provide an average 158 more QALYs. The total incremental costs are estimated to be £2,619,000, giving a cost per QALY of £16,592.

For scenario 4, when comparing simvastatin 80 mg/day with simvastatin 40 mg/day, the avoided events provide an average 97 more QALYs (Table 15) over a lifetime of treatment. The total incremental costs are estimated to be £506,000, giving a cost per QALY of £5226. When comparing atorvastatin 80 mg/day with simvastatin 40 mg/day, the avoided events provide an average 203 more QALYs. The total incremental costs are estimated to be £3,495,000, giving a cost per QALY of £17,217. When comparing rosuvastatin 40 mg/day with simvastatin 40 mg/day, the avoided events provide an average 276 more QALYs. The total incremental costs are estimated to be £3,393,000, giving a cost per QALY of £12,277.

The cost-effectiveness plane for scenario 1 (Figure 2) shows the individual results for each of the treatment regimens compared with simvastatin 40 mg/day, with each point representing the result of one of the Monte Carlo samples. As can be seen, a large proportion of the results for each regimen would be considered cost-effective when using a cost per QALY threshold of £20,000 per QALY: 98% for simvastatin 80 mg/day, 91% for rosuvastatin 40 mg/day and 66% for atorvastatin 80 mg/day.

FIGURE 2.

Cost-effectiveness plane: scenario 1, generated using 5000 Monte Carlo simulations.

The cost-effectiveness plane for scenario 2 (Appendix 6, Figure 6) shows that a proportion (21%) of the results for simvastatin 80 mg/day versus simvastatin 40 mg/day have a higher cost with a smaller benefit, and just 30% of results would be considered cost-effective when using a threshold of £20,000 per QALY. Using a threshold of £20,000 per QALY, 10% (56%) of the results for the comparison atorvastatin 80 mg/day versus simvastatin 40 mg/day (rosuvastatin 40 mg/day versus simvastatin 40 mg/day) would be considered cost-effective.

The cost-effectiveness plane for scenario 3 (Appendix 6, Figure 7) shows that 38% of the results for simvastatin 80 mg/day versus simvastatin 40 mg/day have a higher cost with a smaller benefit, and 30% of the results would be considered cost-effective when using a threshold of £20,000 per QALY. Using a threshold of £20,000 per QALY, 75% (90%) of the results for the comparison atorvastatin 80 mg/day versus simvastatin 40 mg/day (rosuvastatin 40 mg/day versus simvastatin 40 mg/day) would be considered cost-effective.

The cost-effectiveness plane for scenario 4 (Appendix 6, Figure 8) shows that a large proportion of the results for each regimen would be considered cost-effective when using a threshold of £20,000 per QALY: 99% for simvastatin 80 mg/day, 92% for rosuvastatin 40 mg/day and 68% for atorvastatin 80 mg/day.

Comparing all treatment regimens

The ICERs for all possible treatment comparisons for each scenario are provided in Table 16. For scenario 1, when ranking according to the benefits of the individual treatments, rosuvastatin 40 mg/day dominates atorvastatin 80 mg/day with greater QALYs gained (7.86 versus 7.78) at a smaller cost (£18,464 versus £18,572). The hierarchy of treatments shows a similar trend for each of the scenarios.

TABLE 16 - Hierarchy of treatments (per patient)

CER, cost-effectiveness ratio; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Rosuvastatin 40 mg/day versus simvastatin 80 mg/day.

Dominated = higher costs and lower benefits.

Extendedly dominated.

	Cost	QALY	CER	ICER
Scenario 1
Rosuvastatin 40 mg/day	£18,464	7.86	£2349	£16,344a
Atorvastatin 80 mg/day	£18,572	7.78	£2388	Dominatedb
Simvastatin 80 mg/day	£15,110	7.66	£1973	£28,540c
Simvastatin 40 mg/day	£14,522	7.55	£1924	£5319
Scenario 2
Rosuvastatin 40 mg/day	£18,206	7.74	£2351	£16,137a
Atorvastatin 80 mg/day	£18,306	7.67	£2386	Dominatedb
Simvastatin 80 mg/day	£15,338	7.57	£2027	£28,091
Simvastatin 40 mg/day	£14,511	7.54	£1924	£35,445
Scenario 3
Rosuvastatin 40 mg/day	£17,851	7.54	£2367	£13,683a
Atorvastatin 80 mg/day	£17,971	7.51	£2394	Dominatedb
Simvastatin 80 mg/day	£15,830	7.39	£2141	£18,663
Simvastatin 40 mg/day	£15,232	7.38	£2063	£59,200
Scenario 4
Rosuvastatin 40 mg/day	£17,940	7.82	£2294	£16,079a
Atorvastatin 80 mg/day	£18,042	7.75	£2329	Dominatedb
Simvastatin 80 mg/day	£15,053	7.64	£1970	£28,150
Simvastatin 40 mg/day	£14,547	7.54	£1928	£5226

Net benefit

For scenario 1, when assessing the net benefit of the interventions, simvastatin 40 mg/day is the most cost-effective treatment if the maximum threshold is below £5000 per QALY (Figure 3). Simvastatin 80 mg/day is the most cost-effective treatment if the threshold is between £5000 and £16,000 per QALY and rosuvastatin 40 mg/day is the most cost-effective treatment if the threshold is greater than £15,000 per QALY. Atorvastatin 80 mg/day is never the most cost-effective treatment irrespective of the threshold. Similar results are observed for scenario 4 (Appendix 6, Figure 11). For scenarios 2 and 3 (Appendix 6, Figures 9and10respectively), simvastatin 40 mg/day is the most cost-effective treatment if the maximum threshold is below £18,000 per QALY. Rosuvastatin 40 mg/day is the most cost-effective treatment if the threshold is greater than this threshold. Simvastatin 80 mg/day and atorvastatin 80 mg/day are never the most cost-effective treatments irrespective of the threshold.

FIGURE 3.

Cost-effectiveness acceptability curve: scenario 1.

Cost of atorvastatin

The annual cost for atorvastatin 80 mg/day is currently £367.74 but when the patent expires in 2011 this cost is likely to fall substantially. When reducing the cost for atorvastatin 80 mg/day to £92 per annum, the cost per QALY (compared with simvastatin 40 mg/day) reduces to £3172 for scenario 1. The corresponding value for scenario 2 (scenario 3, scenario 4) is £7331 (£4739, £3155) per QALY.

If the cost of atorvastatin reduces in line with that observed for simvastatin when it came off patent, for scenario 1, assuming an annual cost for atorvastatin 80 mg/day of £20.78, when assessing the net benefit of the interventions the most cost-effective treatment is atorvastatin 80 mg/day (Figure 4). Assuming an annual cost of £92 for atorvastatin 80 mg/day, the most cost-effective treatment below a threshold of £4000 per QALY is simvastatin 40 mg/day (Appendix 6, Figure 12), whereas atorvastatin 80 mg/day is the most cost-effective treatment for thresholds between £5000 and £30,000 per QALY.

FIGURE 4.

Cost-effectiveness acceptability curve assuming lower cost for atorvastatin: scenario 1: atorvastatin 80 mg/day = £20.78 per annum.

Univariate sensitivity analyses

A series of one-way sensitivity analyses (Table 17) were conducted to determine the effect on the results when varying key parameter variables. The results are robust to changes in values for the health state costs. However, if it is assumed that there are no additional monitoring costs associated with the more potent doses, the ICERs are reduced by approximately 20%. The ICERs decrease with starting age of treatment as would be expected, reflecting the higher risk of the older population and thus the potential to avoid events. When decreasing the utilities for all health states the ICERs increase by approximately 14% reflecting the decrease in benefits from events avoided. Increasing the utilities decreases the ICERs by approximately 25%. It was assumed that utility values for the post event health states increased by 10% in the base case and the results were robust to changes in this assumption (Appendix 6, Table 22).

TABLE 17 - Results of the univariate sensitivity analyses

MI, myocardial infarction; RR, relative risk; UA, unstable angina.

Dominates: greater benefits with lower costs.

Adherence scenario	Parameter	Incremental cost-effectiveness ratio
		Simvastatin 80 mg/day vs simvastatin 40 mg/day	Atorvastatin 80 mg/day vs simvastatin 40 mg/day	Rosuvastatin 40 mg/day vs simvastatin 40 mg/day
Deterministic base case
Scenario 1		£5494	£17,819	£12,783
Scenario 2		£33,135	£29,496	£18,502
Scenario 3		£63,083	£22,348	£16,949
Scenario 4		£5494	£17,819	£12,783
Undiscounted
Scenario 1	0%	£3043	£13,144	£9026
Scenario 2	0%	£30,102	£23,403	£14,021
Scenario 3	0%	£63,083	£22,348	£16,949
Scenario 4	0%	£2996	£12,973	£8884
Baseline age of cohort
Scenario 1	Age 50 years	£7007	£20,389	£14,848
Scenario 2	Age 50 years	£46,707	£34,716	£21,800
Scenario 3	Age 50 years	£77,004	£25,933	£19,903
Scenario 4	Age 50 years	£6963	£20,255	£14,733
Scenario 1	Age 70 years	£3996	£15,511	£10,851
Scenario 2	Age 70 years	£22,167	£24,637	£15,378
Scenario 3	Age 70 years	£50,867	£19,261	£14,337
Scenario 4	Age 70 years	£3891	£15,189	£10,589
Health state costs
Scenario 1	Plus 50%	£3161	£15,480	£10,438
Scenario 2	Plus 50%	£31,076	£27,226	£16,209
Scenario 3	Plus 50%	£60,878	£20,055	£14,655
Scenario 4	Plus 50%	£3102	£15,267	£10,264
Scenario 1	Minus 50%	£7816	£20,148	£15,118
Scenario 2	Minus 50%	£35,184	£31,755	£20,784
Scenario 3	Minus 50%	£65,277	£24,631	£19,234
Scenario 4	Minus 50%	£7732	£19,908	£14,916
Health state utility values
Scenario 1	Plus 20%	£4729	£15,347	£11,016
Scenario 2	Plus 20%	£28,523	£25,389	£15,933
Scenario 3	Plus 20%	£54,198	£19,201	£14,565
Scenario 4	Plus 20%	£4666	£15,150	£10,851
Scenario 1	Minus 20%	£4729	£15,347	£11,016
Scenario 2	Minus 20%	£28,523	£25,389	£15,933
Scenario 3	Minus 20%	£54,198	£19,201	£14,565
Scenario 4	Minus 20%	£6778	£21,991	£15,744
No additional monitoring costs for higher-dose therapies
Scenario 1	Monitoring = zero	Dominates	£13,819	£9812
Scenario 2	Monitoring = zero	£1905	£23,404	£14,552
Scenario 3	Monitoring = zero	£6312	£17,542	£13,268
Scenario 4	Monitoring = zero	Dominates	£13,638	£9661
Using upper confidence interval from the MI RR to represent RR for UA
Scenario 1		£5812	£18,251	£13,236
Scenario 2		£33,654	£30,053	£19,089
Scenario 3		£63,800	£22,924	£17,587
Scenario 4		£5743	£18,035	£13,059

Because there is no established link between reductions in LDL-c and unstable angina we assumed that the RR for MI was representative of the benefits for unstable angina. Using the upper confidence intervals for the RR of MI to represent the RR for unstable angina had little effect on the ICERs as these were applied for all statin doses.

Chapter 5 Discussion

The clinical review and the Bayesian mixed treatment meta-analysis demonstrated a clear dose–response relationship in terms of reductions in LDL-c, with rosuvastatin 40 mg/day achieving the greatest percentage reduction (56%), followed by atorvastatin 80 mg/day (52%), simvastatin 80 mg/day (45%) and simvastatin 40 mg/day (37%). These data are similar to those reported by Soran and Durrington. 57 When combined with the relationship between absolute reductions in LDL-c and RRs of events, the RRs for simvastatin 40 mg/day are also as expected when compared with those in a large meta-analysis of placebo-controlled trials. 59

Although the safety of statins (as a class) is well reported,59 there are no specific systematic reviews and meta-analyses of RCTs solely focusing on the adverse effects associated with moderate-dose statins (i.e. simvastatin 40 mg/day). The long-term RCT evidence for simvastatin 40 mg/day is limited. In the principal 4S trial,84 two-thirds of patients received simvastatin 20 mg/day, whereas only one-third received simvastatin 40mg/day. In the HPS trial,34 which used simvastatin 40 mg/day, there was a 6-week active treatment run-in period during which those experiencing adverse effects could drop out before randomisation. The safety profile associated with intensive-dose statin therapy is less clear because of the smaller number of RCTs using intensive-dose treatments. The evidence generally suggests a dose–response relationship in which increasing the dose leads to more adverse events. A meta-analysis of seven trials (involving 29,395 patients with CAD)67 comparing intensive statin therapy with less intensive statin therapy found that more intensive regimens [atorvastatin 80 mg/day (six trials) or simvastatin 80 mg/day (one trial)] were associated with higher levels of aminotransferases (1.5% versus 0.4%; OR 4.14; 95% CI 2.30 to 7.44), myalgia (3.3% versus 2.8%; OR 1.26; 95% CI 0.98 to 1.63) myopathy (2.2% versus 1.8%; OR 1.91; 95% CI 0.11 to 32.13) and rhabdomyolysis (0.05% versus 0.04%; OR 0.97; 95% CI 0.29 to 3.24) than less intensive statin therapy (atorvastatin 10 mg/day, lovastatin 5 mg/day, pravastatin 40 mg/day, simvastatin 20 mg/day). Josan et al. 67 also showed that the more intensive regimens were associated with small statistically non-significant increases in rates of discontinuation (OR 1.34; 95% CI 0.98 to 1.83) compared with less intensive statins. Evidence for rosuvastatin 40 mg/day is very limited. 117 Although the product information for rosuvastatin indicates a higher risk of adverse events with the 40 mg/day dose than with lower doses (rosuvastatin < 20 mg/day),74 recently published data114,115 show that there was no significant difference in the adverse event rates at any dose ratio when compared with atorvastatin (maximum doses being rosuvastatin 40 mg/day and atorvastatin 80 mg/day).

Although documented serious adverse events are rare, individuals receiving the more potent doses should be screened for contraindications and monitored if symptoms are reported. The evidence suggests that long-term adherence to standard-dose statins is low in general clinical practice, with a large proportion of individuals discontinuing therapy during the first 12 months; however, there is evidence that adherence could be higher in individuals with a history of CVD and in those who receive regular monitoring. 88,94,98,99

Although several meta-analyses of randomised statin trials have not detected any clinically meaningful effect of statins on cancer incidence,6,118,119 data from epidemiological studies suggest an inverse association between serum cholesterol levels and incident cancer. 120 The recent results of a meta-regression analysis of data from 15 randomised clinical trials indicated that, although an inverse association between on-treatment LDL-c and incident cancer occurs, there was no evidence that statins themselves increased the risk of cancer. 121 Despite this, there is still concern that achieving low levels of LDL-c may increase the risk of cancer. 122–124 Long-term follow-up and registry data on adherence rates and adverse reactions to statins of all types and doses would be a useful contribution to the existing evidence base.

The economic results suggest that, if adherence levels in general practice are similar to those observed in clinical trials (scenario 1), all three higher-dose statins would be considered cost-effective compared with simvastatin 40 mg/day when using a threshold of £20,000 per QALY. When comparing all four treatment regimens, atorvastatin 80 mg/day is dominated by rosuvastatin 40 mg/day with smaller benefits (7.86 versus 7.94 QALYs) and higher costs (£18,213 versus £18,116). Assessing the net benefit of the interventions, simvastatin 40 mg/day is the optimal treatment when using a threshold of £5000 per QALY, simvastatin 80 mg/day is the optimal treatment if the threshold is between £5000 and £16,000 per QALY and rosuvastatin 40 mg/day is the optimal treatment if the threshold is greater than £15,000 per QALY. However, simvastatin 80 mg/day is not well tolerated and a substantial proportion of patients are unlikely to adhere to this treatment. Recently published results show that the incidence of myopathy in individuals receiving simvastatin 80 mg/day was 26 times higher than incidence rates in those receiving simvastatin 20 mg/day. With defined premyositis also increased, simvastatin 80 mg/day cannot be recommended. 79

Although this analysis shows that atorvastatin 80 mg/day is never the most cost-effective alternative at any tested threshold, when the patent for atorvastatin expires in 2011 it is probable that there will be a substantial decrease in the cost of this treatment. If the cost of atorvastatin decreases in line with that observed for simvastatin, atorvastatin 80 mg/day will be the most cost-effective treatment at all thresholds. If the cost of atorvastatin reduces to 25% of the current cost, atorvastatin 80 mg/day will be the most cost-effective treatment for thresholds between £5000 and £30,000 per QALY.

The results reported above are generated using the unadjusted effectiveness rates obtained from the clinical trials, which typically report adherence rates in the region of 80–90%. If it is assumed that the RCT adherence rates are representative of adherence to simvastatin 40 mg/day, but that the level of adherence to the more potent doses is lower in general practice (scenario 2), using a threshold of £30,000 per QALY all three higher-dose statins would be considered cost-effective compared with simvastatin 40 mg/day, and using a threshold of £20,000 per QALY rosuvastatin 40mg/day would be considered cost-effective. As in scenario 1, when comparing all four treatment regimens, atorvastatin 80 mg/day is again dominated by rosuvastatin 40 mg/day. If adherence rates are adjusted to reflect the trends in the limited evidence available for the different statins (scenario 3), compared with simvastatin 40 mg/day, atorvastatin 80 mg/day and rosuvastatin 40 mg/day remain cost-effective using a threshold of £20,000 per QALY but simvastatin 80 mg/day would not be considered cost-effective using a threshold of £30,000 per QALY.

It is likely that an individual with a history of a recent acute cardiovascular event would be offered an alternative if they did not tolerate the more potent doses. In scenario 4 we used the same levels of adherence as in scenario 2 and assumed that individuals who do not adhere to the higher-dose statins receive simvastatin 40 mg/day. The results generated using these assumptions are comparable with the results for scenario 1.

In general, the results are reasonably robust to changes in the majority of parameter values and are driven by the differences in the adherence rates modelled and the monitoring costs associated with the more potent doses. However, there is evidence that adherence could be higher in individuals with a history of a recent cardiovascular event and in those who receive regular monitoring. Thus, within the limitations of the evidence available, the results for scenario 1 and scenario 2 could be considered the most accurate representations of the cost-effectiveness of the different interventions for individuals who adhere to treatment.

There are several major limitations in the evidence base used to estimate the benefits associated with the treatment regimens, which may have implications when interpreting the results generated by the economic model. First, the individuals enrolled in the RCTs used in the mixed treatment meta-analysis were screened before randomisation and some studies excluded individuals who had recently experienced an ACS episode. Consequently, when examining the dose–response rates to the treatments, we are assuming that these will be generalisable to individuals with ACS.

Second, the data used in the mixed treatment comparison came from studies having a duration of 6 weeks, 12 weeks, 24 weeks/6 months, 9 months, 1 year, 3 years or 5 years. Although at least one of the included studies for simvastatin 40 mg/day, simvastatin 80 mg/day and atorvastatin 80 mg/day was of at least 6 months in duration, the data for rosuvastatin 40 mg/day were obtained from studies having a duration of 12 weeks or less. Consequently, although we accounted for heterogeneity using a Bayesian random-effects model, we did not postulate plausible statistical models to link the data across time periods. Indeed, data were available only for placebo and simvastatin 40 mg/day beyond 1 year, and there were no data available on rosuvastatin 40 mg/day beyond 12 weeks. If the effectiveness of the treatments decreases over the long term it is likely that the benefits of rosuvastatin are overestimated, particularly as the economic evaluation extrapolates the results over a lifetime. In addition, the current model will also underestimate the uncertainty associated with the effectiveness of treatment beyond 1 year.

Third, the link between changes in LDL-c and RRs of events was derived predominantly from individuals who were not receiving the more potent doses of statins. 6 Although the analysts reported that their findings were independent of characteristics such as baseline LDL-c values or cardiovascular risk, we are extrapolating beyond the evidence base used. Although our economic results suggest that atorvastatin 80 mg/day is dominated by rosuvastatin 40 mg/day, clinical data supporting the assumption that rosuvastatin-induced reductions in LDL-c (and its greater potential to increase HDL-c)will translate into corresponding reductions in clinical events are limited.

Cardiovascular disease is a complex field and the economic model focuses on the following major events: hospitalisation for unstable angina, MI, stroke, fatal CHD and fatal non-cardiac vascular events. Other analysts have constructed models that include health states such as heart failure and revascularisation procedures, which were not included in the current evaluation. 105 Heart failure was not included as the evidence for and against prescribing statins for people with heart failure is limited, conflicting and unclear. Although several studies (i.e. post hoc subgroup analyses in prospective RCTs; subgroup analysis of the evidence of statin use in large heart failure trials of different medications and medical devices; retrospective observational studies and prospective RCTs of statins in non-ischaemia) lend support for a beneficial effect of statins in heart failure,125 there are concerns that the routine use of statins may be harmful in such patients. First, non-RCT evidence suggests that lower cholesterol levels are associated with a worse prognosis in heart failure patients. 125,126 Second, statins in heart failure may adversely affect mitochondrial function through inhibition of ubiquinone (coenzyme Q10) levels, thus affecting cardiac muscle function. Finally, statins may decrease selenoproteins, which could result in decreased myocardial function. 125,126 In addition, the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)127 is the first prospective randomised placebo-controlled clinical outcome trial with statins (rosuvastatin 10 mg/day) focused specifically on older patients (at least 60 years of age) with systolic heart failure. Over a median follow-up of 33 months there were no significant differences in the primary end point or in all-cause mortality, the rate of coronary events, the effects on New York Heart Association class or the rate of newly diagnosed diabetes. Other large clinical trials (GISSI-HF)128 are also under way to further clarify the effects of statin treatment in heart failure.

Although data show that statins reduce the number of revascularisation procedures, the current model does not include this as a subsequent event. As revascularisations are considered to be a treatment as opposed to a cardiac event, to avoid double counting costs and utility we chose to model potential reductions in subsequent procedures by including these in the hospitalisation for unstable angina and MI health states. We assume that by reducing the number of cardiac events we also take into account potential reductions in revascularisation procedures due to statin treatment. 13,16

Finally, we assume that the relationship between reductions in LDL-c and the RR of any stroke reported by the cholesterol trialist collaborators is representative of the relationship between reductions in LDL-c and the RR of non-fatal stroke. 6 As the RRs for fatal strokes are generally not significant,59 it is possible that we are underestimating the benefits in terms of the number of non-fatal strokes avoided.

Chapter 6 Conclusion

The Bayesian mixed treatment meta-analysis demonstrated a clear dose–response relationship in terms of reductions in LDL-c, with rosuvastatin 40 mg/day achieving the greatest percentage reduction (56%), followed by atorvastatin 80 mg/day (52%), simvastatin 80 mg/day (45%) and simvastatin 40 mg/day (37%). Although the literature suggests that serious adverse events are rare for all statins, incidence rates are likely to be higher for individuals receiving the more potent doses. Adherence rates in general clinical practice are lower than those reported in clinical trials, may be correlated with less severe adverse event rates such as for myalgia, and are likely to vary by statin type and dose.

Using a threshold of £20,000 per QALY, if it is assumed that the benefits and adherence rates observed in the clinical trials are generalisable to a clinical setting, or if it is assumed that individuals who do not tolerate the higher-dose statins are prescribed simvastatin 40 mg/day, then simvastatin 80 mg/day, atorvastatin 80 mg/day and rosuvastatin 40 mg/day would all be considered cost-effective compared with simvastatin 40 mg/day in individuals with ACS. However, because of high incidence rates of myopathy/myalgia in individuals receiving simvastatin 80 mg/day, adherence is likely to be poor and simvastatin 80 mg/day cannot be recommended.

With current treatment costs and existing evidence our results show that rosuvastatin 40 mg/day is potentially the most cost-effective treatment. However, these results are based on the assumption that the larger benefits in LDL-c measurements will produce an equivalent reduction in cardiovascular event rates. Although data on event rates supporting this assumption are beginning to emerge, the evidence base for atorvastatin 80 mg/day is more robust. If the cost of atorvastatin decreases when the patent ends in 2011, atorvastatin 80 mg/day will be the most cost-effective treatment.

Chapter 7 Recommendations for further research

Large long-term RCTs reporting effects in terms of clinical events are required to determine the optimum statin use for subgroups. These will include head-to-head studies comparing higher-dose statins with lower-dose statins, studies of rosuvastatin and studies comparing high-dose statin monotherapy with combination therapies such as low-dose statins combined with alternative lipid modifications. Studies recruiting high-risk groups typically excluded from RCTs, such as individuals with recent ACS events or heart failure, diabetics and Asian people, should be considered. Long-term registry data are required to determine adherence rates and adverse event profiles for individual statins and doses when used in general clinical practice. Studies exploring the effects of interventions designed to increase adherence to statin therapy in general clinical practice and in subgroups are required.

Acknowledgements

Our thanks to Professor Paul Durrington (Professor of Medicine, University of Manchester), Professor Tim Reynolds (Queen’s Hospital, Burton on Trent) and Dr Anthony S. Wierzbicki (Senior Lecturer, St Thomas’ Hospital, London) who provided clinical advice on this project. Thanks also to Gill Rooney and Andrea Shippam (Project Administrators, ScHARR) for their help in the retrieval of papers and the preparation and formatting of the report.

Matt Stevenson and Eva Kaltenthaler are guarantors.

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227. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96.
228. The Diabetes Atorvastin Lipid Intervention (DALI) Study Group . The effect of aggressive versus standard lipid lowering by atorvastatin on diabetic dyslipidemia: the DALI study: a double-blind, randomized, placebo-controlled trial in patients with type 2 diabetes and diabetic dyslipidemia. Diabetes Care 2001;24:1335-41.
229. Mohler ER. Therapy insight: peripheral arterial disease and diabetes – from pathogenesis to treatment guidelines. Nature Clin Pract Cardiovasc Med 2007;4:151-62.

Appendix 1 Example of MEDLINE search strategy

Appendix 2 QUOROM trial flow chart (clinical effectiveness)

FIGURE 5.

QUOROM trial flow chart.

Appendix 3 List of excluded studies with rationale

Appendix 4 Quality assessment criteria

Appendix 5 Synopsis of placebo-controlled RCTs included in the NICE HTA meta-analysis59

Of the 25 studies (n = 35,721 for statins; n = 35,432 for placebo) included in the meta-analysis used in the current evaluation, three of the four fluvastatin studies (FLARE,215 FLORIDA,216 LIPS217) used the maximum dose of 80 mg/day whereas the LiSA study218 increased the starting dose of 40 mg/day to 80 mg/day 6 weeks after randomisation if the decrease in LDL-c was less than 30%. All but two of the pravastatin studies used the maximum dose of 40mg/day (CAIUS,219 CARE,220 PLAC-I,221 REGRESS222). In the remaining two studies (PLAC-II223 and PMSG224) the dose could be increased to 40 mg/day in participants whose LDL-c levels had not responded to the starting dose of 20 mg/day. Two34,45 of the six simvastatin studies used 40 mg/day throughout whereas the MAAS study225 used a dose of 20 mg/day throughout. The remaining three studies (4S,186 CIS,138 SCAT205) used a starting dose of 20 mg/day, which could be increased to 40 mg/day if this was necessary to achieve an adequate reduction in LDL-c. By contrast, the atorvastatin studies generally used doses well below the maximum dose of 80 mg/day: the ASCOT-LLA226 and CARDS227 studies used a fixed dose of 10 mg/day. Only the small DALI228 (n = 145 on atorvastatin) and Mohler229 (n = 240 on atorvastatin) studies used a dose of 80 mg/day: each had two treatment arms, one on a fixed dose of 10 mg/day and the other on 80 mg/day. Assuming that atorvastatin 10 mg/day, fluvastatin 80 mg/day, pravastatin 40 mg/day and simvastatin 20/40 mg/day provide similar benefits, the results can be used to represent the effectiveness achieved through standard statin treatment compared with no treatment.

Appendix 6 Additional tables for economic evaluation

FIGURE 6.

Cost-effectiveness plane: scenario 2: generated using 5000 Monte Carlo simulations.

FIGURE 7.

Cost-effectiveness plane: scenario 3: generated using 5000 Monte Carlo simulations.

FIGURE 8.

Cost-effectiveness plane: scenario 4: generated using 5000 Monte Carlo simulations.

FIGURE 9.

Cost-effectiveness acceptability curve: scenario 2.

FIGURE 10.

Cost-effectiveness acceptability curve: scenario 3.

FIGURE 11.

Cost-effectiveness acceptability curve: scenario 4.

FIGURE 12.

Cost-effectiveness acceptability curve: scenario 1: atorvastatin 80 mg/day = £92 per annum.

Glossary

Acute coronary syndrome

Symptoms compatible with acute myocardial ischaemia (primarily unstable angina or myocardial infarction).

Angina, unstable

Unstable angina is a syndrome that is intermediate between stable angina and myocardial infarction (heart attack). It is characterised by an accelerating or ‘crescendo’ pattern of chest pain that lasts longer than in stable angina.

Atherosclerosis

A condition in which fatty deposits (atheromas) develop in the arteries; these narrow the blood vessels and can rupture to form a complete blockage resulting in heart attack or stroke (depending on location).

Cardiovascular

Pertaining to the heart and blood vessels.

Cardiovascular disease

A term generally used to refer to all vascular disease caused by atherosclerosis.

Coronary arteries

The arteries that supply the heart muscle with blood.

Coronary artery disease

The condition that arises from accumulation of plaque that narrows the inside diameter of arteries that supply the heart muscle with blood.

Coronary heart disease

Narrowing or blockage of the coronary arteries, which reduces the blood supply to the heart and potentially causes angina or myocardial infarction. Also known as coronary artery disease or ischaemic heart disease.

Diabetes mellitus

A disorder caused by insufficient production of insulin by the pancreas (type 1 diabetes) or by insensitivity to the effects of insulin (type 2 diabetes).

Heterozygous

Possessing two different forms of a particular gene.

High-density lipoprotein

Class of lipoproteins, varying in their size (8–11 nm in diameter) and contents, which carry cholesterol from the body’s tissues to the liver.

Homozygous

Possessing two identical forms of a particular gene.

Hypercholesterolaemia

High blood cholesterol.

Hyperlipidaemia

High blood lipids.

Hypothyroidism

A condition in which the body lacks sufficient thyroid hormone.

Infarction

Death of tissue following interruption of the blood supply.

Ischaemic heart disease

Coronary heart disease.

Low-density lipoprotein

Class and range of lipoprotein particles, varying in their size (18–25 nm in diameter) and contents, which carry fatty acid molecules in the blood and around the body for use by cells.

Myalgia

Diffuse muscle pain, tenderness and weakness.

Myocardial infarction

Permanent damage to an area of heart muscle as a result of interruption of the blood supply to the area caused by narrowed or blocked blood vessels (‘heart attack’).

Myopathy

Muscle pain, tenderness or weakness associated with abnormal elevations in creatine kinase levels (greater than 10 times the upper limit of normal).

Nephrotic syndrome

A condition characterised by high levels of protein in the urine, low levels of protein in the blood, tissue swelling and high cholesterol.

Premature death

Death before the age of 75 years.

Primary (familial) hypercholesterolaemia

High cholesterol level caused by an underlying genetic defect.

Primary prevention

Activity intended to delay or prevent the onset of a disease.

Revascularisation

The restoration of blood supply, either pharmacologically or surgically.

Rhabdomyolysis

A syndrome resulting from destruction of skeletal muscle resulting in myoglobinuria, muscle weakness, pain, swelling and cramps. Serious complications of rhabdomyolysis include acute renal failure, ischaemia, disseminated intravascular coagulation and respiratory failure.

Secondary (non-familial) hypercholesterolaemia

Hypercholesterolaemia caused by another disease state or by drug therapy. Also known as ‘acquired’ hypercholesterolaemia.

Secondary prevention

Activity intended to delay the recurrence of, or prevent mortality from, a disease.

Stroke

The sudden death of some brain cells when the blood supply to the brain is impaired by the blockage or rupture of an artery.

Total cholesterol

Total cholesterol is the sum of all of the cholesterol in the blood.

Triglycerides

Glycerides in which the glycerol is esterified with 3- fatty acids. They constitute the majority of the fat that is stored in the fat tissue to be used as energy.

List of abbreviations

ACS

acute coronary syndrome

ALT

alanine aminotransferase

AMI

acute myocardial infarction

AST

aspartate aminotransferase

CABG

coronary artery bypass grafting

CAD

coronary artery disease

CHD

coronary heart disease

CI

confidence interval

CK

creatine kinase

CVD

cardiovascular disease

EQ-5D

EuroQol 5 dimensions

HDL-c

high-density lipoprotein cholesterol

HMG-CoA

3-hydroxy-3-methylglutaryl coenzyme A

HRQoL

health-related quality of life

HTA

Health Technology Assessment

ICER

incremental cost-effectiveness ratio

ITT

intention to treat

LDL-c

low-density lipoprotein cholesterol

MI

myocardial infarction

NICE

National Institute for Health and Clinical Excellence

OR

odds ratio

PCT

primary care trust

PTCA

percutaneous transluminal coronary angioplasty

PVD

peripheral vascular disease

QALY

quality-adjusted life-year

QUOROM

Quality of Reporting of Meta-analyses

RCT

randomised controlled trial

RR

relative risk

TIA

transient ischaemic attack

Notes