Cost-Effectiveness Analysis of N-3 PUFA (Omacor) Treatment in Post-MI Patients

S. Quilici; M. Martin; A. Mcguire; Y. Zoellner

Int J Clin Pract. 2006;60(8):922-932. 

Summary

This study evaluates the cost-effectiveness of OMACOR treatment as a standard prevention measure post-MI in the UK. A cost-effectiveness model was developed based on the GISSI-P trial, combining a survival and a Markov model, over a lifetime period. The base case results for OMACOR, at 4 years and over a lifetime, respectively, were: Cost per QALY gained: £3,717 and £15,189; cost per life years gained (LYG): £2,812 and £12,011. The cost per death avoided at 4 years was £31,786. Deterministic and probabilistic sensitivity analyses did not change the base case results substantially. The use of Omacor as a standard post-MI prevention treatment seems warranted in the UK, both on the basis of its efficacy, which is in addition to other prophylactic treatments as evidenced by the results of the GISSI-P trial, and on cost-effectiveness grounds - both at 4 years and over a lifetime's time-horizon, using the current cost-effectiveness thresholds.

Background and Objective

Cardiovascular disease (CVD) - encompassing coronary heart disease (CHD), peripheral vascular disease and stroke - has long been acknowledged as a major cause of mortality and morbidity in Europe, causing about 4 million deaths every year in Europe[1] and over 235,000 in the UK.[2] CHD incidence varies by country, with higher rates in Northern and Eastern than in Southern and Western European countries, as evidenced by the MONICA study.[3] Belfast and Glasgow, representing the UK, had a particularly high incidence. It is estimated that about 268,000 myocardial infarctions (MIs), often the outcome of CHD, occur per year in the UK - 147,000 in men and 121,000 in women.[1] About 30% of MIs are currently fatal, although death rates for CVD, including MIs, are falling in the UK. A 36% decrease in mortality from CVD was registered between 1989 and 1999 for adults under 75 years. Nevertheless, UK death rates from MI are still among the highest of leading developed nations.[4]

In response, the NHS set up a national service framework for CHD[5] in 2000 to reduce the incidence of CHD and to improve cardiac care.

Coronary heart disease has major economic implications; one study reports a cost to the national health service of £1.75 billion, and £5.3 billion from a societal perspective because of lost workdays.[1] Another study reports a cost to the UK healthcare system of £1.73 billion or a total annual cost to the overall UK economy of £7.06 billion, which includes informal care and productivity losses.[6] In the light of this information, it is clear that CHD and CVD prevention programmes can result in economic benefits. Primary prevention programmes are being introduced by the UK National Health Service. The need for secondary prevention following an MI has been highlighted by the ASPIRE study[7] (Action on Secondary Prevention through Intervention to Reduce Events) and the EUROASPIRE I and II studies.[8,9]

Current secondary prevention measures in the UK include a combination of lifestyle measures, pharmacological therapy with antiplatelet treatments, beta-blockers, ACE-inhibitors and statins and cardiac rehabilitation. Lifestyle measures post-MI consist of smoking cessation, exercise and diet changes.

The benefits of the consumption of n-3 polyunsaturated fatty acids (n-3 PUFA) have long been recognised,[10,11] although the evidence on the preventative use of fish oils in general is relatively limited. However, the benefits of OMACOR (900 mg n-3 PUFA per capsule) were clearly demonstrated in the GISSI-P trial,[12] which showed that OMACOR treatment over 3.5 years significantly reduced the rate of the cumulative endpoint of all-cause death, non-fatal MI and non-fatal stroke. A recent observational meta-analysis confirmed the GISSI-P results that fish consumption is associated with a significantly lower risk of fatal and total CHD.[13] Although OMACOR has only a limited cholesterol lowering effect, it seems to stabilise the myocardium electrically, and has an antiarrhythmic effect, reducing the risk of sudden death.[11] This resulted in the recommendation from the American Heart Association to people suffering from CVD, of a daily intake of n-3 PUFA of 1 g/day.[14]

There is currently only one n-3 PUFA treatment on the market in the UK with a marketing authorisation for secondary prevention after MI, namely OMACOR, containing 900 mg of highly purified n-3 PUFA (eicosapentaenoic acid, 46%; decosahexaenoic acid, 38%).

The most important RCT using OMACOR was conducted in Italy. One other, smaller trial involving 300 patients was conducted in Norway.[15] This study, however, was not included in the analysis because it had a different focus (namely the effect of n-3 PUFA on serum lipid concentrations post-MI), it was not powered to detect a difference between treatment arms, and it involved a differently dosed n-3 PUFA treatment regimen. The GISSI-P trial[12] included 11,324 post-MI patients, 89% with a first MI and 11% having suffered more than one previous MI. Patients were randomly assigned to receive supplements of OMACOR alone, vitamin E alone, OMACOR and vitamin E combined, or no supplement at all. Patients were followed for a period of 3.5 years (42 months). The combined primary endpoints used in GISSI-P were:

  1. The cumulative rate of all-cause death, non-fatal MI and non-fatal stroke.

  2. The cumulative rate of cardiovascular (CV) death, non-fatal MI and non-fatal stroke.

The results were analysed for each supplement group separately (4-way analysis), in order to demonstrate the effects of OMACOR vs. no supplement taken, and for the two arms receiving OMACOR supplement (OMACOR arm and the OMACOR + vitamin E arm) vs. those not receiving OMACOR (2-way analysis). The trial demonstrated that OMACOR treatment alone significantly lowered the risk of the primary endpoint of the cumulative rate of all-cause death, non-fatal MI and non-fatal stroke, resulting in a relative risk reduction (RRR) of 10% (95% CI: 1-18) for the 2-way analysis and 15% (95% CI: 2-26) for the 4-way analysis when used alone. This benefit was attributable to a decreased risk of death in both the 2- and 4-way analyses, of 14% (95% CI: 3-24) and 20% (95% CI: 6-33), respectively; and CV death, with a RRR of 17% (95% CI: 3-29) and 30% (95% CI: 13-44), respectively. A recent publication confirmed the results of GISSI-P that the use of supplemental vitamin E does not reduce CV events[16] (  ).

Table 1.  Four-way Results of the GISSI-P Trial

  4-way analysis
OMACOR Control
Number of patients 2,836 2,828
Sex (male/female) 2,403/433 (85%/15%) 2,407/421 (85%/15%)
All cause death 236 (8.3%) 293 (10.4%)
Death, non-fatal myocardial infarction (MI), non-fatal stroke 356 (12.3%) 414 (14.6%)
Cardiovascular death, non-fatal MI, non-fatal stroke 262 (9.2%) 322 (11.4%)

Objectives and Study Question

The routine use of the highly purified OMACOR treatment as a secondary prevention measure post-MI will allow UK patients to benefit from the positive effects of this treatment. However, in the current climate of limited funds, it is no longer sufficient to demonstrate efficacy; it is also necessary to demonstrate cost-effectiveness, allowing scarce healthcare resources to be deployed in a way to ensure a maximum return. UK decision-makers prefer to see results expressed as cost per quality-adjusted life year (QALY) gained, as this facilitates comparisons between treatments used for different illnesses. Currently, the National Institute of Health and Clinical Excellence (NICE) has set a threshold of between £20,000 and £30,000 per QALY for acceptance of new treatments,[17] based on cost-effectiveness ratios alone. Further arguments are needed to justify the use of treatments with ratios over £30,000.

This cost effectiveness analysis was developed to establish whether OMACOR is a cost-effective treatment in post-MI patients in the UK.

Methods

For this cost-effectiveness analysis, we combined a decision-analytic model to predict costs with a survival model to estimate mortality, using data from GISSI-P, as patient-level data were not available.

Survival Model

The survival model is based on the 2-way analysis from GISSI-P,[18] and was used to replicate survival curves for the 4-way analysis, as no data were presented in the GISSI-P publications for the interval between the 12 and 42 months. Firstly, we had to estimate survival curves for this period for the 2-way analysis, for which a non-linear regression was applied to fit a parametric survival distribution of the observed survival data for the 2-way analysis. Among various distributions frequently used to model survival data, we compared for the 0-42 months time period the estimated data to the observed data. The Weibull distribution fitted the observed data best and was selected. The data were subsequently adjusted to fit the results of the 4-way analysis. This adjustment consisted of combining the number of events at 42 months and the relative risk ratios for the 4-way analysis with the 2-way analysis estimation. The relative risk ratios for CV death (0.70), non-CV death (0.99) and all fatal death (0.80) were assumed to be constant over time. This yielded survival curves for the period of the trial duration for the 4-way analysis. These curves were then extrapolated to a lifetime where we assumed that OMACOR treatment would not be continued beyond the trial duration of 42 months.

The relatively advanced average age of the patients at trial conclusion of 63 years had as a consequence that death from all causes (natural death including sudden death and cardiac death) could not be considered constant. To extrapolate the survival curves beyond the 42-months trial duration, the GISSI-P survival curves were fitted with survival curves from a study involving a similar population terms of patient characteristics. A Canadian study[19] provided survival curves over a period of 5 years for a subgroup of 15,590 patients with recent MI (≤1 month) using CAPRIE trial[20] selection criteria and with a mean age of 67 years. Survival was estimated using Weibull and Gompertz survival functions. The comparison of overall survival in Canada and the UK showed that the survival is higher in Canada, requiring an adjustment of the survival curves for the UK. Overall survival curves for the UK for 2000 fitted very well with the Canadian overall survival for 1997. We therefore assumed that the survival curves obtained from the Canadian study using 1997 data would yield similar results for the UK based on 2000 data. We used the survival curves from the study to extrapolate the survival curve of our control group. The OMACOR survival curve was then fitted using a proportional function of the resulting standard treatment survival curve. The mortality rates obtained from these survival curves were used in the Markov model (Figure 1).

Figure 1.

 

Survival curves for trial duration and extrapolation

Markov Model

A Markov cohort model was developed in Excel using data from GISSI-P such as average age, concomitant prophylactic treatments usage and efficacy for the trial duration, to estimate costs incurred by patients over the duration of the trial and over their remaining lifetime. The model used a cohort of 1,000 patients and includes nine different health states to reflect the outcomes used in GISSI-P. Patients could transit to these health states during the 41 cycles, each equalling 1 year, over which the model was run, until patients had reached the age of 100 years or had died, as is standard practice in health economic modelling. Transition rates for the first 4 years were obtained from GISSI-P and were calibrated to reproduce trial results. For subsequent cycles, transition rates were obtained from the literature. No further benefits from treatment were assumed to be incurred post-trial. For the extrapolation phase, three transition matrices were developed to account for the change in transition rates, because of an increase or decrease in risk, with increasing age: one for ages 64-74 (for all patients immediately post-trial), one for ages 75-89 and the last one for patients over 90 years of age. These three transition matrices applied to both the OMACOR and control patients after the 4 years of the trial (see  ). Information on these transition rates was obtained from the literature. Post-trial mortality rates were obtained from the extrapolated survival curves using average mortality rates from the control group for three age bands: 64-74, 75-89 and over 90 years (  and Figure 2).

Appendix 1.  Annual Post-trial Transition Rates for Three Age-groups for Both OMACOR and Control Patients

  Postmyocardial
infarction
(post-MI)
Subsequent
MI
Subsequent MI
with PTCA/
CABG
Post-
subsequent
MI
Stroke Post-
stroke
Subsequent
stroke
Post-
subsequent
stroke
All causes
of death
(64-74) age group
   Post-MI 0.913 0.024[45] 0.025[45] 0.000 0.008[45] 0.000 0.000 0.000 0.030
   Subsequent MI 0.000 0.000 0.000 0.970 0.000 0.000 0.000 0.000 0.030
   Subsequent MI with PTCA/CABG 0.000 0.000 0.000 0.970 0.000 0.000 0.000 0.000 0.030
   Post-subsequent MI 0.000 0.024[45] 0.025[45] 0.859 0.008[45] 0.000 0.055[46] 0.000 0.030
   Stroke 0.000 0.000 0.000 0.000 0.000 0.970 0.000 0.000 0.030
   Post-stroke 0.000 0.024[45] 0.025[45] 0.000 0.000 0.867 0.055[46] 0.000 0.030
   Subsequent stroke 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.970 0.030
   Post-subsequent stroke 0.000 0.024[45] 0.025[45] 0.000 0.000 0.000 0.000 0.921 0.030
   All causes of death 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 1.000
(75-89) age group
   Post-MI 0.845 0.045[45,47] 0.004[45,47] 0.000 0.014[45] 0.000 0.000 0.000 0.092
   Subsequent MI 0.000 0.000 0.000 0.908 0.000 0.000 0.000 0.000 0.092
   Subsequent MI + PTCA/CABG 0.000 0.000 0.000 0.908 0.000 0.000 0.000 0.000 0.092
   Post-subsequent MI 0.000 0.045[45,47] 0.004[45,47] 0.791 0.014[45] 0.000 0.055[46] 0.000 0.092
   Stroke 0.000 0.000 0.000 0.000 0.000 0.908 0.000 0.000 0.092
   Post-stroke 0.000 0.045[45,47] 0.004[45,47] 0.000 0.000 0.805 0.055[46] 0.000 0.092
   Subsequent stroke 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.908 0.092
   Post-subsequent stroke 0.000 0.045[45,47] 0.004[45,47] 0.000 0.000 0.000 0.000 0.859 0.092
   All causes of death 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 1.000
>90 age group
   Post-MI 0.431 0.045[45,47] 0.004[45,47] 0.000 0.037[45] 0.000 0.000 0.000 0.483
   Subsequent MI 0.000 0.000 0.000 0.517 0.000 0.000 0.000 0.000 0.483
   Subsequent MI + PTCA/CABG 0.000 0.000 0.000 0.517 0.000 0.000 0.000 0.000 0.483
   Post-subsequent MI 0.000 0.045[45,47] 0.004[45,47] 0.376 0.037[45] 0.000 0.055[46] 0.000 0.483
   Stroke 0.000 0.000 0.000 0.000 0.000 0.517 0.000 0.000 0.483
   Post-stroke 0.000 0.045[45,47] 0.004[45,47] 0.000 0.000 0.413 0.055[46] 0.000 0.483
   Subsequent stroke 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.517 0.483
   Post-subsequent stroke 0.000 0.045[45,47] 0.004[45,47] 0.000 0.000 0.000 0.000 0.468 0.483
   All causes of death 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 1.000

Table 2.  GISSI-P Transition Rates

From
health
state
To health state Value
treatment
group
Value
control
group
Reference
Post-MI Subsequent MI 0.0028 0.0032 GISSI-P[12]
Post-MI Subsequent MI with PTCA/CABG 0.0083 0.0095  
Post-MI Stroke 0.0041 0.0033  
Stroke Subsequent MI with PTCA/CABG 0.0083 0.0095  
Post-stroke Subsequent MI 0.0028 0.0032  
Post-subsequent MI Stroke 0.0041 0.0033  
Any state All cause death 0.0245 0.0307  

 

PTCA = Percutaneous Transluminal Coronary Angioplasty.
CABG = Coronary Artery Bypass Graft.

Figure 2.

 

Markov state transition diagram

The perspective chosen for this analysis was that of the NHS.

The model was designed to calculate several outcomes. These outcomes were chosen to provide the maximum amount of information on the effects of the use of OMACOR:

  1. Life years gained

  2. Deaths avoided over 4 years.

As the UK decision-makers often prefer to see results expressed as cost per quality adjusted life year (QALY) gained, utility weights were applied to the health states to adjust the extrapolated survival benefit for quality of life.

  1. QALYs gained.

Life years gained, QALYs and deaths were discounted to present values at 3.5% per annum as is recommended by the NICE.[21]

Resource Use, Costs and Utilities

Resource utilisation for subsequent MIs, CHD-related and all-cause death, non-fatal MI, fatal and non-fatal stroke was based on information from the literature. The model makes a distinction between resource use in the year in which an event occurred and the subsequent years when the patient is expected to be stable. Annual costs were estimated for each event using the perspective of the NHS. For stroke, we assumed the average resource use based on the resource use for a moderate stroke.[22] Daily treatment costs of concomitant preventative treatments were obtained from the DIN-LINK database.[23] Preventative treatments considered were aspirin, cholesterol lowering treatments, beta-blockers, ACE inhibitors, calcium antagonists, nitrates and diuretics and OMACOR, exclusively for the treatment group for 42 months. Where necessary, costs were inflated to 2004 values using the recommended Hospital and Community Health Services inflation rate of 1.3%.[24] Costs were discounted to present value using a rate of 3.5% per annum as recommended by NICE[21] (  ).

Table 3.  Costs

Treatment costs Drug costs
Health state Annual
treatment
cost (£)
Treatment Annual
cost (£)
First stroke 3,144 Aspirin 6
Subsequent stroke 3,144 Cholesterol lowering drugs (statins) 272
Post-stroke 573 Beta-blockers 31
Post-subsequent stroke 573 ACE-inhibitors 108
Subsequent MI medical 1,439 Calcium antagonists 129
Subsequent MI PTCA/CABG 5,868 Nitrates 39
Post-subsequent MI 52 Diuretics 17
Death 0 OMACOR 181

Age-specific, population utility weights were used to convert life expectancy into QALYs, using weights from the Health Survey for England 1996.[25] Disease-specific utilities for the different health states were obtained from the literature and compared with the age-specific utility. For patients not suffering an event, the age-specific utility (U) from 59 to 100 years of age was used. For patients suffering an event, the utility of a health state was used (Ue), except where it was higher than the respective age-specific utility. Then to calculate the age-specific utility post event (Upe), the reported decrement for that health state was applied to the age-specific utility: Upe = U − (1 − Ue). Disease-specific utilities for stroke and MI were obtained from Schleinitz et al.[26,27] (  ).

Table 4.  Utilities

Health state Utility Source
Stroke and subsequent stroke
  Severe 0.11 (0-0.35) Schleinitz MD[26]
   Moderate 0.39 (0.25-0.55)  
   Mild 0.76 (0.55-0.95)  
Post-stroke Relevant age-related
utility, possibly corrected
for permanent stroke
disability
Assumption
MI 0.87 (0.80-0.95) Schleinitz MD[26]
Age: 63 years old
Post-MI Relevant age-related utility Assumption
Men
  55-64 0.80 [28]
   65-74 0.80  
   75+ 0.76  
Women
  55-64 0.78 [28]
   65-74 0.76  
   75+ 0.71  
Death, immediate death 0 Generally accepted value

Sensitivity Analyses

Several deterministic sensitivity analyses were conducted for this analysis to test the robustness of the model to changes in key parameters.

  1. Discount rates of 0% and 6% for both costs and effects.

  2. Rehabilitation costs stroke increased by 200%.

  3. MI follow-up costs increased by 200%.

  4. Percentage of patients receiving post-MI treatment using the current UK market data obtained from the DIN-LINK database.

A probabilistic sensitivity analysis for the base case was performed on the following parameters, to obtain a confidence interval (CI) around the cost-effectiveness point-estimate:

  1. MI hospitalisation costs.

  2. PTCA and CABG costs.

  3. Health state utility values for both MI and stroke.

In the absence of better information, only uniform distributions were introduced allowing us to use the respective minimum and maximum values of the base case values.

Results

Cost-Effectiveness Analyses

The incremental cost-effectiveness ratios (ICERs) are expressed as extra cost per QALY gained when comparing the OMACOR strategy to 'no treatment'. Over a lifetime horizon and over 4 years, the ICERs of the base case are £3,717 and £15,189 per QALY, respectively, using a 3.5% discount rate. The base case results expressed as cost per LYG, over a lifetime and 4 years, are £2,812 and £12,011, respectively. The incremental number of life-years saved by OMACOR during the 4 years' follow-up was 0.054 per patient, or 54 per 1000 patients.

If we consider the cost per death avoided at 4 years, then the numerical ICER values are greater than when expressed as cost per LYG, as one death avoided will represent several LYG. The cost per death avoided at 4 years is £31,768 (  ).

Table 6.  Base Case Results (Rounded)

  OMACOR
arm
Control
arm
Increment Incremental
cost-effectiveness
ratios
Cost(£)/QALY
  Lifetime
    Costs (£) 6,471,024 5,700,688 770,336 3,723
     Utility 9,309 9,102 207  
  4 years
    Costs (£) 1,789,148 1,140,143 649,005 15,189
     Utility 2,839 2,797 43  
Cost(£)/LYG
  Lifetime
    Costs (£) 6,471,024 5,700,688 770,336   2,812
     Life years 12,037 11,763 274  
  4 years
    Costs (£) 1,789,148 1,140,143 649,005 12,011
     Life years 3,452 3,397 54  
Cost(£)/death avoided
  4 years
    Costs (£) 1,789,148 1,140,143 649,005 31,768
     Deaths 85 106 20  

Both deterministic and probabilistic sensitivity analyses were performed on the impact of various key parameters on the ICERs. None of the deterministic sensitivity analyses had a substantial effect on the ICERs as is shown graphically by the 'spider web' graph. The more the line between points stays in line with the web as outlined by the dotted lines, the less variability the sensitivity analysis has on the results. The discounting of the costs and outcomes by 0% for both, or by 6% for the outcomes and 0% for the costs, has the greatest impact on the ICERs, although this is still small. Overall, the figure reveals very little variability around the base case results, even under extreme assumptions of post event costs (Figure 3).

Figure 3.

 

Spiderweb diagram

Probabilistic sensitivity analysis using Monte-Carlo simulation (10,000 runs) varied several cost parameters (including MI hospitalisation, PTCA and CABG costs) as well as the health state utilities for MI and stroke over a uniform distribution (  ).

Table 7.  Probabilistic Sensitivity Analysis Parameters

Parameters Distribution Values Reference
Base case Min Max
Costs (£)
   MI Hospitalisation Uniform 1,077 905 1,423 [29]
   CABG Uniform 6,537 3,185 7,397 [29]
   PTCA Uniform 3,024 864 3,132 [29]
Utilities
   MI Uniform 0.87 0.8 0.95 Schleinitz (2004)[26]
   Stroke - severe Uniform 0.11 0 0.35 Schleinitz (2004)[26]
   Stroke - moderate Uniform 0.39 0.25 0.55 Schleinitz (2004)[26]
   Stroke - mild Uniform 0.76 0.55 0.95 Schleinitz 2004[26]

The means used for the base case differed slightly from the base case and therefore the mean results of the PSA are not identical to the base case results (with a very small increase in the value of the ICUR and IC/LYG ratios); £15,189 and £15,303 (95% CI: 15,298-15,308) for the ICERs over 4 years for the deterministic and probabilistic results, respectively, and £3,725 and £3,723 (95% CI: 3,724-3,726) for the ICERs over a lifetime. The 95% CIs are narrow, indicating that the model is not very sensitive to change in these parameters, confirming the results of the deterministic sensitivity analysis (  and Figure 4).

Table 8.  Probabilistic Sensitivity Analysis Results

Forecast Base Forecast
mean
SD LL 95% CI UL 95% CI
ICUR 4 years (£) 15,189 15,303 234 15,298 15,308
ICUR lifetime (£) 3,723 3,725 62 3,724 3,726
IC/LYG 4 years (£) 12,011 12,088 50 12,087 12,089
IC/LYG Lifetime (£) 2,812 2,813 3 2,813 2,813

 

ICUR = Incremental Cost Utility Ratio.

Figure 4.

 

Cost-effectiveness plane

Discussion

The ICERs obtained for OMACOR are all below the NICE threshold £20,000 to £30,000. Therefore, OMACOR is a cost-effective prophylactic treatment for patients after an MI, both in terms of cost per LYG and QALY gained, namely £12,011 and £15,189, respectively, over a lifetime; or of £2,812 and £3,717, respectively, over a 4-year period. The cost per death avoided is higher, as one death avoided represents several LYG.

The results from this analysis should be seen as conservative estimates, as it was assumed that OMACOR treatment was used for only 4 years with no continuation of effect post-treatment, whereas in real life, OMACOR treatment would probably be taken for a longer period of time, thus possibly resulting in greater benefits and lower ICERs.

When the ICERs for OMACOR are compared with cost-effectiveness ratios found for other secondary prophylactic treatments used post-MI, the OMACOR ratios are in the same order of cost-effectiveness, demonstrating that it is of both clinical and economic benefit to use OMACOR as a standard post-MI treatment option.

This study has several limitations. For cost-effectiveness analyses based on a clinical trial, it is desirable to use patient-level efficacy data and economic data collected prospectively alongside the trial. For the present study, patient-level data from the GISSI-P trial were not available, and efficacy data had to be obtained from the published literature. As a consequence, resource use in this study did not reflect the trial resource use. However, this did allow us to use resource use assumptions based on the UK clinical practice and avoided the inclusion of any protocol-driven resource use.

A third limitation is that the current UK use of secondary prevention treatments in post-MI patients is somewhat higher in the case of beta-blockers, ACE inhibitors and cholesterol-lowering drugs. This could have as a consequence that the full benefit of the combination of prophylactic treatments with OMACOR was underestimated.

In addition, this analysis involves an extrapolation of clinical results, for both patient survival and the Markov model. There are many issues associated with extrapolation of results, and all of these are certainly applicable to this study. However, by not assuming any additional treatment benefit post-trial, we are of the opinion that we have taken a conservative approach.

Finally, we were limited in the information available on which to base the distribution used for the different variables for the PSA. In the absence of such information, only uniform distributions were used.

The results from an Italian cost-effectiveness analysis of GISSI-P[30] are very similar to the results obtained in this study. The incremental number of LYG by OMACOR treatment during 3.5 years' follow-up was 0.0368 per patient. When the costs in the Italian study are inflated from 1999 levels to 2004 and based on 3.5 years' follow-up, the cost per LYG was about £19,000 (95% CI £17,000-£21,000; using current €/£ exchange rates), i.e. comparatively close to the £15,189 from this analysis.

This study is based on GISSI-P - a trial, which was conducted several years ago in Italy. As the study was not conducted in the UK, the issue of transferability of results needs to be addressed. We are of the opinion that the trial results can be transferred to the UK setting based on the similar post-MI management in both GISSI-P and the current UK guideline.[31] In addition, the percentage of additional prophylactic treatments used in GISSI-P is similar to the UK setting, although some differences were seen in use of beta-blockers, ACE inhibitors and cholesterol-lowering drugs, which are currently higher in the UK than in GISSI-P [namely 54% vs. 34%, 50% vs. 32% and 75% vs. 34%, respectively ([23,30])]. The average age of 59.3 (±10.6)[18] years in the GISSI-P trial population at trial initiation, i.e. shortly after the index MI, is also similar to the average age of persons suffering a first heart attack in the UK, which is 62 years. The proportion of males with previous MI, on the other hand, was somewhat higher in GISSI-P than in the UK population, namely 85% vs. 65%, respectively.[32]

GISSI-P evaluated the use of OMACOR in combination with other standard post-MI secondary prevention treatments, thus generating important evidence: While benefits from different prophylactic treatments are not necessarily additive, GISSI-P provided proof that that the reported benefits from OMACOR are indeed in addition to other prevention measures, making the yielded cost-effectiveness ratios even more attractive.

After the success of OMACOR in post-MI patients, several follow-up trials have been initiated to evaluate the efficacy of OMACOR in other patient populations, e.g. GISSI-HF,[33] testing OMACOR and rosuvastatin in heart failure, and the ASCEND[34] trial, which assesses the effects of aspirin and of omega-3 fatty acids in diabetes.

GISSI-Pprovided information on the number needed to treat (NNT) for OMACOR, namely 172 per year. The NNT is the number of people who need to be treated in order to prevent one event - in this case, to save one life. We found several other publications reporting NNTs for prophylactic treatments; for aspirin used in primary prevention for MI, an NNT of 220 per year[35]; for lipid-lowering treatments, an NNT of 181 per year[34]; various lipid-lowering treatments' NNTs ranged from 163 to 661.[28] Therefore, the NNT found for OMACOR is similar to the NNT for established prophylactic treatments, again underlining the benefit of OMACOR use post-MI.

Conclusions

The use of OMACOR as a standard post-MI prevention treatment seems warranted both on the basis of the efficacy of the product - as evidenced by the results of the GISSI-P trial - and the cost-effectiveness ratios, both at 4 years and over a lifetime horizon. The benefits offered by OMACOR are in addition to statins and other prophylactic treatments, making the cost-effectiveness ratios even more advantageous.


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