Renin-angiotensin-aldosterone system (RAAS) inhibitors are a class of drugs that have gained increasing popularity for treating high blood pressure, kidney diseases and heart problems. However, there are concerns of early worsening of kidney function or rises in potassium (hyperkalemia) due to the use of these drugs. Although consensus guidelines suggest stopping RAAS inhibitors in severe episodes of acute kidney injury and hyperkalemia, no study has been conducted to support this recommendation or confirm an appropriate threshold of acceptable change across the continuum of metrics of kidney function and potassium. This problem is potentially inflated because those with greatest risk of developing complications after starting RAAS inhibitors may also be those with greatest potential to benefit. This study makes use of a threshold rule postulated by a major clinical guideline in the UK in order to test the real-life effectiveness of RAAS inhibitors therapy for patients located near the threshold. Thanks to the large number of patients included in CPRD and the extensive time horizon during which these patients were observed, we are not only able to study the short- and long-run effects of RAAS inhibitors, but also the difference in effects across various groups of patients. Given the widespread use of RAAS inhibitors therapy, the results of this study have direct implications for clinical care.
Previous studies investigating the health effects of RAAS inhibitors therapy administered to patients are largely limited to controlled clinical trials. While these studies have pointed towards the efficacy of RAAS inhibitors therapy in improving key health outcomes, they might not be able to fully capture treatment effectiveness during routine care and frequently lack the necessary time horizon to study long-run benefits and risks. Non-experimental studies, in contrast, may fail to establish causality due to insufficient control of confounding factors. This study seeks to measure the effects of RAAS inhibitors therapy on short-, mid-, and long-term clinical outcomes (mortality, hospitalizations, major adverse cardiac and kidney events) and safety outcomes (recurrent hyperkalemia and acute kidney injury (AKI)) in a routine care set-up for patients who just started the RAAS inhibitors therapy. We will also measure the effects for different sample splits, including men and women of various age groups, with and without diabetes, with or without heart failure, ethnicity and from different socio-economic backgrounds. To establish causality, we make use of a regression discontinuity (RD) design taking advantage of a major UK clinical guideline, which recommends ceasing RAAS inhibitors therapy based on threshold rules related to patients’ serum potassium levels (as the use of RAAS inhibitors can also increase serum potassium and the risk of hyperkalemia). Because physicians base their treatment decisions on additional considerations besides clinical guidelines, we use an instrumental variable approach that is robust to partial compliance. We evaluate the robustness of results by gradually narrowing down the bandwidth around the treatment threshold and thus only including patients with serum potassium levels increasingly close to the treatment threshold level. The findings of this study are expected to provide novel insights into the effectiveness of RAAS inhibitors therapy in a real-life setting and can directly inform clinical practice.
Primary outcomes:
To be analysed after one year and five years from RAAS inhibitors cessation:
- frequency of all-cause emergency hospitalizations
- frequency of major adverse cardiovascular or kidney events (any of the following: heart failure, myocardial infarction event, stroke, dialysis, estimated GFR<15, or estimated GFR drop by 40% and more)
- frequency of adverse safety events (any of the following: recurrent hyperkalemia, AKI, or worsening of proteinuria
To be analysed after five years and ten years from RAAS inhibitors cessation:
- all-cause mortality
Secondary outcomes:
To be analysed after 3 months, one year and five years from RAAS inhibitors cessation:
- frequency of all-cause hospitalizations
- frequency of severe adverse health events (analyse of the following separately heart failure, myocardial infarction event, stroke, dialysis, estimated GFR<15, or estimated GFR drop by 40% and more, recurrent hyperkalemia, AKI, or worsening of proteinuria)
To be analysed after five years and ten years from RAAS inhibitors cessation:
- mortality of renal or cardiac cause
Till Bärnighausen - Chief Investigator - University of Heidelberg
Min Xie - Corresponding Applicant - University Hospital Heidelberg
Anant Jani - Collaborator - University of Surrey
Christian Bommer - Collaborator - University of Heidelberg
Julia Lemp - Collaborator - University of Heidelberg
Justine Davies - Collaborator - University of Birmingham
Pascal Geldsetzer - Collaborator - University of Heidelberg
Sebastian Vollmer - Collaborator - Georg-August-Universität Göttingen
Simon Sawhney - Collaborator - University of Aberdeen
2011 Rural-Urban Classification at LSOA level;HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation