AusPAR: Ivabradine - Therapeutic Goods Administration

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AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3 Final 31 October 2012 Therapeutic Goods Administration years with HR ≥ 75 bpm at baseline” (N=856 [n=424 ivabradine, n=432 placebo]), “aged ≥ 65 years” (N=2464 [n=1265 ivabradine, n=1209 placebo]), “aged ≥ 65 years with HR ≥75 bpm at baseline” (N=1467 [n=721 ivabradine, n=746 placebo]) and the results are presented below together with the results in the overall study population in Tables 19 and 20. It is unclear why the HR criterion of ≥75 bpm was chosen. 36 Table 19. Primary and main secondary endpoints in the overall population, in patients aged ≥ 70 years and in patients aged ≥ 70 years with HR ≥ 75 bpm at baseline Table 20. Primary and main secondary endpoints in the overall population, in patients aged ≥ 65 years, and in patients aged ≥ 65 years with HR ≥ 75 bpm at baseline The results showed that in the subgroup of patients aged ≥ 65 years, the relative risk reduction for the primary composite endpoint was not statistically significant. Similar to the results in the overall population, the mortality endpoints were mostly not statistically significant (only the endpoint of death from heart failure was statistically significant [relative risk reduction of 31%, p=0.0380]). Analysis in the endpoint of all-cause mortality showed there was no increased risk with ivabradine 36 Sponsor comment: “The sponsor subsequently explained in its Pre ACPM response that the criterion of ≥75 bpm was chosen because the EMA indicated in its evaluation of the SHifT study that ‘the baseline heart rate (HR) for patients with a positive benefit/risk balance may be higher than 75 bpm which could be considered as a relevant threshold in clinical practice.’ It is also the mean heart rate of the population included in the Euro Heart Survey conducted by the European Society of Cardiology. The sponsor considered the EMA’s advice and complementary analyses were subsequently performed to evaluate the efficacy and the safety of ivabradine treatment in this sub-group, ≥ 75 bpm. Therefore, the sponsor did not follow any specific methodology in arriving at a threshold of > 75 bpm.“ Page 50 of 101
AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3 Final 31 October 2012 Therapeutic Goods Administration compared to placebo. Only the disease-specific hospitalisation endpoints (hospitalisation for worsening heart failure and any cardiovascular hospitalisation) were statistically significant but the relative risk reductions were less than that for the overall population, with much higher p values. Approximately 60% of the subgroup of patients aged ≥ 65 years had baseline HR ≥ 75 bpm. In this subgroup the relative risk reduction in the primary composite endpoint and the secondary endpoints were all statistically significant, except for the endpoint of all-cause mortality. The appropriate comparator group in the overall population would be the subgroup of patients in the overall population with a baseline HR ≥ 75 bpm but this was not provided by the sponsor. In the subgroup of patients aged ≥ 70 years, the relative risk reduction on the primary composite endpoint (16%) was similar to that in the overall population (18%) but the result was barely statistically significant (p=0.0478). Interestingly, unlike the results in the overall population, more mortality endpoints yielded statistically significant results, while the morbidity endpoints were mostly not statistically significant (only the endpoint of hospitalisation for worsening heart failure was statistically significant but was near the threshold of non-significance [p= 0.0434] and with a relative risk reduction that was lower than in the overall population [20% versus 26%]). The disease specific mortality endpoints were statistically significant and yielded greater relative risk reductions than in the overall population. Approximately 60% of the subgroup of patients aged ≥ 70 years had baseline HR ≥ 75 bpm, and the relative risk reduction in the primary composite endpoint and the secondary endpoints were all statistically significant, except for the endpoint of all-cause mortality. Again, the appropriate comparator group in the overall population would be the subgroup of patients in the overall population with a baseline HR ≥ 75 bpm but this was not provided by the sponsor. Overall, these additional analyses showed that for the subgroup of patients aged ≥65 years, there were statistically significant relative risk reductions in favour of ivabradine over placebo in cardiovascular (disease-specific) morbidity endpoints, although these reductions were less than in the overall population, suggesting that the improvements in clinical outcomes may be less in this subgroup of patients. No increased risk of overall mortality was detected with ivabradine compared to placebo. Increasing the age criterion to ≥ 70 years appeared to improve the mortality outcomes but worsen the morbidity outcomes. These results need to be considered in the context of the safety results in this subgroup of elderly patients, in order to establish if the apparently lower efficacy would affect the benefit-risk balance. This will be discussed below. In addition, in the main study analyses, the apparently lower effect of ivabradine on those aged ≥ 65 years was detected in the analyses in the RSBBdose population. Additional analyses on the subgroup of elderly patients in the RSBBdose population were not provided by the sponsor. 37 With regards to the NYHA classes, only 1.7% (n=111) of the study population were in NYHA Class IV. Subgroup analysis combined patients with NYHA III and those with NYHA IV into the same subgroup, thus not allowing any analysis of the sub-population of patients with NYHA IV. It is recommended that patients with NYHA IV be excluded from the proposed indication, as the claimed efficacy was only studied in a limited number of patients with NYHA IV. Comment: The reply from the sponsor to EMA regarding the question pertaining to “The risk/benefit balance is not established in NYHA Class IV patients” was noted by the clinical evaluator. The sponsor did an analysis of the primary composite 37Sponsor comment: “The sponsor provided this data in its response to the first clinical evaluation report and also in its review of the final clinical evaluation report.” Page 51 of 101
Page 1 and 2: Australian Public Assessment Report
Page 3 and 4: Contents AusPAR Coralan Ivabradine
Page 5 and 6: Product background AusPAR Coralan I
Page 7 and 8: AusPAR Coralan Ivabradine Servier L
Page 17 and 18: Table 1. Analysis Sets and Subsets
Page 25 and 26: Table 6. Causes of deaths by treatm
Page 27 and 28: Analyses performed across trials (p
Page 31 and 32: Table 10. (ii) Pre-specified subgro
Page 37 and 38: Patient exposure AusPAR Coralan Iva
Page 39 and 40: Treatment-related adverse events (a
Page 41 and 42: Table 15. Continued AusPAR Coralan
Page 49: Clinical summary and conclusions Fi
Page 63 and 64: Table 25. Incidence of TEAEs by age
Page 65 and 66: Second round benefit-risk assessmen
Page 67 and 68: Safety specification AusPAR Coralan
Page 69 and 70: CL3-067 (Follow up Measure; Ophthal
Page 85 and 86: Risk management plan AusPAR Coralan
Page 95 and 96: Table 35 AusPAR Coralan Ivabradine
Page 101:
Therapeutic Goods Administration PO
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AusPAR: Ivabradine - Therapeutic Goods Administration

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