Omega-3-acid ethyl esters 90, soft capsule, 1,000 mg, Omacor®

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Product: Omega-3-acid ethyl esters 90, soft capsule, 1,000 mg, Omacor®
Sponsor: Abbott Products Pty Ltd
Date of PBAC Consideration: November 2010

1. Purpose of Application

The submission requested a Restricted Benefit listing as adjuvant treatment in secondary prevention after myocardial infarction (MI).

2. Background

This drug had not previously been considered by the PBAC.

3. Registration Status

Omega-3-acid ethyl esters 90 (O-3EE) was TGA registered on 5 August 2010 for the following indications:

  • Post Myocardial Infarction: Adjuvant treatment in secondary prevention after myocardial infarction, in addition to other standard therapy (e.g. statins, antiplatelet medicinal products, beta-blockers, ACE inhibitors).
  • Hypertriglyceridaemia: Endogenous hypertriglyceridaemia as a supplement to diet when dietary measures alone are insufficient to produce an adequate response. Treatment is indicated for the following types of dyslipidaemia (Fredrickson classification) only:
    • Types IV & V as monotherapy and with close monitoring of LDL-C levels
    • Type IIb as add-on therapy to statins, when control of triglycerides with statins has been shown to be insufficient.

Omega-3-acid ethyl esters 90 is not indicated in exogenous hypertriglyceridaemia (Type I hyperchylomicronaemia). There are insufficient data to support the use in patients with secondary endogenous hypertriglyceridaemia including patients with diabetes mellitus.

4. Listing Requested and PBAC’s View

Restricted benefit
Adjuvant treatment in secondary prevention after myocardial infarction.

For PBAC’s view, see Recommendation and Reasons.

5. Clinical Place for the Proposed Therapy

Myocardial infarction is a condition involving an interruption of blood supply to part of the heart, causing heart cells to die. Following a myocardial infarction, a patient is at a further risk of developing a recurrence or experiencing a further cardiovascular related event (e.g. stroke). To decrease the chance of these further events from occurring, patients are encouraged to implement lifestyle changes (i.e. stop smoking, have a balanced diet, reduce alcohol consumption, increase physical activity, reduce weight) and are usually prescribed a combination from the following classes of drugs depending on individual circumstances (standard therapy): beta-blockers, ACE inhibitors, antiplatelet agents and/or lipid lowering agents (i.e. statins).

The submission proposed that the place in therapy of O-3EE is as adjuvant treatment to standard therapy in the secondary prevention of further cardiovascular related events post MI. O-3EE is proposed to be added to standard therapy and not expected to substitute for any of the standard therapies.

6. Comparator

The submission nominated placebo as the main comparator. The PBAC considered that this is not the only appropriate comparator.

For PBAC’s view, see Recommendation and Reasons.

7. Clinical Trials

The submission presented one randomised trial (GISSI-P) comparing O-3EE (1g, 460-380 mg of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) with control (no additional treatment) in patients who started therapy within 3 months of having an MI.

The submission excluded the OMEGA trial on the basis that the trial was underpowered to detect a difference in mortality between treatment arms and short duration to observe sufficient events. Details and results of the OMEGA trial were included in the evaluation, as this trial utilised the formulation of O-3EE for which listing is sought and appeared to enrol patients who were more representative of the Australian population (at least in terms of baseline concomitant medications) than the GISSI-P trial

Details of the published studies presented in the submission are in the table below
 

Trial ID / First author Protocol title / Publication title Publication citation

GISSI-P GISSI-P investigators

Marchioli R, et al

Marchioli R, et al

Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.

Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) - Prevenzione.

Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial.

Lancet 1999; 354(9177): 447-445

Circulation 2002; 105(16): 1897-903

Lipids 2001; 36(Suppl): S119-S126
OMEGA Rauch B, et al Highly purified omega-3 fatty acids for secondary prevention of sudden cardiac death after myocardial infarction – aims and methods of the OMEGA-study. Cardiovasc Drugs Ther 2006; 20(5): 365-75


For PBAC’s view of the trials presented in the submission, see Recommendation and Reasons.
 

8. Results of Trials

The GISSI-P trial had four treatment arms, O-3EE, O-3EE plus vitamin E, vitamin E and control (no additional treatment). The purpose of the addition of vitamin E was to assess whether it would provide a possible complementary role (i.e. vitamin E could improve the role of O-3EE through protection from lipid peroxidation, by acting independently on the same or closely related artherogenic and thrombotic mechanisms, or both). The GISSI-P trial conducted two analyses:
i) two way factorial design comparing the efficacy of O-3EE (O-3EE with or with out vitamin E) compared with no O-3EE (Control with or without vitamin E); and
ii) four way efficacy analysis of O-3EE, vitamin E and O-3EE plus vitamin E compared with control, as well as the efficacy of the combined treatment (O-3EE plus vitamin E) compared with individual interventions (i.e., versus O-3EE and vitamin E alone).

The PBAC noted that the results of both the two-way and four-way analyses demonstrated a statistically significant decrease in the primary composite outcome of “death, non fatal MI/ non fatal stroke” (RD: -1.3% [95% CI -2.5, -0.01] and RD: -2.2% [95% CI -3.9, -0.4] respectively), “death all causes” (RD: -1.3% [95% CI -2.4, -0.3] and RD: -2.2% [95% CI -3.7, -0.6] respectively) (driven by differences in CV death), “CV death” (RD: -1.0% [95% CI -1.9, -0.2] and RD: -2.1% [95% CI -3.4, -0.9] respectively) and “Fatal & non fatal MI” (RD: -1.2% [95% CI -2.3, -0.1] and RD: -2.4% [95% CI -3.9, -0.8] respectively) in patients treated with O-3EE compared with those treated with control. The four-way analysis also demonstrated a statistically significant decrease in the primary composite outcome of “Cardiovascular death, non fatal MI/ non fatal stroke” (RD: -2.3% [95% CI -3.9, -0.7]), this outcome was of borderline statistical significance in the two-way analysis. In all cases, the magnitude of the difference was greater in the four-way compared with the two-way analysis.

The results from the OMEGA trial, summarised during the evaluation, indicated statistically significant increases for non-fatal stroke and implantable cardioverter-defibrillator terminated ventricular tachycardia/ventricular fibrillation (ICD-terminated VT/VF) for patients treated with O-3EE compared with placebo. No differences in the other reported outcomes were observed between treatment groups. This may have been due to the trial being underpowered to detect a difference.

The submission did not report safety results from the GISSI-P trial, but a summary of adverse events reported during the GISSI-P trial was extracted from the trial report during the evaluation. Dyspepsia and nausea were the two most reported adverse events, but had a low incidence (less than 4%). No safety results are available for the OMEGA trial.

The submission also provided the details of the latest Periodic Safety Update Report (PSUR) which did not indicate any specific safety concerns. Two safety issues that were highlighted in the addendum included elevated LDL (21 events reported) and gout (19 events reported). In addition, high doses of Omacor (4 g) have been associated with an increased risk of bleeding events. The PBAC noted that despite a trend for a higher rate of stroke reported in the O-3EE treatment arms of GISSI-P (non-significant) and OMEGA (statistically significant), the PSUR did not indicate any increase in stroke with O-3EE treatment.

9. Clinical Claim

The submission claimed that O-3EE has superior efficacy (reduced mortality) compared to usual care (control) and similar toxicity to placebo.

The PBAC considered there was inadequate clinical data to establish efficacy in the proposed Australian population, and that the claim of an adverse event profile similar to placebo was uncertain.

10. Economic Analysis

The submission presented a trial-based and a modelled economic evaluation.

The submission nominated the four-way comparison of O-3EE and control as being the most relevant comparison and used these results in the modelled economic evaluation.

The submission’s trial-based economic evaluation included costs for MI and stroke hospitalisation, revascularisation procedures (CABG and PCI) following an MI and a cost for CV death which was attributed to 25% of deaths as 75% of patients were assumed to have died before reaching hospital. These costs were attributed to the number of events observed in the GISSI-P trial. Also included were costs for concomitant medications (e.g., aspirin, beta-blockers and cholesterol lowering drugs). The proportion of patients on these background therapies differed between the O-3EE and placebo arms and the assumed proportions of patients on these background therapies was not consistent with the proportions reported for patients enrolled in the GISSI-P trial. A trial-based economic evaluation only considering the costs of O-3EE was conducted during the evaluation.

The trial-based economic evaluation resulted in an incremental cost per extra death avoided over 3.5 years of between $105,000 - $200,000.

In the modelled economic evaluation, all patients started the model in the “post MI” health state, and were either treated with O-3EE or placebo. Patients moved through the model according to transition probabilities derived from the GISSI-P trial during the “within trial” portion of the model (7 years/14 cycles) and from values sourced from the literature in the extrapolated portion of the model. The ICER for the base case in the modelled economic evaluation was between $15,000 and $45,000 per Quality Adjusted Life Year (QALY).

The submission also presented the results of a series of sensitivity analyses conducted around a re-specified base case using the 2-way GISSI-P results. The ICER for the re-specified base case was increased, but within the same range.

11. Estimated PBS Usage and Financial Implications

The submission estimated the financial cost per year to the PBS to be up to $30 - $60 million in Year 5.

For PBAC’s view, see Recommendation and Reasons.

12. Recommendation and Reasons

The PBAC noted that some data presented by the clinician during the hearing were from trials not included in the evaluation of the submission (GISSI-HF and JELIS).

The submission nominated placebo as the comparator for adjuvant treatment in secondary prevention after myocardial infarction. However, the PBAC considered that this is not the only appropriate comparator. Other potential comparators would include over-the-counter (OTC) fish oil or a diet high in oily fish. The submission provided no justification for exclusion of these potential comparators. Although the PBAC noted that the sponsor’s pre-PBAC response argued that omega-3 ethyl esters (O-3EE) differs from fish oil omega-3 triglycerides and that it is difficult for most Australians to consume sufficient oily fish to get the required amount of omega-3 fatty acids, the PBAC was also aware that there are a number of other similarly high potency omega-3 products available OTC.

The submission presented a single randomised trial (GISSI-P, conducted in 1993 to 1995) in patients within 3 months of having a myocardial infarction. The PBAC considered that the patients enrolled in GISSI-P were unlikely to be representative of the current Australian population, with less than 5% of patients taking statins at baseline, and fewer than 50% of patients taking ACE inhibitors and/or beta-blockers. The PBAC noted that current Australian Guidelines recommend the use of aspirin/clopidogrel, beta-blockers, ACE inhibitors and statins, among others, post-MI, which suggests that a large proportion of Australian patients would be on these standard therapies post-MI. The PBAC considered that the age of the GISSI-P trial (published in 1999) largely explained why it does not represent current clinical practice. Additionally, GISSI-P enrolled Italian patients and the PBAC considered that there may be differences in dietary habits between the Italian and Australian populations and may also indicate that patients enrolled in GISSI-P are not representative of the Australian population.

The GISSI-P trial had four treatment arms, O-3EE, O-3EE plus vitamin E, vitamin E and control (no additional treatment). Two analyses were conducted:
i) two way factorial design comparing the efficacy of O-3EE (O-3EE with or without vitamin E) compared with no O-3EE (Control with or without vitamin E); and
ii) four way efficacy analysis of O-3EE, vitamin E and O-3EE plus vitamin E compared with control, as well as the efficacy of the combined treatment (O-3EE plus vitamin E) compared with individual interventions (i.e. versus O-3EE and vitamin E alone).

The PBAC noted that the results of these analyses demonstrated statistically significant decreases in the primary composite outcome of ‘death, non-fatal MI/non-fatal stroke’, ‘death all causes’, ‘CV death’ and ‘fatal and non-fatal MI’ in patients treated with O-3EE compared with control. The magnitude of the difference was greater in the four-way analyses compared with the two-way analyses in all cases.

The submission used the results of the four-way comparison in the modelled economic evaluation. The PBAC agreed that the base case of the modelled economic evaluation should consider the totality of the evidence and should therefore be based on the 2-way rather than the 4-way results. The PBAC also noted that use of the 4-way analysis in the model required construction of survival curves to infer 6-monthly results data as this was only reported for the 2-way analysis.

The PBAC agreed that the omission of the OMEGA trial was inappropriate and insufficiently justified. The PBAC noted that the OMEGA trial was double blinded and that the majority of patients (greater than 80%) were taking concomitant statins, beta-blockers, ACE inhibitors and anti-platelet therapies at rates comparable to patients that would be eligible for O-3EE should it become available on the PBS and that this trial appeared to enrol patients more likely to be representative of the Australian population. The results of the OMEGA trial indicated only statistically significant increases for non-fatal stroke and implantable cardioverter-defibrillator terminated ventricular tachycardia/ventricular fibrillation in patients treated with O-3EE compared with placebo, but no differences in other outcomes were reported. The PBAC considered that this is suggestive that the incremental benefit of O-3EE in addition to other standard therapies is minimal.

The PBAC noted that high doses of O-3EE have been associated with an increased risk of bleeding events. The PBAC noted that the submission did not address the issue of potential drug-drug interactions, particularly with drugs whose bioavailability is increased in the presence of high fat foods.

The PBAC noted the ICER for the base case in the modelled economic evaluation was between $15,000 and $45,000/QALY. The ICER for the respecified base case, using the 2-way results from GISSI-P was higher, but within the same range. The PBAC noted that the results of sensitivity analyses demonstrated that the model is most sensitive to assumptions regarding the treatment effect demonstrated for O-3EE compared with control/placebo for overall mortality. The PBAC considered that given the uncertainty regarding whether the GISSI-P population is representative of the proposed PBS population there is uncertainty that the treatment effect observed in the GISSI-P trial would apply to the proposed population. Together with the fact that the ICER is sensitive to assumptions regarding effectiveness, the PBAC considered the ICER to be highly uncertain.

The PBAC noted that according to a Queensland Health survey in 2005, the OTC fish oil market was growing at a rate of 38% per annum. In addition, the PBAC noted that O-3EE is also TGA registered for treatment of hypertriglyceridaemia and that there is considerable potential for use outside the requested restriction at an extremely high total cost to the PBS.

The PBAC therefore rejected the submission on the basis of inadequate clinical data to establish efficacy in the proposed Australian population and therefore a highly uncertain cost-effectiveness ratio.

Recommendation:
Reject

13. Context for Decision

The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.

14. Sponsor’s Comment

Abbott believes that the GISSI-P study demonstrates that Omacor is a safe and effective secondary prevention treatment in patients who have had a myocardial infarction. Unfortunately, the OMEGA study was underpowered to show a difference in outcomes. Abbott will continue to work with the PBAC to have Omacor listed on the PBS to provide Australians with what Abbot considers to be an effective treatment option for secondary prevention of cardiovascular events following an MI.