Ivabradine hydrochloride, film coated tablets, 5 mg and 7.5 mg, Coralan®, July 2008
Public summary document for Ivabradine hydrochloride, film coated tablets, 5 mg and 7.5 mg, Coralan®, July 2008
Page last updated: 31 October 2008
Public Summary Documents
Product:Ivabradine hydrochloride, film coated
tablets, 5 mg and 7.5 mg, Coralan ®
Sponsor: Servier Laboratories (Australia) Pty
Ltd
Date of PBAC Consideration: July 2008
1. Purpose of Application
This second submission sought an Authority required PBS listing for
the treatment of chronic stable angina due to atherosclerotic
coronary artery disease in patients contraindicated or intolerant
to beta blockers and with a heart rate of 75 beats per minute or
greater.
2. Background
At the November 2007 meeting, the PBAC rejected a first submission
for ivabradine for an Authority required listing for chronic stable
angina due to artherosclerotic coronary artery disease because of
difficulty in interpreting the clinical comparison with diltiazem
and, critically, because of insufficient evidence to support the
claim that ivabradine’s superiority over diltiazem and/or
amlodipine in terms of heart rate reduction, translates into
reduced cardiovascular mortality, thus providing an insufficient
basis to support the cost-effectiveness analysis. (See PBAC
Public Summary Document – November 2007)
3. Registration Status
Ivabradine was TGA registered on 27 October 2006 for the treatment
of chronic stable angina due to atherosclerotic coronary artery
disease in patients with normal sinus rhythm who are unable to
tolerate or have a contraindication to the use of beta
blockers.
4. Listing Requested and PBAC’s View
Authority Required
Treatment of chronic stable angina due to atherosclerotic coronary
artery disease in patients with normal sinus rhythm who are unable
to tolerate or who have a contraindication to the use of beta
blockers and have a resting heart rate of 75 bpm or greater.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Ivabradine would provide an alternative option for the treatment of
chronic stable angina, due to atherosclerotic artery disease in
patients with normal sinus rhythm, who are unable to tolerate or
have a contra-indication to the use of beta-blockers and have a
resting heart rate of 75bpm or greater.
6. Comparator
The submission nominated diltiazem as the main comparator and
amlodipine as the secondary comparator.
Although the PBAC agreed that diltiazem and amlodipine are
reasonable comparators, the PBAC reiterated its view that a
comparison with the long acting nitrates was also
appropriate.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
No changes were made to the ivabradine trial data presented in the November 2007 submission.
However, one indirect comparison was re-performed and new diltiazem meta-analysis
data were presented in this submission.
The submission presented the following trials:
- 10 randomised trials indirectly comparing ivabradine (7.5mg/5mg twice daily) and diltiazem (180mg to 360mg daily) using either amlodipine (3 trials) or placebo (7 trials) as the common reference.
- One direct randomised trial (CL3-023) comparing ivabradine (7.5mg twice daily) to the minor comparator, amlodipine (10mg once daily).
The trials published at the time of submission are as follows:
| Trial ID-Phase/ First author | Protocol title/ Publication title | Publication citation |
| Indirect comparison: common reference of placebo | ||
| Ivabradine | ||
| CL2-009- Phase II a Fox, K. | Ivabradine: a selective and specific I f inhibitor: efficacy and safety in stable angina | Eur Heart J 2003; 5(suppl):G36-G45 |
| Borer, J.S., et al | Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomised, double-blind, multicentered, placebo-controlled trial | Circulation 2003;107(6):817-823 |
| Diltiazem | ||
| Go, M.,et al | Improved efficacy of high-dose versus medium- and low-dose diltiazem therapy for chronic stable angina pectoris | Am J Cardiol, 1984; 53:669-73 |
| Hossack, K.F., et al | Long-term study of high-dose diltiazem in chronic stable exertional angina | Am Heart J,1984; Vol 107:1215 |
| Khurmi, N.S., et al | Long-term efficacy of diltiazem assessed with multistage graded exercise tests in patients with chronic stable angina pectoris. | Am J Cardiol, 1984; 54:738-743 |
| Maranhao, M.F.C., b et al | Translated title: Myocardial ischemia with stable angina pectoris:clinical ergometric evaluation with diltiazem | Arq Bras Cardiol, 1992; 58(2):149-55 |
| Strauss, W.E., et al | Safety and efficacy of diltiazem hydrochloride for the treatment of stable angina pectoris: report of a cooperative clinical trial. | Am J Cardiol, 1982; 49:560-66 |
| Weiner, D.A., et al | Efficacy and safety of sustained-release diltiazem in stable angina pectoris. | Am J Cardiol, 1986; 57:6-9 |
| Indirect comparison: common reference of amlodipine | ||
| Diltiazem | ||
| Chugh, S.K., et al | A randomised, double-Blind comparison of the efficacy and tolerability of once-daily modified-release Diltiazem Capsules with once-daily amlodipine tablets in patients with stable angina. | J Card Pharm, 2001; 38:356-64 |
| Merchand, X., et al | Translated from French: Evaluation of amlodipine in stable effort angina. Comparison with diltiazem in terms of efficacy, safety and maintenance of the anti-ischemic action 24 hours after last dose. | Ann de Cardiol et D’Angeiol, 1996; 45(2):74-82 |
| Ivabradine | ||
| CL3-023- Phase III Ruzyllo, W., et al | Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: A 3-month randomised, double-blind, multi-centre, non-inferiority trial. | Drugs, 2007;67(3):393-405 |
| Direct comparison: ivabradine versus the minor comparator, amlodipine | ||
| CL3-023- Phase III | As above | As above |
a consists of two main sub-studies: a dose ranging double blind randomised placebo
controlled trial (2 weeks in duration: also called P1-P2 period) followed by a “two
or three month” (as defined in the clinical study report: CL2-009) open-label safety
study of 10mg ivabradine and a one-week run-out phase period (P3 period); b foreign language with only abstract available in English; S16257 = ivabradine; If = funny current.
8. Results of Trials
The results of the indirect comparison of ivabradine and diltiazem were expressed
in terms of heart-rate reduction effect.
The results of the comparisons of heart-rate reduction are summarised in the table
below:
Summary of Indirect Comparisons of Ivabradine and Diltiazem – Incremental difference
in Heart Rate Lowering Effects, at various doses.
| Diltiazem 240mg d | Diltiazem 360mg d | |
| Ivabradine 5mg bd | -5.51 (unknown 95% CI) | -4.79 (unknown 95% CI) |
| Ivabradine 7.5mg bd | -4.09 (unknown 95% CI) | -5.89 (unknown 95% CI) |
Heart-rate reduction was not directly a patient relevant outcome, nor was it specified
as a primary outcome in the trials. The need to accept that heart-rate is a valid
surrogate for mortality, and that a reduction in heart rate alone (through medication)
causes a reduction in mortality, underpinned the entire submission.
Results of indirect comparisons and other pooled analyses on which economic evaluation
is based
| Study | Ivabradine HR reduction (bpm), (95%CI) | Diltiazem HR reduction (bpm). No CIs provided | Incremental difference |
| Indirect comparison a via placebo | Adjusted -9.91 c (-14.48, -5.34) | Adjusted -4.40 d Adjusted -5.12 e | -5.51 d -4.79 e |
| Indirect comparison b via amlodipine | Adjusted -11.09 (-12.58, -9.59) | Adjusted -7.0 d Adjusted -5.2 e | -4.09 d -5.89 e |
| CAR 1 post-hoc sub-group analysis: HR ≥75 bpm | Unadjusted -16.56 (-17.43, -15.69) | - | |
| Diltiazem meta-analysis f , HR 74-84 | Unadjusted: -6.1 Adjusted -3.9 | ||
| Diltiazem meta-analysis f , HR ≥85 | Unadjusted: -10.7 Adjusted -4.9 | ||
| Economic Evaluation | Uses CAR-1 results (above) | Arbitrary values: -3, -4, -5 or -6 | -13.56 to -10.36 |
a ivabradine 5mg bd (from CL2-009), b ivabradine 7.5mg bd (from CL3-023), c In this study HR increased from baseline in placebo arm (making adjusted effect size
> unadjusted effect size) whereas in all other studies HR decreased in placebo or
comparator arm (making adjusted effect sizes < unadjusted effect sizes); d vs diltiazem 240mg (multiple studies, pooled), e vs diltiazem 360mg (multiple studies, pooled), f Boden et al.
HR = heart rate; bpm = beats per minute, CI = confidence intervals, CAR = Complementary
Analyses Report (pooled results from 5 phase II/III studies of various design, including
those used for the indirect comparisons, with extensive post hoc subgroup analyses)
Source: Compiled during the evaluation
Given the uncertainty of effect size around the diltiazem results, the submission
used a range of arbitrary results that covered the plausible range in the economic
evaluation.
The primary outcomes of the key ivabradine trials were (i) CL3-023 (vs amlodipine)
total exercise duration from bicycle exercise tolerance tests, and (ii) CL2-009 (vs
placebo) time to limiting angina and time to 1mm ST segment depression.
The PBAC noted that these results were reported, and appeared to show ivabradine was
no worse than amlodipine, but were not the basis of the submission.
The submission presented new longer-term toxicity data which was not comparative.
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission described ivabradine as
1) equivalent in terms of comparative effectiveness in the
immediate outcome of exercise tolerance, and
2) superior in terms of comparative effectiveness in the outcome of
heart-rate lowering (proposed as a surrogate for the long-term
outcome of mortality), and
3) equivalent in terms of comparative safety compared to
diltiazem.
The PBAC did not agree with this claim.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented updated modelled economic evaluations,
based on new epidemiological data, new risk equations and revised
estimates of treatment effect (for both ivabradine and the
comparators). The submission presented 540 ICER calculations that
ranged from less than $15,000 to $45,000 – $75,000 per
incremental life-year gained.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year to
be between 15,000 – 20,000 in Year 5, compared with less than
10,000 in the previous submission.
The submission estimated the financial cost per year to the PBS to
be less than $5 million in Year 5. The PBAC considered this might
be an underestimate given the offsets were relatively
overestimated.
12. Recommendation and Reasons
The PBAC considered, that in the event listing were to be
recommended on the basis requested by the sponsor, the restriction
proposed by the Restrictions Working Group more appropriately
defines the patient group for whom treatment is intended than the
restriction proposed by the sponsor, noting that the former
proposal is based on the restriction for topiramate in the recently
PBS listed indication of migraine prophylaxis.
The Committee continued to have major concerns about the clinical
positioning of ivabradine. Although the Committee agreed that
diltiazem and amlodipine are reasonable comparators (in the
pre-subcommittee response the sponsor asks the committee to focus
on the comparison with amlodipine in preference over diltiazem),
the PBAC reiterated its view that in the indication for which
listing is sought, a comparison with the long acting nitrates is
also appropriate. Notwithstanding the submission’s claim that
there is no evidence that the nitrates lower heart rate or reduce
mortality, patients will be prescribed ivabradine first and
foremost because they have chronic stable angina and this fact
alone makes a comparison with nitrates relevant.
The PBAC accepted, as previously, that with respect to short term
outcomes (exercise tolerance, episodes angina), ivabradine appears
non-inferior to amlodipine in controlling the symptoms of angina.
The PBAC agreed that the indirect comparison of ivabradine and
diltiazem in terms of improvements in exercise tolerance is
difficult to interpret. Although the Committee considered that it
is likely that ivabradine is superior to diltiazem in terms of
heart rate reduction, its confidence in this finding was reduced by
the lack of an appropriate error measurement or estimate of
uncertainty in the indirect comparison and by the documented
anomalies in the results of this comparison compared with the
dose-response curve of diltiazem.
The Committee agreed with the sponsor that the comparison of
ivabradine with amlodipine is based upon stronger evidence than the
comparison of ivabradine with diltiazem. In recognition of this,
the PBAC accepted that the comparison with amlodipine is more
relevant for decision making in this context than the comparison
with diltiazem.
However overall the PBAC agreed that it is difficult to understand
how the submission can claim superiority of ivabradine in terms of
mortality in angina patients, when it appears to be non-inferior
and clearly not superior to amlodipine, on intermediate outcomes
relating to angina symptoms. The efficacy advantages claimed by the
submission remain uninterpretable in relation to the broader
efficacy of ivabradine as an anti-anginal drug, and further
clinical trial data relating to the effect of ivabradine on angina
are required.
The current comparison with amlodipine does not support the higher
price for ivabradine requested by the sponsor because of the
uncertainties inherent in the post-hoc subgroup analyses CAR 1 and
CAR 3. Additionally, this comparison also relies upon the
assumption that the heart rate reduction achieved by ivabradine is
a valid surrogate for mortality, and, as discussed below, PBAC
continues to have doubts about the validity of this
assumption.
The PBAC also remained concerned about the comparative toxicity of
ivabradine and diltiazem, noting there are no direct comparative
data on the toxicity profiles of the two drugs. Given its unique
mechanism of action, ivabradine has a distinctly different toxicity
profile to diltiazem and other anti-anginal agents, such that an
assessment of relative toxicity concerns might best be considered
through impact on quality of life.
In addition to the areas of clinical uncertainty described above,
the PBAC continued to have concerns with the submission’s use
of the heart rate reduction outcome to support its claim that
ivabradine represents a cost-effective treatment intervention
compared to diltiazem or amlodipine. Although the new analyses
using the CASS, CCHS and GPRN data as discussed in the
pre-subcommittee response and at the hearing, go some way towards
addressing the possible confounding effect of blood pressure
reductions on the heart rate results from the Cucherat
meta-analysis, they nonetheless rely upon a series of mathematical
simulations which are based upon the results of diverse cohort
studies. The direct effect of an ivabradine induced reduction in
heart rate on the cardiovascular mortality of an individual patient
remains highly uncertain. In other words, although it is accepted
that individuals with a lower heart rate per se have reduced
cardiovascular mortality compared to those with a higher heart
rate, and although the resubmission provides some reassurance that
a reduction in heart rate may be associated with a reduction in
mortality, there remains no direct evidence to show that a
reduction in heart rate mediated by ivabradine reduces the
mortality of patients with a high initial heart rate to that
experienced by individuals with a lower baseline heart rate. This
means that the cost-effectiveness analyses presented by the
submission is only weakly supported and does not justify the price
premium requested by the submission.
The Committee continued to consider that the results of the large
long term outcome study (BEAUTIFUL) may better inform this issue,
as patients with long term stable angina are likely to represent a
significant proportion of subjects in the study.
The PBAC noted a number of other clinical and economic concerns
with the data presented and agreed that they would need to be
addressed in any future submission. The Committee noted the comment
made by ESC about the drug zatebradine but decided that it was not
relevant for its decision.
Therefore the PBAC rejected the submission because of incomplete
evidence of comparative clinical effectiveness and safety for
ivabradine with the appropriate comparators in the treatment of
angina. Additionally there remains insufficient evidence to
directly support the claim that ivabradine’s putative
superiority in reducing heart rate over diltiazem or amlodipine
translates into reduced cardiovascular mortality, thus providing an
insufficient basis to support the cost-effectiveness analysis
presented.
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 chose not to comment.
