Studies have shown that co-prescription of aldosterone antagonists (such as spironolactone and eplerenone) and renin-angiotensin system drugs [such as angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB)] improve survival in patients with heart failure. However, guidelines recommend that these drugs should be co-prescribed with caution, and regular monitoring is recommended to reduce the risk of complications such as high levels of potassium in the blood (also known as hyperkalaemia) and kidney dysfunction.
Hyperkalaemia is associated with an increased chance of being admitted to hospital, spending longer in hospital, and can be fatal in severe cases. In 2016, the Medicines and Healthcare Product Regulatory Agency (MHRA), the UK drug regulator, published reminders that caution should be used when prescribing these types of medicines together, and also reminded healthcare professionals about regular blood monitoring. More recently, studies in the UK have reported that monitoring of patients receiving these drugs occurs less frequently than guidelines recommend. A rise in the associated number of hyperkalaemia cases has also been reported.
This study will explore the extent of patients (aged 18 years or over) receiving prescriptions for these two types of medication simultaneously, as well as adherence to treatment monitoring guidelines, between 2014 and 2018. This will provide indirect evidence whether the reminder issued to healthcare professionals in 2016 by the MHRA resulted in safer prescribing behaviour.
While trials have reported on the clinical benefit of co-prescribing aldosterone antagonist and renin-angiotensin system (RAS) drugs in heart failure patients, follow up studies found inappropriate monitoring and higher rates of complications, such as hyperkalaemia, in clinical practice compared to the trials. In 2016, following a coroners report, the MHRA issued a reminder to healthcare providers in Drug Safety Update (DSU) of the risk of hyperkalaemia and the need for frequent monitoring. The overall aim of the study is to evaluate the impact of the regulatory advice communicated by the MHRA on the co-prescription of aldosterone antagonists (spironolactone or eplerenone) and ACEI or ARB drugs. Using CPRD data we will assess the pattern of such co-prescriptions as well as adherence to the recommended blood monitoring over time (2014-2018) in all patients, aged 18 years and over, co-prescribed these drugs, and also specifically patients with heart failure.
We will conduct the analysis in a phased approach in which firstly we will perform a descriptive analysis to evaluate any patterns of co-prescribing. If the descriptive analysis shows notable differing trends before and after the MHRA reminder, then an interrupted time series (ITS) analysis will be conducted to assess the trend and level change. This will be a quasi-experimental design to examine prescribing trends and also adherence to blood monitoring for patients being co-prescribed aldosterone antagonists and ACEI/ARB before and after the regulatory advice. In addition, CPRD data will be linked to HES, as a sensitivity analysis, to assess whether a more complete ascertainment of patients with heart failure and hyperkalaemia can be ascertained from hospital records.
Primary outcomes:
Co-prescription of aldosterone antagonist and ACEI or ARB; Adherence to recommended blood monitoring guidelines for potassium and creatinine after co-prescription
Secondary outcomes: Hyperkalaemia (potassium > 6 mmol/L); Adherence to discontinuation guidelines in case of hyperkalaemia
Katherine Donegan - Chief Investigator - MHRA
Preeti Datta-Nemdharry - Corresponding Applicant - MHRA
Dervla Quinn - Collaborator - MHRA
Stephanie Dellicour - Collaborator - MHRA
HES Admitted Patient Care