Ticagrelor, tablet, 90 mg, Brilinta® - July 2011
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Public Summary Document
Product: Ticagrelor, tablet, 90 mg,
Brilinta®
Sponsor: AstraZeneca Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought an Authority Required (STREAMLINED) listing
for treatment of acute coronary syndromes (ACS) (myocardial
infarction (MI) or unstable angina) in combination with
aspirin.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Ticagrelor was TGA registered on 21 June 2011 for use in
combination with aspirin, for the prevention of atherothrombotic
events (cardiovascular death, myocardial infarction and stroke) in
adult patients with acute coronary syndromes (unstable angina [UA],
non-ST elevation myocardial infarction [NSTEMI] or ST elevation
myocardial infarction [STEMI]) including patients managed
medically, and those who are managed with percutaneous coronary
intervention (PCI) or coronary artery by-pass grafting
(CABG).
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Treatment of acute coronary syndromes (myocardial infarction or
unstable angina) in combination with aspirin.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Acute coronary syndrome is a term used to describe the symptoms of
coronary artery disease, which include unstable angina, non-ST
elevation MI and ST-elevation MI. Acute coronary syndrome is
associated with atherosclerosis (build up of cholesterol-laden
plaques) and is usually precipitated by acute thrombosis, induced
by a ruptured or eroded atherosclerotic plaque, with or without
concomitant vasoconstriction, causing a sudden and critical
reduction in coronary blood flow.
Platelets play a central role in the pathogenesis of
atherothrombosis and the formation of thrombi following
percutaneous coronary intervention (with or without stenting).
Activated platelets are recruited to sites of coronary plaque
rupture and intra-arterial stenting, thereby forming aggregates
that may lead to platelet-rich thrombi, vascular occlusion, tissue
ischemia, and MI.
When oral anti-platelet therapy is indicated, ticagrelor is
proposed as an alternative treatment option to existing
agents.
6. Comparator
The submission appropriately nominated clopidogrel as the main
comparator.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented one head-to-head randomised trial (PLATO)
comparing ticagrelor with a loading dose of 180 mg to 270 mg and a
maintenance dose of 90 mg twice daily with clopidogrel with a
loading dose of 300 mg to 600 mg and a maintenance dose of 75
mg/day (both used in combination with aspirin) in patients with
acute coronary syndromes (myocardial infarction or unstable
angina). Publication details of the PLATO trial as presented in the
submission are presented in the table below.
Trial ID / First author | Protocol title / Publication title | Publication citation |
PLATO | ||
Wallentin L, et al | Ticagrelor versus clopidogrel in patients with acute coronary syndromes | N Eng J Med 2009; 361(11): 1045-1057 |
Cannon CP, et al | Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study | The Lancet 2010; 375: 283-293 |
James S, et al | Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. | Am. Heart J. 2009; 157(4): 599-605 |
Storey RF, et al | Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes. | J. Am. Coll. Card. 2010; 56: 1456-1462 |
Wallentin L, et al | Effect of CYP2C19 and ABCB1 singe nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial | The Lancet 2010; 376: 1320-1328 |
Montalescot G, Silvain J. | Ticagrelor in the renal dysfunction subgroup: Subjugated or substantiated? | Circulation 2010; 122(11): 1049-1052. |
Kleiman NS. | PLATO study of ticagrelor versus clopidogrel in patients with high-risk acute coronary syndromes. | Curr. Cardiol. Rep. 2010; 12(4): 283-285. |
Husted S, et al | Changes in inflammatory biomarkers in patients treated with ticagrelor or clopidogrel. | Clin. Cardiol. 2010; 33(4): 206-212. |
James S, et al | Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: Results from the platelet inhibition and patient outcomes (PLATO) trial. | Circulation 2010; 122(11): 1056-1067. |
8. Results of Trials
The table and figure below summarise the results of the primary outcome of the PLATO
trial – a composite of vascular death, MI (excluding silent MI) and stroke.
Results of primary outcomes of the PLATO trial (up to 12 months follow up)
Endpoint | Ticagrelor N=9,333 n (%) | Clopidogrel N=9,291 n (%) | HR (95% CI) | P-value |
Composite of vascular death/MI (excluding silent MI)/Stroke | 864 (9.3) | 1,014 (10.9) | 0.84 (0.77, 0.92) | 0.0003 |
Bolded typography indicates statistically significant differences between treatment
groups
For the primary endpoint in the PLATO trial, a statistically significant difference
between treatments was observed favouring ticagrelor (Hazard Ratio: 0.84 [95% CI:
0.77, 0.92]), although it was noted that the difference in stroke events was not statistically
significant.
The submission performed exploratory analyses by sub-groups to assess consistency
of treatment effect for the primary efficacy endpoint. In analyses of the 31 predefined
subgroups, overall the benefit of ticagrelor over clopidogrel was found to be consistent.
The observed benefit of ticagrelor appears to be reduced in patients weighing less
than the median weight for their sex, patients not taking lipid-lowering drugs at
randomisation and patients enrolled in North America. (which represented approximately
10% of the overall population studied). This may well represent a simple artefact
of retrospective subgroup analysis in only about 10% of the total enrolment. However,
it was noted that half of US patients received an aspirin maintenance dose of 325
mg, whereas the majority of non-US patients received 75 or 100 mg. Higher maintenance-doses
of aspirin were associated with relatively unfavourable outcomes with ticagrelor.
Following consideration of this and other possible explanations contained within a
US FDA discussion paper on the issue, the PBAC was reassured of ticagrelor’s comparative
benefits over clopidogrel.
For PBAC’s comments on these results, see Recommendation and Reasons.
The table below summarises the main adverse events in the PLATO trial (up to 12 months
follow up).
Summary of the main adverse events in the PLATO trial (up to 12 months follow up)
Endpoint | Ticagrelor N=9,235 n (%) | Clopidogrel N=9,186 n (%) | HR (95% CI) | P-value |
Primary Safety Endpoint (PLATO defined) | ||||
Total major bleeding | 961 (10.4) | 929 (10.1) | 1.04 (0.95, 1.13) | 0.4336 |
Secondary Safety Endpoints – Total major bleeding by severity (PLATO defined) | ||||
Major fatal/life-threatening | 491 (5.3) | 480 (5.2) | 1.03 (0.9, 1.16) | 0.6988 |
Fatal | 20 (0.2) | 23 (0.3) | 0.87 (0.48, 1.59) | 0.6553 |
Life-threatening a | 471 (5.1) | 459 (5.0) | - | - |
Major other a | 494 (5.3) | 474 (5.2) | - | - |
Major Bleeding | ||||
CABG related (all patients) PLATO defined ‘Major’ bleeding events and similar TIMI-defined bleeding events | ||||
PLATO-defined major | 619 (6.7) | 654 (7.1) | 0.95 (0.85, 1.06) | 0.32 |
TIMI-defined major | 657 (7.1) | 638 (6.9) | 1.03 (0.93, 1.15) | 0.5669 |
TIMI-defined major + minor | 946 (10.2) | 906 (9.9) | 1.05 (0.96, 1.15) | 0.3272 |
Non-CABG related PLATO defined ‘Major’ bleeding events and similar TIMI-defined bleeding events | ||||
Total major bleeding (PLATO defined) | 362 (3.9) | 306 (3.3) | 1.19 (1.02, 1.38) | 0.0264 |
Major fatal/life-threatening (PLATO defined) | 171 (1.9) | 151 (1.6) | 1.14 (0.91, 1.41) | 0.2516 |
TIMI-defined major bleeding | 221 (2.4) | 177 (1.9) | 1.25 (1.03, 1.53) | 0.0246 |
TIMI-defined major + minor | 360 (3.9) | 295 (3.2) | 1.23 (1.05, 1.43) | 0.0093 |
PLATO-defined ‘Combined major + minor bleeding events | 1,339 (16.1) | 1,215 (14.6) | 1.11 (1.03, 1.2) | 0.0084 |
Non-procedural bleeding events by severity (PLATO defined) | ||||
Combined major + minor b | 457 (4.9) | 332 (3.6) | 1.39 (1.21, 1.60) | <0.0001 |
Major | 235 (2.5) | 180 (2.0) | 1.31 (1.08, 1.60) | 0.0058 |
Fatal/life Threatening | 103 (1.1) | 95 (1.0) | 1.09 (0.82, 1.44) | 0.5456 |
Fatal c | 13 (0.1) | 12 (0.1) | 1.09 (0.50, 2.38) | 0.8331 |
Minor bleeding | ||||
Minor bleeding study criteria | 442 (4.8) | 349 (3.8) | 1.26 (1.10, 1.45) | <0.05 |
Minor bleeding - non procedural related | 237 (2.6) | 161 (1.8) | 1.46 (1.20, 1.79) | <0.05 |
General AEs (including bleeding events) | ||||
Any AE Mild Moderate Severe | 6,714 (72.7) 5,655 (61.2) 3,322 (36.0) 1,019 (11.0) | 6,398 (69.6 ) 5,292 (57.6) 3,073 (33.5) 1,061 (11.6) | - - - - | - - - - |
Any SAE SAE excluding death Death | 1,864 (20.2) 1,712 (18.5) 218 (2.4) | 1,866 (20.3) 1,685 (18.3) 285 (3.1) | - - - | - - - |
Leading to study drug discont SAE | 687 (7.4) 259 (2.8) | 500 (5.4) 218 (2.4) | - - | - - |
Dyspnoea d | 1,270 (13.8) | 721 (7.8) | - | - |
a time to first event is not calculated for ‘life-threatening’ and ‘major other’ bleeding
because it may be proceeded by a more severe bleed. Patients may be counted in >1
bleeding event category.
b patients may be counted in >1 bleeding event category
c >1 fatal bleeding event was ICAC-adjudicated for 1 patient in the clopidogrel group
d patients with at least 1 event, Source: Table 68, p270 of the PLATO trial report,
OR (95% CI)=1.84 (1.68, 2.02) Wallentin et al (2009)
n= patients with adverse events, TIMI=Thrombolysis in Myocardial Infarction, discont=discontinuation
Patients treated with ticagrelor were observed to have an increase in non-CABG related
PLATO defined ‘Major’ bleeding events and similar Thrombolysis in Myocardial Infarction
(TIMI)-defined bleeding events, non-procedural bleeding events by severity (PLATO
defined), minor bleeding and dyspnoea. Ticagrelor was not associated with a significant
increase in total major or fatal/life-threatening bleeds.
The PBAC also noted the special report from the FDA on ticagrelor (Gaglia, M. & Waksman,
R. ‘Overview of the 2010 Food and Drug Administration Cardiovascular and Renal Drugs
Advisory Committee Meeting Regarding Ticagrelor’, Circulation 2011; 123: 451). Some of the key findings from this report included:
The sponsor estimated that 9 in 1000 patients would discontinue ticagrelor because of dyspnoea. Data was also presented showing that patients with cardiopulmonary disease at baseline did not have an increased relative risk of dyspnoea. Furthermore, patients taking ticagrelor did not have measurable changes in pulmonary function.
Patients taking ticagrelor versus clopidogrel had more ventricular pauses ≥3 seconds on Holter monitoring during the first week of treatment (5.8% versus 3.6%; P = 0.01). These pauses, however, did not result in an increase of other arrhythmias or need for pacemaker insertion. Furthermore, the benefit of ticagrelor with regard to the primary end point was maintained in patients with pauses.
The PBAC considered that these were not major concerns.
9. Clinical Claim
The submission described ticagrelor as superior in terms of
comparative effectiveness and equivalent in terms of comparative
safety over clopidogrel in combination with aspirin. Based on the
supporting data, the PBAC considered this description was
reasonable for the claim regarding comparative effectiveness, but
the claim regarding comparative safety may not be reasonable.
For further details of PBAC’s view, see Recommendation
and reasons.
10. Economic Analysis
A stepped economic evaluation was presented. The model consisted of
five health states: event-free, MI, stroke, CV death and other
death. Patients in the model were based on those in the PLATO trial
(average age of 62 years, 29% women); they had had an ACS event and
entered the model in the event-free state. In the first year, the
model has 4 cycles of varying length. Patients transit from the
event-free health state to the other health states by transition
probabilities derived for the specified time periods from
patient-level data from the PLATO trial. The model appropriately
also included adverse events (non-CABG major bleed, minor bleeds
and dyspnoea). For the remaining 9 years of the time horizon, the
model has annual cycles.
The base case of the modelled economic evaluation assumed that the
duration of treatment were 246 days for ticagrelor and 250 days for
clopidogrel (derived from the PLATO trial) for an estimated 9 packs
of each therapy over 12 months. In addition, the submission assumed
that for the treatment duration patients adherence (defined as
taking ≥80% of medication) was 83% in both treatment groups. The
requested restriction for ticagrelor does not specify duration of
treatment and it is implied to be life-long.
The base case incremental cost per quality adjusted life year
(QALY) gained was less than $15,000.
The ICER was sensitive to assumptions regarding the costs for the
index ACS event and assumptions regarding treatment duration and
compliance.
Sensitivity analyses presented by the sponsor to address the
uncertainty regarding duration of treatment produced an ICER of
between $15,000 and $45,000 when a continued treatment costs for 4
years and a constant treatment effect based on the combined event
rate from the last period of the trial are assumed.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year to
be between 50,000 and 100,000 in Year 5, at an estimated net cost
to the PBS of between $50 and $100 million in Year 5.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC recommended the listing of ticagrelor 90 mg as an
Authority Required (Streamlined) benefit for the treatment of acute
coronary syndrome (myocardial infarction or unstable angina) in
combination with aspirin on the basis of acceptable
cost-effectiveness compared with clopidogrel in combination with
aspirin.
Given that the submission was based on clinical efficacy data up to
12 months and the fact that clinical guidelines recommend therapy
for up to 12 months in the treatment of ACS, the PBAC considered
whether it would be appropriate for the restriction to limit
treatment up to a maximum of 12 months duration. However, the PBAC
considered that length of treatment should be determined by the
treating clinician and noted that the restrictions for similar
drugs, clopidogrel and prasugrel, do not define treatment duration
despite the listing of these drugs also being based on trials that
limited treatment duration.
The PBAC accepted the Restriction Working Group’s advice that
‘acute coronary syndrome’ in place of ‘acute
coronary syndromes’ better describes the PBS-eligible
population and that such wording should also flow onto the current
PBS restrictions for clopidogrel and clopidogrel with
aspirin.
The submission’s nominated comparator, clopidogrel, was
considered appropriate by the PBAC. Consideration of prasugrel as a
relevant comparator was discussed by the PBAC but it was noted that
between clopidogrel and prasugrel as antithrombotic agents,
clopidogrel currently has the majority of use in clinical practice
and has a restriction which is the same as the requested
restriction for ticagrelor. Also, it was noted that unlike
clopidogrel, prasugrel is only available for a subgroup of ACS
patients (i.e. those with ACS managed by PCI).
The PBAC considered that the results of the PLATO trial presented
in the submission support the claim of superior comparative
effectiveness of ticagrelor over clopidogrel. For the primary
endpoint in the PLATO trial which was a composite of cardiovascular
death, MI (excluding silent MI) and stroke up to 12 months of
follow up, a statistically significant difference between
treatments was observed favouring ticagrelor (Hazard Ratio: 0.84,
95% CI: 0.77, 0.92), although it was noted that the difference in
stroke events was not statistically significant.
The PBAC noted clinical efficacy data that suggested that
ticagrelor is less effective than clopidogrel in terms of reducing
the number of ACS events in North American patients. This may well
represent a simple artefact of retrospective subgroup analysis in
only about 10% of the total enrolment. However, it was noted that
half of US patients received an aspirin maintenance dose of 325 mg,
whereas the majority of non-US patients received 75 or 100 mg.
Higher maintenance-doses of aspirin were associated with relatively
unfavourable outcomes with ticagrelor. Following consideration of
this and other possible explanations contained within a US FDA
discussion paper on the issue, the PBAC was reassured of
ticagrelor’s comparative benefits over clopidogrel.
The PBAC considered the submission’s claim of comparable
safety to clopidogrel may not be reasonable. It was noted that
patients treated with ticagrelor were observed to have an increase
in non-CABG related PLATO defined ‘Major’ bleeding
events (Hazard Ratio: 1.04, 95% CI: 0.95, 1.13) (p<0.4436) and
similar TIMI-defined bleeding events, non-procedural bleeding
events by severity (PLATO defined), minor bleeding and dyspnoea.
The PBAC further noted a lack of long term safety data beyond 12
months and FDA reports of discontinuations because of dyspnoea and
ventricular pauses. However, with respect to dyspnoea and
ventricular pauses, these were not major concerns for the
PBAC.
A stepped economic evaluation was presented through a cost-utility
analysis and a cost-effectiveness analysis (estimating the
incremental cost per events avoided from ‘within’ the
PLATO trial and life-years-gained). The PBAC considered the
submission’s ICER of less than $15,000 per QALY gained to be
acceptable. The PBAC noted that the economic model was most
sensitive to duration of treatment and that the modelled economic
evaluation assumed duration of treatment to be one year. However,
the PBAC noted that the requested listing did not limit treatment
to one year and considered that in reality, it is likely that
treatment will continue beyond one year in some patients.
To address the uncertainty regarding duration of treatment, in its
pre-PBAC response, the sponsor presented a sensitivity analyses
based on an extended duration of treatment and constant treatment
effect. In the most extreme case, assuming continued treatment
costs for 4 years and a constant treatment effect based on the
combined event rate from the last period of the trial, the ICER
increased to between $15,000 and $45,000 per QALY gained. The PBAC
considered this revised ICER to still represent acceptable cost
effectiveness.
The PBAC considered the submission’s estimates on ticagrelor
PBS usage and financial implications to be uncertain due to the
high potential for ticagrelor to be used in non-ACS conditions by
clinicians. On the other hand, may be less than predicted due to
adverse events associated with ticagrelor (e.g. increased non-CABG
bleeding) and potentially lower compliance arising from a twice
daily dosing schedule compared to clopidogrel’s once daily
dosing. The high potential for ticagrelor to be prescribed for
non-ACS conditions was of particular concern to the PBAC as use in
such conditions has the potential to result in high costs to the
PBS. To address the issue of ticagrelor’s potential use
outside any PBS restriction, the PBAC recommended that the
Department enter into a risk share agreement with the
sponsor.
The PBAC recommended that ticagrelor be included in the PBS
medicines for prescribing by nurse practitioners within a shared
care model.
Recommendation:
TICAGRELOR, tablet, 90mg
Restriction:
Authority Required (STREAMLINED)
Treatment of acute coronary syndrome (myocardial infarction or
unstable angina) in combination with aspirin.
Maximum Quantity 56
No. of 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
The sponsor had no comment