Sacubitril / Valsartan (2) – Entresto®

• Clinical trials
  • The double-blind, randomised, controlled PANORAMA-HF trial was submitted for the assessment of the additional benefit of sacubitril/valsartan in the treatment of heart failure in children aged 1 year and over and adolescents.
  • The study compared treatment with sacubitril/valsartan versus enalapril in children aged 1 month and over and adolescents.

Children and adolescents aged 1 to 17 years with symptomatic, chronic heart failure with left ventricular dysfunction

• An additional benefit is not proven
• An overall review of the results in the categories of mortality, morbidity, health-related quality of life and side effects reveals no differences between the treatment arms that are relevant to the benefit assessment.
• mortality
  • Overall mortality and, as a supplementary endpoint, cardiovascular death
  • There are no statistically significant differences between the treatment arms for either the endpoint ‘overall mortality’ or the additionally reported endpoint ‘cardiovascular death’.
• Morbidity – Severe heart failure events
  • ‘UNOS status 1A for heart transplantation’
  • ‘VAD/ECMO/mechanical ventilation/intra-aortic balloon pump required for life support’
  • ‘Hospitalisation due to heart failure’
  • “Total hospitalisation”
  • For the above-mentioned endpoints, which represent severe heart failure events, there were no statistically significant differences between the treatment arms in any case.
• Morbidity – Symptoms (PGIS, PGIC)
  • The endpoint ‘symptoms’ was assessed using the PGIS and PGIC, respectively.
  • For both endpoints, there were no statistically significant differences between the treatment arms.
• Health-related quality of life (PedsQL)
  • For the health-related quality of life endpoint category, the PedsQL questionnaire was used for children aged 5 years and over.
  • For younger children, the parent-reported version of the questionnaire was used.
  • For the PedsQL endpoint, there were no statistically significant differences between the sacubitril/valsartan and enalapril arms in either the patient- or parent-reported versions.
• Side effects – overall rates
  • Serious adverse events (SAEs) and discontinuation due to adverse events (AEs)
  • For the endpoints of SAE and discontinuation due to AEs, no statistically significant differences were observed between the treatment arms.
• Side effects – Specific adverse events
  • Angioedema (AE), hyperkalaemia (SAE) and hypotension (SAE)
  • In detail, for the specific AEs/SAEs angioedema (AE), hyperkalaemia (SAE) and hypotension (SAE), there were no statistically significant differences between the treatment arms.
  • Disorders of the nervous system (SAE)
  • In detail, a statistically significant difference was observed in favour of the sacubitril/valsartan arm compared with the enalapril arm for the specific SAE ‘nervous system disorders’.
• Overall assessment
  • For the early benefit assessment of sacubitril/valsartan for the new indication for the treatment of paediatric heart failure, the pharmaceutical manufacturer has submitted the randomised, double-blind PANORAMA-HF study comparing sacubitril/valsartan with enalapril.
  • Overall, the children and adolescents in the study were treated with either sacubitril/valsartan or enalapril for a duration of 52 weeks.
  • The study assessed endpoints in the categories of mortality, morbidity, health-related quality of life and side effects.
  • For the mortality category, neither the ‘all-cause mortality’ endpoint nor the additionally reported ‘cardiovascular mortality’ endpoint showed any statistically significant differences between the treatment arms.
  • In the morbidity category, for endpoints relating to symptoms and severe heart failure events – including hospitalisations due to heart failure – as well as in the health-related quality of life category, there were no statistically significant differences between the treatment arms.
  • With regard to side effects, there were no statistically significant differences between the groups for the overall rates of SAEs or for the endpoint ‘discontinuation due to AEs’.
  • Overall, there are no differences between sacubitril/valsartan and the appropriate comparator therapy, enalapril, that are relevant to the benefit assessment. An additional benefit for sacubitril/valsartan is therefore not proven.

Courtesy translation only, please refer to the German original.