key: cord-0826593-gatzbmnm
authors: Wong, Martin C.S.; Wong, Sunny; Huang, Junjie; Yan, Bryan
title: Relating angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers with incidence or mortality of COVID‐19
date: 2020-07-28
journal: ESC Heart Fail
DOI: 10.1002/ehf2.12952
sha: d5a735a12422876cb6727ed057003ac63573e8b6
doc_id: 826593
cord_uid: gatzbmnm

The present Perspective examined the latest evidence on the association between the use of angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and the incidence/mortality of coronavirus disease 2019 (COVID‐19). Our critical appraisal from existing literature does not support discontinuation of ACEIs/ARBs in clinical practice as there is absence of solid evidence. However, we do recommend future research perspective in formulation and implementation of practice‐changing guidelines.

The coronavirus disease 2019 (COVID-19) pandemic has affected 216 countries or regions, inducing a substantial burden on health care services. Because the disease is highly infectious with human-to-human transmission, patients with chronic diseases such as hypertension, heart failure, and nephropathy are at higher risk of developing COVID-19. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are often used to treat these medical conditions. It has previously been demonstrated that SARS-CoV-2 harnesses angiotensin-converting enzyme (ACE) 2 as a viral receptor to gain access into alveolar and enteric epithelial cells; moreover, the receptor may convert angiotensin 2 (AT2) into the vasodilator and antitrophic heptapeptide (Ang-(1-7)). 1 There have been concerns where the use of ACEIs or ARBs may increase expression of the co-receptor ACE2 and hence the susceptibility of the viral host propagation and viral host cell entry. This has been reported in animal models where increased expression of ACE2 and presentation at the cell surface were observed after treatment of these pharmacotherapies, although a recent study did not observe such change in human tissues. 2 On the other hand, the renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of acute lung injury caused by ventilator-induced injury, acute pancreatitis, lipopolysaccharides, and sepsis. ACEIs/ARBs have been demonstrated to be effective in ameliorating lung injury. 3 The Position Statement of the Council on Hypertension of the European Society of Cardiology (ESC) strongly recommended that treatment with their usual antihypertensive therapy should be continued, because no clinical or scientific evidence suggested that ACEIs or ARB pharmacotherapy should be discontinued due to COVID-19 infection. 4 Whilst we agree with this recommendation, an appraisal of evidence on the association between ACEI/ARB use and the incidence/mortality of COVID-19 will inform future clinical practice and guideline formulation. We aim to review what has been published thus far on this research topic, making reference to a recent meta-analysis (see footnote of Table 1 ).

The largest-scale study was performed by Fosbøl and colleagues, 5 which is a retrospective cohort study of 4480 COVID-19 patients and a nested case-control study of 494 170 hypertensive patients using the Danish national administrative registries. In the two sub-studies, they found that the use of ACEIs or ARBs was not significantly associated with COVID-19 mortality and diagnosis, respectively. Undoubtedly, their work has laid down a solid foundation for future studies Nevertheless, we wish to supplement several considerations regarding data interpretation of the Danish study, which is the largest in scale. Firstly, the retrospective cohort study has not controlled for indication bias, such as the use of propensity score matching, 7 making comparison of the two groups (ACEI/ARB users vs. non-users) on COVID-19related outcomes challenging. Also, the median age of the ACEI/ARB users was significantly older than that of the non-users (72.8 vs. 50.1 years). The former group was reported to have lower socio-economic status and more concomitant co-morbidities/chronic medications. A single multivariate regression analysis might not be sufficient as the two groups are relatively distinct. The criteria adopted by the Centres for Disease Control and Prevention (CDC) for 'high risk of COVID-19' include patients older than 65 years, residence in nursing home or long-term care facilities, severe obesity, and a number of immunocompromised conditions. 8 There has been no adjustment for several potential confounders, including smoking, bone marrow and organ transplant, chronic liver disease, body mass index, poorly controlled immune deficiencies, and prolonged use of corticosteroids. Besides, the absolute mortality rate (20.2% vs. 8.3%), composite endpoint of mortality or severe COVID-19 (32.6% vs. 14.7%), and severe COVID-19 (22.6% vs. 10.4%) in the ACEI/ARB users were all substantially higher than that of non-users by more than 10%. The study by Reynold and colleagues considered 'substantial difference' between groups when the upper boundary of the 95% CI is higher than 10%. 7 Also, another retrospective, multi-centre study of 1128 adult hypertensive patients with COVID-19 in Hubei, China, 9 showed that in-hospital use of ACEI or ARB was significantly associated with lower odds of all-cause mortality when compared with ACEI/ARB non-users. The mixed effect Cox proportional hazard model adjusting for propensity score showed that patients on ACEI/ARB had lower adjusted hazard ratio of 0.37 (95% CI 0.12-0.70, P = 0.01) in terms of all-cause mortality when compared with non-users. The findings remained consistently significant in additional sensitivity analyses using various matching variables. We listed further studies that were performed on the same research topic in Table  1 , [10] [11] [12] [13] and unfortunately, the findings were inconsistent. The topic of continuing these two antihypertensive drug classes in patients with heart failure was complicated further-whilst ACEIs could potentially be a risk factor for COVID-19 due to up-regulation of the ACE2 receptor, there is also translational evidence that the inhibition of the RAAS could exert a protective effect on the cardiovascular system. Another example is the possible shift of the RAAS system from an ACEI/ATII signalling pathway to the ACE2/angiotensin 1-7 route that could exert a protective impact on lung tissues. On the other hand, the absence of a causative linkage between ACEI/ARB use and COVID-19 infection does not necessarily mean 'status quo', especially when clinicians could easily provide an alternative antihypertensive agent without compromising control of blood pressure or heart failure, given the entry risk map of how SARS-CoV-2 enters the human cells. 14 Indeed, data from the Italian Health Institute on 3200 deaths due to COVID-19 in Italy showed that up to 52% of these patients were ACEI/ARB users. 15 Therefore, current evidence is relatively scanty and conflicting to support a definitive conclusion on the effect of ACEIs/ARBs on patients' vulnerability to COVID-19. A prospective study recruiting patients taking ACEIs/ARBs will be required to examine the association between their use and COVID-19 infection, preferably with a randomized controlled design. Addressing this clinical question will be crucial as the findings may inform prescription practices for patients with various indications for ACEIs or ARBs. Before we propose practice-changing recommendations on the use of ACEI/ARB, we believe future studies should consider additional issues, such as the impact of drug dosage, time period of medication exposure, adequacy of follow-up duration to observe for COVID-19 and its related outcomes, and meticulous confounder control. The Heart Failure Society of America, the American College of Cardiology, and the American Heart Association have recently issued a joint statement calling for urgent research into this topic. Apart from testing for COVID-19, the outcome measures may also include immunoglobulin G against SARS-CoV-2 RNA, as it might provide a more accurate estimate and tends to persist for a longer period of time after viral infection clearance.

Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19'

Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors usage is associated with improved inflammatory status and clinical outcomes in COVID-19 patients with hypertension

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

SARS-CoV-2 receptor ACE2 gene expression and RAAS inhibitors

Angiotensin converting enzyme inhibitors and angiotensin receptors blockers and outcome of COVID-19: a systematic review and metaanalysis. medRxiv preprint

Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers

Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality

Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19)

Renin-angiotensin-aldosterone system inhibitors and risk of COVID-19

Centers for Disease Control and Prevention. People of any age with underlying medical conditions

Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19

Hypertension in patients hospitalized with COVID-19 in Wuhan, China: a single-center retrospective observational study

Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients

Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors usage is associated with improved inflammatory status and clinical outcomes in COVID-19 patients with hypertension

ACE-inhibitors and angiotensin-2 receptor blockers are not associated with severe SARS-COVID19 infection in a multi-site UK acute Hospital Trust

Switching to another antihypertensive effective drug when using ACEIs/ARBs to treat arterial hypertension during COVID-19

COVID-19 Surveillance Group. Characteristics of COVID-19 patients dying in Italy Report based on available data on

Relating ACEIs or ARBs with incidence or mortality of COVID-19