Interruption of Renin-Angiotensin-Aldosterone System Inhibition Treatment and Associations with Adverse Outcomes

Application Number
17_022
Lay Summary

AstraZeneca is developing a new drug to treat hyperkalemia (HPK), which happens when there is too much potassium in the blood. A class of drugs called renin-angiotensin-aldosterone system inhibitors (RAASi) is used to treat hypertension, heart failure, and chronic kidney disease, and these drugs have been shown to be associated with HPK. Overall, this study will help understand RAASi use in people in England, including patterns of use and frequency of HPK in people who receive RAASi therapy. An important goal of this study is to describe patterns of RAASi use, including how often and why patients change their dose of RAASi treatment or stop taking RAASi treatment. Further, this study will examine consequences of changes to RAASi treament, such as how often poor clinical outcomes occur in patients who change or stop RAASi treatment.

Technical Summary

The overall goal of this study is to provide a population-based descriptive analysis of patients receiving RAASi treatment in the UK, with a specific goal of understanding the implications of treatment interruption. RAASi therapy can increase the risk of hyperkalemia, and physicians may decide to reduce the dose or discontinue RAASi therapy following hyperkalemia. The frequency of dose changes and drug discontinuations is not well understood; nor are the subsequent implications in terms of potentially higher event rates. This study will utilize the Clinical Practice Research Datalink (CPRD) database linked to the Hospital Episodes Statistics (HES) database. We will also be requesting ONS Mortality linkage to confirm date of death. The cohort to be studied is patients on RAASi therapy, and we will examine treatment patterns, clinical event rates, factors associated with treatment interruptions, and subsequent events following RAASi treatment interruptions. Event rates and 95% CIs for pre-specified outcomes of interest will be reported. RAASi treatment patterns will be examined using proportion of days covered, interruptions, cessations, and dose changes. A Cox proportional hazards model will be used to examine factors associated with interruption/cessation. Cox models will also be used to examine associations between interruptions/cessations and clinical events of interest.

Health Outcomes to be Measured

Hyperkalemia; Heart failure hospitalizations; Acute kidney injury; All-cause mortality; Cardiac arrhythmia; Worsening CKD; All-cause hospitalizations; Cardiac arrest; Initiation of dialysis.

Collaborators

David Gilbertson - Chief Investigator - CDRG
David Gilbertson - Corresponding Applicant - CDRG
Akhtar Ashfaq - Collaborator - Astra Zeneca Inc - USA
Heng Yan - Collaborator - CDRG
James Wetmore - Collaborator - CDRG
Jiannong Liu - Collaborator - CDRG
Laura Horne - Collaborator - Astra Zeneca Inc - USA
Robert LoCasale - Collaborator - Astra Zeneca Inc - USA
Sharon MacLachlan - Collaborator - Evidera, Inc
Tanya Natwick - Collaborator - CDRG
Xinyue Wang - Collaborator - CDRG
Yi Peng - Collaborator - CDRG

Linkages

ONS Death Registration Data