The fixed-dose combination of sacubitril and valsartan (trade name: Entresto) has been approved since November 2015 for adults with symptomatic chronic heart failure with reduced pump function. In its early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) derived an indication of considerable added benefit versus the appropriate comparator therapy enalapril from the data: The positive effects regarding mortality, hospitalizations and quality of life largely outweighed the negative effect in non-severe side effects.
In the following commenting procedure, the drug manufacturer subsequently submitted sensitivity analyses and data, and a possible effect modification by the subgroup characteristic diabetes mellitus was pointed out. IQWiG investigated this in an addendum and concluded that there is an indication of a minor added benefit for diabetes patients. For patients without diabetes, in contrast, an indication of considerable added benefit of the drug combination remains.
Sensitivity analyses did not change assessment of the added benefit
The PARADIGM-HF study, on which the dossier was based, contained a so-called run-in phase to ensure that the participants tolerated the target dose of the study medication. About 20 per cent of the participants dropped out of the study in this phase. As noted by IQWiG in its dossier assessment, the rate of adverse events may be underestimated as a result, and more so under the drug combination than in the comparator arm.
To account for this, the manufacturer now presented sensitivity analyses. However, these analyses neither considered the outcomes of interest nor were methodologically adequate to remedy this deficiency. They did therefore not change the assessments from the dossier assessment.
Quality of life: indication of added benefit confirmed
Regarding health-related quality of life and health status, the manufacturer subsequently submitted analyses that increase the certainty of conclusions in comparison with the dossier assessment. For quality of life, there is now an indication of an added benefit both for clinically relevant improvement and for clinically relevant worsening. For health status, there is still no advantage of sacubitril/valsartan. Hence there is still no hint of an added benefit for this outcome.
Diagnosis of diabetes as relevant subgroup characteristic
There was proof of an effect modification in the outcome "mortality": Whereas there was an indication of an added benefit of sacubitril/valsartan in comparison with enalapril for patients without diabetes mellitus, there was no hint of an added benefit for patients with diabetes.
Overall, there were therefore still both positive effects and a negative effect. Due to the effect modification by the characteristic "diabetes", an indication of minor added benefit remains for patients with this disease, whereas there is still an indication of considerable added benefit for patients without diabetes.
G-BA decides on the extent of added benefit
The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the Federal Joint Committee (G-BA). After publication of the manufacturer's dossier and the IQWiG dossier assessment, the manufacturer submitted additional information in the commenting procedure. The G-BA subsequently commissioned IQWiG to assess the data subsequently submitted. IQWiG now presents this assessment in the form of an addendum. The G-BA makes a final decision on the extent of added benefit.