Clopidogrel hydrogen sulfate, tablet, 75 mg (base), Iscover®, Plavix®, March 2009
Public summary document for Clopidogrel hydrogen sulfate, tablet, 75 mg (base), Iscover®, Plavix®, March 2009
Page last updated: 03 July 2009
Public Summary Document
Product: Clopidogrel hydrogen sulfate, tablet, 75 mg (base), Iscover®, Plavix®
Sponsors: Bristol-Myers Squibb Pharmaceuticals, Sanofi-Aventis Australia Pty Ltd
Date of PBAC Consideration: March 2009
1. Purpose of Item
To allow the PBAC to consider the report reviewing the clinical and
cost-effectiveness evidence available for clopidogrel’s use
in preventing atherothrombotic events following coronary artery
stenting, and provide advice to Government.
2. Background
At the June 1999 meeting, the PBAC recommended the listing of
clopidogrel for the secondary prevention of ischaemic stroke,
transient cerebral ischaemic events, myocardial infarction and
unstable angina in patients with a history of cardiac ischaemic
events or cerebrovascular ischaemic episodes while on therapy with
low-dose aspirin. Listing was effective from 1 November 1999.
At the March 2008 meeting, the PBAC recommended extending
clopidogrel’s restriction to include as an Authority Required
(Streamlined) listing, the treatment of acute coronary syndromes
(myocardial infarction or unstable angina) in combination with
aspirin to prevent early and long-term atherothrombotic events on
the basis of an acceptable cost-effectiveness ratio compared to
aspirin therapy alone. Listing was effective from 1 February
2009.
The Committee noted that not all appropriate clinical use of
clopidogrel may be covered by the restrictions applying to
clopidogrel’s PBS listing. The use of clopidogrel following
coronary artery stenting procedures was of most interest. This
indication is not PBS subsidised unless the patient undergoing
stenting qualifies through one of the current PBS listing
restrictions, but preliminary clinical advice indicates that
anti-blood clotting therapy (using both clopidogrel and aspirin) is
a requirement following stenting procedures to prevent blood clots
reforming later. It is likely that some patients with stents may
not access PBS subsidised prescriptions, creating an inequitable
arrangement whereby some patients pay the full cost of a necessary
treatment whilst others do not. The PBAC requested the Department
initiate a cost effectiveness review of clopidogrel with the
objective of finding the best clinical place of clopidogrel as
supported by evidence of efficacy, safety and cost effectiveness,
and to ensure that the PBS indications reflect this use.
At the November 2008 meeting, the PBAC recommended the listing of a
fixed dose combination product containing clopidogrel 75 mg with
aspirin 100 mg as an Authority Required (Streamlined) item on a
cost-minimisation basis compared with clopidogrel alone.
The sponsors were invited to contribute to this review, and did
provide information.
3. Registration Status
From 5 August 2008, clopidogrel was TGA registered for:
- Prevention of vascular ischaemia associated with atherothrombotic events (myocardial infarction, stroke and vascular death) in patients with a history of symptomatic atherosclerotic disease.
- Acute Coronary Syndrome. Clopidogrel is indicated in combination with aspirin for patients with the following:
- Unstable angina or non-ST-elevation myocardial infarction in
order to prevent early and long-term atherothrombotic events
(myocardial infarction, stroke, vascular death or refractory
ischaemia). Clopidogrel is indicated for the treatment of acute
coronary syndrome whether or not patients undergo cardiac
revascularisation (surgical or PCI, with or without stent);
- ST-segment elevation acute myocardial infarction in order to
prevent atherothrombotic events. In this population, clopidogrel
has been shown to reduce the rate of death from any cause and the
rate of a combined endpoint of death, re-infarction or stroke in
medically treated patients eligible for thrombolytic therapy.
4. Summary of the Review and Findings
The Clopidogrel Therapy in Current Clinical Practice report consisted of:
- a summary of previous PBAC considerations
- an international comparison of registration, reimbursement and clinical guidance for clopidogrel,
- a systematic review of the clinical evidence; not previously considered by the PBAC,
- a systematic review of the economic evidence not previously considered by the PBAC; and
- data on the utilisation of clopidogrel in Australia.
The focus of the report was on the evidence of effectiveness and
cost-effectiveness of clopidogrel in patients with stable angina
undergoing stenting.
Guidelines for clinical practice for the use of clopidogrel
therapy in Percutaneous Coronary Intervention (PCI)
Recommendations from national and international guidelines
regarding the appropriateness and duration of clopidogrel treatment
following stent insertion were reviewed as follows:
- Australian/New Zealand guidelines, Cardiac Society of Australia and New Zealand (CSANZ)/National Heart Foundation (NHF) ACS (2006)
- Veteran’s Medicines Advice and Therapeutic Education Services (MATES) program
- United States, American College of Cardiology (ACC)/American Heart Association (AHA)/SCAI 2007
- Europe, European Society of Cardiology (ESC) NSTEACS 2007
In summary, in relation to the use of clopidogrel in patients
undergoing stenting all the guidelines recommend that it be used in
conjunction with aspirin for 12 months or long term for those
patients implanted with drug-eluting stents (DES), although new
evidence is still emerging regarding the optimal duration of
therapy.
Clinical Evidence for clopidogrel use in
stenting
A review of the medical literature was performed to identify
systematic reviews of clopidogrel as monotherapy or as dual therapy
with aspirin in the intervention arm.
In one of the two reviews found, Bowry et al (2008)
conducted a systematic review to clarify the role of clopidogrel
and aspirin as dual-antiplatelet therapy for patients with vascular
diseases. Three studies (PCI-CURE, PCI-CLARITY, and CREDO) assessed
patients who underwent PCI (PCI-CURE and PCI-CLARITY were
sub-studies of the CURE and CLARITY trials of dual therapy versus
aspirin). The time to follow-up ranged from 28 days to 18 months.
The meta-analysis showed that in patients who underwent PCI, use of
clopidogrel plus aspirin significantly reduces the odds of major
coronary events and fatal or non-fatal MI, compared with aspirin
monotherapy.
PCI-CURE: Percutaneous Coronary Intervention-CURE (Mehta et al
2001)
PCI-CURE was a randomised double-blind trial which measured the
benefit of clopidogrel plus aspirin therapy compared to aspirin
monotherapy in non ST elevation myocardial infarction (NSTEMI)
acute coronary syndrome (ACS) patients who underwent a PCI. A total
of 2,658 patients were randomised to: clopidogrel 300 mg loading
dose, followed by a 75 mg clopidogrel/day maintenance dose plus
aspirin (n=1,313) versus a loading dose of placebo prior to PCI,
followed by aspirin monotherapy (n=1,345). In the patients
receiving clopidogrel pre-treatment, 1,080 (82%) patients received
a stent compared to 1,092 (81%) in the aspirin monotherapy group.
The follow-up was for a period of 12 months. The primary outcome
was the composite of urgent target-vessel revascularisation, MI or
vascular death within 30 days of receiving a PCI. Cardiovascular
deaths or MI prior to receiving a PCI and during the follow-up
period were also assessed. The safety-related outcomes were
bleeding complications, which were categorised as life-threatening,
major or minor.
The incidence of the combined primary outcome was significantly
lower in the clopidogrel plus aspirin group (4.5%) versus the
aspirin monotherapy group (6.4%), RR 0.70 (95% CI, 0.50 to 0.97);
p=0.03. The relative risk for the combined endpoint of CV death and
MI from the time of PCI to end of study was 0.75 (95% CI, 0.56 to
1.0); p=0.047. The overall results (events before and after PCI)
for CV death and MI were RR 0.69 (95% CI, 0.54 to 0.87, p=0.002).
No difference was observed between the treatment groups for major
and life-threatening bleeding. A higher event rate for minor
bleeding was observed in the clopidogrel group (3.5%) than for the
placebo group (2.1%) at follow-up (p=0.03). The combined endpoint
of cardiovascular death and myocardial infarction at follow-up in
patients who received a stent was statistically significant in
favour of clopidogrel, RR 0.73, (95% CI, 0.56 to 0.95).
The study authors concluded that pre-treatment with clopidogrel in
addition to aspirin in patients with ACS undergoing a PCI is
beneficial in reducing major ischaemic events up to 30 days after
receiving a PCI.
For PBAC’s view, see Recommendation and
Reasons.
PCI-CLARITY: Percutaneous Coronary Intervention-CLARITY
(Sabatine et al 2005)
PCI-CLARITY was a randomised double-blind trial which assessed the
benefit of clopidogrel therapy plus aspirin compared with aspirin
monotherapy in patients (ST segment elevation MI) undergoing PCI in
the CLARITY study. A total of 1,863 patients were randomised to:
clopidogrel 300 mg loading dose prior to PCI, followed by a 75
mg/day maintenance dose plus aspirin (n=933) versus a loading dose
of placebo prior to PCI, followed by aspirin monotherapy (n=930),
and were followed-up for a period of 30 days. All the patients
received aspirin at a dose ranging from 150 mg to 325 mg on the
first day and then 75 mg to 162 mg daily thereafter. The primary
efficacy outcome for patients who underwent angiography was the
composite of CV death, stroke or recurrent MI. Secondary outcomes
included recurrent MI or stroke before PCI and the composite of
cardiovascular death, recurrent MI, or stroke during the period
from randomisation up to 30 days. The safety-related outcomes were
evaluated for thrombolysis in myocardial infarct (TIMI) major and
minor bleeding.
The rates of the primary efficacy end point were 7.5% in the
clopidogrel plus aspirin group and 12.0 % in the aspirin
monotherapy group, OR 0.59 (95 % CI, 0.43 to 0.81; p=0.001). The
rates for cardiovascular death or MI were 7.2 % in the clopidogrel
plus aspirin group and 11% in the aspirin monotherapy group, OR
0.62 (95 % CI, 0.45 to 0.86; p=0.004). There were no significant
increases in the rates of TIMI major bleeding (0.5% vs. 1.1%), TIMI
minor bleeding (1.4% vs. 0.8%), or the combination (2.0% vs. 1.9%)
following PCI in patients who received clopidogrel pre-treatment
compared to the placebo patient group. The efficacy results for the
sub-group of patients whom received a stent were not provided in
the publication of the trial.
The study authors concluded that clopidogrel pre-treatment
significantly reduced the incidence of cardiovascular death or
ischaemic complications in STEMI patients, both before and after
receiving a PCI, without significantly increasing major or minor
bleeding.
CREDO: Clopidogrel for the Reduction of Events During
Observation (Steinhubl 2002)
CREDO was a randomised double-blind placebo controlled trial that
assessed the efficacy of clopidogrel therapy for a 12-month period.
A total of 2,116 patients referred for PCI were randomised into two
groups: clopidogrel 300 mg loading dose prior to PCI, followed by a
75mg/day maintenance dose plus aspirin (n=1,053) versus a loading
dose of placebo prior to PCI, followed by aspirin monotherapy
(n=1,063), and were followed-up for a period of 12 months. In the
patient group receiving clopidogrel pre-treatment, 807 (90%)
patients received a stent compared to 808 (88%) patients in the
placebo arm. The primary outcome was the composite of stroke, MI or
death. The other outcomes included stroke, MI or death, as separate
outcomes and incidence of major bleeding.
The relative risk reduction for the primary outcome was 27% (95%
CI, 3.9 to 44.4, p=0.02) and was statistically significant.
Non-statistically significant differences were observed in the
relative risk reduction for death 25% (95% CI, -38.9 to 59.1), MI
22% (95% CI, -7.1 to 42.7) and stroke 25% (95% CI, -77.9 to 68.4).
The relative risk reduction for the primary endpoint in patients
who received a stent was 28.8% (95% CI: 3.6 to 47.4) and is
statistically significant (p-value not provided in publication)
favouring clopidogrel. Patients treated with clopidogrel therapy
for one year had non-statistically significant higher incidences of
major bleeding (8.8% clopidogrel plus aspirin versus 6.7% aspirin
monotherapy; p= 0.07).
The study authors concluded that following PCI, long-term (1-year)
clopidogrel therapy significantly reduced the risk of adverse
ischaemic events.
The CREDO trial included a different population to those in the
PCI-CURE and PCI-CLARITY trials. About 33% of patients in each arm
of the CREDO trial had stable angina, which is the population
currently unable to access PBS subsidised clopidogrel.
For PBAC’s view, see Recommendation and
Reasons.
Clopidogrel use in bare metal stents compared to
drug-eluting stents
The review noted that patients in both PCI-CURE and CREDO were
implanted with bare metal stents (BMS), as these studies were
conducted prior to the widespread uptake of drug-eluting stents
(DES). The claim for DES is that they reduce the risk of restenosis
compared to BMS (evidence for this claim is beyond the scope of
this report), although patients receiving either DES or BMS remain
at risk of stent thrombosis.
The most recent guidelines on the duration of use of clopidogrel
have recommended use for at least 12 months following implantation
of DES, and recent case reports of late stent thrombosis in
patients who have received DES have recommended caution in ceasing
clopidogrel at all. All the literature advises that the optimal
duration of clopidogrel use in DES is unknown and requires further
investigation and monitoring, with some suggesting PCI patient
registers as the mechanism by which to do this.
The PBAC noted in the Sponsor’s response the report from
Eisenstein et al (2007) which involved a cohort study in 3165
patients with BMS and 1501 with DES. In patients who had DES and
were event free at six months or at 12 months, clopidogrel use
predicted a statistically significant lower death rate and death or
MI rate at 24 months. However, among patients who had a BMS there
were no statistical differences in death rate or MI.
The PBAC also noted the recent technology appraisal guidance from
the National Institute of Clinical Excellence (NICE),
Drug-eluting stents for the treatment of coronary artery
disease (July 2008) which included relevant information in
relation to clopidogrel therapy for patients receiving a DES.
The PBAC noted that the use of DES would have implications for the
extent of increase in clopidogrel prescribing should its
restriction be extended. Exact data on the ratio of DES to BMS
implantation in Australia was unknown.
New evidence of factors that may adversely affect
clopidogrel efficacy
The review advised of several recent retrospective studies which
have linked the genetic variant CYP2C19 with a decrease in the
effectiveness of clopidogrel. As the evidence is conflicting,
prospective studies are being conducted, and the results will be
included in updated Product Information for clopidogrel.
5. Economic Analysis
A summary of analyses of cost effectiveness of PCI/stent insertion
are presented in the following table. They have generally concluded
that PCI plus clopidogrel and aspirin is cost-effective. However,
the cost effectiveness of clopidogrel beyond 12 months is
uncertain.
Cost effectiveness in percutaneous coronary intervention (PCI)
| Author | Source of Clinical data | Country of analysis | Incremental Health Outcome(s) | Incremental Cost | ICER (95%CI clinical outcome) |
| Lindgren 2005 [42] | PCI-CURE RIKS-HIA | Sweden | LYG: 0.04 | Direct costs: | |
| €449 | € 10,993/LYG | ||||
| Total costs | |||||
| €332 | € 8,127/LYG | ||||
| Mahoney [43] (2005) | PCI-CURE SASK | USA | All PCI patients | ||
| LYG: 0.0885 | US$253 to $423 | US$2,856 - US$4,775 | |||
| PCI at initial hospitalisation | |||||
| LYG: 0.0962 | -US$181 to US$90 | Dominant to US$935 | |||
| Beinart [40] (2005) | CREDO FRAM SASK | USA & Canada | Framingham | ||
| LYG: 0.1526 | US$563 - US$664 | US$3,684 - $4,353/LYG | |||
| Saskatchewan | |||||
| LYG: 0.1920 | US$563 - US$664 | US$2,929 - US$3,460/LYG | |||
| Cowper [41] | CREDO, DISCC, FRAM | USA | MI rate: -2.56% LYG: 0.056 | US$896 | US$34,336/MI prevented US$15,696/LYG low risk: US$26,568/LYG high risk: US$10,333/LYG |
| Ringborg [44] | CREDO Swedish databases | Sweden | LYG: 0.072 QALY: 0.066 | Direct: | |
| €537 | €7,492/LYG €8,184/QALY | ||||
| Total costs: | |||||
| €217 | €3,022/ LYG €3,301/QALY | ||||
PCI-CURE: Percutaneous Coronary Intervention- Clopidogrel in
Unstable angina to prevent Recurrent Events; CREDO: Clopidogrel for
the Reduction of Events During Observation; LYG: Life-Years Gained;
QALY: Quality-Adjusted Life Years; ICER: Incremental
Cost-Effectiveness Ratio; USA: United States of America; FRAM,
Framingham Heart Study; SASK: Saskatchewan Health database; DISCC:
Duke Information System for Cardiovascular Care; RISK-HIA: Swedish
Register of Information and Knowledge about Swedish Heart Intensive
care Admissions.
For PBAC’s view, see Recommendation and
Reasons.
6. Estimated PBS Usage and Financial Implications
Utilisation of clopidogrel in stenting
The review advised there was considerable uncertainty around the
number of patients who do not have ACS and who are therefore not
currently eligible for clopidogrel PBS subsidy but who are
implanted with cardiac stents. The examination of the available
utilisation data, which includes stenting data as well as
clopidogrel data, particularly sought to estimate this proportion
of patients. It should be noted that the ACS indication for
clopidogrel prescribing was available only on 1 February 2009;
therefore the available data does not yet reflect any change in
clopidogrel utilisation as a result of this listing.
The PBAC noted from the Medicare Australia data provided in the
report that there had been a consistent growth in dispensing since
clopidogrel was first listed, although the rate of growth in
dispensing is declining. Data for the period July 2004 to June 2007
from the Drug Utilisation Sub-Committee database indicated that
most of the prescribing was under the PBS/RPBS for use in patients
who are unable to tolerate aspirin. A relatively small number of
scripts were private or below co-payment (~0.3%). Of interest is
that more than 100,000 separations for cardiac stent insertion
occurred over the same period.
However, the number of scripts dispensed for the pre- or
post-angioplasty for RPBS patients has declined over this period,
and the percentage of these scripts prescribed privately has
increased from 1.1% in 2004/2005 up to 25.8% in 2007/2008.
BEACH (Bettering the Evaluation And Care of Health) utilisation
data for clopidogrel were obtained for a 24 month period from April
2005 until March 2007.
In terms of health conditions associated with clopidogrel use, the
BEACH data found the majority of the health conditions treated with
clopidogrel (38%) were classified as ischaemic heart disease, 21%
were classified as ‘other’ conditions, and all other
described conditions were each less than 10% of the total. The
dataset did not contain a specific category for cardiac stenting so
therefore patients with stents potentially could be included in all
described health conditions.
Ostini et al explored the utilisation of clopidogrel therapy in
Australia, in relation to age, geographical location, gender and
cardiac stenting rates and found the factors likely to have
increased the supply of clopidogrel were age, male gender and
living in a major city. The authors noted that these are the same
demographic variables which are important predictors of cardiac
stenting, and postulated that currently between one third and three
quarters of the clopidogrel use is for cardiac stenting. To enhance
clopidogrel utilisation, they recommended a PBS subsidy be sought
for cardiac stenting and suggested that a time limit should be
applied to clopidogrel therapy for this indication, based on best
clinical evidence.
The Sponsors provided data from the Melbourne Interventional Group
(MIG) Register, which looked at the use of clopidogrel in patients
undergoing PCI in Victoria. Recently, a publication in the Medical
Journal of Australia, presented related information from this
Registry, and around 32% of their patients underwent stenting
procedures for stable angina. They showed that when a PCI procedure
is undertaken, 99.5% of all patients receive clopidogrel at
baseline.
Their data also showed that patients with DES were more likely to
be receiving clopidogrel than patients with BMS at both 30 days and
12 months. It was observed at the 12 month follow-up that patients
still taking clopidogrel at day 30 had significantly better
outcomes than patients who had ceased taking clopidogrel prior to
day 30:
- Fewer re-admissions to hospital (relative risk ratio (RRR) 16.7%, p=0.007)
- Decreased 12 month mortality (RRR 71.7%, p<0.0001)
- Decreased 12 month major adverse cardiac events (MACE) (RRR 28.1%, p=0.019).
Premature cessation of clopidogrel at 30 days was associated with
increased hospital re-admission rates, mortality and MACE at 12
months:
- Increased readmissions to hospital (RRR 23.0%, p=0.004)
- Increased 12 month mortality (RRR 80.5%, p<0.0001)
- Increased 12 month MACE (RRR 39.4%, p=0.006).
A PES addendum examining Casemix data on stenting concluded that
the proportion of cardiac stenting patients who would be eligible
for clopidogrel benefits under a cardiac stenting PBS restriction
was potentially large, and their requirement for ongoing therapy,
should DES predominate over BMS, may be long term. However, the
impact on utilisation of clopidogrel as a result of extending the
PBS restriction to cover cardiac stenting was uncertain.
7. Recommendation and Reasons
The PBAC recommended the listing of clopidogrel on the PBS for use
following stent insertion in patients without a prior history of
Acute Coronary Syndrome (ACS) in combination with aspirin. The PBAC
considered that there is evidence that this is best clinical
practice and noted that any increase in use is likely to be minimal
following this listing. Clopidogrel is already being prescribed for
at least 4 – 6 weeks in a majority of patients with stents.
The PBAC expressed concern over the lack of clarity around the
optimal duration of therapy and noted that further discussion with
relevant experts will be needed to progress this issue.
The PBAC considered the evidence presented from the Clopidogrel
Review, which had been undertaken at the PBAC’s request
following the recommendation to list clopidogrel in combination
with aspirin for patients with ACS at the March 2008 meeting. That
decision noted that not all clinically appropriate use of
clopidogrel may be subsidised by the current restrictions applying
to its PBS listing, and that the use of clopidogrel following
coronary artery stenting was of most interest. The PBAC observed
that a coverage gap occurs in patients who have a stent inserted
without a prior history of ACS. It was noted from the review that
clopidogrel use is rising but at a decreasing rate, and that
although stent use is high it also appears to be plateauing.
The PBAC considered the evidence presented in the CREDO trial of
most relevance, as most of the participants who underwent
percutaneous coronary intervention (PCI) received stents. The
objectives of the trial were to compare the long-term use (one year
compared with one month) of clopidogrel post- PCI. Patients were
considered eligible for enrolment in the study if they had
symptomatic coronary artery disease with objective evidence of
ischemia. Patients were randomly assigned to receive a 300-mg
clopidogrel loading dose (n=1053) or placebo (n=1063) 3 to 24 hours
before PCI. Thereafter, all patients received clopidogrel, 75 mg/d,
through day 28. From day 29 through 12 months, patients in the
loading-dose group received clopidogrel, 75 mg/d, and those in the
control group received placebo. Both groups received aspirin
throughout the study. At 1 year, it showed that long term
clopidogrel therapy was associated with a 26.9% relative reduction
in the combined risk of death, MI, or stroke (95% confidence
interval, 3.9%-44.4%; P=.02; absolute reduction, 3%), although the
loading dose did not significantly reduce the combined risk of
death, MI, or urgent target vessel revascularization at 28
days.
The PBAC also considered the evidence presented in the CURE trial,
in which 12,562 pts with ACS were randomised to clopidogrel or
placebo, both in combination with aspirin. 36% of trial
participants had a percutaneous coronary intervention (PCI) or
coronary artery bypass graft (CABG). The results at 30 days showed
early effect of clopidogrel in reducing the hazard ratio, and
demonstrated a 20% relative risk reduction (p= 0.00009) in first
primary endpoints of myocardial infarction (MI), stroke or
cardiovascular death at 12 months. The PBAC considered that CURE
did not provide evidence that PCI with or without stenting is a
treatment effect modifier for clopidogrel, but noted that there is
no direct randomised controlled trial data to provide more
certainty on this.
The PBAC noted that the systematic review of the economic evidence
shows that clopidogrel plus aspirin when compared to aspirin alone
has generally been interpreted as cost-effective for all patients
undergoing a PCI. However there is uncertainty regarding the
optimal duration of clopidogrel therapy after PCI and uncertainty
regarding the effectiveness, and hence cost-effectiveness, beyond
12 months. The Committee noted that they had previously accepted
the incremental cost effectiveness ratio (ICER) presented by the
sponsor for the ACS listing, where the data included patients both
who had and had not undergone PCI. The incremental cost per LYG was
estimated to be at the lower end of the range between $15,000 and
$45,000, and the incremental cost per QALY was estimated to be less
than $15,000. The Committee also noted the recent guidance on Drug
Eluting Stents for the treatment of coronary artery disease from
the National Institute for Health and Clinical Excellence (NICE)
which advised that the ICER in a cost effectiveness model submitted
was highly sensitive to the duration of clopidogrel use.
The PBAC noted that mortality rates are very low in stent
populations, and agreed that while the clinical trials data does
not show statistical significance in mortality alone, survival
trends in the literature consistently favour clopidogrel; however,
the data do not provide a clear answer on the question on how long
treatment should continue. The Committee agreed that evidence
indicates that 6-12 months of treatment results in a better outcome
than shorter treatment, and noted a very recent observational study
from Kimura et al (AntiPlatelet Therapy and Stent Thrombosis
after Sirolimus-Eluting Stent Implantation, Circulation 2009;
119:987-995) which looked at the influence of antiplatelet therapy
discontinuation on the risk of stent thrombosis which concluded
that there was no apparent clinical benefit of thienopyridine use
beyond six months following sirolimus-eluting stent
implantation.
The PBAC noted that the duration of clopidogrel use for patients
with drug-eluting stents (DES) was of particular concern because of
recent reports of late stent thrombosis, a rare but catastrophic
event in DES patients who ceased clopidogrel. It was also noted
that a history of ACS prior to stent implantation seems not to
affect these late events.
The PBAC noted that there is considerable uncertainty in estimating
the number of patients who do not have ACS or are not otherwise
currently eligible for clopidogrel and who require a stent. The
PBAC also accepted that the proportion of patients with stable
angina, who receive a stent, may change in the future but the
direction of this change is highly uncertain. However, the
Committee accepted that available utilisation data suggest that
currently the majority of these patients are receiving subsidised
PBS clopidogrel and therefore it is likely that changing the
listing to include this restriction will have only a small impact
on overall PBS expenditure on clopidogrel.
Recommendation
CLOPIDOGREL HYDROGEN SULFATE, tablet, 75 mg (base)
Extend the listing as follows:
Restriction:
Authority required (STREAMLINED)
Treatment in combination with aspirin following cardiac stent
insertion
Max Qty: 28
Repeats: 5
8. 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.
9. Sponsor’s Comment
The Sponsors appreciated the opportunity to participate in this
review and welcome the recommendation from the PBAC to allow
equitable access to clopidogrel for all patients receiving a
cardiac stent.
