Dapagliflozin (5) – Forxiga®

• Clinical trials
  • The placebo-controlled, double-blind, randomised DAPA-HF trial is available for the benefit assessment of dapagliflozin.

Adults with symptomatic, chronic heart failure with reduced ejection fraction

• Taking into account the uncertainties mentioned, the G-BA concludes that, based on an overall review of the positive effects across all endpoint categories in the DAPA-HF study, there is evidence of a considerable additional benefit.
• mortality
  • In the DAPA-HF study, a statistically significant lower number of patients died in the dapagliflozin arm compared with the control arm (11.6% vs. 13.9%). However, an effect modification was observed with regard to the severity of heart failure according to NYHA class: among patients with NYHA class II, there were statistically significantly fewer deaths in the dapagliflozin arm (7.8% vs. 12.0%). In patients with NYHA Class III/IV, however, there were more deaths in the dapagliflozin arm compared with the control arm (19.7% vs. 17.7%), but there was no statistically significant difference between the treatment groups.
• Morbidity – Total hospitalisations
  • For the endpoint ‘total hospitalisations’, the DAPA-HF study showed a statistically significant reduction in hospitalisations in the dapagliflozin arm compared with the control arm.
• Interim conclusion on morbidity
  • With regard to morbidity, the DAPA-HF study shows statistically significant positive results for the endpoint ‘total hospitalisation’ in favour of dapagliflozin. With regard to health status (EQ-5D VAS and PGIS), statistically significant advantages were observed with dapagliflozin; however, no clinically relevant differences can be inferred from the EQ-5D VAS. For the PGIC, there was no statistically significant difference between the two treatment arms. The results for the health status endpoint are therefore inconsistent. No advantage for dapagliflozin is observed for this endpoint.
  • For the other morbidity endpoints, no statistically significant differences were observed between the treatment arms.
• Quality of life – Kansas City Cardiomyopathy Questionnaire (KCCQ)
  • Results from the KCCQ questionnaire are available for the health-related quality of life endpoint category.
  • For both responder analyses – showing an improvement of 5 points and 15 points respectively – statistically significant differences were observed between the treatment arms, giving dapagliflozin an advantage over the control.
• Side effects – Serious adverse events (SAEs)
  • In the DAPA-HF trial, there were statistically significantly fewer SAE in the dapagliflozin arm compared with the control arm (27.8% vs. 30.7%).
• Overall assessment
  • For the endpoint category of mortality, a statistically significant advantage was observed with dapagliflozin compared with the control group for both the ‘all-cause mortality’ endpoint and the ‘cardiovascular mortality’ endpoint, which is presented as a supplementary measure. For both endpoints, there was an effect modification with regard to the severity of heart failure according to NYHA class: in patients with NYHA class II, there were statistically significantly fewer deaths in the dapagliflozin group. In patients with NYHA Class III/IV, there were no statistically significant differences between the treatment groups.
  • With regard to morbidity, the DAPA-HF study shows statistically significant positive results for the endpoint ‘total hospitalisation’ in favour of dapagliflozin. With regard to health status (EQ-5D VAS and PGIS), although statistically significant advantages were observed with dapagliflozin, no clinically relevant differences can be inferred from the EQ-5D VAS. For the PGIC, there was no statistically significant difference between the two treatment arms. The results for the health status endpoint are therefore inconsistent. No advantage for dapagliflozin is inferred for this endpoint. For the other morbidity endpoints, no statistically significant differences were observed between the treatment arms.
  • With regard to disease-specific quality of life (KCCQ-OSS), statistically significant differences in favour of dapagliflozin were observed between the treatment arms in both responder analyses, with improvements of 5 and 15 points respectively.
  • With regard to the side effect endpoint, it should be noted that the DAPA-HF trial did not systematically record AEs regardless of severity. Only non-serious AEs were recorded, which led to therapy discontinuation or a dose adjustment, or which belonged to a predefined set of AEs specified by the pharmaceutical manufacturer. Overall, the DAPA-HF study shows statistically significant positive results in favour of dapagliflozin for the endpoint ‘SAE’ and, specifically, for the AEs ‘Respiratory, thoracic and mediastinal disorders (SOC)’. For the other endpoints, no statistically significant differences were observed between the treatment arms.
  • An overall review of the results of the DAPA-HF study reveals statistically significant positive effects for dapagliflozin across all endpoint categories: mortality (overall mortality and, as shown in the supplementary data, cardiovascular mortality, though in each case only among patients with NYHA Class II), morbidity (total hospitalisations), health-related quality of life (as measured by the KCCQ-OSS) and side effects (serious SAE and, in detail, a specific AE).
• Overall view
  • An overview of the results of the DAPA-HF study shows that dapagliflozin had statistically significant positive effects across all endpoint categories: mortality (all-cause mortality and, as shown in the supplementary data, cardiovascular mortality, though in each case only in patients with NYHA Class II), morbidity (total hospitalisation), health-related quality of life (as measured by the KCCQ-OSS) and side effects (SAE and, in detail, for a specific AE). With regard to the results for all-cause mortality and cardiovascular mortality, it should be noted that an advantage with dapagliflozin was observed only in patients with NYHA Class II, i.e. those with mild limitations in physical performance. No advantage in terms of mortality was observed in patients with NYHA class III/IV.
  • Nevertheless, the G-BA classifies the extent of the additional benefit of dapagliflozin for the general population as considerable, based on 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.

Courtesy translation only, please refer to the German original.