Prasugrel for the treatment of acute coronary artery syndromes with percutaneous coronary

136 Pages·2009·1.26 MB·English

by  Ruth Lang

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL (STA) SUBMISSION

Prasugrel for the treatment of acute
coronary artery syndromes with
percutaneous coronary intervention

Prepared by Daiichi-Sankyo/Eli Lilly and Company Limited

February 9th 2009
Contents

1 Description of technology under assessment 3
2 Statement of the decision problem 5
3 Executive summary 7
4 Context 13
5 Equity and equality 18
6 Clinical evidence 19
7 Cost effectiveness 65
8 Assessment of factors relevant to the NHS and other parties 118
9 References 125

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Section A – updated following positive opinion

1 Description of technology under assessment
1.1 Give the brand name, approved name and, where appropriate, therapeutic class. For devices
please provide details of any different versions of the same device.
Efient® (prasugrel). Antiplatelet agent (thienopyridine).
1.2 Does the technology have a UK marketing authorisation/CE marking for the indications
detailed in this submission? If so, please give the date on which authorisation was received. If not, please
state current UK regulatory status, with relevant dates (for example, date of application and/or expected
approval dates).
Prasugrel received a positive opinion from the CHMP on December 18th 2008. The European commission
is expected to grant a marketing authorisation within 67 days of this date.
1.3 What are the (anticipated) indication(s) in the UK? For devices, please provide the
(anticipated) CE marking, including the indication for use.
Approved indication:
Prasugrel co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of
atherothrombotic events in patients with acute coronary syndrome (i.e. unstable angina, non-ST segment
elevation myocardial infarction [UA/NSTEMI] or ST segment elevation myocardial infarction [STEMI])
undergoing primary or delayed percutaneous coronary intervention (PCI).
1.4 To what extent is the technology currently being used in the NHS for the proposed indication?
Include details of use in ongoing clinical trials. If the technology has not been launched, please supply the
anticipated date of availability in the UK.
The technology is not yet licensed for use. It will be available following marketing authorisation.
1.5 Does the technology have regulatory approval outside the UK? If so, please provide details.
Not yet – we are awaiting EU approval.
1.6 Is the technology subject to any other form of health technology assessment in the UK? If so,
what is the timescale for completion?
We plan to submit to SMC around launch, with subsequent advice available according to their timelines.
1.7 For pharmaceuticals, what formulation(s) (for example, ampoule, vial, sustained-release
tablet, strength(s) and pack size(s) will be available?
Prasugrel will be available as 5mg and 10mg tablets in pack sizes of 28.
1.8 What is the proposed course of treatment? For pharmaceuticals, list the dose, dosing
frequency, length of course and anticipated frequency of repeat courses of treatment.
From the Summary of Product Characteristics:

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Prasugrel should be initiated with a single 60 mg loading dose (6 x 10mg tablets) and then continued at 10
mg once a day. Patients taking prasugrel should also take aspirin daily (75 mg to 325 mg).
In patients with ACS who are managed with PCI, premature discontinuation of any antiplatelet medication,
including prasugrel, could result in an increased risk of thrombosis, myocardial infarction or death due to
the patient’s underlying disease. A treatment of up to 12 months is recommended unless the
discontinuation of prasugrel is clinically indicated.
The use of prasugrel in patients ≥ 75 years of age is generally not recommended. If, after a careful
individual benefit/risk evaluation by the prescribing physician, treatment is deemed necessary in the
patients age group ≥ 75 years, then following a 60 mg loading dose a reduced maintenance dose of 5 mg
should be prescribed.
For patients weighing < 60kg, prasugrel should be given as a single 60 mg loading dose and then
continued at a 5 mg once daily dose. The 10 mg maintenance dose is not recommended.
1.9 What is the acquisition cost of the technology (excluding VAT)? For devices, provide the list
price and average selling price. If the unit cost of the technology is not yet known, please provide details
of the anticipated unit cost, including the range of possible unit costs.
The list price of prasugrel for both the 5mg and 10mg tablets is £47.56 per pack of 28.
1.10 What is the setting for the use of the technology?
Prasugrel will be initiated in the acute care setting by an appropriately qualified clinician. The longer term
prescribing for the maintenance phase will be in primary care.
1.11 For patients being treated with this technology, are there any other aspects that need to be
taken into account? For example, are there additional tests or investigations needed for selection, or
particular administration requirements, or is there a need for monitoring of patients over and above usual
clinical practice for this condition? What other therapies, if any, are likely to be administered at the same
time as the intervention as part of a course of treatment?
Patients taking prasugrel should also take aspirin daily (75 mg to 325 mg).

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2 Statement of the decision problem
Final scope issued by NICE Decision problem addressed in the submission
Intervention Prasugrel in combination with Prasugrel in combination with aspirin
aspirin
Population Patients presenting with ACS who Patients presenting with ACS undergoing PCI (licensed
are to be managed with PCI indication).
Comparator(s) Clopidogrel in combination with Clopidogrel in combination with aspirin
aspirin
Outcomes The outcome measures to be The outcome measures include:
considered include:
• Mortality.
• mortality
• Primary endpoint - composite of CV death, non fatal
• atherothrombotic events MI, non fatal stroke. Recurrent primary endpoint
events.
• need for revascularisation
• need for revascularisation – Urgent target vessel
• adverse effects of treatment revascularization (UTVR)
• health-related quality of life. • key safety endpoints - TIMI classification major
bleed not related to coronary artery bypass grafting
(CABG), non-CABG related TIMI life threatening
bleed and TIMI major or minor bleeding
• health-related quality of life
Economic The reference case stipulates that Cost-effectiveness analysis results expressed as
Analysis the cost effectiveness of incremental cost per QALY gained.
treatments should be expressed in
terms of incremental cost per
quality-adjusted life year.

The time horizon for the economic
Time horizon is 40 years (a lifetime model).
evaluation should reflect the
chronic nature of the condition.

Costs will be considered from an
Costs are considered from an NHS and Personal Social
NHS and Personal Social Services
Services perspective.
perspective.
Subgroups to be Where the evidence allows, Patients with a history of stroke or TIA are excluded since
considered subgroups at high risk of adverse they are contraindicated in the SPC. Patients ≥75 years
events or which have the potential (generally not recommended) or <60kg are only eligible
for enhanced benefit will be for the 5mg maintenance dose – therefore we analysed
considered. the 10mg target patient population separately
Due to baseline risk and variation in the delivery of care,
patients with STEMI and UA/NSTEMI flow separately
through the model.
Due to the increased baseline risk in diabetic patients, we
analysed the diabetic and non diabetic patients
separately

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Special None
considerations,
including issues
related to equity
or equality

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Section B
3 Executive summary
Approved name, Prasugrel (Brand name Efient). Product will be available following marketing
Brand name, and authorisation.
marketing status
Pharmacological Prasugrel is an inhibitor of platelet activation and aggregation through the
mechanism of action irreversible binding of its active metabolite to the P2Y class of ADP
12
receptors on platelets
Formulation(s) Prasugrel will be available as 5mg and 10mg film-coated tablets in packs of
Strength, Pack 28. The list price of prasugrel for both the 5mg and 10mg tablets is £47.56
size(s), cost per pack of 28.
Indication Prasugrel, co-administered with acetylsalicylic acid (ASA), is indicated for
the prevention of atherothrombotic events in patients with acute coronary
syndrome (i.e. unstable angina, non-ST segment elevation myocardial
infarction [UA/NSTEMI] or ST segment elevation myocardial infarction
[STEMI]) undergoing primary or delayed percutaneous coronary intervention
(PCI).
Recommended Prasugrel should be initiated with a single 60 mg loading dose and then
course of treatment continued at 10 mg once a day. Patients taking prasugrel should also take
ASA daily (75 mg to 325 mg).
In patients with acute coronary syndrome (ACS) who are managed with PCI,
premature discontinuation of any antiplatelet agent, including prasugrel,
could result in an increased risk of thrombosis, myocardial infarction or death
due to the patient’s underlying disease. A treatment of up to 12 months is
recommended unless the discontinuation of prasugrel is clinically indicated.
The use of prasugrel in patients ≥ 75 years of age is generally not
recommended. If, after a careful individual benefit/risk evaluation by the
prescribing physician, treatment is deemed necessary in the patients age
group ≥ 75 years, then following a 60 mg loading dose a reduced
maintenance dose of 5 mg should be prescribed.
For patients weighing <60kg, prasugrel should be given as a single 60 mg
loading dose and then continued at a 5 mg once daily dose. The 10 mg
maintenance dose is not recommended.
(Ref source: SPC)
Comparators Clopidogrel with aspirin

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Key clinical evidence The key clinical evidence comes from the TRITON-TIMI 38 study, a phase 3,
multinational, randomised double blind, parallel-group, head-to-head trial
which compared prasugrel with clopidogrel in 13,608 patients with moderate
to high risk acute coronary syndrome (unstable angina [UA]/non-ST-segment
elevation MI [NSTEMI] and ST-segment elevation MI [STEMI]) with
scheduled percutaneous coronary intervention (PCI). Patients were
randomised to prasugrel 60mg loading dose followed by 10mg daily or
clopidogrel 300mg loading dose followed by 75mg daily for up to 15 months.
The primary objective of the study was to test the hypothesis that prasugrel
is superior to clopidogrel on a background of aspirin in the treatment of
patients with ACS who are to undergo PCI measured by the composite
endpoint of cardiovascular death, nonfatal MI or nonfatal stroke. The key
safety endpoint was TIMI major bleeding (Wiviott 2007).
The TRITON-TIMI 38 study was a collaboration between the independent
TIMI study group, the sponsors (Daiichi-Sankyo and Eli Lilly and Company
Limited) and a steering committee of investigators. All key pre-specified and
exploratory analyses were performed by the TIMI study group using an
independent copy of the complete database.
Main results of RCTs Results from TRITON-TIMI 38 demonstrated that patients in the overall
cohort (UA/NSTEMI and STEMI) who received prasugrel (60 mg loading
dose, followed by a maintenance dose of 10 mg/day) experienced a
large and significant reduction in the primary endpoint (composite of
CV death/MI/stroke) as well as in a number of secondary endpoints
(including stent thrombosis) compared with patients receiving
clopidogrel at the standard approved dose (300 mg loading dose,
followed by a maintenance dose of 75 mg/day).
The primary efficacy end point occurred in 12.1% of patients receiving
clopidogrel and 9.9% of patients receiving prasugrel at 15 months (hazard
ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to
0.90; P<0.001) (Wiviott 2007). The hazard ratio for prasugrel, as compared
with clopidogrel, for the primary efficacy end point at 30 days was 0.77 (95%
confidence interval [CI], 0.67 to 0.88; P<0.001) and at 90 days was 0.80
(95% CI, 0.71 to 0.90; P<0.001).
Similar significant reductions were seen for prasugrel with regard to the pre-
specified secondary end point of death from cardiovascular causes, non-fatal
myocardial infarction, or urgent target-vessel revascularization at 30 days
(hazard ratio, 0.78; 95% CI, 0.69 to 0.89; P<0.001) and at 90 days hazard
ratio, 0.79; 95% CI, 0.70 to 0.90; P<0.001).
There were significant reductions in the prasugrel group compared with
clopidogrel in the rates of stent thrombosis (1.1% vs. 2.4%; hazard ratio,
0.48; 95% CI, 0.36 to 0.64; P<0.001) (Wiviott 2007).
Prasugrel treatment was associated with both early and long-term
improvement in clinical outcomes indicating benefit in the loading-dose
phase and the maintenance dose phase (see Table 12) (Antman 2008). A
significant reduction in the rate of recurrent events was seen as well. Among
patients with an initial non-fatal event, second events were significantly

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reduced with prasugrel compared to clopidogrel (10.8 vs. 15.4%, HR 0.65,
95% CI 0.46–0.92; P = 0.016) (Murphy 2008).
Prasugrel achieved these clinical benefits across the entire spectrum of
patients with ACS (UA/NSTEMI and STEMI) and the efficacy of prasugrel
(primary endpoint) was consistent across major prespecified sub-groups
(sex, age, history of diabetes, type of stent, use of glycoprotein inhibitors,
mono or poly antithrombin use, dose of aspirin, renal function, geographical
region - see Figure 5).
With respect to safety, there was a statistically significant increase in the rate
of TIMI non-CABG major bleeding observed with prasugrel compared with
clopidogrel. TIMI non-CABG major bleeding was observed in 2.4% of
patients receiving prasugrel and in 1.8% of patients receiving clopidogrel
(hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the
prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%;
HR, 1.52, 95% CI 1.08 to 2.13; P = 0.01), including nonfatal bleeding (1.1%
vs. 0.9%; hazard ratio, 1.25, 95% CI 0.87 to 1.81; P = 0.23) and fatal
bleeding (0.4% vs. 0.1%; HR 4.19, 95% CI 1.58 to 11.11; P = 0.002) (Wiviott
2007).
The net clinical benefit (as measured by the composite endpoint of death
from any cause, non-fatal myocardial infarction, non-fatal stroke, and non-
CABG related non-fatal TIMI major bleed) was in favour of prasugrel in the
overall trial population (13.9% of patients in the clopidogrel group vs. 12.2%
in the prasugrel group; hazard ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.004)
(Wiviott 2007).
However, additional analyses identified the very elderly (≥ 75 years), patients
with low body weight (< 60 kg) or those with prior history of TIA/stroke to be
at higher risk of bleeding with the 10 mg maintenance dose, compared with
the overall trial population. Patients with prior TIA/stroke experienced net
clinical harm when treated with prasugrel. Prasugrel is contraindicated in
these patients. In the group of patients <60kg and/or ≥ 75 years of age there
was neutral net benefit from prasugrel. Further analyses in these patient
groups suggested that higher levels of exposure to prasugrel’s active
metabolite occurred and may have been a causative factor in the higher
bleeding rate. A reduction of the maintenance dose to 5mg in patients
<60kg (and in patients ≥ 75 years if treatment deemed necessary following
careful individual benefit/risk evaluation by prescribing physician) is
recommended. The use of prasugrel in patients ≥ 75 years of age is
generally not recommended.
The large majority of patients, namely those aged < 75 years, body weight
≥ 60 kg, and no history of stroke or transient ischaemic attack (around 80%
of the TRITON-TIMI 38 study population), had a significant net clinical
benefit with the prasugrel regimen studied, as compared with the clopidogrel
regimen (10.2% vs 12.5%, HR for prasugrel, 0.80; 95% CI, 0.71 to 0.89; P <
0.001) (Wiviott et al., 2007) (see Table 10). In this patient group prasugrel
demonstrated statistically significant superior efficacy (as measured by the
primary composite endpoint) with numerically higher but not statistically
significant difference in the rate of non-CABG related TIMI major bleed

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(Figure 8) compared to clopidogrel. This is the cohort of patients for whom
the 10mg maintenance dose is most appropriate – the target population.
This is the population of patients who are indicated to receive the 10mg dose
in the SPC.
Economic evaluation
Type of economic A model based upon a series of risk equations was developed using
evaluation and individual patient data from TRITON. Separate risk equations for the primary
justification for the endpoint events were modelled for UA-NSTEMI and STEMI populations.
approach used These analyses used logistic models for events occurring within three days,
and Weibull models over the remainder of the trial period (up to 15 months).
Both primary efficacy and safety (bleed) endpoints predicted by these
equations were disaggregated from their combinations into specific event
types (e.g. cardiovascular death, non-fatal MI and stroke). Data from
TRITON was used to predict rehospitalisations over the period of the trial,
and average rehospitalisation costs were applied to these based on HRGs
assigned to rehospitalisations for cardiac and bleed events. These costs
were applied in the model indefinitely based on the underlying rate of
hospitalisation in the absence of clinical events. Within the trial period
hospitalisation rates reflect the relative impact of current, and earlier (within
trial) events. Rehospitalisations were adjusted for different regions within an
economic sub-sample of the trial to reflect regional variations in
rehospitalisation rates.
The model performs deterministic analyses covering each individual patient
in the trial, and recording the results based upon a duration of 12 months of
therapy in accordance with the product licence and current clinical practice.
These results were then used to estimate average costs and QALY
outcomes for patient groups of interest. An analysis was performed for all
patients in the trial, in order to compare predicted event rates with those
seen in the whole trial population. Analyses then focused on patients who
were free of prior stroke or TIA at baseline (the licensed population – the
decision problem base case). The following groups’ results are also
reported: target population (10 mg licensed population), UA-NSTEMI,
STEMI, diabetes, non-diabetes, and the overall ITT population.
Pivotal assumptions The risk equations played no part in predicting survival beyond the trial.
underlying the Beyond the trial, relative risks for all cause mortality were applied to general
model/analysis population (life table based) mortality rates adjusted to exclude deaths from
cardiovascular causes. The relative risks reflected the index ACS status and
revascularisation of all patients in the trial, and the prognostic implications of
a further MI or stroke within the trial period. The time horizon was lifetime
(40 years) in accordance with the NICE ‘Guide to the methods of technology
appraisal’ (2008).
Mean costs, Over the lifetime horizon, 40 years, prasugrel yielded 0.07 life years and
outcomes and 0.05 QALYs more than clopidogrel. Drug costs for prasugrel were
incremental ratios approximately £162 more than clopidogrel. There were modest
from the evaluation rehospitalisation cost savings over 12 months of £13; applying the actual
case-mix seen in the prasugrel arm of the clinical trial (rather than
substituting this with the clopidogrel result), would see the 12 month
rehospitalisation cost offset rise to £26. Patients continue to accrue costs

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