AusPAR: Ivabradine - Therapeutic Goods Administration

Secondary endpoints in RSBBdose population
All-cause
mortality
Cardiovascular
death
Hospitalisation
for worsening
heart failure
NA= not available
Only the subgroups of
“females”, “ischaemic cause”,
“NYHA Class II”, “no
hypertension” and “baseline HR
≥ 77 bpm”
Only the subgroups of
“females”, “ischaemic cause”,
“NYHA Class II”, “no
hypertension”, “baseline HR ≥
77 bpm”, “age ≥ 65 years”, and
“no DM”
in all the pre-specified
subgroups except the subgroup
of “age ≥ 65 years”.
Table 10. (iii) Analysis in subgroup of age ≥ 75 years
Primary composite
endpoint in RS population
Cardiovascular death in RS
population
Hospitalisation for
worsening heart failure in
RS population
NA= not available
Conclusion and issues
Relative Risk Reduction
(in favour of Ivabradine)
AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3
Final 31 October 2012
Therapeutic Goods Administration
All the interaction tests had pvalues
higher than 0.05
NA
NA
11% NA
29% NA
8% NA
P value
Analysis of heart rate changes confirmed the HR reducing effect of ivabradine, showing
that with the mean doses of ivabradine 5.8 to 6.4mg b.d there was a mean change in HR of
approximately -15 bpm at Day 28 and -12 bpm at last post randomisation visit. Similar
reductions in HR were observed in the subgroup of patients who were on at least 50% of
the target doses of recommended beta blockers (RSBBdose population) and in the subgroup
of “age ≥ 75 years”, suggesting that the HR-reducing effect was exerted in these patient
populations as well. However, the HR-reducing effect of ivabradine was expected based on
its known pharmacodynamic properties. The efficacy results of this study would need to
show whether this reduction in HR observed, which is mediated through a direct effect on
the sino-atrial node independent of any inhibitory effect on the sympathetic system, can
be translated to reduced morbidity or mortality in CHF patients.
In the main analysis in the RS population, although there was a statistically significant
relative risk reduction of 18% in favour of ivabradine for the primary composite endpoint
the result was driven almost entirely by the component endpoint of hospitalisation for
worsening heart failure. All 3 hospitalisation endpoints of all-cause hospitalisation,
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