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
Page last updated: 30 October 2009
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.
Recommendation
PRASUGREL HYDROCHLORIDE, tablets, 5 mg (base) and 10 mg
(base)
Restriction:
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.
