Ivabradine hydrochloride, film coated tablets, 5 mg and 7.5 mg, Coralan, November 2007
Public summary document for Ivabradine hydrochloride, film coated tablets, 5 mg and 7.5 mg, Coralan, November 2007
Page last updated: 14 March 2008
Public Summary Document
Product: Ivabradine hydrochloride, film coated tablets, 5 mg and 7.5 mg, Coralan
Sponsor: Servier Laboratories (Australia) Pty Ltd
Date of PBAC Consideration: November 2007
1. Purpose of Application:
The submission sought an Authority required PBS listing for the treatment of chronic stable angina due to atherosclerotic coronary artery disease.
2. Background:
This drug had not previously been considered by the PBAC.
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:
Ivabradine Hydrochloride
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.
For the PBAC’s view of the requested restriction, see Recommendation and reasons.
5. Clinical place for the proposed therapy:
6. Comparator:
The submission nominated the non-dihydropyridine calcium channel blocker (CCB), diltiazem
as the main comparator and the dihydropyridine CCB, amlodipine as a minor comparator.
For PBAC’s comments, see Recommendation and Reasons.
7. Clinical trials
The basis of the submission was:
- 9 randomised trials indirectly comparing ivabradine (7.5mg/5mg twice daily) and diltiazem (180mg to 360mg daily) using either amlodipine (2 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 were as follows:
|
Trial ID-Phase/ First author |
Protocol title/ Publication title |
Publication citation |
|---|---|---|
|
Indirect comparison: common reference of placebo |
||
|
Ivabradine |
||
|
Fox,K |
Ivabradine: a selective and specific If inhibitor: efficacy and safety in stable angina |
Eur Heart J 2003; 5(suppl):G36-G45 |
|
Diltiazem |
||
|
Go,M |
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,F.K |
Long-term study of high-dose diltiazem in chronic stable exertional angina |
Am Heart J,1984; Vol 107:1215 |
|
Khurmi,N.S |
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. |
Translated title: Myocardial ischemia with stable angina pectoris:clinical ergometric evaluation with diltiazem |
Arq Bras Cardiol, 1992; 58(2):149-55 |
|
Strauss,W.E |
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 |
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 |
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 |
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 |
||
|
Ruzyllo |
Ruzyllo, W., Tendera, M., Fox, K.M. 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 |
8. Results of trials
Results of the indirect comparison for ivabradine (7.5mg bd) compared to diltiazem using amlodipine as the common comparator - change in heart rate at rest
|
Trial |
Incremental heart rate change in bpm |
Ivabradine heart rate change from baseline |
Amlodipine heart rate change from baseline |
Diltiazem heart rate change |
Incremental heart rate change in bpm |
Indirect estimate of effect |
|---|---|---|---|---|---|---|
|
CL3-023 |
-11.00a |
N=381 |
N= 398 |
|||
|
Merchandb, 1996 |
N=35 |
N=28 |
-7 |
-7.20‡ |
||
|
Chughc,d, 1984 |
N=33 |
N=34 |
-5.20 |
-9.10‡‡ |
a unadjusted for country and baseline heart rate; b diltiazem: 180mg per day in three
divided doses for two weeks which was increased to 240mg per day in four divided doses,
amlodipine: 5mg per day as a morning dose for two weeks which was increased to 10mg
per day; c diltiazem: 240mg per day for two weeks which was then increased to 360mg
per day, amlodipine: 5mg per day as a morning dose for two weeks which was increased
to 10mg per day; d baseline heart rate at rest was higher for the diltiazem arm in
Chugh et al (87.4bpm) compared to the ivabradine arm of CL3-023 (78bpm); ‡calculated
by the submission as ivabradine heart rate change (-11.20) minus diltiazem heart rate
from Merchand (-4.00); ‡‡ calculated by the submission as ivabradine heart rate change
(-11.20) minus diltiazem heart rate from Chugh (-2.10); bpm = beats per minute; NR
= not reported in the published article (where standard errors of the change in heart
rate from baseline are unavailable in the published diltiazem trial reports, the submission
utilizes the standard errors of heart rate change from the ivabradine trials; NE =
not evaluable; S.E = standard error; bd = twice daily; bpm = beats per minute; Italics
in the above table represent results adjusted for the common comparator calculated
during the evaluation.
Results of the indirect comparison for ivabradine 5.0mg bd compared to diltiazem 180-360mg/day
using placebo as the common comparator - change in heart rate at rest
|
Trial |
Incremental heart rate change in bpm |
Ivabradine heart rate change from baseline |
Placebo heart rate change from baseline |
Diltiazem heart rate change |
Incremental heart rate change in bpm |
Indirect estimate of effect |
|---|---|---|---|---|---|---|
|
CL2-009 |
-9.91 |
N=59 |
N= 68 |
|||
|
Maranhao b, 1991 |
N=43 |
N=44 |
-4.40 c |
|||
|
Khurmid, 1984 |
N=33 CD |
N=17CD |
-5.20 c (NR) |
|||
|
Hossacke, 1984 |
N=15 |
N=15 |
-3.66c |
|||
|
Gof 1984 |
N=11 |
N=11 |
-7.0 |
|||
|
Weightedg heart rate reduction at rest in beats per minute Mean (S.E.) |
-9.91 |
-5.12‡ |
-5.51 |
aDunnett’s 95% confidence interval for active versus placebo; ;b patients received
diltiazem doses ranging from 180mg/day to 240mg/day; ccould not be verified from the
published report, ddose of diltiazem ranged from 60mg three times a day to 120mg three
times a day; epatients received diltiazem 360mg/day; fall patients received diltiazem,
30mg tablets at increasing doses: first week - placebo, second week – one tablet four
times daily, third week – two tablets four times daily, fourth week – three tablets
four times daily; g weighted according to sample size; ‡ -the submission calculates
1) the value of -5.12 after exclusion of the lower diltiazem dose study, Maranhao
(1991), and 2) the value of -4.40 considering only the lower diltiazem dose study
Maranhao (1991); bpm = beats per minute; NR = not reported in the published article
(where standard errors of the change in heart rate from baseline are unavailable in
the published diltiazem trial reports, the submission utilizes the standard errors
of heart rate change from the ivabradine trials; CD = could not be determined from
the published report;
The direct comparison results between ivabradine and amlodipine - Exercise tolerance
test parameters at baseline and 3 months in the intention-to-treat population, measured
at trough of drug activity - are below:
a E (SE) = estimate and CI is of the difference between ivabradine effect and amlodipine
effect, based on a covariance analysis adjusted on baseline and country factors. Other
values are mean standard deviation; bid = twice daily; od = once daily; p-value for
a non-inferiority margin of -30seconds.
Non-inferiority was established for time to angina onset, 1mm ST-segment depression
and total exercise duration. Treatment with amlodipine 10mg and ivabradine 7.5mg similarly
reduced short-acting nitrate consumption over three months.
Changes in heart rate and rate-pressure product (mean standard deviation) at 3 months
in the intention-to-treat population, measured at trough of drug activity
a E (SE) and CI of the difference between ivabradine effect and amlodipine effect,
based on a covariance analysis adjusted on baseline and country factors. Other values
are mean standard deviation;
b CI of the change within treatment group based on an analysis of variance without
adjustment.
c Student’s t-test based on the overall general linear model (least-squares norm);
dStudent’s t-test based on the overall general linear model (least-squares norm) with
baseline as a covariate and country as a random factor; bid = twice daily; CI = confidence
interval; E (SE) = estimate (standard error); od = once daily; heart rates in beats
per minute.
The submission did not provide any indirect estimates of the relative safety of ivabradine
and diltiazem. For the comparative safety between ivabradine and amlodipine, there
were more adverse events reported in the ivabradine 7.5mg twice daily group than in
the amlodipine 10mg once daily group. The PBAC noted there was inadequate evidence
to support any claim of equivalent safety between ivabradine and diltiazem. The PBAC
also noted that the comparative safety data between ivabradine and amlodipine were
difficult to interpret due to the different treatment periods in the ivabradine and
amlodipine arms and the unblinded ascertainment of safety outcomes.
For further PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission described ivabradine as having superiority in heart rate reduction
over diltiazem, its main comparator and having similar or less toxicity; the submission
described ivabradine as having superiority in heart rate reduction and similar improvement
in exercise tolerance tests over its minor comparator, amlodipine, and having similar
or less toxicity.
For PBAC’s view of this claim, see Recommendation and Reasons.
10. Economic Analysis
The submission did not present a trial-based economic evaluation. This was considered
reasonable given that the evidence for the main comparator was based on a comparison
of multiple trials where surrogate outcomes (heart rate reduction) were measured and
resources were not reported.
The submission presented a modelled economic evaluation. The resources included were
drug costs and costs of cardiac events – myocardial infarction (MI), stroke, chronic
heart failure (CHF) and cardiac surgery.
The modelled incremental discounted cost per extra discounted QALY, at 5 years treatment,
was estimated as follows:
ivabradine 7.5mg vs (generic) diltiazem 360mg: between $45,000 - $75,000;
ivabradine 5mg vs (generic) diltiazem 240mg: between $45,000 - $75,000
ivabradine 7.5mg vs amlodipine 10mg: between $15,000 - $45,000
As the PBAC did not accept the clinical claim of superiority, the PBAC did not accept
the validity of the economic analysis, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications:
The financial cost per year to the PBS minus any savings in use of other drugs was estimated to be less than $10 million in Year 5.
12. Recommendation and Reasons:
The PBAC noted that the submission had nominated the non-dihydropyridine calcium channel
blocker (CCB), diltiazem as the main comparator and the dihydropyridine CCB, amlodipine,
as a minor comparator. The PBAC agreed with the ESC that an additional comparison
with the long-acting nitrates would be appropriate, as in the absence of clinical
endpoint data for ivabradine it is most likely to be used third line after beta-blockers
and non-dihydropyridine CCBs, and thus to compete with the dihydropyridine CCBs and
the long-acting nitrates.
The Committee noted that the indirect efficacy comparison between ivabradine and diltiazem
presented in the submission was difficult to interpret. Further, there is inadequate
evidence in the submission to support any claim of equivalent safety between ivabradine
and diltiazem.
The Committee agreed with the submission that ivabradine 7.5mg twice daily appears
to have comparable clinical efficacy in controlling the symptoms of angina compared
to amlodipine 10mg once daily. The comparative safety data for ivabradine and amlodipine
were difficult to interpret due to the different treatment periods in the ivabradine
and amlodipine arms and the unblinded ascertainment of safety outcomes.
The submission’s choice of the heart rate reduction outcome to support the claim that
ivabradine is superior to diltiazem and/or amlodipine is of critical importance and
the PBAC did not accept this approach, particularly as these three drugs assert there
effects through different means.
The submissions use of heart rate as a surrogate for mortality in the economic model
was also not accepted by the PBAC.The PBAC further noted that a number of other clinical
and economic concerns with the data presented had been raised during the evaluation
and agreed that they needed to be addressed in any future submissions.
Thus, overall, the Committee rejected the application 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 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.
