Empagliflozin (3) – Jardiance®

• Clinical trials
  • The pharmaceutical manufacturer presents the placebo-controlled, double-blind, randomised EMPEROR-Reduced trial, which investigated patients with chronic heart failure in NYHA classes II to IV and a reduced left ventricular ejection fraction (LVEF) of ≤ 40 per cent.

Adults with symptomatic, chronic heart failure with reduced ejection fraction

• Overall, there is a hint of a minor additional benefit.
• Due to the uncertainties described above, the certainty of the evidence is classified as ‘hint’.
• mortality
  • There are no statistically significant differences between the treatment arms for either the ‘all-cause mortality’ endpoint or the ‘cardiovascular death’ endpoint.
• Morbidity – total hospitalisations
  • For the endpoint ‘total hospitalisation’, the EMPEROR-Reduced study shows a statistically significant advantage for empagliflozin compared with the control arm.
• Morbidity – Myocardial infarction
  • For the composite endpoint ‘myocardial infarction’, comprising the individual components ‘non-fatal myocardial infarction’ and ‘fatal myocardial infarction’, there were no statistically significant differences between the treatment arms.
  • Similarly, no statistically significant differences were observed for the individual components.
• Morbidity – Stroke
  • For the composite endpoint ‘stroke’, comprising the individual components ‘non-fatal stroke’ and ‘fatal stroke’, there were no statistically significant differences between the treatment arms.
  • No statistically significant differences were observed for the individual components either.
• Morbidity – Renal morbidity
  • The endpoint ‘renal morbidity’ was assessed as part of a composite endpoint.
  • The individual components ‘chronic dialysis’, ‘kidney transplantation’, and persistent eGFR < 15 ml/min/1.73 m² or < 10 ml/min/1.73 m² are clinically relevant and comparable in terms of the extent of severity.
  • A relative reduction in eGFR of ≥ 40 %, however, is not of comparable severity to the other endpoints.
  • For this reason, combining the three individual components is not meaningful and cannot be interpreted.
  • The endpoint is therefore not taken into account.
• health status
  • Health status was assessed in the study using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • For the improvement of ≥ 15 points at week 52, there is a statistically significant advantage in favour of empagliflozin compared with the control arm.
  • However, this difference is no more than marginal.
• Health-related quality of life – Kansas City Cardiomyopathy Questionnaire (KCCQ)
  • The KCCQ questionnaire was used for the health-related quality of life endpoint category.
  • For the clinical total score KCCQ-OSS, operationalised as an improvement of ≥ 15%, there were no statistically significant differences between the treatment arms.
  • The pharmaceutical manufacturer presents analyses of responder data using the criterion of an improvement of ≥ 5 points.
  • This results in a statistically significant advantage for empagliflozin compared with the comparator arm.
  • These results are taken into account in the present case.
• Side effects – Serious adverse events (SAE)
  • For the SAE endpoint, there is a statistically significant advantage for empagliflozin compared with the control group.
  • However, there is an effect modification for the characteristic of heart failure severity according to NYHA class.
  • For patients in NYHA Class II, there is a statistically significant difference in favour of empagliflozin.
  • By contrast, for patients in NYHA classes III/IV, there is no statistically significant difference between the treatment groups.
• Side effects – discontinuation due to adverse events (AEs)
  • No statistically significant differences were observed between the treatment groups for the endpoint ‘discontinuation due to AEs’.
• Side effects – urinary tract infection, disorders of the genital organs and mammary glands, diabetic ketoacidosis
  • In detail, no statistical differences were observed between the treatment groups for the specific AEs urinary tract infection (PT) and disorders of the genital organs and mammary glands (SOC).
  • No data are available for the endpoint ‘diabetic ketoacidosis’ (PT, AE), as this event occurred in fewer than 1% of study participants per treatment arm.
• Side effects – diseases of the kidneys and urinary tract, liver and biliary tract diseases
  • For the endpoints ‘kidney and urinary tract disorders’ (SOC, SAE) and ‘liver and biliary tract disorders’ (SOC, SAE), a statistically significant advantage was observed between the treatment groups in favour of empagliflozin.
• Side effects – atrial fibrillation
  • For the endpoint ‘atrial fibrillation’ (PT, SAE), there was a statistically significant advantage for empagliflozin compared to the other treatment groups.
  • However, an effect modification was observed for the characteristic ‘severity of heart failure according to NYHA class’ for this endpoint.
  • For patients in NYHA Class II, there is a statistically significant advantage of empagliflozin compared with the comparator arm.
  • In contrast, for patients in NYHA classes III/IV, no statistically significant difference was observed between the treatment arms.
• Overall assessment / Conclusion
  • Taking an overall view of the results, based on the positive effects of empagliflozin in preventing total hospitalisations, the improvement in quality of life, and the advantages in terms of side effects – whilst taking into account that the advantages regarding SAE and atrial fibrillation were only demonstrated in patients in NYHA Class II – a minor additional benefit for empagliflozin compared with the appropriate comparator therapy is concluded.
• Overall review
  • In the overall review of the results, based on the positive effects of empagliflozin in preventing total hospitalisations, the improvement in quality of life, and the advantages in the ‘side effects’ category – whilst taking into account that the advantages for SAE and atrial fibrillation were only demonstrated in patients in NYHA Class II – a minor additional benefit is concluded for empagliflozin compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.