CILOSTAZOL, tablets, 50 mg and 100 mg, Pletal®
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Public Summary Document (PDF 35 KB)
Product: CILOSTAZOL, tablets, 50 mg and 100 mg,
Pletal®
Sponsor: PharmaLink Pty Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
The submission sought an Authority Required listing for the
symptomatic improvement of intermittent claudication as indicated
by increased maximal and pain-free walking distances in patients
who do not have rest pain and who do not have evidence of
peripheral tissue necrosis.
2. Background
At the July 2009 meeting, the PBAC rejected a submission for
cilostazol for an authority required listing for the symptomatic
improvement of intermittent claudication on the basis of uncertain
clinical benefit, uncertain cost-effectiveness and uncertain
utilisation estimates.
Full details in the July 2009 Public Summary
Document.
3. Registration Status
Cilostazol was TGA registered on 29 January 2009 for the
symptomatic improvement of intermittent claudication as indicated
by increased maximal and pain-free walking distances, in patients
who do not have rest pain and who do not have evidence of
peripheral tissue necrosis.
4. Listing Requested and PBAC’s View
Authority Required
Pletal is indicated for the symptomatic improvement of intermittent
claudication as indicated by increased maximal and pain-free
walking distances in patients who do not have rest pain and who do
not have evidence of peripheral tissue necrosis.
The PBAC did not comment on the requested restriction.
5. Clinical Place for the Proposed Therapy
Intermittent claudication (IC) is a common debilitating symptom of
peripheral arterial obstructive disease. IC is characterised by
pain in the legs or buttocks that occurs with exercise and which
subsides with rest.
Cilostazol is a pharmacological alternative to medical treatment
options (supervised exercise programs, angioplasty or bypass
surgery) and if PBS-listed, would provide a treatment option for
the symptoms of IC, such as the distance walked before onset of
pain. There are no products currently listed on the PBS for the
symptomatic treatment of IC.
6. Comparator
As previously, the re-submission appropriately nominated placebo as
the main comparator.
7. Clinical Trials
Clinical trials
The re-submission presented a revised meta-analysis of 11
randomised trials comparing cilostazol 100 mg twice daily with
placebo, compared with a meta-analysis of 10 randomised trials in
the previous submission.
(Refer to the July 2009 Public Summary Document for details of
the published trials presented in the previous
submission.)
The re-submission presented two additional trials, O’Donnell
2009a and O’Donnell 2009b.
A comparison of the two publications suggested that the patients
reported in O’Donnell (2009b) might have been a subset of the
patients reported in O’Donnell (2009a). O’Donnell 2009a
was incorporated into the revised meta-analysis in the
re-submission.
Details of these trials are in the table below:
| Trial ID/ First author | Protocol title/ Publication title | Publication citation |
| O’Donnell ME et al (2009a) | The effects of cilostazol on exercise-induced ischaemia-reperfusion injury in patients with peripheral arterial disease. | Eur J Vasc Endovasc Surg 2009; 37: 326-335 |
| O’Donnell ME et al (2009b) | The vascular and biochemical effects of cilostazol in patients with peripheral arterial disease. | J Vasc Surg 2009; 49:1226-1234 |
8. Results of Trials
The re-submission reaffirmed the claim that the treatment benefit with cilostazol is clinically relevant, and presented the following information to support this claim:
- Transformation of treadmill walking distances in all trials to real life flat-ground walking distances.
- Correlation of improvement in walking distances with improvement in QoL (SF-36 and WIQ) outcomes
- An analysis of patient rated treatment success with cilostazol compared with placebo
- Expert opinion (Prof Dawson 2009).
Compared to the previous submission, only one new trial was
presented in the re-submission in terms of the key outcome of mean
change from baseline Actual Claudication Distance (ACD)
(O’Donnell 2009a).
New results in this re-submission, and a comparison with the
results of the previous submission, are summarised below.
Revised meta-analyses incorporating one additional trial (O’Donnell 2009a):
- Percentage change in ACD from baseline at 24 weeks: difference (weighted mean difference, WMD) between cilostazol 100 mg and placebo = 23.30% (95% CI 7.44 to 39.17), compared to 21.15% (95% CI 5.69 to 36.61) in the previous submission;
- Percentage change in ICD from baseline at 24 weeks: difference = 25.18% (95% CI 3.18 to 47.19), compared to 26.11% (95% CI 2.12 to 50.10) in the previous submission;
New meta-analyses for change in QoL as measured by the WIQ at 24 weeks:
There was statistically significant difference in three (pain or
aching in calves, pain or aching in thighs, weakness in one or both
legs) of the eight items under the walking impairment subscale,
favouring cilostazol 100 mg over placebo. However, there was no
statistically significant difference between cilostazol and placebo
in any of the WIQ subscales (walking impairment, walking distance,
walking speed, stair climbing) at 24 weeks.
The PBAC noted that no new toxicity data were presented in the
re-submission. Adverse events were more common in
cilostazol-treated patients. The most frequently reported serious
adverse events were cardiac (13.3% of patients) and vascular
disorders (10.6% of patients) which may be related to
comorbidities. The most common adverse events were headache,
dizziness, pain, diarrhoea, abnormal stools, peripheral oedema and
palpitations.
For PBAC’s view, see Recommendation and Reasons
9. Clinical Claim
The submission claimed that cilostazol is statistically
significantly superior to placebo for all primary and secondary
endpoints but is associated with greater toxicity. This is
consistent with the clinical claim in the previous submission,
which was accepted by the PBAC.
Concerns about the clinical relevance of the gains in walking
distance were addressed through additional meta-analyses of
trial-based WIQ data and transformations of the trial-based
treadmill distances to flat ground walking distances.
10. Economic Analysis
The re- submission presented an updated cost-effectiveness
evaluation.
The re-submission estimated the incremental cost per additional
QALY gained to be between $105,000 and $200,000. This is compared
to less than $15,000 in the previous submission.
For PBAC’s view, see Recommendation and
Reasons
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated by the
re-submission to be less than 10,000 in Year 5.
The net financial cost per year to the PBS (excluding co-payments)
was estimated by the re-submission to be less than $10 million in
Year 5, and lower than the estimate in the previous
submission.
The re-submission’s estimates were considered uncertain by
the PBAC.
12. Recommendation and Reasons
The PBAC noted the Consumer Impact Statement on the impact of
intermittent claudication (IC) on daily living prepared by the
Consumers Health Forum and that nocturnal cramping was identified
as a major issue. Not all patients experienced claudication when
walking and in those that did, the impact varied
considerably.
The PBAC considered that a stopping rule at 12 weeks was
inappropriate, given that the submission and Pre-Sub-Committee
Response acknowledged that “the maximal effect of cilostazol
is not reached until 24 weeks (or beyond)”.
The comparator was placebo which was previously considered by the
PBAC in July 2009 to be appropriate. The PBAC has also accepted
previously the clinical claim that cilostazol is statistically
significantly superior to placebo for all primary and secondary
endpoints but is associated with greater toxicity. The PBAC noted
that cilostazol has increased toxicity when combined with
anti-platelet therapy and with other drugs which inhibit CYP3A4 and
CYP2C19.
The PBAC noted the results of a systematic review and meta-analysis
of drug therapy for IC (Momsen et al 2009) which suggested that the
highest benefit in terms of walking distance is obtained by
treating patients with lipid lowering agents. The PBAC considered
that as cilostazol is intended to be an add-on therapy to standard
medical management (including lipid lowering agents in many
patients), the incremental benefit of cilostazol treatment that
would be realised in the intended PBS population is
uncertain.
The PBAC noted there was a revised meta-analysis of 11 randomised
trials comparing cilostazol 100 mg twice daily with placebo and
that trial-based treadmill walking distances are transformed to
flat ground equivalent walking distances. Also quality of life
(QoL) outcomes are assessed by the SF-36 and the Walking Impairment
Questionnaire (WIQ). A meta-analysis of the WIQ scores was
performed.
The PBAC noted that there were no statistically significant
differences between cilostazol and placebo in the pooled analyses
of utilities (AQoL or SF-6D) at 24 weeks and there were no QoL data
beyond 24 weeks.
The PBAC noted from the submission and the Pre-Sub-Committee
Response that patients with IC have poor QoL, and considered that
any clinically significant improvement in the symptoms of IC would
reasonably be expected to be reflected in improvements in QoL. The
PBAC remained concerned that no statistically significant
differences in QoL were observed between cilostazol and
placebo.
The PBAC considered that the transformation of treadmill walking
distance to flat ground equivalent walking distances undertaken to
be representative of real life was probably reasonable. However,
the clinical significance for treated patients of improvements in
walking distance of 40.6m in a treadmill test or 94.61m after
conversion to real life remained uncertain as the incremental
distance is small, and it remained unclear what impact this
improvement would have on a patient’s day-to-day quality of
life.
The PBAC noted that the sponsor claimed that cost per QALY is not
meaningful and could not be reliably estimated. An “attempted
cost per QALY” was calculated as being between $105,000 and
$200,000, based on a difference of 0.01 in preliminary utility
gain. The PBAC considered that methodological and dataset issues
precluded derivation of a meaningful QALY and that the attempted
cost per QALY is not neither reliable nor informative. Further, the
PBAC considered that a cost per metre walked is not an appropriate
or informative measure.
The PBAC considered that the estimates of use are very uncertain
and small changes in uptake and diagnosis or proportion of
non-responding patients not stopping therapy have a substantial
effect on the financial costs.
The PBAC therefore rejected the submission on the basis of
uncertain clinical benefit and a high and uncertain
cost-effectiveness ratio.
The PBAC noted that the submission meets the criteria for an
independent review.
Recommendation:
Reject
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 is disappointed that the PBAC has rejected the
application for PBS listing of cilostazol for the treatment of
Intermittent Claudication, a condition that is underdiagnosed and
undertreated.
The inability to show gains in utility with cilostazol treatment is
largely a methodological problem and not evidence that there are no
clinical benefits. The sponsor believes that when a treatment is as
specific and localised as that with cilostazol, the cost per QALY
is not the most appropriate measure of its worth.
The PBAC comments that “the highest benefit in terms of
walking distance is obtained by treating patients with lipid
lowering agents.” The sponsor does not accept that this
reflects the body of evidence. The efficacy of statins has not been
compared head-to head to cilostazol and the data quoted by the
PBAC, which was not part of the submission, has not been fully
reviewed or substantiated.
Further, the PBAC questions the incremental benefit of cilostazol
over statin therapy. The clinical dataset included a large number
of patients in whom incremental benefit was demonstrated with
cilostazol over background statin therapy.
