Non-interventional post-authorization multi-database safety to characterize the risk of angioedema and other specific safety events of interest in association with use of Entresto® (sacubitril/valsartan) in audit patients with heart failure
- Angiotensin II antagonists (e.g. valsartan, lorsartan) are substances that lower blood pressure and cause vasodilation by modulating the renin-angiotensin system. Besides hypertension, some angiotensin II antagonists are also licensed for the treatment of heart failure and for the treatment of patients after myocardial infarction. ACE-inhibitors (e.g. enalapril, ramipril) have similar properties and indications, and are considered first-line therapy for the treatment of hypertension and heart failure.
Since January 2016, a combination of valsartan and sacubitril (Entresto®) has been licensed in Germany for the treatment of heart failure. Compared to ACE-inhibitors and previously available angtiotensin II antagonists, the combination of valsartan with sacubitril is said to cause an improved vasodilation as well as an improvement of kidney function by simultaneously blocking neprilysine and angiotensin II receptors.
Clinical trials before licensing of the drug provided insufficient information on the safety of treatment with entresto if patients had not been treated with ACE-inhibitors or other angiotensin II antagonists before. Additionally, side-effects such as angioedema, hypotension, renal failure and hyperkalemia were identified in these studies, as well as signs for acute liver injury as a possible side effect when using entresto. Further, signs for side effects such as mytoxicity, renal failure and acute pancreatitis due to drug-drug-interaction were seen in concomitant use of entresto with statins. Investigations on the occurrence of these adverse events are part of the risk-management-plan for entresto.
To fulfill the requirements of the risk-management plan, Novartis as manufacturer of entresto will voluntarily conduct post-authorization safety studies (PASS) in the countries where Entresto has been licensed. The study will be assessed by the European Medicines agency (EMA).
Based on data from the German Pharmacoepidemiological Research Database (GePaRD), the risk for angioedema, and other potential side effects such as hyperkalemia, hypotension and renal failure will be investigated in a cohort study comparing entresto users to ACE-users. Additionally, the risk of mytoxicity, kidney failure and acute pancreatitis from drug-drug-interaction between entresto and statins will be assessed in a case-control-study.
Similar studies that are also part of the PASS program are conducted in Denmark, Italy, the Netherlands, Spain and the United Kingdom.
- Begin: January 2019
End: December 2022
- Wiebke Schäfer