Ivabradine hydrochloride, film coated tablets, 5 mg and 7.5 mg, Coralan®, July 2009
Public summary document for Ivabradine hydrochloride, film coated tablets, 5 mg and 7.5 mg, Coralan®, July 2009
Page last updated: 30 October 2009
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: July 2009
1. Purpose of Application
To request an Authority Required (STREAMLINED) listing for
treatment of chronic stable angina due to atherosclerotic coronary
artery disease in a patient subject to certain criteria being
At the November 2007 meeting, the PBAC rejected a submission for
ivabradine for an Authority required listing for chronic stable
angina due to atherosclerotic 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, translated into
reduced cardiovascular mortality, thus providing an insufficient
basis to support the cost-effectiveness analysis.
At its July 2008 meeting, the PBAC continued to have major concerns about the clinical positioning of ivabradine. The PBAC accepted, as previously, that with respect to short term outcomes (exercise tolerance, episodes of angina), ivabradine appeared non-inferior to amlodipine in controlling the symptoms of angina. However overall the PBAC agreed that it was difficult to understand how the submission could claim superiority of ivabradine in terms of mortality in angina patients, when it appeared to be non-inferior and clearly not superior to amlodipine, on intermediate outcomes relating to angina symptoms.
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 remained insufficient evidence to directly support the claim that ivabradine’s putative superiority in reducing heart rate over diltiazem or amlodipine translated into reduced cardiovascular mortality, thus providing an insufficient basis to support the cost-effectiveness analysis presented.
3. Registration Status
Ivabradine was registered by the TGA on 31 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
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Treatment of chronic stable angina due to atherosclerotic coronary artery disease in a patient with a left ventricular ejection fraction (LVEF) of 40% or less and a resting heart rate of 70 bpm or greater, and who
a. is receiving a beta blocker OR
b. is unable to tolerate or has a contraindication to a beta blocker.
Ivabradine is contraindicated in patients with NYHA functional classification III-IV heart failure due to lack of data.
Subsequently, the following revised restriction was requested:
Chronic stable angina due to atherosclerotic disease in patients with normal sinus rhythm and who:
a) Has experienced a side-effect of sufficient severity to necessitate the permanent withdrawal of a beta-blocker; or
b) Has a contraindication to a beta blocker according to the TGA-approved Product Information;
c) Symptoms are not controlled satisfactorily by other suitable PBS-listed drugs; or
d) Side effects have occurred with other suitable PBS-listed drugs; or
e) Has a contraindication to other suitable PBS-listed drugs according to the TGA-approved Product Information; or
f) Drug interactions have occurred with other suitable PBS-listed drugs; or
g) Drug interactions are expected to occur with other suitable PBS-listed drugs
See Recommendation and Reasons for PBAC’s view.
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 other suitable PBS-listed drugs.
The submission nominated placebo as the main comparator.
7. Clinical Trials
The submission presented one key randomised trial comparing
ivabradine (5 mg / 7.5 mg twice daily) with placebo in patients
with coronary artery disease (CAD) and left ventricular dysfunction
(LVD) (the BEAUTIFUL trial). This purpose of this trial was to
evaluate the effectiveness of ivabradine in preventing
cardiovascular events in patients with CAD and LVD. The
participants did not necessarily have angina.
Supplementary trials included one randomised trial comparing ivabradine (7.5 mg twice daily) with atenolol 100 mg daily; one randomised trial comparing ivabradine (7.5 mg twice daily) with amlodipine 10 mg once daily; one three armed randomised trial comparing ivabradine 5 mg/amlodipine combination and ivabradine 7.5 mg/amlodipine combination with placebo/amlodipine; and one randomised trial comparing ivabradine (5 mg / 7.5 mg)/atenolol combination with placebo/atenolol. One randomised trial assessing the relative efficacy and safety of ivabradine 5 mg compared to ivabradine 7.5 mg, and a long term safety study of ivabradine 7.5 mg were also included.
The studies published at the time of submission are as follows:
|Trial ID||Protocol title/ Publication title||Publication citation|
|Direct randomised trial|
|CL3-056 (BEAUTIFUL) Fox K., 2008a Fox K, 2008b Fox K 2008c Fox K, 2006||Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. The BEAUTIFUL study: Randomised trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction - Baseline characteristics of the study population. Rationale and design of a randomised, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBIDity-mortality EvAlUaTion of the I(f) inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) Study.||The Lancet 2008a; 372 (9641):817-821. The Lancet 2008b; 372 (9641):807-816. Cardiology 2008c; 110 (4):271-282. American Heart Journal 2006; 152 (5):860-866.|
|Supplementary randomised trials|
|CL2-006 Borer JS, 2003 Fox K, 2003 Diaz A, 2006||Antianginal and antiischaemic effects of ivabradine, an If inhibitor, in stable angina. Ivabradine-A selective and specific I(f) inhibitor: Efficacy and safety in stable angina. Heart Rate Slowing versus Other Pharmacological Antianginal Strategies.||Circulation 2003; 107:817-823. European Heart Journal, Supplement 2003; 5:G36-G45. Advances in Cardiology 2006; 43:65-78.|
|CL3-017 Tardif J-C, 2005 Diaz A, 2006||Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Heart Rate Slowing versus Other Pharmacological Antianginal Strategies.||European Heart Journal 2005; 26:529-2536. Advances in Cardiology 2006; 43:65-78.|
|CL3-021 López-Bescós L, 2007||Long-Term Safety and Efficacy of Ivabradine in Patients with Chronic Stable Angina.||Cardiology 2007; 108:387-396.|
|CL3-023 Hofler-Speckner S. Ruzyllo W, 2007||Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: A 3-month randomised, double-blind, multicentre, noninferiority trial. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: A 3-month randomised, double-blind, multicentre, noninferiority trial.||Journal fur Kardiologie 2007; 14 (9-10):300 Drugs 2007; 67 (3):393-405.|
|CL3-057 (ASSOCIATE) Tatarchenko I.P, 2008||Comparative efficacy of ivabradine and atenolol in correction of clinical and functional parameters in patients with stable effort angina.||KardiologiiaI 2008; 48 (5):60-61|
BID=twice daily; OD=once daily
8. Results of Trials
The pharmacological treatment of chronic stable angina had two complementary objectives;
to improve prognosis by preventing myocardial infarction (MI) and death (relevant
to all patients with CAD); and to minimise or abolish the symptoms of angina.
The submission presented one key randomised trial in support of the effectiveness of ivabradine in terms of prognostic benefits in patients with CAD and LVD, compared to placebo. The relative effectiveness of ivabradine compared to other second-line anti-anginal agents, in terms of prognostic outcomes, had not been assessed.
A summary of the primary and selected secondary outcomes for the analysis sets in the key randomised trial (BEAUTIFUL trial) is presented in the following table:
|Hazard Ratio (95% CI) a|
|RS b N=10917||RS-HR70 c N=5392|
|Primary composite outcome d||1.11 (0.91, 1.11)||0.91 (0.81, 1.04)|
|Secondary outcomes e|
|Mortality endpoints All-cause death Cardiovascular death Cardiac death||1.04 (0.92, 1.16) 1.07 (0.94, 1.22) 0.89 (0.71, 1.12)||1.02 (0.87, 1.19) 1.02 (0.86, 1.21) 0.84 (0.62, 1.12)|
|Coronary endpoints Hospitalisation for MI Fatal or non-fatal MI Fatal Non-fatal Revascularisation||0.87 (0.72, 1.06) 0.87 (0.73, 1.05) 0.80 (0.56, 1.16) 0.91 (0.74, 1.12) 0.83 (0.67, 1.02)||0.64 (0.49, 0.84) 0.78 (0.62, 0.97) 0.70 (0.52, 0.93)|
CI=confidence interval; MI=myocardial infarction; RS=randomised set.
a Hazard ratio between treatment groups based on an unadjusted Cox’s proportional hazards model
b All patients randomised and who received a treatment kit
c All patients in the RS who had a resting heart rate of 70bpm or greater at baseline.
d Time to occurrence of the first event among cardiovascular death, hospitalisation for acute myocardial infarction, or hospitalisation for new onset or worsening heart failure.
e Time to occurrence of outcome.
There was no statistically significant difference between treatment groups for the primary composite outcome in either of the analysis sets. Any claims of superiority of ivabradine compared to placebo were dependent on the results of secondary outcomes. Although there was an apparent reduction in the risk of hospitalisation for MI and coronary revascularisation in patients with a baseline heart rate (HR) of 70 bpm or greater, there was no corresponding reduction in mortality.
The PBAC was advised the BEAUTIFUL trial was not designed to assess the effectiveness of ivabradine as a treatment for angina. Therefore, the relevance of the results of the BEAUTIFUL trial to the requested listing was questionable.
The submission did not present any comparative safety data on ivabradine versus other second-line anti-anginal agents in the population for whom PBS listing of ivabradine was sought.
In the BEAUTIFUL trial, there were significantly more drug related adverse events (AEs) and AEs leading to study drug withdrawal in the ivabradine treatment group compared to the placebo group, while the incidences of serious AEs, AEs resulting in death and all deaths were similar in both groups. Phosphenes, bradycardia and atrial fibrillation were more frequent in the ivabradine treatment group compared to the placebo group. The most common classes of emergent AEs were cardiac disorders and infections and infestations.
The submission provided data from the most recent Periodic Safety Update Report (PSUR) (October 2005-October 2008), representing 63,241 patient-years of exposure. The most common side effects noted in the PSUR were phosphenes, bradycardia, atrioventricular first degree block, ventricular extrasystoles, headache, dizziness and blurred vision. There was no information regarding the proportion of the patients included in this report who had concurrent LVD.
9. Clinical Claim
The submission described ivabradine 5 mg / 7.5 mg as superior to
placebo in terms of prognostic effectiveness outcomes, in stable
angina patients who also have LVD and a resting heart rate of 70
bpm or greater, and that ivabradine in combination with atenolol
was superior to placebo in combination with atenolol, in terms of
comparative effectiveness on symptomatic outcomes. The submission
also described ivabradine 7.5 mg as non-inferior to amlodipine 10
mg and atenolol 100 mg in terms of symptomatic effectiveness
In summary, the submission stated that in treating stable angina to reduce symptoms and improve exercise tolerance in patients who also have LVD and a resting heart rate of 70bpm or greater, ivabradine conferred prognostic benefit when compared to placebo.
See Recommendations and Reasons for PBAC’s view.
10. Economic Analysis
A modelled economic evaluation was presented. It was a cohort
expected value analysis, with a Markov process.
The Pre-Sub-Committee Response provided an additional scenario analysis using a revised model and including both amlodipine and isosorbide as comparators (trial CL3-023 demonstrated the non-inferiority of ivabradine to amlodipine in terms of symptomatic outcomes in patients with chronic angina). Both scenarios produced a 10 year ICER in the range $15,000- 45,000/QALY.
See Recommendations and Reasons for PBAC’s view.
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year was less than 10,000 in Year 5
and the financial cost per year to the PBS was estimated to be less
than $10 million per year in Year 5.
12. Recommendation and Reasons
The PBAC noted that, at its hearing, the sponsor accepted the
overall ESC advice to PBAC that there was substantial doubt over
whether the PBAC could rely on the submitted evidence and modelling
as a basis to recommend the listing of ivabradine as requested in
the submission. The PBAC further noted that at the hearing a
further price reduction was proposed and also a request put to the
PBAC to consider recommending listing for treatment by
cardiologists for patients with chronic stable angina refractory to
all other PBS-listed medicines. In doing so, the hearing also
referred the PBAC to perhexiline, which is PBS-listed as Authority
Required (Streamlined) for “angina not responding to other
The PBAC agreed with the ESC and the sponsor that the submission did not provide evidence to directly or indirectly address the restriction requested in the submission, noting particularly that the submission sought to rely on a subgroup analysis which was of a subgroup of a post hoc subgroup.
The PBAC interpreted the revised restriction proposed during the hearing as seeking listing of ivabradine as a medicine of last resort for patients with chronic stable angina. However, the PBAC had no evidence to compare ivabradine with perhexiline in patients who are refractory to all other anti-angina therapy, or to assess ivabradine in patients who are also refractory to perhexiline.
The PBAC therefore rejected the submission, deciding that it had no basis upon which to recommend the listing of ivabradine for either requested restriction.
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
Servier is committed to ivabradine being available for some patients with stable angina and will work with the PBAC to achieve listing.