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National Collaborating Centre for Primary Care (UK). Post Myocardial Infarction: Secondary Prevention in Primary and Secondary Care for Patients Following a Myocardial Infarction [Internet]. London: Royal College of General Practitioners (UK); 2007 May. (NICE Clinical Guidelines, No. 48.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Post Myocardial Infarction: Secondary Prevention in Primary and Secondary Care for Patients Following a Myocardial Infarction [Internet].

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Appendix BHealth Economic Modelling

1.1. Economic analysis of cardiac rehabilitation

1.1.1. Introduction

Cardiac rehabilitation (CR) after an acute myocardial infarction (MI) is a recommended therapy with established clinical effectiveness. It comprises mainly of supervised exercise training, relaxation and education. There is evidence that CR reduces the risk of total and cardiac related mortality, subsequent revascularizations, occurrence of non-fatal MI, improvements in work and physical capacity and perceived quality of life. (Oldridge, N. et al 1993), (Joliffe, J. A. et al 2003),(Taylor, R. S. et al 2004), (Clark, A. M. et al 2005) (Beswick, A. D. et al 2004)

In England the National Service Framework for Coronary heart disease (NSF-CHD) identifies patients who have survived acute MI and those who have undergone Coronary artery bypass graft (CABG) and percutaneous transluminal coronary angiography (PTCA) as initial priorities for CR (Department of Health 2000)

The provision of exercise-based CR in the United Kingdom (UK) has increased since the early 1990s. The British Cardiac Society Working Party Report showed that 99 programmes were in place 1989 (Bethell, H. J. et al 2001) (Betell, H. J. N. et al 2000). By 1997 their numbers had tripled. By year 2000 in England alone 220 centres were identified in a survey of implementation of the NSF-CHD but concluded that there is still scope for improving services so that those in need are offered rehabilitation (Beswick, A. D., Rees, K., Griebsch, I. et al 2004)

Although CR is considered effective in quickening recovery and improving prognosis, not all patients participate in a CR programme. Surveys in UK have given diverse estimates of uptake, ranging between 14–59% after MI ((Beswick, A. D., Rees, K., Griebsch, I. et al 2004) (Evans, J. A., Turner, S. C., and Bethell, H. J. N. 2002),(Betell, H. J. N., Turner, S. C., Flint, E. J. et al 2000)

Costs of CR services vary by format of delivery. The most recent survey the British Association of cardiac rehabilitation (BACR) and the British Heart Foundation (BHF) suggest that costs per patient vary widely between £50–£712 depending on level of staffing, equipment used and intensity of the programme. In all cases staff costs ranged between 64–80% of the total (Beswick, A. D., Rees, K., Griebsch, I. et al 2004), (Betell, H. J. N., Turner, S. C., Flint, E. J. et al 2000) (Lewin, B. et al 1992)

The wider economic benefits of CR are believed to derive primarily from reduced secondary utilization of inpatient medical resources. Studies from USA (Ades, P. A., Pashkow, F. J., and Nestor, J. R. 1997), (Oldridge, N., Furlong, W., Feeny, D. et al 1993), Australia (Hall, J. P. et al 2002) and Sweden (Levin, L. A., Perk, J., and Hedback, B. 1991) have shown that CR is cost effective. However, there are no cost effectiveness studies of CR in the UK.

This study had two objectives. The first was to assess the cost effectiveness of comprehensive CR compared to no CR. A second objective was to assess the comparative cost effectiveness of some of the methods used to increase uptake of CR after an MI. The methods considered were firstly the use of telephone calls together with home visits carried out by a healthcare professional (HCP), and secondly invitation letters. Costs relevant to the National Health Service (NHS) were considered.

1.1.2. Methods

Population and sub-groups

The model considered a cohort of patients who had had a recent MI. The trial evidence that the model is based on included relatively few older (>65) or black patients, so the results may not be reliable for these groups.

Interventions compared

The analysis assessed the costs and effects of CR compared with no CR. Additionally it assessed using the output from the CR model, the cost effectiveness of two methods of increasing uptake and adherence compared to ‘current practice/usual care’, i.e. current uptake of CR. These two methods were firstly the use of phone calls together with home visits by a HCP, in which the HCP was assumed to make contact over the phone four times, each followed by a home visit and secondly the use of two consecutive invitation letters to a CR programme over a period of 6 weeks.

Outcomes

The treatment effects were measured in terms of reduction of CVD events: non-fatal MI, revascularisation CVD-related deaths and other deaths. Health outcomes for the cost-effectiveness analysis are summarised in the form of Quality Adjusted Life Years (QALYs), where one QALY represents one year of healthy life.

Model structure and assumptions

A Markov model was developed to evaluate the incremental costs and effects of lifetime intervention with CR in secondary prevention of cardiovascular disease (CVD) events in post MI patients from a UK NHS perspective.

In a Markov model there are a finite number of health states. It is assumed that at any point in time, all patients must be in one and only one of the states. The model then replicates how a hypothetical cohort of people moves between the states. Figure 1 shows a schematic representation of the patients’ pathways. All patients start in the event-free health state. During each six-month cycle of the model, a proportion of patients enter one of the qualifying event health states (MI, revascularisation and death) while the remainder stay in the event free state. Patients can experience more than one non-fatal event in subsequent periods of the model.

Figure 1. Economic Model Structure.

Figure 1

Economic Model Structure.

The rate at which people move through the model is regulated by transition probabilities, which describe the likelihood of moving between states over each model cycle (six months). For illustration, the equivalent annual transition probabilities for a 65-year-old patient receiving no-CR are shown in Table 1. The probabilities are derived from the placebo arms of the meta-analysis of CR trials.

Table 1. Probabilities for a 65-year-old man without Cardiac rehabilitation.

Table 1

Probabilities for a 65-year-old man without Cardiac rehabilitation.

The model was run first assuming that the cohort was to receive no CR. The model was then re-run assuming that the cohort all received CR and complied 100%. Transition probabilities were adjusted to reflect the expected reduction in CVD events and revascularisations. Health care costs and QALYs were then estimated for each option by weighting the time spent in the various states by mean costs and ‘utilities’ (health-related quality of life) of the health states. The cost and utility data used in the model are described below.

The time horizon modelled is lifetime, with an assumed upper age of 100, by which time most of the cohort have died.

Baseline risks

The risks of secondary or subsequent events, following an MI or revascularisation are shown in Table 1. Probabilities of having a re-infarction, and death were taken from the placebo arm of two recent meta-analyses (Joliffe, J. A., Rees, K., Taylor, R. S. et al 2003), (Clark, A. M., Hartling, L., Vandermeer, B. et al 2005) The probabilities of having revascularisation were taken from another meta-analysis (Taylor, R. S., Brown, A., Ebrahim, S. et al 2004). The incidence of MI following revascularisation was taken from Rita 2 and probability of post operative death was taken from the ACC/AHA 2004 Guideline Update for Coronorary Artery Bypass Graft Surgery (Eagle, K. A. et al 2004).

Non-CVD related mortality by age and sex was taken from the life tables for England and Wales prepared by the Government Actuaries Department (GAD) and from the Office for National Statistics (ONS) (Government Actuaries Department 2006), (Office for National Statistics 2006).. In the base case model we assumed that the post MI cohort had a 2 fold increase in risk of non-CVD death compared with the general population, because they are a high risk population (expert opinion). However, we tested this assumption in the sensitivity analysis.

Treatment effects

The effectiveness of CR defined as the reduction in relative risks of mortality and non fatal reinfaction was obtained from systematic (Clark, A. M., Hartling, L., Vandermeer, B. et al 2005) and for revascularisation from (Taylor, R. S., Brown, A., Ebrahim, S. et al 2004). Data on the effectiveness of the strategies aimed at increasing uptake and compliance were obtained from an HTA report (Beswick, A. D., Rees, K., Griebsch, I. et al 2004)

Table 2Relative risks of CR (base case analysis)

OutcomeMeanLower CIUpper CISource
Revascularisation0.850.651.12(Taylor, R. S., Brown, A., Ebrahim, S. et al 2004)
MI0.830.740.94(Clark, A. M., Hartling, L., Vandermeer , B. et al 2005)
Post operative death111Assumption
Death0.850.770.94(Clark, A. M., Hartling, L., Vandermeer , B. et al 2005)

Table 3Relative risks of Letters and phone calls (base case analysis)

InterventionResultsSource
Letters87% intervention group

Compared to 57% in control p=0.0025
(Beswick, A. D., Rees, K., Griebsch, I. et al 2004)
Telephone+ HCP57% vs. 27% in those who did not get the intervention.(Beswick, A. D., Rees, K., Griebsch, I. et al 2004)

Cost data

The NICE reference case specifies that costs should be measured from an NHS and personal social services perspective. These should include the direct cost of drug treatment and also potential savings from avoided treatments due to reduced incidence of CVD and hospitalisations. Costs were calculated using cost weights for each of the states of the model, multiplied by the time spent in each state. Costs are at 2005 prices. As per current NICE guidance, an annual discount rate of 3.5% was used for both costs and health benefits (National Institute for Health & Clinical Excellence. 2006b).

The costs of health states used in the model are shown in Table 4. Costs for revascularization which includes hospitalisation were taken from the NHS reference cost 2005 (Department of Health Reference Costs 2005 2005). It was assumed that 67% of patients will have PCI and 33% will have CABG and the costs were weighted to reflect this (expert opinion). The cost of the well states was assumed to be the outpatient cost which includes the costs of medication and monitoring costs, these were taken from the NICE hypertension guideline 2006 (National Institute for Health and Clinical Excellence. 2006). The cost of CR was taken from a review (Beswick, A. D., Rees, K., Griebsch, I. et al 2004) and included staff costs, equipment, and that of recruiting patients to CR. Costs of acute MI (non-fatal reinfaction) were assumed to be the same as those of patients treated with thrombolysis, which includes the cost of hospitalisation (Hartwell, D. et al 2005). The cost of death was zero.

Table 4. Costs of health states.

Table 4

Costs of health states.

The costs of each strategy used to increase uptake, invitation letters or phone call contacts followed by home visits, were calculated from resource use identified in the HTA (Beswick, A. D., Rees, K., Griebsch, I. et al 2004). The actual unit costs were taken from the Personal Social Services Research Unit PSSRU (PSSRU 2005).

The cost of invitation letters were calculated assuming that letters inviting participants to a CR programme were sent twice, soon after discharge and 3 weeks later. It was assumed that the letters were sent by a medical secretary, and also that 30 minutes work was required to type and send each letter.

For the HCP and phone calls (Beswick, A. D., Rees, K., Griebsch, I. et al 2004) estimated there would be about four visits and a phone call made before each visit. Contact by the HCP was assumed to last 30 minutes and the phone call about 11 minutes. Duration for the phone call and staff costs were taken from the PSSRU (PSSRU 2005)

Table 5other resources

Resource useHourly ratesContact time
social worker£38.0030 minutes per visit X 4
visiting costs£1.204 visits
rehabilitation nurse£21.0011 minutes once
Secretaries£14.0030 minutes to write a letter and post it on two occasions
postage first class+ paper£0.40twice
cost per minute of phone call£0.04
Quality of life (Utility)

In the NICE reference case, the value of health outcomes – including beneficial and harmful impacts of treatment on mortality and morbidity – is estimated using the Quality Adjusted Life Year (QALY) approach. This requires estimates of survival and quality of life associated with each health state included in the model.(National Institute for Health & Clinical Excellence. 2006b)

The utility values used in the model are shown in Tables 6 and 7. The values were taken from literature or the Harvard cost effectiveness registry database (Harvard CEA Registry 1997)

Table 6. Health state utility weights.

Table 6

Health state utility weights.

Table 7. Utility weight by age.

Table 7

Utility weight by age.

Utilities were adjusted to reflect the fact that health related quality of life in the general population decreases with age (i.e. multiply the disease utility weight by age utility weight). Age utility weights were taken from the Department of Health, Health Survey for England (Department of Health 1998)

One study (Oldridge, N., Furlong, W., Feeny, D. et al 1993), found that there was a difference of 0.052 QALYs between patients who participated in CR and those who did not using the time trade off method. This factor was applied to all the well states in the CR arm to take account of this difference in quality of life in sensitivity analysis. The weight attached to death was zero

Cost effectiveness

The results of cost-effectiveness analysis are usually presented as Incremental Cost-Effectiveness Ratios (ICERs), which determine the additional cost of CR per additional QALY gained compared with no CR

ICERs = (cost of CR - cost of no CR)/(QALY of CR - QALY of no CR)

Where more than two interventions are being compared, the ICERs are calculated using the following process:

  1. The drugs are ranked in terms of cost (from the cheapest to the most expensive).
  2. If a drug is more expensive and less effective than the previous one, then it is said to be ‘dominated’ and is excluded from further analysis.
  3. ICERs are calculated for each drug compared with the next most expensive non-dominated option. If the ICER for a drug is higher than that of the next more effective strategy, then it is ruled out by ‘extended dominance’. This means that there is some mixture of two other strategies that is more effective and less expensive.
  4. ICERs are recalculated excluding any drugs subject to extended dominance. (Palmer, S., Sculpher, M., and Philips, Z. 2004)

Sensitivity analysis

The model includes a base case analysis supplemented with both deterministic and probabilistic sensitivity analysis. In the probabilistic sensitivity analysis all parameters in the model were allowed to vary simultaneously according to an assumed distribution reflecting the degree of uncertainty over the parameter value.

1.1.3. Results

The tables 8 & 9 below present the analysis of the incremental cost effectiveness ratio (ICER) for the base-case analysis of

Table 8a. Incremental cost effectiveness of CR vs. No CR, base case results for 65 year old men.

Table 8a

Incremental cost effectiveness of CR vs. No CR, base case results for 65 year old men.

Table 8b. Incremental cost effectiveness of CR vs. No CR, base case results for 65 year old men.

Table 8b

Incremental cost effectiveness of CR vs. No CR, base case results for 65 year old men.

Table 9. Incremental cost effectiveness of the methods used to increase uptake of CR after an MI.

Table 9

Incremental cost effectiveness of the methods used to increase uptake of CR after an MI.

  1. CR versus no CR in post MI patients.
  2. the comparative cost effectiveness of the methods used to increase uptake of CR after an MI

a. Cost effectiveness of Cardiac Rehabiliation vs. no Cardiac Rehabiliation

The base case results are presented in table 8a and b for 65-year-old men and women respectively. This suggests that CR is cost-effective for this population. The ICER of CR compared with no CR is about £7,860 and £8,360 per QALY gained for men and women respectively, which is below the level usually considered to be affordable in the NHS (about £20,000 to £30,000 per QALY).

Figure 2. Cost effectiveness plane, CR compared to no CR in post MI patients.

Figure 2Cost effectiveness plane, CR compared to no CR in post MI patients

b. The comparative cost effectiveness of the methods used to increase uptake of CR after an MI

None of the strategies were ruled out on the basis of dominance. The base case model shows that the strategy of sending letters compared to usual care to increase uptake of CR is about £ 8,000/QALY. The strategy of using phone calls and home visits by a HCP compared to sending letters is about £ 8,400/QALY gained which is below the level usually considered to be affordable in the NHS (about £20,000 to £30,000 per QALY).

While the results of the ICER can be used to determine the optimal decision based on a comparison of mean costs and QALYs, they do not incorporate the uncertainty surrounding this decision. Figure 3 presents the base-case results in the form of cost effectiveness acceptability curves (CEACs) for CR versus no CR. Figure 4 shows the comparison between the three strategies of increasing uptake of CR. These curves detail the probability that each strategy is cost effective over a range of potential maximum values that the NHS is prepared to pay for an additional QALY.

Figure 3. Cost effectiveness acceptability curve, Cardiac rehabilitation versus no cardiac rehabilitation.

Figure 3

Cost effectiveness acceptability curve, Cardiac rehabilitation versus no cardiac rehabilitation.

Figure 4. Cost effectiveness acceptability curve, Usual care vs letters vs telephone + HCP.

Figure 4

Cost effectiveness acceptability curve, Usual care vs letters vs telephone + HCP.

The CEACs demonstrate that CR is highly cost effective. The probability that CR is cost effective increases as the willingness to pay increases. If the NHS is willing to pay upto £10,000 for an additional QALY, the probability that CR is cost effective is around 60%, increasing to 71% if the maximum willingness to pay is £20,000.

In figure 4, the CEACs demonstrate that either the strategy of phone calls plus home visits by a HCP or the strategies of sending letters are cost effective. However by comparison, the strategy of using phone calls plus home visits by a HCP is the optimal strategy. If the NHS is willing to pay upto £10,000 for an additional QALY, the probability that phone calls plus home visits by a HCP is cost effective is around 57%, increasing to 69% if the maximum willingness to pay is £20,000.

Other sensitivity Analysis

Sensitivity analysis was done to explore the robustness of the base case results, including the impact of age, costs of CR and CVD events, quality of life, and efficacy of CR. The model was robust to changes in assumptions about the different parameters except for quality of life.

Quality of life loss due to CR

The impact of cardiac rehabilitation on quality of life was tested. It was assumed that that cardiac rehabilitation will result in disutility or a loss in quality of life. We did a threshold analysis to find the point at which CR becomes cost ineffective due to loss in quality of life. The model estimates that a loss in quality of life due to CR of more than 3.5% will make CR cost ineffective. Thus the model is sensitive to this assumption. This is an unlikely scenario unless CR is provided to very high risk patients whose health is made worse by participating in CR.

Efficacy of CR

The efficacy of CR was tested using the upper and lower confidence intervals. When the lower confidence interval is used, the ICERs are expected to improve and when the upper confidence interval the ICERs is expected to worsen. The model remained robust when both upper and lower confidence intervals were used. Impact of CR on mortality appears to have a bigger impact on the ICERs. When the lower CI is used the ICERs fall to about £5,400/QALY and when the upper CI is used the ICERs rise to about £19,730/QALY which is borderline cost effective.

QALY gain due to CR

The model is not sensitive to changes in additional QALYs as a result of CR. The base case model assumed that there was no difference in QALYs between those who participate in CR and those that do not. We used a multiplier of 0.052 reported by Oldridge et al in the sentivity analysis. The estimated ICERs decrease by almost half to about £4,940 per QALY gained. The model is robust to this assumption since we retrain the original conclusion..

Adherence to CR

The base case model assumed that patients will adhere to CR 100% However studies have shown that compliance rates are high in the first year and fall in subsequent years. The average for the first year is between 60 to 70% in the first 12 months, falling to between 45% to 70% after 3 years.We tested for adherence in our model. The model appears to be slightly sensitive to this assumption since compliance rates below 40% are not cost effective. For instance 40% compliance has an estimated ICER of about £20,000

Cost of CR

The results were sensitive to changes in the cost of rehabilitation but remained robust. The ICER ranged from about £2,320/QALY if the lowest cost per patient per year of £140 cited by Taylor et al is used to about £12,890/QALY when the cost is assumed to be about £800/patient per year cited by Beswich et al. As the cost of rehabilitation increases the ICER become less favourable

RR of non CVD death

The model assumed that patients after MI have a two fold increased risk of dying from any other causes than the general population. We tested this assumption in sensitivity analysis. When we assumed that there was no difference in non CVD mortality between the general population and the post MI patients the ICERs increased slightly to £8,980/QALY. Overall the model was robust to this assumption

Age and sex

Age and sex did not affect the results. However it should be acknowledged that the efficacy data available is mainly for middle aged men usually aged upto 65. Only mortality data was available a by age and sex in our model.

Discounting

The impact of the discounting was also explored. Assuming that there was no discounting, the results of the model remain robust with an estimated ICER of about £6,780/QALY. If the discount rate was raised to 6%, the ICERs slightly increased to £8,680/QALY. Thus the model was not sensitive to this parameter.

Efficacy of letters

When assumptions about the efficacy of letters were changed the model remained robust. When letters were assumed to result in a modest 1% increase in uptake, the ICERs compared to usual care increased to about £15,000/QALY. The ICERs of phone call plus home visit by a HCP improved as the efficacy of letters worsens, and worsens as the efficacy of letters improves. For instance when the efficacy of letters was assumed to result in a 100% increase in the uptake of CR letters the ICERs for letters compared to HCP + phone increased to about £11,000/QALY

Efficacy of phone calls plus home visit by HCP

In the base case model phone calls plus home visits by a HCP resulted in 111% increase in uptake of CR. We did a threshold analysis to find the point at which this intervention ceases to be cost effective. The model estimates that when the efficacy of phone call plus home visits by a HCP was assumed to result in an increase in uptake of CR of less than 55% then phone calls plus home visits by a HCP will not be cost effective at a willingness to pay value of £20,000/QALY. For instance if the strategy of HCP + phone resulted in increase of 50% in uptake of CR, letters will dominate them. Thus the model is sensitive to this assumption, but the analysis is speculative since the ranges used in sensitivity analysis are arbitrary.

HCP used

The HCP used in the base case model was a social worker. The impact of using another HCP assuming the same efficacy observed in the social worker trial was tested. We tested the use of a healthcare assistant whose wages are half those of the social worker. The ICER when letters were compared with phone calls plus home visits by a HCP improved slightly. Other health care professionals considered were community physiotherapist and a practice nurse. The results remained robust, suggesting that the type of health care professional used to increase the uptake of CR does not matter much.

Baseline uptake of CR

The model was not sensitive to assumptions about baseline uptake of cardiac rehabilitation. Studies have shown that participation rates ranges between 14–50%. In The base case model assumed a 40% participation rate. We varied the participation rate between 14% to 85%. The ICERs were below £10,000/QALY for all comparisons thus the model remained robust to this assumption

1.1.4. Limitations of the model

The assumptions about mortality and revascularisation were simplified, assuming that mortality was the same in the first year post MI and subsequent years. Study (Henderson, R. A. et al 1998) demonstrated that mortality may be greater than 6 fold in the first year post MI compared to subsequent years. Revascularisation rates may also differ in the first year post MI compared to subsequent years.

The model does not consider the effect of gender. In particular, most studies of effectiveness from which the data for this model were taken were conducted in predominantly male populations. Therefore these results ought to be interpreted with caution when being generalized to women.

Lack of long term data on clinical endpoints. The follow up in the trials were averaging upto 5 years. Benefits beyond the trial period are not fully known. The model assumed that the benefits observed during the trial period will persist for lifetime. This might not necessarily be true.

Efficacy of interventions used to increase uptake of CR were drawn from very small studies of less than 100 patients in each study. These small studies might not give reliable estimates of effectiveness of these interventions.

Finally, reliable utility data for these patients are lacking. Utility weights were taken from the literature and the estimates were crude, and in some cases, old. Although we believe that the assumptions we used around health state utilities were reasonable, the model showed that the cost-effectiveness of rehabilitation is not dependent on assumptions about health state utilities.

1.1.5. Conclusions

The results suggest that CR is highly cost effective when compared to no CR with 86% probability that CR is cost effective. These results are robust in sensitivity analysis except for quality life.

The results also showed that methods of increasing uptake of CR are cost effective. The ICERs were below £20,000/QALY for all comparisons in the base case model. The optimal strategy is the use of a phone plus a HCP. This result is sensitive to the efficacy of phone plus HCP. The model also shows that the HCP delivering CR does not matter much because the model remains robust in sensitivity analysis.

1.1.6. ADDITIONAL INFORMATION: SENSITIVITY ANALYSIS

Sensitivity analysis for relative risk of non-CVD death

RR of non CVD deathICER (cost/QALY)
0.5£10,120
1£8,980
4£6,940
8£6,070

Interpretation

The model assumed that patients after MI have a two fold increased risk of dying from any other causes than the general population. We tested this assumption in sensitivity analysis. When we assumed that there was no difference in non CVD mortality between the general population and the post MI patients the ICERs increased slightly to £8,980/QALY. Overall the model was robust to this assumption

Sensitivity analysis for Age and sex

AgeICER (cost/QALY) MalesICER (cost/QALY) Females
55£7,670£8,210
65£7,680£8,360
75£7,110£7,610
85£6,790£7,050

Interpretation

Age and sex did not affect the results. However it should be acknowledged that the efficacy data available is mainly for middle aged men usually aged upto 65. Only mortality data was available a by age and sex in our model.

Sensitivity analysis for efficacy of CR

ParameterICER (cost/QALY lower 95% CI)ICER (cost/QALY upper 95% CI)
Revascularisation£8,550£7,330
MI£7,300£8,580
Death£5,410£19,730

Interpretation

The efficacy of CR was tested using the upper and lower confidence intervals. When the lower confidence interval is used, the ICERs are expected to improve and when the upper confidence interval the ICERs is expected to worsen. The model remained robust when both upper and lower confidence intervals were used. Impact of CR on mortality appears to have a bigger impact on the ICERs. When the lower CI is used the ICERs fall to about £5,410/QALY and when the upper CI is used the ICERs rise to about £19,730/QALY.

Sensitivity analysis for reduction in quality of life due to CR

Reduction in QoL due to CRICER (Cost/QALY)
1%£9,440
3%£15,830
3.5%£19,040
4%£23,900

Interpretation

The impact of cardiac rehabilitation on quality of life was tested. It was assumed that that cardiac rehabilitation will result in disutility or a loss in quality of life. Arbitrary figures were used ranging between 1–4%. CR will cease to be cost effective at £20,000/QALY threshold if it resulted in quality of loss of more than 3.5%. This is an unlikely scenario unless CR is provided to very high risk patients whose health is made worse by participating in CR.

Sensitivity analysis for additional QALYs due to CR

Additional QALYs due to CRICER (cost/QALY)
1%£7,060
5.2%£4,940
10%£3,680

Interpretation

The model is not sensitive to changes in additional QALYs as a result of CR. The base case model assumed that there was no difference in QALYs between those who participate in CR and those that do not. We assumed there would be an increase in QALY due to CR ranging from 1% to 10%. The estimated ICERs ranged from £7,060 per QALY gained.for a 1% increase in QALY to about £3,680 for a 10% increase in QALY due to CR

Sensitivity analysis for compliance to CR

Compliance rateICER (cost/QALY)
50%£15,720
40%£19,650
35%£22,460
30%£26,200

Interpretation

The base case model assumed that patients will adhere to CR 100% However studies have shown that compliance rates are high in the first year and fall in subsequent years. The average for the first year is between 60 to 70% in the first 12 months, falling to between 45% to 70% after 3 years. We tested for adherence in our model. The model appears to be slightly sensitive to this assumption since compliance rates below 40% are not cost effective. For instance 40% compliance has an estimated ICER of about £20,000

Sensitivity analysis for Cost of CR

Cost of CR/patient/yearICER (cost/QALY)
£140£2,320
£300£4,880
£600£9,680
£800£12,890

Interpretation

The results were sensitive to changes in the cost of rehabilitation but remained robust. The ICER ranged from about £2,320/QALY if the lowest cost per patient per year of £140 cited by Taylor et al is used to about £12,890/QALY when the cost is assumed to be about £800/patient per year. As the cost of rehabilitation increases the ICER become less favourable

Sensitivity analysis for Cost of CVD events and procedures

ParameterICER Lower costs (50% less) (cost/QALY)ICER Upper costs (100% more) (cost/QALY)
Revascularisation£7,920£7,750
MI£7,730£7,920
Subsequent MI£7,790£7,990

Interpretation

The model is not sensitive to outcome costs. The mean costs were reduced by 50% and increased by 100% and the results remained robust, all below £8,000/QALY.

Sensitivity analysis for discounting

Discount rateICER (cost/QALY)
0%£6,780
6%£8,680

Interpretation

The impact of the discounting was also explored. Assuming that there was no discounting, the results of the model remain robust with an estimated ICER of about £6,780/QALY. If the discount rate was raised to 6%, the ICERs slightly increased to £8,680/QALY. Thus the model was not sensitive to this parameter

Sensitivity analysis for baseline uptake of CR

Baseline uptakeLetters vs. usual carePhone call plus home visit by HCP vs. Letters
14%£8,257£9,474
60%£7,952£8,236
85%£7,925£8,125

Interpretation

The model was not sensitive to assumptions about baseline uptake of cardiac rehabilitation. Studies have shown that participation rates ranges between 14–50%. In The base case model assumed a 40% participation rate. We varied the participation rate between 14% to 85%. The ICERs were below £10,000/QALY for all comparisons thus the model remained robust to this assumption

Sensitivity analysis for efficacy of letters

Efficacy of lettersLetters vs. usual carePhone call plus home visit by HCP vs. Letters
1%£14,969£8,167
10%£8,570£8,195
20.%£8,214£8,232
80.00%£7,948£8,953
100%£7,930£10,943

Interpretation

When assumptions about the efficacy of letters were changed the model remained robust. When letters were assumed to result in a modest 1% increase in uptake, the ICERs compared to usual care increased to about £15,000/QALY. The ICERs of phone call plus home visit by a HCP improved as the efficacy of letters worsens, and worsens as the efficacy of letters improves. For instance when the efficacy of letters was assumed to result in a 100% increase in the uptake of CR letters the ICERs for letters compared to HCP + phone increased to about £11,000/QALY

Sensitivity analysis for efficacy of phone plus HCP

Efficacy of phonesLetters vs. usual carePhone call plus home visit by HCP vs. Letters
50 %£7,998Dominated by letters
60 %£7,998£11,629
80 %£7,998£9,029

Interpretation

In the base case model phone calls plus home visits by a HCP resulted in 111% increase in uptake of CR. We did a threshold analysis to find the point at which this intervention ceases to be cost effective. The model estimates that when the efficacy of phone call plus home visits by a HCP was assumed to result in an increase in uptake of CR of less than 55% then phone calls plus home visits by a HCP will not be cost effective at a willingness to pay value of £20,000/QALY. For instance if the strategy of HCP + phone resulted in increase of 50% in uptake of CR, letters will dominate them. Thus the model is sensitive to this assumption, but the analysis is speculative since the ranges used in sensitivity analysis are arbitrary.

1.2. Economic analysis of ACE inhibitors in low risk patients with preserved LVDF

An additional analysis was undertaken to examine the cost effectiveness of treatment with ACE inhibitors compared to placebo in patients with preserved left ventricular dysfunction. The analysis used effectiveness data from a meta-analysis (Al-Mallah, M. H. et al 2006) which meta-analysed data from six trials (Braunwald, E. et al 2004), (Nissen, S. E. et al 2004), (Fox, K. M. and EURopean, trial On reduction of cardiac events with Perindoprilin stable coronary Artery disease Investigators 2003), (Arnold, J. M. O. et al 2003), (MacMahon, S. et al 2000) and (Pitt, B. et al 2001).

1.2.1. Methods

Population and sub-groups

The model considered a cohort of low risk post MI patients with preserved left ventricular dysfunction. Low risk is defined as the population who met the inclusion criteria of the meta-analysis (Al-Mallah, M. H., Tleyjeh, I M., Abdel-Latif, A. A. et al 2006) seen in primary and secondary care.

Interventions compared

The analysis assessed lifetime costs and effects of ACE inhibitors compared with placebo.

Outcomes

The treatment effects were measured in terms of reduction of cardiovascular events: non-fatal MI, revascularisation, unstable angina, heart failure, cardiovascular -related deaths and other deaths. Health outcomes for the cost-effectiveness analysis are summarised in the form of Quality Adjusted Life Years (QALYs).

Model structure and assumptions

A Markov model was developed to evaluate the incremental costs and effects of lifetime treatment with ACE inhibitors in secondary prevention of CVD events in low risk post MI patients from a UK NHS perspective.

In a Markov model there are a finite number of health states. It is assumed that at any point in time, all patients must be in one and only one of the states. The model then replicates how a hypothetical cohort of people moves between the states. Figure 1 shows a schematic representation of the patients’ pathways. All patients start in the event-free health state. During each six-month cycle of the model, a proportion of patients enter one of the qualifying event health states (MI, heart failure, unstable angina, revascularisation and death) while the remainder stay in the event free state. Patients can experience more than one non-fatal event in subsequent periods of the model.

Figure 1. Model structure for the cost effectiveness of ACE inhibitors in low risk patients with preserved LVDF compared to placebo.

Figure 1

Model structure for the cost effectiveness of ACE inhibitors in low risk patients with preserved LVDF compared to placebo.

The rate at which people move through the model is regulated by transition probabilities, which describe the likelihood of moving between states over each model cycle (six months). For illustration, the equivalent annual transition probabilities for a 65-year-old patient on placebo are shown in Table 1. The probabilities are derived from the placebo arm of the meta-analysis (Al-Mallah, M. H., Tleyjeh, I M., Abdel-Latif, A. A. et al 2006).

Table 1. Annual probabilities for an untreated 65 year old men.

Table 1

Annual probabilities for an untreated 65 year old men.

The model was run first assuming that the cohort was to receive placebo. The model was then re-run assuming that the cohort all received ACE inhibitors and complied 100% with transition probabilities adjusted to reflect the expected reduction in CVD events and revascularisations. Health care costs and QALYs were then estimated for each option by weighting the time spent in the various states by mean costs and ‘utilities’ (health-related quality of life) of the health states. The cost and utility data used in the model are described below.

The time horizon modelled is lifetime, with an assumed upper age of 100, by which time most of the cohort have died.

1.2.1.1. Baseline risks

The risk of secondary or subsequent events, following an MI, unstable angina, heart failure and revascularisation were taken from the placebo arm of the meta-analysis (Al-Mallah, M. H., Tleyjeh, I M., Abdel-Latif, A. A. et al 2006). The incidence of MI following revascularisation was taken from (Henderson, R. A., Pocock, S. J., Clayton, T. C. et al 2003).

Non-CVD related mortality by age and sex was taken from the life tables for England and Wales prepared by the Government Actuaries Department (GAD) (Government Actuaries Department 2006) and from data on the proportion of deaths due to CVD-related causes from the Office for National Statistics (Office for National Statistics 2006). In the base case model we assumed that the post MI cohort had a 2 fold increase in risk of non-CVD death compared with the general population, because they are a high risk population (expert opinion).

Table aBaseline non CVD related death

Deaths by age, sex and underlying cause, 2004 registrations, England and Wales
All cause ICD10: A00-R99Circulatory ICD: I00-I99Non-circulatory as proportion of all deaths (p)
MFMFMF
4512,4178,1393,9301,3620.680.83
5527,11717,6499,3303,5410.660.80
6552,70937,04119,78311,3040.620.69
7587,36788,40435,60735,9580.590.59
8551,329109,48820,81646,4700.590.58

Relative risk of death from non-circulatory causes in cohort compared with general population: 2

All cause mortaliy, estimated from life tables, 2002–4, England
Annual probability of death in age band
MF
450.00370.0025
550.00930.0059
650.02360.0154
750.05370.0406
850.08700.0807
Estimated non-circulatory deaths for post MI cohort
Annual probability of death in age band
MF
450.51%0.41%
551.23%0.94%
652.95%2.14%
756.37%4.82%
8510.35%9.30%

Treatment effects

The effectiveness of ACE inhibitors defined as the reduction in relative risks of mortality, heart failure, revascularisation and non fatal reinfaction was obtained from the meta-analysis (Al-Mallah, M. H., Tleyjeh, I M., Abdel-Latif, A. A. et al 2006).

Table bRelative risks of treatment (base case analysis)

COMPARATOR
Relative risks
INTERVENTIONMeanLower 95% CIUpper 95% CI
ACE inhibitorsRevascularisation0.930.871.00
MI0.840.750.94
Unstable angina0.930.831.05
Heart failure0.710.590.86
Mortality0.870.810.94
Cost data

The NICE reference case specifies that costs should be measured from an NHS and personal social services perspective. These should include the direct cost of drug treatment and also potential savings from avoided treatments due to reduced incidence of CVD and hospitalisations. Costs were calculated using cost weights for each of the states of the model, multiplied by the time spent in each state. Costs are at 2005 prices. As per current NICE guidance, an annual discount rate of 3.5% was used for both costs and health benefits (National Institute for Health & Clinical Excellence. 2006b).

The costs of health states used in the model are shown in Table 2c. Costs for revascularization which includes hospitalisation were taken from the NHS reference cost 2005.(Department of Health Reference Costs 2005 2005) It was assumed that 67% of patients will have PCI and 33% will have CABG and the costs were weighted to reflect this (expert opinion). The cost of the well states was assumed to be the outpatient cost which includes the costs of medication and monitoring costs were taken from the Statin HTA (National Institute for Health & Clinical Excellence. 2006a). The subsequent costs of MI and unstable angina were assumed to be the same and were taken from the NICE hypertension guideline 2006 (National Institute for Health and Clinical Excellence. 2006). Costs of acute MI (non-fatal reinfaction) were assumed to be the same as those of patients on thrombolysis, which includes the cost of hospitalisation, (Hartwell, D., Colquitt, J., Loveman, E. et al 2005). The cost of death was zero. Costs of drugs were taken from the drug tariff (Prescription Pricing Authority 2006)

Table c. Costs of health states.

Table c

Costs of health states.

Cost of heart failure was taken from the NHS reference cost 2005,(Department of Health Reference Costs 2005 2005) and subsequent costs after heart failure were assumed to be the same as those seen in subsequent MI patients (expert opinion). Costs of events were reduced by 50% and doubled in sensitivity analysis.

Quality of life (Utility)

In the NICE reference case, the value of health outcomes – including beneficial and harmful impacts of treatment on mortality and morbidity – is estimated using the Quality Adjusted Life Year (QALY) approach. This requires estimates of survival and quality of life associated with each health state included in the model.(National Institute for Health & Clinical Excellence. 2006b)

The utility values used in the model are shown in Table 2d and Table 2e. The values were taken from literature or the Harvard cost effectiveness registry database (Harvard CEA Registry 1997)

Table d. Health state utility weights.

Table d

Health state utility weights.

Table e. Utility weight by age.

Table e

Utility weight by age.

Utilities were adjusted to reflect the fact that health related quality of life in the general population decreases with age (i.e. multiply the disease utility weight by age utility weight). Age utility weights were taken from the Department of Health, Health Survey for England (Department of Health 1998)

1.2.1.2. Cost effectiveness

The results of cost-effectiveness analysis are presented as Incremental Cost-Effectiveness Ratios (ICERs), which determine the additional cost of ACE inhibitors per additional QALY gained compared with placebo

ICERs = (cost of ACE inhibitors - cost of placebo)/(QALY of ACE inhibitors - QALY of placebo)

Sensitivity analysis

The model includes a base case analysis supplemented with both deterministic and probabilistic sensitivity analysis. The impact of utility, costs of revascularisation, cost of ACE inhibitors and baseline risks for mortality, revascularisation second MI, heart failure and unstable angina were assessed.

1.2.2. Results

The base case results are presented for 65-year-old low risk men and women post MI with preserved left ventricular dysfunction. The results suggests ACE inhibitors are cost-effective with an estimated ICER of about £3,400/QALY gained for men and about £3,700 for women compared with placebo which is well below the level usually considered to be affordable in the NHS (about £20,000 to £30,000 per QALY).

Table fBase case results 65 year old male

Cost (£)Effect (QALYs)Incremental cost (£)Incremental effect (£)ICER (£/QALY)
Placebo£3,8477.72
ACE inhibitors£5,6338.24£1,7860.52£3,424

Table gBase case results 65 year old female

Cost (£)Effect (QALYs)Incremental cost (£)Incremental effect (£)ICER (£/QALY)
Placebo£4,2658.40
ACE inhibitors£6,1768.92£1,9110.52£3,707

Probabilistic sensitivity analysis

A probabilistic sensitivity analysis was also done, where all parameters are assigned a distribution and are allowed to vary at the same time. The results are reported below in the form of cost effectiveness acceptability curves (CEACs). These curves detail the probability that each strategy is cost effective over a range of potential maximum willingness to pay values that the NHS can afford to pay for an additional QALY.

The CEACs demonstrate that ACE inhibitors are cost effective when compared to placebo. The probability that ACE inhibitors are cost effective is around 70% at £20,000/QALY threshold. As expected the probability that an intervention is cost effective improves as the willingness to pay increases. Thus for a threshold of £5,000/QALY the probability that ACE inhibitors are cost effective is 59%, while at £30,000/QALY the probability increases to 72%.

Figure 2. Cost effectiveness acceptability curve, Cost effectiveness plane ACE Inhibitors versus placebo.

Figure 2Cost effectiveness acceptability curve, Cost effectiveness plane ACE Inhibitors versus placebo

Deterministic sensitivity analysis

A range of univariate sensitivity analyses were conducted to assess the impact of different input parameters on the base case results. Detailed results for all parameters are shown in the appendix.

Quality of life

The base case model assumed that the side effect profile of ACE inhibitors was the same as in the placebo arm. However when it was assumed that ACE inhibitors will result in loss of quality due to side effects of more than 2.1%, then ACE inhibitors would no longer be cost effective at £20,000/QALY threshold. For instance if the loss in quality of due to side effects are assumed to be about 2.5% the estimated ICERs is about £230,200/QALY. If the loss was 3% ACE inhibitors are dominated by placebo. Overall the result is sensitive to loss in quality of life due side effects of treatment.

Health state utilities were arbitrarily reduced and increased by 0.2. This did not affect the base case conclusions suggesting the model was is not sensitive to changes in health state utilities. The ICERs ranged between £3,370 to about £3,480/QALY.

Costs

Cost of events (cost of treating MI, heart failure, revascularizations, and unstable angina) were increased by 100% and reduced by 50%. The model remained robust with ICERs remaining ranging between about £3,300/QALY and £3,400/QALY in all cases examined.

Worse case scenario

A worse case scenario was examined were the cost of events were doubled, and treatment effects were set at their upper limit of the 95% confidence interval. In this case the ICERs increased to about £8,400/QALY. This is still within acceptable limits of what is usually considered affordable by the NHS. Thus the model is robust to the worse case scenario assumption.

Efficacy

Assumptions about the efficacy of treatment were tested using the 95% confidence interval. The model was robust in all cases when either the lower or the upper 95% confidence interval was used. When the upper 95% CI was used, the ICERs increased to about £6,100/QALY but were still within the range considered affordable by NHS.

RR of non CVD death, age and sex

Then model was robust to assumptions about the relative risk of death from other causes between the post MI cohort and the general population. The base case assumed a relative risk of 2. When it was assumed that there was no difference in mortality from other causes between the general population and the post MI cohort, the ICERs slightly increased to about £4,100/QALY.

The model was also robust to assumptions about age and sex. The estimated ICERs ranged between about £3,000/QALY for a 85 year old men to about and about £5,000/QALY for a 55 year old men. For women it ranged between £4,000/QALY for an 85 year old to about £5,500/QALY for 55 year old women. There was no big difference between sexes; ICERs were more favourable to men than women.

1.2.3. Limitations of the model

The model was based on various assumptions that could possibly bias the results.

The first limitation of the model arises because of the nature of Markov models. These assume that the probability of an individual moving to any given health state in one time period depends only on their current health state (there is no longer ‘memory’ in the model). Thus the probability of heart failure for a patient whose last CVD event was an MI is assumed to be the same irrespective of how many CVD events they have previously had. Similarly, a patient’s health outcome and health care costs incurred are assumed to depend only on their current health state. These assumptions are unlikely to be strictly true, and will tend to underestimate overall costs and overestimate health outcomes for the cohort. Thus, interventions that prevent more CVD events will tend to appear rather less cost-effective than they may be in reality. So the model is conservative in this respect.

A second potentially important limitation of the model is the lack of utility data for the side effects of the drug. However sensitivity analysis was done, assuming that ACE inhibitors would result in loss of quality of life. Assuming a loss in quality of life greater than 2.1%, ACE inhibitors will no longer be cost effective at £20,000/QALY threshold suggesting that the side effects profile of ACE inhibitors affects the model results yet there is no quality of life data that is available.

There is also lack of outcome data by age and sex and non white population. This implies that it is difficult to predict the relative cost-effectiveness of ACE inhibitors in these sub-groups. There is also lack of standard errors needed for the probabilistic sensitivity analysis. In the model we assumed the standard errors were a tenth of the observed mean values used in the base case model which might not always be the case.

Another limitation of the model relates to the treatment of withdrawals and non-concordance with treatment. Since the treatment effects are based on ‘intention-to-treat’ analyses, the impact of withdrawals and non-concordance from the trials is already included in the model. However, the model continues to attribute drug costs for all patients throughout their lifetime. This is a conservative assumption that will tend to underestimate the cost-effectiveness of treatment.

1.2.4. Conclusions

The use of ACE inhibitors in low risk patients with preserved left ventricular function is cost effective. The model is sensitive to assumptions about loss of quality of life due to assumed treatment side effects.

1.2.5. ADDITIONAL INFORMATION: SENSITIVITY ANALYSIS

Sensitivity analysis; quality of life loss due to side effects

% loss of QoL due to treatment side effectsCost/QALY
1%£5,650
2%£16,160
2.1%£20,000
2.5%£230,200
3%DOMINATED
Interpretation

The base case model assumed that the side effect profile of ACE inhibitors was the same as in the placebo arm. However when a threshold analysis was done, if ACE inhibitors treatment resulted in loss of quality of more than 2.1%, then ACE inhibitors would no longer be cost effective at £20,000/QALY threshold. For instance if the loss in quality of due to side effects are assumed to be about 2.5% the estimated ICERs is about £230,200/QALY. If the loss was 3% ACE inhibitors are dominated by placebo. Overall the result is sensitive to loss in quality of life due side effects of treatment. This however should be interpreted with caution since there was no published evidence supporting the idea that ACE inhibitor treatment resulted in side effects that were significantly different from placebo.

Sensitivity analysis; health state utilities ± 0.2

Health state(−0.2) cost/QALY(+ 0.2) cost/QALY
Revasularisation£3,420£3,420
Post Revasularisation£3,520£3,370
MI£3,420£3,430
Post MI£3,400£3,440
Unstable angina£3,420£3,430
Post unstable angina£3,480£3,370
Heart failure£3,420£3,430
Post HF£3,390£3,450
Interpretation

Health state utilities were arbitrarily reduced and increased by 0.2. This did not affect the base case conclusions suggesting the model was is not sensitive to changes in health state utilities. The ICERs ranged between £3,370 to about £3,480/QALY.

Sensitivity analysis cost of CVD events/health state costs

Cost of events50% less (cost/QALY)100% more (cost/QALY)
No event£3,320£3,630
Revasularisation£3,430£3,420
Post Revasularisation£3,380£3,510
MI£3,450£3,370
MI (subsequent)£3,440£3,400
Unstable angina£3,430£3,420
Unstable angina subsequent£3,390£3,480
Heart failure£3,440£3,390
Post HF£3,440£3,400
Interpretation

Cost of events (cost of treating MI, heart failure, revascularizations, and unstable angina) were increased by 100% and reduced by 50%. The model remained robust with ICERs remaining ranging between about £3,300/QALY and £3,400/QALY in all cases examined.

Sensitivity analysis; worse case scenario 1, doubling the cost of events and using upper confidence limit of the 95% CI

Cost (£)Effect (QALYs)ICER (£/QALY)
Placebo£7,6907.7193
ACE inhibitors£9,5307.9394£8,360
Interpretation

A worse case scenario was examined were the cost of events were doubled, and treatment effect was set at its upper limit of the 95% confidence interval. In this case the ICERs increased £8,400. This is still within acceptable limits of what is usually considered affordable by the NHS. Thus the model is sensitive to the worse case scenario assumption.

Sensitivity analysis; efficacy of ACE inhibitors treatment

OutcomeLower 95% CIUpper 95% CI
Revasularisation£3,270£3,600
MI£3,320£3,540
Unstable angina£3,280£3,600
Heart failure£3,330£3,550
Mortality£2,600£6,090
Interpretation

Assumptions about the efficacy of treatment were tested using the 95% confidence interval. The model was robust in all cases when either the lower or the upper 95% confidence interval was used. When the upper 95% CI was used, the ICERs increased to about £6,100/QALY but were still within the range considered affordable by NHS.

Sensitivity analysis; relative risk of non CVD death

Relative risk of non CVD deathcost/QALY
1£4,060
2£3,420
4£2,960
8£2,540
Interpretation

Then model was robust to assumptions about the relative risk of death from other causes between the post MI cohort and the general population. The base case assumed a relative risk of 2. When it was assumed that there was no difference in mortality from other causes between the general population and the post MI cohort, the ICERs slightly increased to about £4,100/QALY.

Sensitivity analysis; age and sex

Agecost/QALY (Males)cost/QALY (Females)
55£4,740£5,520
65£3,420£4,060
75£2,990£3,790
85£2,890£4,040
Interpretation

The model was also robust to assumptions about age and sex. The estimated ICERs ranged between about £3,000/QALY for a 85 year old men to about and about £5,000/QALY for a 55 year old men. For women it ranged between £4,000/QALY for an 85 year old to about £5,500/QALY for 55 year old women. There was no big difference between sexes; ICERs were more favourable to men than women.

1.3. Beta blockers economic model results

An additional analysis was undertaken which examined the cost effectiveness of a “new” generation beta blocker carvedilol in selected in post MI patients. Only one trial (Dargie, H. J. 2001) was identified which compared carvedilol with placebo. An economic analysis was performed using data from this trial and the results are presented below

1.3.1. Methods

Population and sub-groups

The model considered post MI patients with left ventricular dysfunction who met the inclusion criteria of the Carvedilol Post Infarct Survival Control in left ventricular Dysfunction (CAPRICORN) trial (Dargie, H. J. 2001). The model was run separately for different cohorts, defined by age (65, 75 and 85) and sex. The base case analysis is presented for 65-year-old men and women. However the trial evidence that the model this is based on included relatively few women (27%) or black patients, so the results may not be reliable for these sub-groups.

Interventions compared

The analysis assessed the costs and effects of carvedilol compared with placebo.

Outcomes

The treatment effects were measured in terms of prevention of cardiovascular events: non-fatal MI, hospital admission for heart failure, and cardiovascular-related deaths. Other cardiovascular events, including onset of stable or unstable angina, stroke, and peripheral vascular disease were not modelled, as they were not reported in the trial. Health outcomes for the cost-effectiveness analysis are summarised in the form of Quality Adjusted Life Years (QALYs), where one QALY represents one year of healthy life.

Model structure and assumptions

A Markov model was developed to evaluate the incremental costs and effects of lifetime treatment with third generation beta blockers for post MI patients with left ventricular dysfunction seen in primary care from a UK NHS perspective.

In a Markov model there are a finite number of health states. It is assumed that at any point in time, all patients must be in one and only one of the states. The model then replicates how a hypothetical cohort of people moves between the states.

shows a schematic representation of the patients’ pathways. All patients start in the event-free health state. During each six-month cycle of the model, a proportion of patients enter one of the qualifying event health states (MI, heart failure, or death) while the remainder remains in the event free state. Patients can experience more than one non-fatal event in subsequent periods of the model.

Figure 2. Model structure for third generation beta blockers.

Figure 2Model structure for third generation beta blockers

The rate at which people move through the model is regulated by transition probabilities, which describe the likelihood of moving between states over each model cycle (six months). These transition probabilities are adjusted for each subgroup by age and sex. For illustration, the equivalent annual transition probabilities for untreated 65-year-old men are shown in Table 1.

Table 1. Probabilities for a 65-year-old untreated man.

Table 1

Probabilities for a 65-year-old untreated man.

The model was run first assuming that the cohort received no intervention (placebo). The model was then re-run for the treatment arm with transition probabilities adjusted to reflect the expected reduction in CVD events from the clinical trial data. Health care costs and QALYs are then estimated for each option by weighting the time spent in the various states by mean costs and ‘utilities’ (health-related quality of life) of the health states. The cost and utility data used in the model are described below.

The time horizon modelled is lifetime, with an assumed upper age limit of 100, by which time most of the cohort have died.

1.3.1.1. Baseline risks

The probabilities of secondary cardiovascular events were taken from the placebo arm of the CAPRICORN trial (Dargie, H. J. 2001) Non-cardiovascular related mortality by age and sex was taken from the life tables for England and Wales prepared by the Government Actuaries Department (GAD) (Government Actuaries Department 2006) In the base case model we assumed that post MI cohort is at increased risk of non-cardiovascular death (2 fold risk) compared with the general population (expert opinion).

Table 2Baseline non-CVD related death

Deaths by age, sex and underlying cause, 2004 registrations, England and Wales
All cause ICD10: A00-R99Circulatory ICD: I00-I99Non-circulatory as proportion of all deaths (p)
MFMFMF
4512,4178,1393,9301,3620.680.83
5527,11717,6499,3303,5410.660.80
6552,70937,04119,78311,3040.620.69
7587,36788,40435,60735,9580.590.59
8551,329109,48820,81646,4700.590.58

Relative risk of death from non-circulatory causes in cohort compared with general population: 2

All cause mortaliy, estimated from life tables, 2002–4, England
Annual probability of death in age band
MF
450.00370.0025
550.00930.0059
650.02360.0154
750.05370.0406
850.08700.0807
Estimated non-circulatory deaths for post MI cohort
Annual probability of death in age band
MF
450.51%0.41%
551.23%0.94%
652.95%2.14%
756.37%4.82%
8510.35%9.30%

Treatment effects

The relative treatment effects of third generation beta blockers were taken from the CAPRICON trial (Dargie, H. J. 2001).

Table 3Relative risks of third generation beta blockers (base case analysis)

INTERVENTIONRelative risks
MeanLower CLUpper CL
Beta blockersMI0.590.390.90
heart failure0.860.671.09
Death0.750.580.96

Cost data

The NICE reference case specifies that costs should be measured from an NHS and personal social services perspective. These should include the direct cost of drug treatment and also potential savings from avoided treatments due to reduced incidence of CVD disease. Costs were calculated using cost weights for each of the states of the model, multiplied by the time spent in each state. Costs are at 2005/06 prices. As per current NICE guidance, an annual discount rate of 3.5% was used for both costs and health benefits. (National Institute for Health & Clinical Excellence. 2006b)

The cost of health states used in the model are shown in Table 4. Costs of acute MI (non-fatal reinfaction) were assumed to be the same as those of patients on thrombolysis, which includes the cost of hospitalisation Hartwell 2005 (Hartwell, D., Colquitt, J., Loveman, E. et al 2005). Costs of heart failure were taken from NHS reference costs. Subsequent MI costs were taken from NHS hypertension guideline 2006.(National Institute for Health and Clinical Excellence. 2006) Subsequent heart failure costs were assumed to be the same as those of MI (expert opinion)

Table 4. Costs of health states.

Table 4

Costs of health states.

Drug costs were taken from the prices quoted in the Drug Tariff, (Prescription Pricing Authority 2006) based on the usual dose for post MI patients. In the base case model a conservative approach was taken, using the most expensive dose of carvedilol 25mg and the use of the smaller dose of 6.25mg was tested in sensitivity analysis.

Table 5Drug costs

DrugCost per year (£)
Drug used in the model (25mg)6.25 mg
Carvedilol£113.67£81.08

1.3.1.2. Quality of life (Utility)

In the NICE reference case, the value of health outcomes – including beneficial and harmful impacts of treatment on mortality and morbidity – is estimated using the Quality Adjusted Life Year (QALY) approach. This requires estimates of survival and quality of life associated with each health state included in the model (National Institute for Health & Clinical Excellence. 2006b).

The utility estimates for MI was taken from study (Palmer, S., Sculpher, M., and Philips, Z. 2004), heart failure and post MI were taken from the Harvard cost effectiveness registry (Harvard CEA Registry 1997). Post heart failure was assumed to be the same as heart failure state.

Utilities were adjusted to reflect the fact that health related quality of life in the general population decreases with age (i.e. multiply the disease utility weight by age utility weight). Age utility weights were taken from the Department of Health, Health Survey for England (1996) (Department of Health 1998).

The base case model assumed that there was no loss in quality of life due to treatment side effects. This assumption was tested in the sensitivity analysis, assuming that treatment resulted in a reduction in quality of life of up to 10%.

Table 6Health state utility weights

Table 7Utility weight by age

Age groupAge utility weightSource
45–540.85(Department of Health 1998)
55–640.79
65–740.78
75+0.73

Cost effectiveness

The results of cost-effectiveness analysis are usually presented as Incremental Cost-Effectiveness Ratios (ICERs), which determine the additional cost of using one drug (X) per additional QALY gained compared with no intervention or another drug (Y):

ICERs = (cost of X - cost of Y)/(QALY of X - QALY of Y)

Sensitivity Analysis

The model includes a base case analysis supplemented with both univariate deterministic and probabilistic sensitivity analyses to test the impact of uncertainty over various model parameters and assumptions.

1.3.2. Results

The base case results are presented in tables Table 4 and Table 5 for 65-year-old men and women post MI with left ventricular dysfunction. The results suggests that third generation beta blockers are highly cost-effective for this population with an estimated ICER of about £1,100/QALY gained, compared with placebo which is well below the level usually considered to be affordable in the NHS (about £20,000 to £30,000 per QALY).

Table 4. Base case results 65 year old male.

Table 4

Base case results 65 year old male.

Table 5. Base case results 65 year old female.

Table 5

Base case results 65 year old female.

Figure 3. Base case results 65-year-old male, Cost effectiveness plane.

Figure 3Base case results 65-year-old male, Cost effectiveness plane

Figure 4. Base case results 65-year-old female, Cost effectiveness plane.

Figure 4Base case results 65-year-old female, Cost effectiveness plane

Probabilistic sensitivity analysis

A probabilistic sensitivity analysis was also done, where all parameters are allowed to vary at the same time. The results are reported below in the form of cost effectiveness acceptability curves (CEACs). These curves detail the probability that each strategy is cost effective over a range of potential maximum willingness to pay values that the NHS can afford to pay for an additional QALY.

The CEACs demonstrate that beta blockers are cost effective when compared to placebo. The probability that beta blockers are cost effective is around 93% at £20,000/QALY threshold. Even at lower thresholds such as £5,000/QALY beta blockers are still highly cost effective with a 90% probability of being cost effective. This suggest that beta blocker treatment in patients with left ventricular dysfunction is value for money.

Figure 3–4. Cost effectiveness acceptability curve.

Figure 3–4Cost effectiveness acceptability curve

Deterministic sensitivity analysis

A range of univariate sensitivity analyses were conducted to assess the impact of different input parameters on the base case results. Detailed results for all parameters are shown in the appendix. The following parameters were tested costs of drugs, cost of events, discount rate, utility, age, and relative risk of non-CVD deaths and efficacy of treatment.

Efficacy of treatment

The results are not sensitive to uncertainty over the magnitude of treatment effects estimated from the CAPRICON trial (Dargie, H. J. 2001). When the relative risks of carvedilol compared with no intervention were increased to their upper 95% confidence limits and reduced to their lower 95% confidence limits the results remained robust. The ICERs ranged between about £800/QALY to about £1500/QALY when both lower and upper confidence intervals are used.

Relative risk of non CVD death

Relative risk of non CVD mortality does not affect the conclusions of the model. If its assumed that patients post MI have the same risk of dying from non circulatory causes as the general population, the ICERs increase by £20 to £1110. If it was assumed that post MI patients have a six fold increase in risk of dying from non circulatory causes, the ICERs slightly fell by £60 to £1030/QALY. This suggests that the model is robust to this assumption.

Quality of life loss due to treatment side effects

The model is robust assumptions about loss of quality of life as a result of treatment side effects. If it was assumed that beta blocker treatment would result in a 1% loss in quality of life, the estimated ICERs would be about £1090/QALY and if the loss was assumed to be as big as 10%, the ICERs will increase four fold to £4360/QALY, still within the range considered affordable by NHS.

Health state utilities

The results are not sensitive to assumptions about the health state utilities used in the base case model. When the observed health state utilities were arbitrarily reduced by 0.2, the model remained robust. When they increased by 0.2 the results did not change. The ICERs ranged between about £1100 to about £1200/QALY.

Cost of health states

The model is not sensitive to assumptions about the health state costs. When they were doubled or reduced by 50% the ICERs ranged between about £1,000/QALY to about £1,300/QALY.

Age and sex

The model is robust to assumptions about age and sex. However it should be noted that efficacy data by age and sex is not available except for baseline mortality. The trial data mainly had male population aged between 60–65 years. For ages below 55 and above 70 and to females the results need to be interpreted with caution.

Worse case scenarios

A worse case scenario was examined were the cost of events were doubled, and treatment effect was set at its upper 95% confidence interval. In this case the ICERs increased by ten fold, to about £11,000/QALY. This however was still within the range of what is considered affordable by the NHS. Thus in this worse case scenario, the model remained robust.

Another scenario was tested where in addition to doubling the costs of events and using the upper 95% confidence interval for treatment effect, it was also assumed that ACE inhibitors will result in a 1% loss in quality of life due to side effects of treatment. The ICER increased to about £55,000/QALY. The model was not robust to this worse case scenario. It is however important to note that this is an unlikely scenario since the cost of events/ health states are not as high as suggested in this assumption and the efficacy of beta-blockers is not as low as again suggested in this assumption.

1.3.3. Limitations of the model

The model was based on various assumptions that could possibly bias the results.

The first limitation of the model arises because of the nature of Markov models. These assume that the probability of an individual moving to any given health state in one time period depends only their current health state (there is no longer ‘memory’ in the model). Thus the probability of heart failure for a patient whose last CVD event was an MI is assumed to be the same irrespective of how many CVD events they have previously had. Similarly, a patient’s health outcome and health care costs incurred are assumed to depend only on their current health state. These assumptions are unlikely to be strictly true, and will tend to underestimate overall costs and overestimate health outcomes for the cohort. Thus, interventions that prevent more CVD events will tend to appear rather less cost-effective than they may be in reality. So the model is conservative in this respect.

A second potentially important limitation of the model is the lack of utility data for the side effects of the drug. However exploratory sensitivity analysis was done assuming that carvedilol would result in loss of quality of life of upto 10%, but the results remained robust. This suggests that side effects profile might not affect the base case conclusions.

There is also lack of outcome data by age and sex and non white population. This implies that it is difficult to predict the relative cost-effectiveness of third generation beta blockers in these sub-groups. There is also lack of standard errors needed for the probabilistic sensitivity analysis. In the model we assumed the standard errors were a tenth of the observed mean values used in the base case model which might not always be the case.

Another limitation of the model relates to the treatment of withdrawals and non-concordance with treatment. Since the treatment effects are based on ‘intention-to-treat’ analyses, the impact of withdrawals and non-concordance from the trials is already included in the model. In CAPRICON (Dargie, H. J. 2001) 20% of patients were permanently withdrawn from treatment. However, the model continues to attribute drug costs for all patients throughout their lifetime. This is a conservative assumption that will tend to underestimate the cost-effectiveness of treatment.

1.3.4. Conclusions

This analysis suggests that treatment with third generation beta blockers is cost effective. This result is robust for all the parameters tested in sensitivity analysis including a worse case scenario.

1.3.5. Addaitional information: Sensitivity analysis

All sensitivity analysis applies to 65 year old men

Sensitivity analysis, efficacy of beta blocker treatment (95% CI)
OutcomeICER for Lower 95% CIICER for Upper 95% CI
MI£880£1,420
Heart failure£790£1,530
Mortality£1,060£1,530
Interpretation

The model is stable to assumptions about the efficacy of treatment. The ICERs ranges between about £800/QALY to about £1500/QALY when both lower and upper confidence intervals are used.

Sensitivity analysis, quality of life loss due to treatment side effects
Quality of life loss due to treatment side effectscost/QALY
1%£1,180
2%£1,180
5%£1,750
10%£4,360
Interpretation

The model is robust assumptions about loss of quality of life as a result of treatment side effects. If it was assumed that beta blocker treatment would result in a 1% loss in quality of life, the estimated ICERs would be about £1090/QALY and if the loss was assumed to be as big as 10%, the ICERs will increase four fold to £4360/QALY, still within the range considered affordable by NHS.

Sensitivity analysis; health state utilities ± 0.2
Health state(0.2 less) cost/QALY(0.2 more) cost/QALY
MI£1,090£1,100
well post MI£1,100£1,090
Heart failure£1,090£1,090
well post heart failure£1,180£1,020
Interpretation

The results are not sensitive to assumptions about the health state utilities used in the base case model. When the observed health state utilities were arbitrarily reduced by 0.2, the model remained robust. When they increased by 0.2 the results did not change. The ICERs ranged between about £1100 to about £1200/QALY.

The model is very robust to all assumptions tested with ICERs remaining the same as in the base case or differing very slightly as shown in the table above.

Sensitivity analysis; relative risk of non CVD death
Relative risk of non CVD mortalityICER (Cost/QALY)
1£1,110
2£1,090
4£1,060
6£1,030
Interpretation

Relative risk of non CVD mortality does not affect the conclusions of the model. If its assumed that patients post MI have the same risk of dying from non circulatory causes as the general population, the ICERs increase by £20 to £1110. If it was assumed that post MI patients have a six fold increase in risk of dying from non circulatory causes, the ICERs slightly fell by £60 to £1030/QALY. This suggests that the model is robust to this assumption.

Sensitivity analysis; health state costs
Cost of health state50% less (cost/QALY)100% more (cost/QALY)
WELL£1,010£1,260
MI (ACUTE)£1,150£980
Well post MI£1,080£1,110
Heart Failure£1,100£1,070
Well post heart failure£970£1,330
Interpretation

The model is not sensitive to assumptions about the health state costs. When they were doubled or reduced by 50% the ICERs ranged between about £1,000/QALY to about £1,300/QALY.

Sensitivity analysis; Age and sex
AGEMALE cost/QALYFEMALE cost/QALY
55£1,070£1,080
65£1,090£1,100
75£1,110£1,120
85£1,070£1,080
Interpretation

The model is robust to assumptions about age and sex. However it should be noted that efficacy data by age and sex is not available except for baseline mortality. The trial data mainly had male population aged between 60–65 years. For ages below 55 and above 70 and to females the results need to be interpreted with caution.

Sensitivity analysis; Worse case scenario 1, costs of health state doubled, treatment effects set the upper limit of the 95% CI
Cost (£)Effect (QALYs)ICER (£/QALY)
Placebo£48303.402509
Beta Blockers£55003.4643036£10870
Interpretation

A worse case scenario was examined were the cost of events were doubled, and treatment effect was set at its upper 95% confidence interval. In this case the ICERs increased by ten fold, to about £11,000/QALY. This however was still within the range of what is considered affordable by the NHS. Thus in this worse case scenario, the model remained robust.

Sensitivity analysis; Worse case scenario 2, costs of health states doubled, treatment effects set at the upper limit of the 95% CI, 1% loss in quality of life due to treatment side effects
Cost (£)Effect (QALYs)Incremental cost (£)Incremental effect (£)ICER (£/QALY)
Placebo£4,8283.402509
Beta Blockers£5,4993.4148236£671.420.0123147£54,522
Interpretation

Another scenario was tested where in addition to doubling the costs of events and using the upper 95% confidence interval for treatment effect, it was also assumed that ACE inhibitors will result in a 1% loss in quality of life due to side effects of treatment. The ICER increased to about £55,000/QALY. The model was not robust to this worse case scenario. It is however important to note that this is an unlikely scenario since the cost of events/ health states are not as high as suggested in this assumption and the efficacy of beta-blockers is not as low as again suggested in this assumption.

1.4. Economic analysis of omega-3 fatty acid supplementation compared to no supplements for patients following MI

1.4.1. Introduction

During validation of the Post Myocardial Infarction guideline some questions were raised about the robustness of the evidence of effectiveness and cost-effectiveness for the recommendation on use of omega-3 fatty acid supplements. NICE’s Guidance Executive has asked the NCC and GDG to reconsider this evidence and do a further economic analysis on the cost-effectiveness of omega-3 fatty acids.

1.4.2. Clinical evidence

The recommendation in the draft guideline was based on the GISSI-P trial (GISSI Prevenzione Investigators. 1999), which found a reduced incidence of cardiovascular deaths in patients recruited within 3 months of an acute MI treated with an omega-3-acid ethyl ester supplement (850–882mg EPA and DHA as ethyl esters in the average ratio of EPA/DHA of 1:2.

There are many other trials of omega-3 fatty acids, dietary and supplemental, in various patient populations at different levels of cardiovascular risk. A Cochrane review (Hooper, L. et al 2004) found significant heterogeneity in these data, essentially due to one large study in patients with angina (Burr, M. L. et al 2003) When this study was taken out, the heterogeneity was removed and the meta-analysis suggested a significant reduction in mortality with omega 3, largely due to two studies in patients recruited shortly after acute myocardial infarction DART1(Burr, M. L. et al 1989) and (GISSI Prevenzione Investigators. 1999) The negative effects of DART2 appeared to offset the positive effects in DART1 and GISSI-P.

(Hooper, L., Griffiths, E., Abrahams, B. et al 2004) considered various possible explanations for this difference and concluded:

“It may be that the effect of omega 3 fats on cardiovascular disease is smaller than previously thought (if indeed the effect does exist). Alternatively it may be that effects in those who have had a myocardial infarction are protective of death, but the effects in men with angina and no infarction are not…” (p16 Hooper et al 2004)

The researchers on the DART1 and DART2 studies suggested that the effect might be due to interaction between fish oil and medication in angina patients (Burr, Dunstan and George 2005). Other hypotheses are that the benefits of omega-3 could be due to promotion of electrical stability, reduced platelet thrombogenicity or avoidance of damage from unstable plaques in the early post-MI period.

1.4.3. Cost-effectiveness evidence

Two cost-effectiveness analyses based on GISSI-P were available to the GDG – one from a company submissionSalvoy 2004, (Innovus Research (UK) Ltd. 2004) and another from a published study (Franzosi, M. G. et al 2004), part funded by another company (Pharmacia & Upjohn). The Solvay submission estimated an incremental cost effectiveness ratio (ICER) of £15,189 over the four-year trial period, and £3,717 per QALY extrapolated over the patients’ lifetimes. Though generally of good methodological quality, the Solvay submission did not report the sensitivity of their findings to the effectiveness data or assumptions.

The published analysis by Franzosi and colleagues (Franzosi, M. G., Brunetti, M., Marchioli, R. et al 2004) used rather more conservative assumptions, and estimated an ICER of 24,603 euros per life year gained (LYG) (with a range of 15,721 to 52,524 euros for a best-case and worst-case analysis). It is unclear whether this estimate would lie below the NICE threshold of £20–30,000 per QALY.

Another cost-effectiveness analysis based on the GISSI-P trial has since been published Lamotte et al (Lamotte, M. et al 2006). This analysis, also funded by Solvay, presented results from the perspective of the Australian, Canadian, German, Polish and Belgian health care systems. It used a different modelling approach to that in the Solvay submission, but arrived at similar results (5,346 to 8,315 euro per LYG, compared with £2,812 per LYG in the submission). Lamotte et al estimated that treatment would still be cost-effective (relative to the five countries’ maximum willingness-to-pay), if the risk of cardiovascular death with treatment were up to 24% to 40% higher than observed in GISSI-P. They also conducted a probabilistic sensitivity analysis, in which they estimated the impact of uncertainty over the relative risk reductions, as reflected in the 95% confidence intervals from the GISSI-P trial. According to this analysis, the probability that supplementation is cost-effective was estimated at around 98%. However, this did not allow for uncertainty over other model assumptions or parameters. For example, the model assumed that patients dying in the study period lost 12–13 years of life and this was not tested in sensitivity analysis.

On balance the current evidence suggests that omega-3 supplements may be a cost-effective intervention for patients after MI. However, there is considerable uncertainty over this finding. In particular, it was unclear whether the cost-effectiveness of supplements is robust to different methods of estimating their clinical effectiveness.

1.4.4. Aim for further economic analysis

To estimate the cost-effectiveness of omega-3 fatty acid supplementation for patients following MI who cannot comply with dietary recommendations.

1.4.5. Methods for economic analysis

Population

Patients who have had an MI within 3 months and who are unable to eat sufficient oily fish of 2–4 portions per week to meet the recommended intake of approximately 3.5g eicosapentaenoic acid (EPA) and 2.5g decosahexaenoic acid (DHA) per week. Subgroup analysis was performed to estimate the cost-effectiveness of supplementation for people who partially comply with the recommended dietary intake of oily fish.

Intervention

The analysis compared increased intake of omega-3 fatty acids from supplemental sources compared with no supplementation. The supplements considered were:

  • 1g per day omega-3-acid ethyl esters (460mg EPA, 380mg DHA per capsule) (Omacor)
  • 3g per day omega-3-marine triglycerides (170mg EPA, 115mg DHA per capsule) (Maxepa)

Both of the above options provide the recommended levels of EPA and DHA, assuming no dietary intake. The cost-effectiveness of supplements for patients who partially meet the recommended dietary intake of oily fish was estimated by assuming that patients use half the above doses: one capsule every other day for Omacor; or for Maxepa, instead of taking the supplements twice a day they will take them once a day.

The use of other over-the-counter supplements was not considered due to potential concerns about contamination in unlicensed products. The Cochrane review (Hooper, L., Griffiths, E., Abrahams, B. et al 2004) discusses potential concerns over cancers and neurological deficits that could possibly be increased due to dioxin and PCB contamination of fish oils. Although they found no direct evidence for this in the RCT or cohort data, they note that there is a lack of data on important outcomes. They conclude “independent analysis of the levels of toxins in named brands of fish oil supplements and oily fish sold for food should be more widely available” (p20 Hooper et al 2004).

Source of effectiveness data

In the absence of evidence of a difference in effect between dietary and supplemental sources of omega-3 fats, we assume equivalence (at equivalent doses of EPA/DHA). Thus evidence from trials of dietary or supplemental sources was pooled where relevant. Thus estimates of effectiveness for the base case analysis were taken from a meta-analysis of the results of DART 1 (Burr, M. L., Fehily, A. M., Gilbert, J. F. et al 1989) and GISSI-P trials.(GISSI Prevenzione Investigators. 1999) In addition data from GISSI-P and DART 1 was considered in the sensitivity analysis. This is based on the hypothesis that the effect observed in these trials is specific to patients who have recently had an MI, and that the results of the other main trial DART2 (Burr, M. L., shfield-Watt, P. A., Dunstan, F. D. et al 2003) are not relevant to this population.

The outcomes considered were total deaths, non-fatal MI, non-fatal stroke and revascularisations. Other outcomes such as heart failure, peripheral artery disease were not considered because very few events were recorded in both trials.

Table 1Treatment effect used in the model

Meta-analysis (Base model)GISSI-P aloneDART1 alone
OutcomeMeanLower CLUpper CLMeanLower CLUpper CLMeanLower CLUpper CL
MI1.140.751.740.960.801.141.490.972.30
STROKE1.220.911.641.190.881.612.510.4912.89
Revascu1.050.971.131.050.971.131.050.971.13
CVD death0.790.670.930.840.720.970.700.530.91
Total mortality0.810.680.960.860.770.970.710.550.92

The company submission used the results of a four way analysis from the GISSI-P trial, and for our base model, we used the same results from the meta-analysis and did sensitivity analysis to estimate the impact of uncertainty over the treatment effects (as reflected in the 95% confidence intervals estimated from the meta-analysis) and various other model parameters.

The model was not adjusted for non-compliance. We assumed compliance issues were accounted for in the intention-to-treat results. Assuming 100% compliance tend to over-estimate costs, thus our model is conservative biasing the results against treatment.

The Cochrane review (Hooper, L., Griffiths, E., Abrahams, B. et al 2004) found no evidence of long-term side effects of omega-3. However, they did find that increased omega-3 intake was significantly associated with drop outs due to side effects and gastrointestinal (GI) side effects. The model included a loss of quality-of-life due to GI side effects, based on the estimated incidence in the Cochrane review, pooling results across all levels of cardiovascular risk. This assumes that the rates of such side effects do not differ for the post-MI population.

Estimation of costs and effects

The costs and effects of treatment were estimated over a lifetime horizon using a cohort Markov modelling approach. We used a twelve-month model cycle length. This period was deemed sufficiently short to ensure that it is unlikely that patients would experience two events within the same cycle.

Baseline non-CVD mortality rates in the absence of additional omega-3 were estimated by age from population data for England and Wales. That is Governments Actuary’s Department and Office for National Statistics (Government Actuaries Department 2006) (Office for National Statistics 2006) and adjusted for assumed increased risks following a first MI. Incidence rates for CVD mortality, non-fatal MI and stroke following a first MI, in the absence of treatment, were estimated from the observed rates in the trial control groups. Estimates for sensitivity analysis were also taken from a cohort study by Kaplan 2002 (Kaplan RC, Heckbert SR Furberg CD Psaty BM. 2002), in which 2677 patients were followed up for an average of 3.4 years after an MI. The Kaplan data was also used to estimate the distribution of CVD death, non-fatal MI and non-fatal stroke by age, and the proportion of these events that occurred in the first year after an initial MI. Risks of stroke following a first stroke were estimated from a cohort study by Hardie et al 2004 (Hardie K, Hankey GJ Jamrozik K Broadhurst RJ Anderson C. 2004). The incidence of revascularisation by age was estimated from Johansen et al 1998 (Johansen H, Nair C Taylor G. 1998).

It has been reported that the survival benefits of omega-3 following myocardial infarction appear early and do not persist in the longer term Ness et al 2002 (Ness, A. R. et al 2002). In the base case analysis we assumed that treatment effects do not persist beyond the longest trial period (3.5 years for GISSI-P), and that supplements are only used for this time. We tested these assumptions in sensitivity analysis.

Costs were estimated from the perspective of the NHS and discounted at an annual rate of 3.5% in accordance with NICE guidance (National Institute for Health & Clinical Excellence. 2006b).. The cost of omega-3 supplements were taken from the BNF (British National Formulary 2007). The cost for non-fatal MI and strokes were based on those reported in the NICE technology appraisal of statins Ward et al 2005 (National Institute for Health & Clinical Excellence. 2006a), adjusted for inflation.

Outcomes were estimated in the form of quality adjusted life years (QALYs). The quality of life (‘utility’) associated with various health states in the post-MI population was also taken from the NICE statin technology appraisal (National Institute for Health & Clinical Excellence. 2006a) Utility was adjusted for age, using estimates from a representative general population sample in the Health survey of England 1996 (Department of Health 1998). QALYs were discounted at 3.5% per annum.

Cost effectiveness

The results of cost-effectiveness analysis are presented as Incremental Cost-Effectiveness Ratios (ICERs), which estimate the additional cost per additional QALY gained using Omega 3 supplements compared with no supplements.

Sensitivity Analysis

The model includes a base case analysis supplemented with univariate deterministic sensitivity analyses to test the impact of uncertainty over various model parameters and assumptions.

1.4.6. Results

The base case results are presented for patients aged 55 years in Table 2. These suggest that for post-MI patients who do not comply with dietary advice to eat 2–4 portions of oily fish per week, omega-3-acid ethyl esters supplements are cost-effective, with an estimated ICER of about £12,500 per QALY.

Table 2. Base case results for omega-3-acid ethyl esters supplements compared with no supplements in 55 year old patients after MI who do not comply with dietary recommendations.

Table 2

Base case results for omega-3-acid ethyl esters supplements compared with no supplements in 55 year old patients after MI who do not comply with dietary recommendations.

The supplements are estimated to be rather less cost-effective for younger patients and more cost-effective for older patients (see Table 3 below).

Table 3. Estimated cost-effectiveness by age – base case assumptions.

Table 3

Estimated cost-effectiveness by age – base case assumptions.

It will be more cost-effective from an NHS perspective if some or all of the recommended intake of omega 3 fatty acids could be obtained from dietary sources. For example, if only half the quantity of supplements is required, the estimated ICER for a 55 year old falls to £9,267 per QALY.

Duration of treatment costs and effects

In the base model we assumed that the benefits and costs of supplementation persist for 3.5 years, as this was the longest duration of demonstrated effectiveness (GISSI Prevenzione Investigators. 1999). The duration of the other included trial (Burr, M. L., Fehily, A. M., Gilbert, J. F. et al 1989) was two years, and a long-term follow-up study found that treatment effects did not persist beyond two years (Ness, A. R., Hughes, J., Elwood, P. C. et al 2002) If we assume that treatment costs and effects only last for two years, omega 3 supplementation appears to be less cost-effective (Table 4). At age 55 the estimated ICER is £23,400, which is above the £20,000 threshold. Conversely, if we assume that treatment effects and costs persist for life, supplementation appears to be more cost-effective: £6,600 per QALY for 55 year olds.

Table 4. Sensitivity to duration of treatment costs and effects.

Table 4

Sensitivity to duration of treatment costs and effects.

Clearly if the benefit of omega 3 is of limited duration, it will not be cost-effective to continue using, and paying for, supplements beyond this period. If we assume that the benefits will cease at 3.5 years and costs will persist for life – that is that people continue to receive omega 3 supplements but they do not derive any benefit from them - omega-3-acid ethyl esters supplements would only appear to be cost-effective for older patients (age 65 and over).

Source of effectiveness data

The base model used estimates of treatment effects from a meta-analysis of DART 1 and GISSI-P trials. When we considered results of the GISSI-P trial alone, the ICERs increased slightly (Table 5). Treatment remained cost-effective with the GISSI-P data, except for the 45 year old group, for whom the estimated ICER was above the £20,000 per QALY threshold. The results using the DART1 data alone were very similar to those using the pooled data.

Table 5. Sensitivity to source of effectiveness estimates.

Table 5

Sensitivity to source of effectiveness estimates.

Uncertainty over the size of treatment effects

The robustness of the results to uncertainty over the size of treatment effects was assessed using the upper and lower 95% confidence intervals from the meta-analysis (Table 6). The model results remained robust when the treatment effects were improved (set to their lower confidence interval) and worsened (upper confidence interval) for all outcomes except for all cause mortality. When the upper 95% confidence limits were used for all cause mortality, omega-3-acid ethyl esters supplements were no longer cost effective at the £20,000/QALY threshold. The estimated ICER was about £130,700 per QALY for a person aged 55 years, £37,800 for a 65 year old and £20,400 for a 75 year old.

Table 6. Sensitivity to upper and lower confidence limits of treatment effects: age 55.

Table 6

Sensitivity to upper and lower confidence limits of treatment effects: age 55.

Outcomes included in model

In the meta-analysis, only all cause mortality was found to be significantly different between treatment groups. If we assume no effect for the other outcomes (non-fatal MI, non-fatal stroke and revascularisation) and model mortality alone, the results become slightly more favourable (Table 7). Thus the model results are largely driven by the treatment effect on all cause mortality.

Table 7. Sensitivity to inclusion of non-fatal outcomes (MI, stroke and revascularisation).

Table 7

Sensitivity to inclusion of non-fatal outcomes (MI, stroke and revascularisation).

Source of baseline event rates

In the base case model, the annual risks of cardiovascular disease events (non-fatal MI, non-fatal stroke, revascularisation and cardiovascular disease-related mortality) in the absence of supplements was taken from the rates observed in the control groups of the included trials (Burr, M. L., Fehily, A. M., Gilbert, J. F. et al 1989) and (GISSI Prevenzione Investigators. 1999) These included 6,676 patients followed up for an average of 3.3 years. Estimates from a cohort study (Kaplan RC, Heckbert SR Furberg CD Psaty BM. 2002) gave rather higher ICERs (less cost-effective) (Table 8). Supplements still appeared to be cost-effective for people aged 55 and older, but not for 45 year olds (based on the £20,000 per QALY cost-effectiveness threshold).

Table 8. Sensitivity to source of baseline cardiovascular disease risks (MI, stroke, revascularisation, cardiovascular disease-related death).

Table 8

Sensitivity to source of baseline cardiovascular disease risks (MI, stroke, revascularisation, cardiovascular disease-related death).

Relative Risk of non cardiovascular disease mortality

Packham C et al (Packham C Gray D Silcocks P Hampton J 2000) and Robinson M et al {Robinson, 2005 5309 /id} estimated that the relative risk of dying from non cardiovascular disease in a cohort of patients with coronary heart disease compared with the general population lies between 2 and 8. We used a conservative estimate of 2 for the base case model. If we assume that there is no difference in non cardiovascular mortality between the general population and those with coronary heart diseases, the ICERs rise and treatment no longer appears to be cost-effective for younger patients (Table 9). When the risk is assumed to be around 4, the ICERs fall.

Table 9. Sensitivity to assumed relative risk of non-cardiovascular disease mortality.

Table 9

Sensitivity to assumed relative risk of non-cardiovascular disease mortality.

Cost of supplements

The base model used Maxepa, which was used in the DART1 trial and costs about £150 a year. We also tested the use of the supplement used in the GISSI-P trial (Omacor), which is slightly more expensive (£181 a year). The model results remained cost effective, although for younger patients the estimated ICER was very close to the £20,000 per QALY threshold (Table 10). If we assume clinical equivalence between these supplements, it will not be cost-effective to use the more expensive product.

Table 10. Sensitivity to price of supplements.

Table 10

Sensitivity to price of supplements.

Impact of treatment side effects

The base model assumes that there is a 0.07% loss in quality of life due to treatment side effects. This is probably an over-estimate, as it is based on the assumption that the additional 5% of patients who reported gastrointestinal (GI) side effects in omega-3-acid ethyl esters supplement trials (Hooper et al 2004) all experience a permanent loss of quality of life of 1.4%, which is an estimate for of the quality of life loss due to “nausea, vomiting or diarrhoea for 5 days” Anderson 1985 (Anderson JP, Moser RJ. 1985). In reality many of these patients would have only experienced transient effects, and those with longer lasting or more serious effects would have been likely to stop taking the supplements.

The Hooper review (Hooper, L., Griffiths, E., Abrahams, B. et al 2004) found that there were significantly more drop outs due to side effects with omega 3 than in the control groups, although overall drop out rates were not significantly different. Any loss of effectiveness due to drop outs is included in the model through the intention-to-treat estimates of treatment effects. No adjustment is made for the reduced cost of supplements due to drop outs, but if anything this will tend to bias the model against supplementation.

In addition to the quality of life loss, the base case model assumes that an additional GP visit (cost £24) is required per patient per year to treat side effects. This is also likely to be conservative, since only a minority of patients report side effects and these appear to be relatively minor in nature.

Assumptions about the cost and quality of life loss due to side effects made little difference to the base case results, which still showed that omega-3-acid ethyl esters supplements were cost effective, except possibly for younger patients with particularly high treatment costs for side effects (2 or 3 additional GP visits for every patient each year) – see Table 11.

Table 11. Sensitivity to cost and quality of life loss due to side effects.

Table 11

Sensitivity to cost and quality of life loss due to side effects.

Discounting

NICE (National Institute for Health & Clinical Excellence. 2006b) recommends we discount both cost and benefits at 3.5% per annum. We tested three different scenarios: no discounting, 3.5% for effects and 6% for costs, and 6% for both costs and effects. The model was not sensitive to assumptions (Table 12).

Table 12. Sensitivity to discount rates for costs and effects (QALYs).

Table 12

Sensitivity to discount rates for costs and effects (QALYs).

Health state utilities

The health state utilities used in the model were obtained from the literature. We tested the assumption that the mean health state utilities were 0.2 less or more than the ones we got from the literature. The model was not sensitive to this assumption.

Table 13Sensitivity to health state utility values: age 55

Utility values (0–1)ICER (£/QALY)
Health StateBase caseRangeLower limitUpper limit
 MI (year one)0.76(0.56 to 0.96)£12,654£12,310
 Post MI0.88(0.68 to 1.00)£13,389£11,991
 Stroke (year one)0.63(0.43 to 0.83)£12,550£12,410
 Post stroke0.63(0.43 to 0.83)£13,004£11,996
 Revascularisation (year one)0.80(0.60 to 1.00)£12,685£12,281
 Post revascularisation0.88(0.68 to 1.00)£14,259£11,610

Costs of cardiovascular disease events

The costs of cardiovascular disease events do not affect the model results. When the costs were increased by 100% or reduced by 50%, the ICERs changed very little (Table 14).

Table 14. Sensitivity to cost of cardiovascular disease events.

Table 14

Sensitivity to cost of cardiovascular disease events.

1.4.7. Discussion

Our results are broadly consistent with other published economic evaluations. (Franzosi, M. G., Brunetti, M., Marchioli, R. et al 2004) and (Lamotte, M., Annemans, L., Kawalec, P. et al 2006) all concluded that omega 3 supplements were cost effective compared with no supplements.

The submission by Solvay 2004 (Innovus Research (UK) Ltd. 2004) estimated an incremental cost effectiveness ratio (ICER) of £15,189 over the four-year trial period, and £3,717 per QALY extrapolated over the patients’ lifetimes. Their estimated ICERs are comparable with ours which we estimated to be £12,500 over 3.5 years and £6,600/QALY over lifetime. If we use the same effectiveness data (GISSI-P alone) and drug costs (Omacor) as used in the Solvay analysis, our model gives an estimate ICER of £18,500 per QALY for a 55 year old.

The Solvay model was of good methodological quality. Their main limitation was that they did not report the sensitivity of their findings to the effectiveness data or assumptions. Our results were highly sensitive to uncertainty over the treatment effects: at the upper 95% confidence limit for the relative risk of total mortality, omega 3 supplementation was not cost-effective, with an ICER of over £130,000 per QALY.

Our model slightly differed from the Solvay model (Innovus Research (UK) Ltd. 2004). We included the outcome of revascularisation while their model did not. However, this made little difference to the results. Our base model used pooled treatment effects from (Burr, M. L., Fehily, A. M., Gilbert, J. F. et al 1989) and (GISSI Prevenzione Investigators. 1999), while the Solvay submission used data from (GISSI Prevenzione Investigators. 1999) alone. We tested this in sensitivity analysis and this did not change model results. We also modelled loss of quality of life of due to treatment side effects which the Solvay model did not consider. Again, this made little difference to the results. Despite these identified methodological differences, our conclusions are similar.

Our analysis had some weakness especially with regards to lack of data on relative treatment effects for under-55s and over 75 year olds. This means that it is difficult to predict the relative cost-effectiveness of omega-3-acid ethyl esters in these age groups. Most of the efficacy data relates to mainly middle aged men 60–75 years. As such extrapolating this evidence to longer-term outcomes (cardiovascular disease events) is more difficult for these age groups.

The model also assumes that a patient’s health outcome and health care costs incurred are assumed to depend only on their current health state. This is unlikely to be strictly true, and will tend to underestimate overall costs and overestimate health outcomes for the cohort. Thus, interventions that prevent more CVD events will tend to appear rather less cost-effective than they may be in reality. So the model is conservative in this respect.

1.4.8. Conclusions

Our analysis found that omega-3-acid ethyl esters supplements are cost effective when compared with no supplements in patients soon after MI. Using the best available data and assumptions, we estimated ICERs of about £12,500. This result was sensitive to uncertainty over the size of treatment effects - supplements did not appear to be cost-effective at the upper confidence limit for the relative risk of mortality.

These results depend on the assumption that treatment effects do not persist beyond the longest trial period, 3.5 years for the GISSI-P trial,(GISSI Prevenzione Investigators. 1999) and that supplements are not continued after this time. DART1, (Burr, M. L., Fehily, A. M., Gilbert, J. F. et al 1989)was of shorter duration (2 years), and benefits were not observed to continue beyond this in a follow-up study Ness et al 2002 (Ness, A. R., Hughes, J., Elwood, P. C. et al 2002). Although this was beyond the intervention time, and while there were still differences in fish intake between the two groups, the differences were less than during the trial period (Ness, A. R., Hughes, J., Elwood, P. C. et al 2002) If we assume that treatment costs and effects only last for two years, supplements are of borderline cost-effectiveness (£23,400 per QALY).

We assumed clinical equivalence for dietary and supplemental sources of omega 3 supplements, provided that the patient consumes the correct quantities of omega 3 fatty acids. From an NHS perspective, it will clearly be more cost-effective for patients to obtain this from dietary sources. But if a patient is unable to do this, provision of supplements does appear to be a cost-effective use of NHS resources. We assumed use of the cheapest available supplement with the correct quantities of EPA and DHA (Maxepa). Although the other such supplement (Omacor) also appears to be cost-effective compared with no supplementation, it will not be cost-effective compared with the cheaper alternative (assuming clinical equivalence between these products).

Finally, the validity of this analysis depends on acceptance of the proposition that the benefits of omega 3 are confined to people with a recent MI. We only included effectiveness data from the two trials in this population (DART1 and GISSI-P). If we were to broaden this evidence base to include the DART2 trial in angina patients, omega-3 supplementation would not appear to be effective or cost-effective.

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