Cilostazol, tablets, 50 mg and 100 mg, Pletal®
Public summary document for Cilostazol, tablets, 50 mg and 100 mg, Pletal®
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Public Summary Document
Product: Cilostazol, tablets, 50 mg and 100 mg,
Pletal®
Sponsor: PharmaLink Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
To request an Authority Required listing for 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
This drug had not previously been considered by the PBAC.
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
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.
See Recommendation and Reasons for PBAC’s view.
5. Clinical place for the proposed therapy
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 intermittent claudication (IC).
6. Comparator
The submission nominated placebo, for standard medical management
as the main comparator. The PBAC considered the main comparator
appropriate.
7. Clinical trials
The submission presented a meta-analysis of 10 randomised
controlled trials, of either 12, 16 or 24 weeks duration, comparing
cilostazol 100 mg and 50 mg tablets with placebo and one 3 year
randomised controlled trial to assess morbidity and mortality
compared to placebo. Seven trials used constant load treadmills and
three used variable load (stepped) treadmills to assess walking
distance. Three trials included pentoxifylline 400 mg in comparison
to cilostazol 100 mg and placebo.
Details of the published randomised trials presented are shown in
the following table.
| Trial ID | Protocol title/ Publication title | Publication citation |
| 21.90.201 Dawson 1998 | Dawson DL. Cutler BS. Meissner MH. Strandness DE Jr. Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial. | Circulation.1998 98(7):678-86 |
| 21.92.202 Beebe 1999 | Beebe HG. Dawson DL. Cutler BS. Herd JA. Strandness DE Jr. Bortey EB. Forbes WP. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. | Archives of Internal Medicine. 1999 159(17):2041-50 |
| 21.93.201 Elam 1998 | Elam MB. Heckman J. Crouse JR. Hunninghake DB. Herd JA. Davidson M. Gordon IL. Bortey EB. Forbes WP. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. | Arteriosclerosis, Thrombosis & Vascular Biology. 1998 18(12):1942-7 |
| 21.94.201 Strandness 2002 | Strandness DE Jr. Dalman RL. Panian S. Rendell MS. Comp PC. Zhang P. Forbes WP. Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. | Vascular & Endovascular Surgery. 2002 36(2):83-91 |
| 21.94.203 Money 1998 | Money SR. Herd JA. Isaacsohn JL. Davidson M. Cutler B. Heckman J. Forbes WP. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. | Journal of Vascular Surgery. 1998 27(2):267-74; discussion 274-5 |
| 21.96.202 Dawson 2000 | Dawson DL. Cutler BS. Hiatt WR. Hobson RW 2nd. Martin JD. Bortey EB. Forbes WP. Strandness DE Jr. A comparison of cilostazol and oxpentifylline for treating intermittent claudication. | American Journal of Medicine. 2000 109(7):523-30 |
| 21.98.214 CASTLE | Hiatt WR, Money, SM, Brass EP Long-term safety of cilostazol in patients with peripheral artery disease: The CASTLE study (Cilostazol: A Study in Long-term Effects) . | J Vascular Surgery, 47(2):330-336 |
| Stone, WM, Demaerschalk, BM, Fowl, RJ and Money, SR. Type 3 Phosphodiesterase Inhibitors May Be Protective Against Cerebrovascular Events in Patients with Claudication. | Journal of Stroke and Cerebrovascular Diseases, 2008: 17(3) 129-133 |
8. Results of trials
The primary outcome was Actual Claudication Distance (ACD),
reported as weighted mean absolute change from baseline in metres
walked, weighted mean percentage change from baseline of metres
walked and Ln (distance walked at endpoint/distance walked at
baseline) at 12 weeks, 24 weeks and endpoint intervals for variable
load, constant load and combined treadmill data sets. Similar
measures of the key secondary outcome of Initial Claudication
Distance (ICD) were also presented. The patients enrolled in the
clinical trials were generally representative of the Australian
population likely to be treated.
The baseline walking distances for the patient populations showed
substantive heterogeneity across the trials in the distance walked
at baseline, large changes in the placebo arm as well as
heterogeneity in the size of the treatment effect.
There were statistically significant differences in the ratio of
geometric mean, change in distance walked and % change in distance
walked for all ACD and ICD analyses for cilostazol 100 mg versus
placebo.
The key outcomes used in the economic evaluation were the absolute
change in ACD and the absolute change in ICD from baseline in
metres walked at 24 weeks following cilostazol 100 mg twice daily.
For these outcomes, the average change in ACD was 40.60 metres
(95%CI: 12.71, 68.49), and average change in ICD was 24.31 metres
(95% CI: 8.48, 40.15).
While there was a statistically significant improvement in mean ACD
and ICD (change from baseline at 24 weeks) for cilostazol 50mg
versus placebo in trial 21.92.202, there was no statistically
significant difference between cilostazol 50mg and placebo in ACD
and ICD in trial 21.94.201.
The results of the meta-analyses of the quality of life results
(Medical Outcomes Scale SF-36) from 7 trials showed statistically
significant differences in the mean change from baseline score in
favour of cilostazol 100 mg in 3 of 8 health concepts; Bodily Pain,
Physical Function and Role Limitations due to Physical
Health.
The incidence of serious adverse events (SAEs) was low and
comparable between cilostazol 100 mg and placebo trial arms. The
most frequent reported SAEs were cardiac disorders (13.3% of
patients) and vascular disorders (10.6% of patients) which may be
related to the underlying clinical condition. Cilostazol is
contraindicated in patients with heart failure. Headache,
dizziness, pain, diarrhoea, abnormal stools, peripheral oedema and
palpitations were the most commonly reported adverse events, and
were statistically significantly more likely in the cilostazol
treated patients compared to placebo.
The safety profile of cilostazol 100mg in the three year CASTLE
trial was consistent with the safety profile established in the
shorter clinical trials. There was no increase in incidence or
severity of adverse events, no differences between the cilostazol
and placebo in cardiovascular morbidity and mortality and no
differences between the cilostazol and placebo and adverse events
related to bleeding (with or without concomitant clopidogrel,
aspirin or both).
9. Clinical Claim
The submission described cilostazol as superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over placebo.
For PBAC’s views see Recommendation and
Reasons.
10. Economic analysis
The submission presented a trial-based economic evaluation. The
incremental cost per metre gained in walking distance was
calculated from the cost of cilostazol over 24 weeks (168 days)
over the mean weighted change from baseline in metres walked. The
submission calculated incremental cost effectiveness ratios based
on both ACD and ICD for cilostazol 100 mg. The incremental cost per
additional metre walked at 24 weeks in ACD was < $100 and in ICD
approximately 67% more that the ACD value.
The Pre-PBAC response provided an indicative incremental
cost-effectiveness ratio (ICER) of < $15,000 per QALY gained
based on a utility gain calculated using data from Letterstal et al
(2008).
For PBAC’s views see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications:
The estimated financial cost per year to the PBS was < $10
million in Year 5. The DUSC advised the uptake of cilostazol was
uncertain, noting the proportion of eligible patients who may be
treated to be very uncertain.
12. Recommendation and Reasons:
The PBAC considered the main comparator, placebo for standard
medical management, appropriate, noting however, that the
comparative data against pentoxifylline, which is not PBS listed,
was also informative.
It was noted that the TASC II Guidelines for the treatment of
peripheral arterial disease submitted as the clinical management
algorithm for the treatment of intermittent claudication were from
an industry supported group including the manufacturer of
cilostazol.
The PBAC noted that for the outcome measures of Actual Claudication
Distance (ACD) and Initial Claudication Distance (ICD), the
meta-analyses showed a statistically significant improvement in
both measures for cilostazol 100 mg versus placebo. However, while
there was a statistically significant improvement in mean ACD and
ICD for cilostazol 50 mg versus placebo in trial 21.92.202, there
was no statistically significant difference between cilostazol 50
mg and placebo in ACD and ICD in trial 21.94.201.
The PBAC noted that there was substantial variability in ACD and
ICD results within the trials, as well as across the trials, as
shown by the heterogeneity in both the baseline and the change from
baseline walking distances for the trials included in the
meta-analysis. This heterogeneity increased the uncertainty around
the pooled estimates for the weighted mean difference in both ACD
and ICD. The ICD, a measure of distance before initial claudication
pain, was considered to be the more relevant clinical endpoint, and
it was noted the meta-analyses showed a gain at the 24 week time
point of 24.31 m, compared to a gain of 40.6 m for ACD.
The Pre-PBAC Response advised that the reason for the apparent
heterogeneity across the trials in the distance walked at baseline,
including changes in the placebo arm as well as in the size of
treatment effect was due to two different treadmill protocols. The
PBAC acknowledged this point but still considered that it did not
deal with the uncertainty about the extent of clinical benefit with
cilostazol.
Given that the FDA and the TGA have expressed concerns in relation
to drug interactions between cilostazol and other platelet
aggregation agents, the PBAC was pleased to note that the safety
profile of cilostazol 100 mg in the three year CASTLE trial was
consistent with the safety profile established in the shorter
clinical trials. However, the lack of data on drug interactions
with other antiplatelet agents was noted.
Based on the clinical data submitted the PBAC accepted that
cilostazol 100 mg was superior in comparative effectiveness and
inferior in terms of comparative safety to placebo. However, it was
uncertain as to the clinical significance of the small walking
distances gained in ACD and ICD.
The PBAC did not consider that the primary analysis providing
incremental cost-effectiveness in terms of cost per additional
metre gained at 24 weeks was informative, given the uncertainty
around the clinical benefits gained. It was considered than an ICER
expressed in terms of QALY gained, given the availability of SF-36
data at 24 weeks from 7 of the comparative trials would have been
more appropriate. The Committee noted with interest that the SF-36
data showed statistically significant differences in favour of
cilostazol 100 mg in 3 of 8 health concepts only (bodily pain,
physical function and role limitations due to physical
health).
The Pre-PBAC response provided an indicative ICER of < $15,000
per QALY gained based on a utility gains calculated using data from
Letterstal et al (2008) . However, the PBAC had the several
concerns with this calculation. The PBAC considered these concerns
cast doubt on the applicability of the utility weights.
The PBAC noted the DUSC advised the estimates of patients treated
may be an underestimate, that there is substantial uncertainty in
the derivation of the eligible population and the likely treated
population owing to limited and poor quality data sources to
substantiate the estimate, and that usage may result in net costs
> $10 million per year to the PBS.
The PBAC therefore rejected the submission on the basis of
uncertain clinical benefit, uncertain cost-effectiveness and
uncertain utilisation estimates.
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
PharmaLink is working with PBAC to address the issues
.
