The challenge

ACE inhibitors (ACE-I) and angiotensin receptor blockers (ARB) are medications that are commonly prescribed by GPs to treat high blood pressure, diabetes, heart problems or kidney disease. There have been some concerns that these medications might increase the risk of death for people who are infected with coronavirus (COVID-19). This is because ACEI and ARBs may work on the same pathway as COVID-19. However, this has never been studied in humans. Evidence is urgently needed to help decisions about the continued use of these medications in people infected with COVID-19.

Relevance

Globally, the total number of cases and mortality related to COVID-19 has been high amongst those with hypertension, cardiovascular disease, and type 2 diabetes. There have been some reports that ACE-I and ARBs are frequently prescribed in those with worse outcomes.

COVID-19 binds to target cells through angiotensin-converting enzyme 2 (ACE2) which is expressed by epithelial cells in the lungs, kidneys and blood vessels. ACE-I and ARBs are thought to increase the expression of ACE2. It is hypothesised that these medications, therefore, make people more susceptible to COVID-19 and could also increase the severity of the infection leading to ARDS and death.

This has caused some concern amongst prescribers and is leading to non-compliance amongst patients such that the British and Irish Hypertension Society, European Hypertension Society, Renal Association have released position statements calling for urgent evidence.

Given that 65 million prescriptions of ARB/ACE-I have been issued by GPs in the UK in the last year alone and the COVID-19 epidemic is close to reaching its peak, it is essential and timely that this hypothesis is tested.

Significance

This research will offer insights into the sociodemographic and clinical variables of people affected with the disease to inform the characteristics of at-risk groups for prediction modelling and planning of services. The specific question on ARB/ACE-I use and risk of death needs answering and the availability of large databases with measures of medication prescribing, COVID-19 testing and mortality is an opportunity to examine this. The results may provide provisional data about the credibility of existing concerns thus triggering appropriate larger scale follow-on work.

This project will also allow researchers to determine COVID-19 case definition and drug exposure status in a large primary care database. This has implications for how GPs code information during the pandemic and is an opportunity to examine likely feasibility and implications of the potential numbers and workload, if these drugs need changing. If there is no link between ARB/ACE-I and death, this research will still contribute to alleviating concern amongst patients.

The research

The research is based on a live GP surveillance database of ongoing and new cases to provide up to date knowledge on patterns of COVID-19 amongst five million patients. We will use an electronic database that includes 5 million routinely collected patient records across 530 GP practices. We will carry out statistical modelling to estimate the link, if any, between these medications and the risk of death from COVID-19. We will present descriptive epidemiology to characterise those infected who do and do not survive by sociodemographic and clinical variables, which is essential if we are to understand who in the population is at higher risk of death.

The current guidance is non-specific and suggests that all people over 70 years with multi-morbidity are at risk of COVID-19 complications but this accounts for at least 10 million people in the UK. A more detailed understanding of the characteristics of those infected with complications could allow GPs to identify high-risk individuals faster and thus lower clinical thresholds for concern. Public Health England has reported nearly 50 000 COVID-19 related deaths so far in the UK. We don’t know if ARB/ACE-I might contribute to these numbers so it is essential to generate rapid evidence to potentially save lives or reassure the public about the importance of maintaining compliance on existing medications.

Implications

The research will result in one of two outcomes

1. If an association between ACE-I/ARB use and all-cause mortality in COVID-19 positive patients is shown, this will indicate the urgent need for larger-scale studies. Continued use of these medications during the current pandemic will need to be reviewed to balance the risks and benefits with respect to a patient's underlying indications.
2. Alternatively, if there is no evidence of any association, patients and clinicians can be reassured that continued use is likely to be appropriate. Either outcome can have significant benefits to public health during this outbreak. Moreover, we intend to use this research to explore case-definition for COVID-19, coding of drugs within a large GP database and to generate estimates to inform a further NIHR bid.

Making a difference

Given that these medications are some of the most commonly prescribed in the UK, there needs to be some urgent clarity about their role. Our research could provide rapid provisional answers to help efforts aimed at reducing death from COVID-19 or deliver the reassurance that patients need to carry on taking their medications.

Websites

University of Southampton: https://www.southampton.ac.uk/medicine/academic_units/projects/ace-inhibitors.page

SPCR: https://www.spcr.nihr.ac.uk/projects/ace-inhibitors-angiotensin-receptor-blockers-and-risk-of-death-for-people-infected-with-covid-19-a-prospective-cohort-study

Funded by: National Institute for Health Research School for Primary Care Research (NIHR SPCR)