Prasugrel hydrochloride, tablets, 5 mg (base) and 10 mg (base), Effient®, July 2009

Public Summary for Prasugrel hydrochloride, tablets, 5 mg (base) and 10 mg (base), Effient®, July 2009

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Public Summary Document

Product: Prasugrel hydrochloride, tablets, 5 mg (base) and 10 mg (base), Effient®
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: July 2009

1. Purpose of Submission

The submission sought an Authority required (Streamlined) listing for the treatment of acute coronary syndromes (myocardial infarction or unstable angina) in combination with aspirin in patients who are to undergo percutaneous coronary intervention (PCI).

2. Background

This drug had not previously been considered by the PBAC.

3. Registration Status

Prasugrel was registered by the TGA on 11 June 2009 as follows:

Prasugrel, co-administered with aspirin, is indicated for the prevention of atherothrombotic events (myocardial infarction, stroke and cardiovascular death) in
patients with acute coronary syndromes (moderate to high risk unstable angina (UA), non ST-segment elevation myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI)) who are to undergo percutaneous coronary intervention (PCI).

4. Listing Requested and PBAC’s View

Authority Required (STREAMLINED)

Treatment of acute coronary syndromes (myocardial infarction or unstable angina) in combination with aspirin in patients with acute coronary syndromes who are to undergo percutaneous coronary intervention to prevent early and long-term atherothrombotic events.

Continuing treatment where the patient has previously been issued with a thienopyridine in combination with aspirin for treatment of acute coronary syndrome undergoing PCI.

For the PBAC‘s view, see Recommendations and Reasons.

5. Clinical place for the proposed therapy

Acute Coronary Syndrome (ACS) is a term used to describe the symptoms of coronary artery disease, which include unstable angina, and myocardial infarction. ACS is associated with atherosclerosis (build up of cholesterol-laden plaques) and is usually precipitated by acute thrombosis, causing a sudden and critical reduction in coronary blood flow.

Platelets play a central role in the development of atherothrombosis and the formation of thrombi following PCI (with or without stenting). Prasugrel, an inhibitor of platelet activation and aggregation, would provide an alternative treatment option for ACS.

6. Comparator

The submission nominated clopidogrel with aspirin as the main comparator.

7. Clinical trials

The submission presented one randomised head-to-head trial (TAAL 2007) comparing prasugrel with a loading dose of 60 mg and a maintenance dose of 10 mg/day with clopidogrel with a loading dose of 300 mg and a maintenance dose of 75 mg/day (both used in combination with aspirin) in patients with ACS who undergo a PCI. Seven supplementary publications of the single RCT comparing prasugrel with aspirin and clopidogrel with aspirin were also presented.

Details of the studies included in the submission are presented below:

Trial ID/First Author Protocol title/ Publication title Publication citation
Direct randomised trial
TAAL (2007) A comparison of PRASUGREL and Clopidogrel in Acute Coronary Syndrome Subjects who are to Undergo Percutaneous Coronary Intervention/TIMI 38. (TRITON-TIMI 38)
Additional analysis: other publications from TAAL
Wiviott et al (2007) Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. New England Journal of Medicine 2007; 357: 2001-2015
Wiviott et al (2006) Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the Trial to assess Improvement in Therapeutic Outcomes by optimising platelet InhibitioN with prasugrel Thrombolysis in Myocardial Infarction 38. American Heart Journal 2006; 152: 627-635
Wiviott et al (2008) Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. The Lancet 2008; 371: 1353-1363
Antman et al (2008) Early and Late Benefits of Prasugrel in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: A TRITON–TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction) Analysis. Journal of the American Academy of Cardiology (JAAC) 2008; 21: 2028-2033
Murphy et al (2008) Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial. European Heart Journal 2008; 29: 2473-2479
Wiviott, Braunwald, Angiolillo et al (2008) Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38. Circulation 2008; 118: 1626-1636
Montalescot et al (2009) Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. The Lancet 2009;, 373(9665), 723-731

8. Results of trials

The TAAL trial showed that significantly fewer patients in the prasugrel trial (9.9 %) than in the clopidogrel group (12.1 %) met the primary efficacy end point, a composite of a subject experiencing MI, stroke or cardiovascular death.

There was a significant reduction in the TAAL trial in the incidence of each of the secondary composite endpoints (MI/Stroke/CV death through 30 days, 90 days, MI/CV death or UTVR through 30 days, 90 days, at study end, all cause death/MI/Stroke at study end, MI/Stroke/CV death or rehospitalisation at study end, definite/probable stent thrombosis) for UA/NSTEMI, STEMI and All ACS populations. In addition, there was a significant reduction in nonfatal MI, all MI and urgent target vessel revascularisation (UTVR) for all 3 populations.

A statistically significantly greater proportion of patients treated with prasugrel experienced haemorrhagic adverse events compared with those treated with clopidogrel. In addition, a statistically significantly greater proportion of patients treated with prasugrel reported the incidence of colon cancer in the TAAL trial.

With respect to the primary safety end point (non-Coronary Artery Bypass Graft (CABG) -related TIMI major bleeding) the rate at 15 months was 1.8 % in the clopidogrel group, which was significantly lower than in the prasugrel group (2.4 %) (P = 0.03).

9. Clinical Claim

The submission claimed that prasugrel is superior in terms of comparative effectiveness and inferior in terms of comparative safety over clopidogrel when used in combination with aspirin.

For PBAC’s views, see Recommendation and Reasons

10. Economic Analysis

The submission presented trial based and modelled economic evaluations in the form of cost-effectiveness analyses against clopidogrel.

In the trial-based economic evaluation, the incremental cost/extra CV death/MI/stroke avoided over 15 months for prasugrel (in combination with aspirin) compared to clopidogrel (in combination with aspirin) was estimated to be less than $15,000.

In the modelled economic evaluation, the incremental cost per QALY over 40 years in the ITT population from TAAL (including stroke) and various other patient groups for treatment with prasugrel compared to clopidogrel, was also estimated to be less than $15,000.

11. Estimated PBS Usage and Financial Implications

The submission estimated the likely number of patients/year, accounting for market share as necessary, to be in the range of 10,000 – 50,000 for each of the acute setting and the maintenance settings. The submission assumed that there is no net increase in thienopyridine prescribing with the listing of prasugrel, and that utilisation will be based entirely on the substitution of prasugrel for clopidogrel.

The financial cost/year to the PBS was estimated to be less than $10 million in Year 5.

12. Recommendation and Reasons

The PBAC recommended the listing of prasugrel on the PBS on the basis of acceptable cost effectiveness compared with clopidogrel. The PBAC accepted that prasugrel is more effective but causes a higher incidence of adverse bleeding events than clopidogrel. However, the PBAC considered that the superior comparative clinical benefit of prasugrel, in terms of reduced non-fatal myocardial infarction events, marginally outweighed the inferior comparative safety profile.

The PBAC noted that from the trial data most of the benefits appear to accrue early when patients are most at risk and then reduce over time (there was an absolute 3 % reduction at 30 days (9.5 versus 6.5 %), but the reduction was only 2.4 % at 15 months (12.4 % versus 10 %); Montalescot 2008)). On the other hand, the bleeding risks appear to remain constant or increase over time. The PBAC considered that it might be beneficial for patients to switch from prasugrel to clopidogrel after an initial 3 to 6 months of therapy in terms of reducing the risk of bleeding. However, the PBAC agreed there would be significant quality use of medicines issues involved in managing a restriction that mandated a switch from one therapy to another.

A major area of concern was the use of prasugrel in the elderly and the low-weight. The sponsor’s recommendation that this sub-group of patients be given prasugrel at a lower dose is not supported by any clinical outcome data demonstrating either benefit or safety. Recent advice from the TGA recommends that the 10 mg dose not be used in either patients aged greater than 75 years or weighing less than 60 kg, and cautions that the 5 mg recommended dose is not based on clinical outcome data. The PBAC noted that a clinical trial is underway that includes a 5 mg dose option for these patient sub-populations and would be interested in the outcomes when they become available. The Committee was also advised that provision of these data was part of a risk-management plan required by the TGA.

A number of issues concerning the modelled economic evaluation, including the manner in which the utility and disutility values were applied in the modelled economic evaluation, were noted. However, the PBAC was re-assured by examination of the sensitivity analyses that the incremental cost effectiveness ratios remained within acceptable margins.

The PBAC suggested that the NPS consider providing a RADAR document to ensure quality use of medicines.

PRASUGREL HYDROCHLORIDE, tablets, 5 mg (base) and 10 mg (base)

Authority Required (STREAMLINED)
Treatment of acute coronary syndrome (myocardial infarction or unstable angina) managed by percutaneous coronary intervention in combination with aspirin.

Max Qty: 28
Repeats: 5

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

Eli Lilly Australia welcomes the PBAC recommendation for prasugrel to be listed on the PBS.