Does the use of ACEis or ARBs increase the risk of death in those with COVID-19?

A recent study of the clinical characteristics of patients who died with COVID-19 showed that the most prevalent comorbidity was hypertension.1

In addition, several reports have indicated that there is a theoretical increased risk of worse outcomes in patients with hypertension prescribed angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) if they become infected with COVID-19.2,3

Under normal circumstances, angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, which is a potent vasoconstrictor and this effect is blocked by ACEis whereas, ARBs, block the action of angiotensin II. Studies have shown that a related form of ACE, angiotensin converting enzyme 2 (ACE2) acts to oppose the actions of ACE by breaking down angiotensin II. ACE2 is present in several different tissues in the body and appears to have a protective role, improving the symptoms of acute lung injury that result from viral infection.4

In 2005 researchers discovered that the severe acute respiratory syndrome (SARS) virus, which is related to COVID-19, utilised ACE2 on alveolar epithelial cell membranes, to gain entry to cells and subsequently replicate and that SARS also downregulated ACE2.5 The recent concerns over ACEis and ARBs have arisen out of work which showed that intravenous infusion of both types of antihypertensive, lead to an increase the amount of ACE,2,6 raising the possibility that patients prescribed either of these types of drugs could experience worse outcomes if infected with COVID-19.

In an effort to address these potential concerns, a recent retrospective analysis published in JAMA Cardiology has observed that these theoretical risks in those prescribed either ACEi or ARBs are unfounded.7 The study reviewed 1178 patients hospitalised with COVID-19 infection, of which, 362 (30.7%) were prescribed antihypertensives. In total, 189 (52.2%) of these patients were prescribed either an ACEi or ARBs. Compared to those not taking an ACEi/ARB, there were no differences in the laboratory profiles, apart from a higher alkaline phosphatase level in those NOT taking ACEi/ARBs. When the authors compared both disease severity and survival, there were no significant differences between patients taking either ACEi or ARBs and those not prescribed these drugs. For example, in terms of survival, the composite of ACEi/ARBs versus those without these drugs, was 27.3% vs 33.0%, p = 0.34. The authors also explored whether there were differences in outcomes based on comorbidities between those taking ACEi/ARBs and those without and again found no difference. They concluded that it was hypertension per se which remains an important factor increasing the risk of mortality rather than the type of antihypertensive used.

In light of the reported risks in the media from taking either ACEi or ARBs, the European Society of Cardiology released a statement on 13 March, prior to the most recent publication, stating that there is a lack of evidence supporting harmful effect from ACEi or ARBs in the context of the pandemic COVID-19 outbreak.8 Finally, a report from the UK found that of 205 patients with COVID-19, 53 died. While based on a small sample size, the authors found that for patients receiving ACEi, there was a lower risk of death.9

In summary, it seems that the theoretical risk that treatment with either an ACEi or ARB by increasing ACE2, could potentially worsen infection with COVID-19, the available evidence does not support this risk. Patients should be advised to continue with their treatment unless otherwise advised by their doctor.

References

1. Xie J, Tong Z, Guan X. Clinical characteristics of patients who died with coronavirus disease 2019 in China. JAMA Netw Open 2020; 3(4):e205619.
2. Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med 2020; Mar 18 [Online ahead of print]
3. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020 Apr 8(4):e21.
4. Oudit GY et al. The role of ACE2 in pulmonary diseases – relevance for the nephrologist. Nephrol Dial Transplant 2009;24:1362-5.
5. 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;11(8): 875-9.
6. Ferrario CM et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111(20)2605–10.
7. Li J et al. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalised for coronavirus disease 2019 infection in Wuhan, China. JAMA Cardiol 2020; Apr 23 [online ahead of print]
8. European Society of Cardiology. Position statement of the ESC Council on hypertension on ACE-inhibitors and angiotensin receptor blockers. www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang (accessed April 2020).
9. Bean DM T et al. Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute Hospital Trust. Medrxiv. www.medrxiv.org/content/10.1101/2020.04.07.20056788v1.full.pdf (accessed April 2020).