Ivabradine, tablets (film-coated), 5 mg and 7.5 mg (as hydrochloride), Coralan® - November 2011
Page last updated: 14 September 2012
Public Summary Document
Product: Ivabradine, tablets (film-coated), 5 mg
and 7.5 mg (as hydrochloride), Coralan®
Sponsor: Servier Laboratories (Australia) Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
To request an Authority Required listing for the initial and
continuing treatment of symptomatic systolic heart failure in a
patient in sinus rhythm, with heart rate at or above 70 bpm
stabilised on conventional therapy, which includes a beta blocker
(unless intolerant or contraindicated) at a maximum tolerated
This indication for ivabradine had not previously been considered
by the PBAC.
3. Registration Status
Ivabradine 5 mg and 7.5 mg tablets were registered by the TGA on 24 July 2012 for the following indication:
- Treatment of symptomatic chronic heart failure of NYHA Classes II or III and with documented left ventricular ejection fraction (LVEF) less than or equal to 35% in adult patients in sinus rhythm and with heart rate at or above 77 bpm, in combination with optimal standard chronic heart failure treatment.
Ivabradine 5 mg and 7.5 mg tablets were also registered by the TGA since 31 October 2006 for the following indications:
- Treatment of coronary artery disease.
- 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, OR in combination with atenolol 50mg once daily when heart rate is at or above 60 bpm and angina is inadequately controlled.
- Treatment of chronic heart failure.
4. Listing Requested and PBAC’s View
Symptomatic systolic heart failure in a patient in sinus rhythm, with heart rate at or above 70 bpm stabilised on conventional therapy, which includes a beta-blocker (unless intolerant or contraindicated) at a maximally tolerated dose.
Continuing PBS-subsidised treatment of heart failure where the patient has previously been issued with an authority prescription for ivabradine.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Chronic heart failure (CHF) is associated with recurrent and
life-threatening decompensatory episodes, with exacerbations of
concurrent disease states (e.g. respiratory failure or renal
failure). Common causes of CHF are ischaemic heart disease,
hypertension, valvular heart disease, (stenosis or regurgitation)
and idiopathic dilated cardiomyopathy.
Management of CHF aims to improve symptoms and reduce hospitalisations and mortality. Patients with CHF are usually treated with angiotension-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and beta-blockers.
The submission proposed that the place in therapy of ivabradine was to provide an additional treatment option for heart failure in patients with a heart rate ≥ 70 bpm who remain symptomatic despite treatment with conventional therapy, including a beta-blocker (if tolerated).
The submission nominated placebo (standard medical management) as
the main comparator.
The PBAC agreed that placebo (standard medical management) is the appropriate comparator if ivabradine is used in accordance with the proposed restriction as add-on therapy to optimal heart failure treatment with a maximally tolerated dose of a beta-blocker unless contraindicated or intolerant.
7. Clinical Trials
The submission presented one randomised trial, Systolic Heart
failure treatment with If inhibitor ivabradine Trial
(SHIfT), comparing ivabradine with placebo in HF patients with
systolic dysfunction (left ventricular ejection fraction (LVEF)
≤35%), with a history of documented hospital admission for
worsening HF within 12 months, and with a resting heart rate ≥70
bpm who are treated with optimal and unchanged therapies or at
least 4 weeks.
The selection criteria for SHIfT required study subjects to have a history of hospital admission within 12 months before the trial.
The SHIfT trial involved a total of 625 centres across 37 countries, with a vast majority of subjects recruited in countries where clinical practice differs from that in Australia (<10% of the subjects in SHIfT were from Australia and Western Europe countries; no centres in the United States were involved in SHIfT).
Details of the trials published at the time of submission are in the table below.
Trials and associated reports presented in the submission
|Trial ID / First author||Protocol title / Publication title||Publication citation|
|Ivabradine trials vs placebo|
|SHIfT - Study CL3-16257-063|
|Swedberg, K., M. Komajda, et al.||Ivabradine and outcomes in chronic heart failure (SHIfT): A randomised placebo-controlled study.||The Lancet 2010; 376(9744): 875-885.|
|Swedberg, K., M. Komajda, et al.||Erratum: Ivabradine and outcomes in chronic heart failure (SHIfT): A randomised placebo-controlled study (Lancet (2010) 376 (875-885)).||The Lancet 2010c: 376(9757): 1988.|
|Bohm, M., K. Swedberg, et al.||Heart rate as a risk factor in chronic heart failure (SHIfT): The association between heart rate and outcomes in a randomised placebo-controlled trial.||The Lancet 2010: 376(9744): 886-894.|
|Swedberg, K., M. Komajda, et al.||Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: The Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIfT).||European Journal of Heart Failure 2010: 12(1): 75-81.|
8. Results of Trials
The primary outcome of the SHIFT trial was a composite endpoint of the first event
of cardiovascular (CV) death (including death from unknown cause) or hospitalisation
for worsening HF. The results are presented in the table below.
Incidence of primary composite outcome and its components (RS)
|Outcomes b||Ivabradine n/N (%)||Placebo n/N (%)||HR a [95% CI]||p -value||RRR||NNT [95% CI]|
|Primary composite endpoint|
|CV death or hospitalisation for worsening HF||793/3,241 (24.5)||937/3,264 (28.7)||0.82 [0.75,0.90]||<0.0001||18%||24 [16,48]|
|CV death||449/3,241 (13.9)||491/3,264 (15.0)||0.91 [0.80,1.03]||0.128||9%||84 [35,193]|
|Hospitalisation for worsening HF||514/3,241 (15.9)||672/3,264 (20.6)||0.74 [0.66,0.83]||<0.0001||26%||21 [15,35]|
CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio;
NNT = number needed to treat; RRR = relative risk reduction; RS = randomised set
a Estimate of the HR between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake at randomisation as a covariate
b All outcomes were observed over a median follow-up of 22.9 months.
95% CIs of NNT were calculated during the evaluation.
Within a mean follow-up period of 22 months, ivabradine was associated with a statistically significant 18% reduction in the primary composite endpoint risk of CV death or HF hospitalisation (hazard ratio (HR): 0.82 (95% confidence interval (CI): [0.75, 0.90]). For the two components of the primary endpoint, the HR was statistically significant for HF hospitalisation (HR: 0.74, 95% CI: [0.66, 0.83]), but not for CV mortality (HR: 0.91, 95% CI: [0.80, 1.03]).
Hospital admissions and reasons for all pre-specified events (defined as death from any cause and hospitalisation from any cause) were judged by the investigators, and then adjudicated by the Endpoint Validation Committee (EVC) based on the supporting documentation prepared by the investigators.
Ivabradine did not demonstrate a statistically significant effect in terms of reducing all-cause mortality (HR: 0.90, 95% CI: [0.80, 1.02]) or cardiovascular mortality (a component of the primary composite endpoint) (0.91, 95% CI: [0.80, 1.03]). Statistically significant decrease in the risk of heart failure death (a component of cardiovascular death) was reported in patients treated with ivabradine (HR: 0.74, 95% CI: [0.58, 0.94]), however this was a secondary outcome.
Statistically significant differences between the two intervention arms were reported for all-cause hospitalisation (HR: 0.89, 95% CI: [0.82, 0.96]) and for CV hospitalisation (HR: 0.85, 95% CI: [0.78, 0.92]).
The results of the primary outcome for the pre-specified group of patients who received greater than or equal to 50% target daily dose of beta-blockers at randomisation (RSBBdose) are presented in the table below.
Incidence of primary composite outcome and components (RSBBdose)
|Outcomes||Ivabradine n/N (%)||Placebo n/N (%)||HR a [95% CI]||p -value||RRR||NNT [95%CI]|
|Primary composite endpoint|
|CV death or hospitalisation for worsening HF||330/1,581 (20.9)||362/1,600 (22.6)||0.90 [0.77, 1.04]||0.155||10%||57 [22, 90]|
|CV death||176/1,581 (11.1)||175/1,600 (10.9)||1.00 [0.81,1.24]||0.986||0%||NNH 514 [NNT 50 to ∞ to NNH 42]|
|Hospitalisation for worsening HF||213/1,581 (13.5)||260/1,600 (16.3)||0.81 [0.67, 0.97]||0.021||19%||37 [19, 325]|
CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio;
NNT = number needed to treat to benefit, except where indicates otherwise; NNH = number
needed to treat to harm; RRR = relative risk reduction; RSBBdose = patients of the randomised set receiving at least half of target daily dose of
beta-blockers at randomisation
a Estimate of the HR between treatment groups based on an unadjusted Cox proportional hazards model
95% CIs of NNT or NNH were calculated during the evaluation.
No significant benefit was demonstrated in the primary composite outcome for the pre-specified sub-group of patients who received greater than or equal to 50% target daily dose of beta -blockers at randomisation. Despite the apparent significant reduction in the risk of hospitalisation for worsening heart failure (HR: 0.81, 95% CI: [0.67, 0.97]), ivabradine did not change the risk of cardiovascular death (HR: 1.00, 95% CI: [0.81, 1.24]).
The PBAC noted that the sponsor also presented a post-hoc sub-group analysis of patients with a baseline heart rate of >75 bpm. Ivabradine demonstrated a statistically significant reduction in the risk for the primary composite endpoint. Statistically significant differences were also reported for both components, ie CV death and HF hospitalisation.
For PBAC’s view of these results, see Recommendation and Reasons.
In SHIfT, about three-quarters of the patients in both arms developed adverse events. The most common classes of adverse events were cardiac disorders, infections, investigations, metabolism and nutrition disorders, and vascular disorders. There were more drug-related adverse events in the ivabradine group compared to the placebo group (574 (17.8%) vs 271 (8.3%)). Bradycardia, atrial fibrillation, phosphenes were more frequent in patients receiving ivabradine treatment than those in the placebo group. Ivabradine was associated with a slightly higher rate of adverse events leading to treatment withdrawal (14.5% vs 12.8%), but a lower rate of serious adverse events (42.4% vs 45.4%). The two treatment groups were comparable in terms of the incidences of overall adverse events (74.7% vs 73.4%) and adverse events with fatal outcome (12.4% vs 13.1%).
9. Clinical Claim
The submission described ivabradine as superior to placebo in terms
of effectiveness and equivalent to placebo in terms of safety in
patients with symptomatic systolic HF, with a heart rate ≥70 bpm
who are treated with optimal therapy including maximally tolerated
dose of a beta-blocker (unless contraindicated).
The PBAC considered that the real treatment effect of ivabradine in the context of the proposed PBS listing was highly uncertain, see Recommendation and Reasons.
10. Economic Analysis
The submission presented a stepped economic evaluation for both the
ITT population and the subgroup with a baseline heart rate ≥
The time horizon of the modelled economic evaluation was 10 years.
The results of the stepped economic evaluation for the ITT population resulted in a cost/QALY in the range of $15,000 - $45,000.
Sensitivity analyses indicated that the model is most sensitive to the baseline HF hospitalisation rate from stable HF (reflected in the placebo group and is a proxy of HF hospitalisation rate from current Australian clinical practice) and the efficacy of ivabradine (relative reduction in HF hospitalisation rate from ivabradine treatment).
The submission provided a sensitivity analysis to examine the impact of likely older age of PBS population on the modelled incremental cost-effectiveness ratio (ICER). The pre-specified subgroup analysis of patient ≥ 65 years did not find a statistically significant difference between ivabradine and placebo treatment groups in terms of the primary composite outcome.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The total net financial cost to the PBS (less patient co-payment)
was estimated by the submission to be between $10 - $30 million in
12. Recommendation and Reasons
The PBAC agreed that placebo (standard medical management) is the appropriate comparator
if ivabradine is used in accordance with the proposed restriction as add-on therapy
to optimal heart failure treatment with a maximally tolerated dose of a beta-blocker
unless contraindicated or intolerant. The PBAC noted that not all patients in the
key clinical trial (SHIfT) were on optimised therapy.
The PBAC was concerned about the applicability of the SHIfT trial to the Australian treatment setting given that the trial was dominated by Eastern Europe countries with less than 10% of the subjects in SHIfT from Australia and Western Europe countries and no participants from the USA. The PBAC considered this was likely to impact particularly on hospital admissions, which may differ substantially in Eastern European health systems compared with Australian clinical practice. The PBAC also considered that the Australian population likely to be treated with ivabradine would be significantly older (mean age in the mid to high 70s) than the trial population in SHIfT (mean age in the 60s). Also, the patient population in SHIfT seemed to have fewer co-morbidities than would be expected in patients in Australian clinical practice.
The primary outcome of the SHIfT trial was a composite endpoint of the first event of cardiovascular death (including death from unknown cause) or hospitalisation for worsening heart failure. The PBAC noted that although ivabradine was associated with a statistically significant 18% reduction in the primary composite endpoint (HR: 0.82, [0.75, 0.90]) the statistical significance was driven by heart failure hospitalisation, the threshold for which is likely to be different in Australia, compared to eastern Europe.
The Committee noted that ivabradine demonstrated no statistically or clinically significant effect in terms of reducing all-cause mortality (HR: 0.90 [0.80, 1.02]) or cardiovascular mortality (a component of the primary composite endpoint) (0.91 [0.80, 1.03]). Although a statistically significant decrease in the risk of heart failure death (a component of cardiovascular death) was reported in patients treated with ivabradine (HR: 0.74 [0.58, 0.94]) the PBAC noted that this was a secondary outcome which was hard to interpret given that it is a secondary endpoint and subject to problems of statistical multiplicity.
The PBAC was concerned that no significant benefit was demonstrated in the primary composite outcome for the pre-specified sub-group of patients who received ≥ 50% target daily dose of beta-blockers at randomisation. Despite the apparent reduction in the risk of hospitalisation for worsening heart failure, ivabradine did not change the risk of cardiovascular death (HR: 1.00 [0.81, 1.24]). The PBAC considered that the trial did not test the hypothesis that ivabradine provides additional benefit to patients on optimal heart failure treatment and that based on this sub-group analysis the data could be interpreted as suggesting that there is no additional benefit of ivabradine if a patient is receiving a beta-blocker at greater than 50% of target dose.
In addition, the PBAC considered that patients in the SHIfT trial were not on optimal background therapy with maximally tolerated doses of beta-blockers. Only 23% of trial patients were at the target dose of beta-blockers, only 49% of trial patients were at 50% of target dose of beta-blockers and 10% of trial patients were not on any beta-blocker therapy.
Further, the role of ivabradine in patients for whom beta-blockers are contraindicated or not tolerated is unclear. The test for interaction on the pre-specified subgroup analysis of the 10% of patients not on a beta -blocker was not statistically significant. The PBAC noted that the SHIfT report published in the Lancet stated that “we can draw no inferences about the relative effects of ivabradine in absence of beta-blockers or by replacing them by ivabradine.”
For the post-hoc sub-group analysis of patients with a baseline heart rate of >75 bpm, upon which an alternative proposed restriction is based, ivabradine demonstrated a statistically significant reduction in the risk for the primary composite endpoint by 24% (HR; 0.76 [0.68, 0.85]). However, the PBAC considered that a restriction which limited treatment to patients with a heart rate at or above either 70 bpm or 75 bpm would be unworkable as there is considerable potential for variability in this measurement.
Overall, the PBAC considered that the real clinical treatment effect of ivabradine in the context of the proposed PBS listing was highly uncertain, particularly given the concerns regarding maximal therapy with beta-blockers in the SHIfT trial and that when used in addition to beta-blockers, at or near target doses, ivabradine did not reduce the risk of the primary composite endpoint. The Committee considered that the place of ivabradine in the treatment algorithm for heart failure was still unclear despite the SHIfT trial.
The PBAC considered that the limitations associated with the clinical trial data flowed into the modelled economic evaluation making the resultant ICERs for the ITT population and the sub-group population with a baseline heart rate >75 bpm highly uncertain. Most of the uncertainty stemmed from the numerous applicability issues of the trial to Australian clinical practice which impacts on the economic model. The PBAC noted that modelling a difference in the rate of heart failure hospitalisations and consequently death from heart failure between the two treatment arms, especially in the first five years of the model, resulted in an apparent overall mortality advantage from ivabradine even though there was no statistically significant evidence from the SHIfT trial that ivabradine reduces mortality.
The PBAC therefore rejected the submission because of the high uncertainty around the clinical evidence to support the clinical claim and the resultant high uncertainty in the economic analysis.
The PBAC also acknowledged and noted the consumer comments on this item.
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 has no comment.