AusPAR: Ivabradine - Therapeutic Goods Administration

AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3
Final 31 October 2012
Therapeutic Goods Administration
blocker dose. In addition, although the subgroup analysis in the general patient population
showed effect in favour of ivabradine over placebo in both subgroups of “age < 65 years”
and “age ≥ 65 years”, the relative risk reductions were greater in the subgroup of “age < 65
years” than that of “age ≥ 65 years although interaction tests showed that the differences
were not statistically significant (Table 11). Subgroup analysis in RSBBdose population of the
endpoint of all-cause mortality also showed that there was no effect in favour of
ivabradine compared to placebo. All these suggest that the beneficial effect of ivabradine
appeared to be less in CHF patients ≥ 65 years old. Although analysis in subgroup of age ≥
75 years in the RS population showed relative risk reduction in favour of ivabradine in the
primary composite endpoint and the component endpoints of cardiovascular death and
hospitalisation for worsening heart failure, of 11%, 29%, and 8% respectively, statistical
significance was not done or presented and the sample size was small (n=722) and thus
these results did not help in characterising efficacy in the elderly age group.
Table 11. Relative risk reductions in subgroups of “age < 65 years” and “age ≥ 65 years”, RS
population
Primary composite
endpoint
Cardiovascular
death
Hospitalisation for
worsening heart
failure
RRR: Relative risk reductions
Relative risk reductions (in
favour of ivabradine over
placebo)
“age < 65
years”
(n=4031)
“age ≥ 65
years”
(n=2474)
24% 11% P=0.0993
12% 7% P=0.6514
33% 17% P=0.0794
P value (statistical
significance of difference in
RRR between subgroups)
With regards to improvement in symptoms, a statistically significant higher proportion of
patients in the ivabradine group compared with those in the placebo group improved by
≥1 NYHA class relative to baseline, had an improved Patient Reported Global Assessment
and an improved Physician Reported Global Assessment. However, the differences
between treatment groups were small (27.6% versus 24%, 72% versus 68%, and 61%
versus 57%, respectively). In addition, these assessments were done by study
investigators or patients who were not blinded to the heart rates or blinding could not be
assured, leading to the possibility of bias.
Comment: The reply from the sponsor to EMA regarding its question on the issue of
blinding in the context of the differential effects of ivabradine and placebo on HR
was noted by the clinical evaluator. The sponsor has responded that “it is unlikely
that knowing the change in heart rate could have jeopardized the blind of the study
as the mean significant reduction in heart rate observed in the overall population of
patients treated with ivabradine compared to placebo does not apply consistently at
an individual level”. The sponsor presented data which showed that more than 30%
of the patients in the placebo group had a heart rate reduction greater than 10 bpm
at Day 28 and at 1 year, while conversely, in the ivabradine group 14% and 19% of
patients had a heart rate reduction of less than 5 bpm at Day 28 and at 1 year,
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