15th March 2020
Are ACEI/ARB drugs causally associated with risk of mortality in COVID-19?
Early evidence from case series of patients with severe COVID-19 suggests that hypertension is a risk factor for an increased risk of severe outcomes during COVID-19 infection [1-5]. However, most series did not adjust for multiple confounders (such as indication for drug use) and where this was done, hypertension was not associated with increased risk . There is evidence that the renin-angiotensin system is important in coronavirus infection since the virus gains entry to cells by utilizing ACE2 . However, there is conflicting evidence from basic science studies about the likely effect that modulation of the renin-angiotensin system would have on infection and ACEI/ARB drugs have been suggested to be both beneficial and harmful [7-8].
Lessons from the association of AKI with ACEI/ARB
The current situation is analogous to the discussion about whether ACEI/ARB cause AKI. Clinicians see AKI in patients admitted to hospital taking ACEI/ARB very frequently and often infer a causal association. Reasoning based on physiology and basic science shows very plausible reasons why the drugs may both cause  and protect from  AKI. Observational studies conducted in hospitals or ITUs often demonstrate that ACEI/ARB use is a risk factor for AKI . However, large observational cohorts based in primary care, comparing patients taking ACEI/ARBs to carefully matched comparator patients suggest that there is no or very minimal increased risk of AKI associated with the drugs [12-14]. Indeed, these studies suggest that the risk is predominantly driven by the underlying conditions for which patients are prescribed the drugs, suggesting that many of the studies conducted in hospital settings are driven by ‘confounding by indication’.
Potential for adverse outcomes
The widespread discussion of this issue in the media is likely to lead to high concern about risk associated with ACEI/ARB drugs and many may stop them. The renal and cardiology communities have recently developed consensus guidance about the use of ACEI/ARB drugs in patients with heart failure with reduced ejection fraction (HFrEF) who are acutely unwell , motivated by concern that these drugs were being inappropriately stopped. Decompensation in HFrEF with pulmonary oedema could make diagnosis and management of severe COVID-19 more difficult. Previous advice from ‘Think Kidneys’ has counselled against generalised patient-led drug cessation (‘sick day guidance’) due to the conflicting evidence base, with concern that it is misunderstood by patients [16-17]. Clear guidance exists for when clinicians faced with an unwell patient should consider ACEI/ARB cessation (Figure 1) [15,18].
This advice is consistent with the current opinions issued by the European Society of Cardiology and the European Society of Hypertension [19,20].
Figure 1. Suggested management of patients with AKI or worsening renal function who are receiving ACEI/ARB medications (from ref 15)
Position statement for patients
Recent media reports that ACE Inhibitor drugs (‘pril’ drugs) and Angiotensin receptor blockers (‘sartan’ drugs) may increase the risk of death from novel corona virus (COVID-19) infection will provoke anxiety for many people with kidney disease and leave them uncertain about the best action to take.
Patients are prescribed these medications for a number of reasons and for some people, particularly those with heart failure, stopping the drugs suddenly can lead them to become unwell. This can cause people to become more breathless and may create uncertainty about whether symptoms are due to infection (such as COVID-19), or to underlying health problems.
The evidence that these medications increase the risk of death is unconvincing: the reports may simply reflect the fact that people taking the drugs are more likely to have conditions that place them at high risk of severe COVID-19 infection.
We therefore advise people taking these medications to continue to take them. If they become unwell such that they need to seek medical help, the doctor may advise stopping the drugs depending on their clinical condition.
We are continuing to review the evidence as it comes in and will update this advice as needed.
- Guan WJ, Ni ZY, Hu Y, et al. China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28. doi: 10.1056/NEJMoa2002032. PMID: 32109013.
- Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Feb 7:e201585. doi: 10.1001/jama.2020.1585. PMID: 32031570
- Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb. 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Erratum in: Lancet. 2020 Jan 30: PMID: 31986264.
- Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Mar 13. doi: 10.1001/jamainternmed.2020.0994. PMID: 32167524.
- Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study et al. Lancet. 2020 March 11. DOI:https://doi.org/10.1016/S0140-6736(20)30566-3
- Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-9. doi: 10.1038/nm1267. PMID: 16007097.
- Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020 Epub: March 11, 2020 https://doi.org/10.1016/PII
- Online responses to ‘Response to the emerging novel coronavirus outbreak’ : examples at: https://www.bmj.com/content/368/bmj.m406/rr-11 and https://www.bmj.com/content/368/bmj.m406/rr-19 Accessed 14/3/2020
- Perazella MA, Coca SG. Three feasible strategies to minimize kidney injury in ‘incipient AKI’. Nat Rev Nephrol. 2013 Aug;9(8):484-90. doi: 10.1038/nrneph.2013.80. PMID: 23649020.
- Pannu N, Nadim MK. An overview of drug-induced acute kidney injury. Crit Care Med. 2008 Apr;36(4 Suppl):S216-23. doi: 10.1097/CCM.0b013e318168e375. PMID: 18382197.
- Chaumont M, Pourcelet A, van Nuffelen M, et al. Acute Kidney Injury in Elderly Patients With Chronic Kidney Disease: Do Angiotensin-Converting Enzyme Inhibitors Carry a Risk? J Clin Hypertens. 2016 Jun;18(6):514-21. doi: 10.1111/jch.12795. PMID: 27080620.
- Bedford M, Farmer CK, Irving J, Stevens PE. Acute kidney injury: an acceptable risk of treatment with renin-angiotensin system blockade in primary care? Can J Kidney Health Dis. 2015 Apr 9;2:14. doi: 10.1186/s40697-015-0044-y. PMID: 25926996
- Mansfield KE, Nitsch D, Smeeth L, Bhaskaran K, Tomlinson LA. Prescription of renin-angiotensin system blockers and risk of acute kidney injury: a population- based cohort study. BMJ Open. 2016 Dec 21;6(12):e012690. doi:10.1136/bmjopen-2016-012690. PMID: 28003286
- Scott J, Jones T, Redaniel MT, et al. Estimating the risk of acute kidney injury associated with use of diuretics and renin angiotensin aldosterone system inhibitors: A population based cohort study using the clinical practice research datalink. BMC Nephrol. 2019 Dec 30;20(1):481. doi: 10.1186/s12882-019-1633-2. PMID: 31888533
- Clark AL, Kalra PR, Petrie MC, Mark PB, Tomlinson LA, Tomson CR. Change in renal function associated with drug treatment in heart failure: national guidance. Heart. 2019 Jun;105(12):904-910. doi: 10.1136/heartjnl-2018-314158. PMID: 31118203
- Think Kidneys position statement on ‘Sick Day Guidance’ available at: https://www.thinkkidneys.nhs.uk/aki/wp-content/uploads/sites/2/2018/01/Think-Kidneys-Sick-Day-Guidance-2018.pdf Accessed 14/3/2020
- Doerfler RM, Diamantidis CJ, Wagner LA, et al. Usability Testing of a Sick-Day Protocol in CKD. Clin J Am Soc Nephrol. 2019 Apr 5;14(4):583-585. doi: 10.2215/CJN.13221118. PMID: 30867156;
- Think Kidneys guidance on ‘Changes in kidney function and serum potassium during ACEI/ARB/diuretic treatment in primary care’ available at: https://www.thinkkidneys.nhs.uk/aki/wp-content/uploads/sites/2/2017/10/Changes-in-Kidney-Function-FINAL.pdf Accessed 14/3/2020
- Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers, available at: https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang Accessed 14/3/2020
- Statement of the European Society of Hypertension on hypertension, Renin Angiotensin System blockers and COVID-19, available at: https://www.eshonline.org/spotlights/esh-statement-on-covid-19/ Accessed 14/3/2020