COVID-19 and drugs acting on the renin angiotensin system

Date of ISAC Approval: 
16/04/2020
Lay Summary: 
This research aims to inform patient management during the present COVID-19 coronavirus pandemic. The SARS-CoV-2 virus, which causes COVID19, mainly enters the body through lung cells. It interacts with a protein molecule called angiotensin-converting enzyme 2 (ACE2) receptor. The ACE2 molecule is part the renin-angiotensin system, which regulates body salt content and blood pressure. Drugs acting on the renin-angiotensin system, including angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI), are widely used in the treatment of high blood pressure and diabetes. This has raised concerns that these drugs might increase the risk of either patients getting COVID-19 or having worse outcomes if they have the infection. We are conducting two studies with COVID-19 patients to test these hypotheses. We have discussed the signals from these studies with the MHRA, which recommended we conduct a third study using CPRD data. In order to estimate whether ARBs or ACEIs are associated with the risk of COVID-19 infection, we will compare antihypertensive-treated COVID-19 patients with antihypertensive-treated controls of the same age and sex from the same general practice, to see if the cases are more likely to be treated with ARBs or ACEIs. In order to estimate whether ARBs or ACEIs may be associated with the course of the COVID-19 illness, we will follow-up all patients diagnosed with COVID-19 and determine whether they develop pneumonia, sepsis, or acute kidney injury or are admitted to hospital, or have a fatal outcome. We will compare the risks for patients according to ARB/ACEI treatment allowing for other differences including underlying health conditions. We know that a study like this has many limitations and it may not be possible to draw conclusions about causation.
Technical Summary: 
The SARS-CoV-2 virus, which causes COVID19, interacts with the angiotensin-converting enzyme 2 (ACE2) receptor. Drugs acting on the renin-angiotensin system, including angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI), are widely used in the treatment of high blood pressure and diabetes. This has raised concerns that these drugs might increase the risk of either patients acquiring COVID-19 or having worse outcomes when are infected. We are conducting two studies with data from hospital and community-based COVID-19 patients to test these hypotheses. We have discussed the signals from these studies with the MHRA, which recommended we conduct a third study using CPRD data. We will conduct a case-control study, nested within the cohort of CPRD patients who were ever prescribed antihypertensive drugs, to estimate whether ARBs or ACEIs are associated with higher odds of COVID-19 diagnosis. We will compare antihypertensive-treated COVID-19 patients with antihypertensive-treated controls matched for age, sex and general practice. The association with ARB/ACEI therapy will be evaluated using conditional logistic regression adjusting for confounders. We will conduct a cohort study of all patients diagnosed with COVID-19 to compare the incidence of pneumonia, sepsis, acute kidney injury or hospital admission, or mortality according to ACEI/ARB exposure. We will estimate hazard ratios using the proportional hazards model according to ARB/ACEI treatment allowing for confounding including age, comorbidity and co-prescribing. We are requesting access to linked HES data but we expect to report initial results using CPRD data only, because HES linkage takes time to complete. We acknowledge that the study has limitations because not all COVID-19 patients are recorded in general practice, with only a minority of the latter having confirmatory tests. Nevertheless, the results should be applicable to those with a clinical diagnosis.
Health Outcomes to be Measured: 
Clinical diagnoses of COVID-19. Record of pneumonia after COVID-19 record. Record of sepsis or shock after COVID-19 record. Record of acute kidney injury after COVID-19 record. Hospital admission with COVID-19. Mortality with COVID-19.
Collaborators: 

Martin Gulliford - Chief Investigator - King’s College London
Abdel Douiri - Collaborator - King’s College London
Ajay Shay - Collaborator - King’s College London
Charles Wolfe - Collaborator - King’s College London
Emma Rezel-Potts - Collaborator - King’s College London
Martin Gulliford - Corresponding Applicant - King’s College London
Phil Chowienczyk - Collaborator - King’s College London
Vasa Curcin - Collaborator - King’s College London

Linkages: 
Patient IMD;Practice IMD (Standard)