Sacubitril / Valsartan (1) – Entresto®

• Clinical trials
  • In the dossier, the pharmaceutical manufacturer bases the benefit assessment on the results of the PARADIGM-HF trial.
  • This study is the pivotal registration trial for sacubitril/valsartan, which included adult patients with symptomatic, chronic heart failure (NYHA functional classes II to IV) and a reduced ejection fraction (≤ 35%).
  • The PARADIGM-HF study involved a 5- to 10-week sequential, single-blind run-in phase for all patients enrolled after screening, during which enalapril was administered, followed by sacubitril/valsartan.
  • Following the sequential run-in phase, 8,442 patients were randomised in a 1:1 ratio, with 4,209 patients assigned to the sacubitril/valsartan arm and 4,233 patients to the enalapril arm.

a) Patients without diabetes mellitus

• For the treatment of symptomatic, chronic heart failure with reduced ejection fraction in adult patients without diabetes mellitus, there is a hint of considerable additional benefit from sacubitril/valsartan compared with the appropriate comparator therapy, enalapril (each in combination with a beta-blocker).
• Overall, for adult patients with symptomatic chronic heart failure with reduced ejection fraction who do not have diabetes mellitus, sacubitril/valsartan is found to provide considerable additional benefit compared with enalapril, in each case in combination with a beta-blocker.
• mortality
  • For the endpoint of all-cause mortality, a statistically significant difference in favour of sacubitril/valsartan was observed in the overall population (HR 0.84; 95% CI [0.76; 0.93]; p < 0.001; 25th quantile of survival time in months, sacubitril/valsartan: n/a; 95% CI [39.3; n/a]; enalapril: n.a., 95% CI [35.4; 39.5]).
  • The endpoint ‘all-cause mortality’ reflects mortality regardless of the cause of death and thus provides a more comprehensive picture than the endpoint ‘cardiovascular mortality’. Therefore, the endpoint ‘all-cause mortality’ is used to derive the additional benefit.
  • For patients without diabetes mellitus, there is a statistically significant advantage in favour of sacubitril/valsartan (HR 0.77; 95% CI [0.68; 0.88]; p < 0.001). Consequently, for the endpoint of all-cause mortality in patients without diabetes mellitus, sacubitril/valsartan offers a considerable additional benefit over enalapril (each in combination with a beta-blocker).
• Morbidity – hospitalisation for heart failure
  • For the endpoint of hospitalisation for heart failure, there was a statistically significant difference in favour of sacubitril/valsartan compared with the appropriate comparator therapy, enalapril, in each case in combination with a beta-blocker (HR 0.79; 95% CI [0.71; 0.89]; p < 0.001).
• Morbidity – Myocardial infarction
  • No statistically significant differences were observed for the endpoint of fatal myocardial infarction. Therefore, there is no hint of additional benefit from sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). An additional benefit for the endpoint of fatal myocardial infarction is therefore not proven.
  • For the endpoint of non-fatal myocardial infarction, there is no statistically significant difference between the treatment groups. Consequently, there is no hint of additional benefit from sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). There is therefore no proof of additional benefit for the endpoint of non-fatal myocardial infarction.
  • For the endpoint of myocardial infarction, there is no statistically significant difference between the treatment groups. This provides no hint of an additional benefit of sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). Additional benefit is not proven for the endpoint of myocardial infarction (all events).
• Quality of life – Clinical total score of the KCCQ (KCCQ-OSS; responders showing a clinically relevant improvement)
  • In the analysis of the KCCQ-OSS, in which the most recent recorded value was used for both living and deceased patients, a statistically significant difference was observed between the treatment groups in favour of sacubitril/valsartan compared with the appropriate comparator therapy, enalapril (in each case in combination with a beta-blocker; RR 1.07, 95% CI [1.01; 1.14]; p < 0.032).
• Side effects – hypotension
  • For the endpoint of hypotension, operationalised as NMQ, there was a statistically significant disadvantage of sacubitril/valsartan compared with enalapril, in each case in combination with a beta-blocker (RR 1.31, 95% CI [1.21; 1.43]; p < 0.001). However, due to the way the NMQ hypotension endpoint is operationalised, the extent of the increased risk associated with sacubitril/valsartan is non-quantifiable.
  • For the NMQ hypotension endpoint, there is an indication of an effect modification by the characteristic ‘diagnosis of diabetes mellitus’. In this regard, the result is statistically significant to the detriment of sacubitril/valsartan for both patients with diabetes mellitus and those without.
• Overall assessment
  • The G-BA classifies the extent of the additional benefit of sacubitril/valsartan as ‘considerable’ on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease in patients without diabetes mellitus.
  • Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit that has not previously been achieved, as a moderate prolongation of overall survival is achieved.
  • However, when the available results on mortality, morbidity and quality of life are considered as a whole, together with the results on side effects which cannot be conclusively assessed, sacubitril/valsartan does not demonstrate a sustained and, compared with the appropriate comparator therapy, previously unattained major improvement in treatment-related benefit; in particular, no cure of the disease, no significant prolongation of life, no long-term freedom from severe symptoms and no substantial avoidance of serious side effects. Therefore, classification as ‘major additional benefit’ is not justified.

b) Patients with diabetes mellitus

• For the treatment of symptomatic, chronic heart failure with reduced ejection fraction in adult patients with diabetes mellitus, there is a hint of a minor additional benefit of sacubitril/valsartan compared with the appropriate comparator therapy, enalapril (each in combination with a beta-blocker).
• Overall, for adult patients with symptomatic chronic heart failure with reduced ejection fraction who have diabetes mellitus, a minor additional benefit of sacubitril/valsartan compared with enalapril is observed, in each case in combination with a beta-blocker.
• For patients with diabetes mellitus, however, the result is not statistically significant; an additional benefit of sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker) is therefore not proven for the endpoint of all-cause mortality in these patients.
• Morbidity – Hospitalisation for heart failure
  • For the endpoint of hospitalisation due to heart failure, a statistically significant difference was observed in favour of sacubitril/valsartan compared with the appropriate comparator therapy, enalapril, in each case in combination with a beta-blocker (HR 0.79; 95% CI [0.71; 0.89]; p < 0.001).
• Morbidity – Myocardial infarction
  • No statistically significant differences were observed for the endpoint of fatal myocardial infarction. Therefore, there is no hint of additional benefit from sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). An additional benefit for the endpoint of fatal myocardial infarction is not proven.
  • For the endpoint of non-fatal myocardial infarction, there is no statistically significant difference between the treatment groups. Consequently, there is no hint of an additional benefit of sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). The additional benefit for the endpoint of non-fatal myocardial infarction is not proven.
  • For the endpoint of myocardial infarction, there is no statistically significant difference between the treatment groups. This provides no hint of an additional benefit of sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). An additional benefit for the endpoint of myocardial infarction (all events) is therefore not proven.
• Morbidity – stroke
  • For the endpoint of non-fatal stroke, there is no statistically significant difference between the treatment groups. Consequently, there is no hint of additional benefit from sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). The additional benefit for the endpoint of non-fatal stroke is not proven.
  • There are no statistically significant differences for the endpoint of fatal stroke. Therefore, there is no hint of additional benefit from sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). Additional benefit is not proven for the endpoint of fatal stroke.
  • For the endpoint of stroke, there is no statistically significant difference between the treatment groups. Therefore, there is no hint of additional benefit from sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). There is therefore no proof of additional benefit for the endpoint of stroke.
• Morbidity – End-stage renal failure
  • For the endpoint of end-stage renal failure, there is no statistically significant difference between the treatment groups. Therefore, there is no hint of additional benefit from sacubitril/valsartan compared with enalapril (each in combination with a beta-blocker). Additional benefit is not proven for the endpoint of end-stage renal failure.
• Quality of life – Clinical total score of the KCCQ (KCCQ-OSS; responders showing a clinically relevant improvement)
  • In the analysis of the KCCQ-OSS, in which the most recent recorded value was used for both living and deceased patients, a statistically significant difference was observed between the treatment groups in favour of sacubitril/valsartan compared with the appropriate comparator therapy, enalapril (in each case in combination with a beta-blocker; RR 1.07, 95% CI [1.01; 1.14]; p < 0.032).
• Side effects – hypotension
  • For the endpoint of hypotension, operationalised as NMQ, there was a statistically significant disadvantage of sacubitril/valsartan compared with enalapril, in each case in combination with a beta-blocker (RR 1.31, 95% CI [1.21; 1.43]; p < 0.001). However, due to the way the NMQ hypotension endpoint is operationalised, the extent of the increased risk associated with sacubitril/valsartan is non-quantifiable.
  • For the NMQ hypotension endpoint, there is an indication of an effect modification by the characteristic ‘diagnosis of diabetes mellitus’. In this context, the result is statistically significant to the detriment of sacubitril/valsartan for both patients with diabetes mellitus and those without.
• Overall assessment
  • The G-BA classifies the extent of the additional benefit of sacubitril/valsartan as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic goal in the treatment of the disease in patients with diabetes mellitus.
  • Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as a minor improvement in health-related quality of life (responders showing clinically relevant improvement as well as responders showing clinically relevant deterioration) and a reduction in non-serious symptoms are achieved.
  • Taking into account the available results on mortality, morbidity and quality of life, together with the results on side effects which cannot be conclusively assessed, it appears that sacubitril/valsartan does not demonstrate a sustained and, compared with the appropriate comparator therapy, previously unachieved significant improvement in treatment-related benefit; in particular, there is no prolongation of life, no alleviation of serious symptoms and no relevant reduction in serious side effects. Therefore, classification as ‘considerable additional benefit’ is not justified.

Courtesy translation only, please refer to the German original.