Relating angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers with incidence or mortality of COVID‐19

Abstract

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 ).

Table 1.

Studies that examined the association between use of ACEIs/ARB and the incidence and/or mortality of COVID‐19

Studies/publication date a	Patients	Intervention group (Anatomical Therapeutic Group code)	Comparator group	Outcomes	Findings
1. Fosbøl EL et al. (19 June 2020)	4480 COVID‐19 patients; 494 170 hypertensive patients	Filling of ACEI/ARB in a 6 month period prior to the index date based on C09: C09AA: ACEIs; C09CA: ARBs. C09BA: combinations of ACEIs and diuretics and C09DA: combinations of ARBs and diuretics	Non‐users of ACEI/ARB	(1) All‐cause death (2) A composite of death or severe COVID‐19 (3) Severe COVID‐19	No significant association between ACEI/ARB use and all outcomes
2. Mehta N et al. (05 May 2020)	18 472 patients tested for COVID‐19	Users of ACEI/ARB identified by validated automated feeds from electronic health records and manual review	Non‐users of ACEI/ARBs	(1) Positive laboratory test result for COVID‐19 (2) Hospital admission, admission to the ICU, and mechanical ventilation during index hospitalization among COVID‐19 patients	No significant association between ACEI/ARB use and increased likelihood of COVID‐19 test positivity; ACEI/ARB use associated with worse clinical outcomes
3. Reynolds HR et al. (01 May 2020)	12 594 patients who received COVID‐19 tests	Users of ACEI/ARB within the preceding 18 months where there was no evidence that the medication was discontinued for ≥1 month before the COVID‐19 test	Non‐users of ACEI/ARB, including patients on other antihypertensive drug classes	(1) Positive COVID‐19 test result (2) Severe COVID‐19 (admission to the intensive care unit, the use of invasive or non‐invasive mechanical ventilation, or death)	ACEI/ARB users not associated with a higher risk of COVID‐19; no substantially higher risk (by ≥10%) of severe COVID‐19
4. Zhang P et al. (17 April 2020)	128 adult patients with hypertension diagnosed with COVID‐19	In‐hospital use of ACEI/ARB	Non‐users of ACEI/ARB, including patients taking other antihypertensive medications	All‐cause mortality	Lower risk of COVID‐19 mortality in ACEI/ARB users than ACEI/ARB non‐users [adjusted hazard ratio, 0.37 (95% CI 0.12–0.70); P = 0.01]
5. Zeng Z et al. (Preprint; 11 April 2020)	274 patients, 75 with hypertension and 199 without hypertension	Previously taken ACEI/ARB drugs for antihypertensive treatment	Not previously taken ACEI/ARB drugs for antihypertensive treatment	Development of severe pneumonia after infection with SARS‐CoV‐2	No statistical significant difference in the outcome (P = 0.064) between ACEI/ARB users and non‐users
6. Liu Y et al. (Preprint; 12 May 2020)	511 COVID‐19 patients	Any users of ACEI/ARB	Patients taking no antihypertensive agents	The risk of COVID‐19‐S (severe disease)	Risk of COVID‐19‐S significantly decreased in ARB users (OR = 0.343, 95% CI 0.128–0.916, P = 0.025)
7. Yang G et al. (Preprint; 04 April 2020)	126 COVID‐19 patients with pre‐existing hypertension matched with 125 age‐matched and sex‐matched non‐hypertensive controls	Any users of ACEI/ARB	Patients using antihypertensive agents other than ACEI/ARB	Proportion of critical patients and rate of death due to COVID‐19	No significant association between ACEI/ARB use and both outcomes
8. Bean D et al. (02 June 2020)	1200 acute inpatients with COVID‐19	Any users of ACEI/ARB	Patients not using ACEI/ARBs	Death or transfer to a critical care unit for organ support within 21 days of symptom onset	Adjusted odds ratio for ACEI/ARB users for the outcome: 0.63 (CI 0.47–0.84, P < 0.01)

The inclusion of these studies in the table made reference to a meta‐analysis that searched the literature up to 25 April 2020: Ghosal S, Mukherjee JJ, Sinha B, Gangopadhyay KK. ‘The effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on death and severity of disease in patients with coronavirus disease 2019 (COVID‐19): a meta‐analysis’. medRxiv 2020. doi: https://doi.org/10.1101/2020.04.23.20076661. ACEIs, angiotensin‐converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CI, confidence interval; OR, odds ratio.

^aReferences: (1) Fosbøl EL, Butt JH, Østergaard L, et al. ‘Association of angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker use with COVID‐19 diagnosis and mortality’. JAMA. Published online June 19, 2020. doi:10.1001/jama.2020.11301; (2) Mehta N, Kalra A, Nowacki AS, et al. ‘Association of use of angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID‐19)’. JAMA Cardiology 2020 May 5, 2020. doi:10.1001/jamacardio.2020.1855; (3) Reynolds HR, Adhikari S, Pulgarin C, et al. ‘Renin‐angiotensin‐aldosterone system inhibitors and risk of COVID‐19’. N Engl J Med. Published online May 1, 2020. doi:10.1056/NEJMoa2008975; (4) Zhang P, Zhu L, Cai J, et al. ‘Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID‐19’. Circ Res 2020;Apr 17:[Epub ahead of print]; (5) Zeng Z, Sha T, Zhang Y, et al. ‘Hypertension in patients hospitalized with COVID‐19 in Wuhan, China: a single‐center retrospective observational study’. MedRxiv. doi: https://doi.org/10.1101/2020.04.06.20054825; (6) Liu Y, Huang F, Xu J, et al. ‘Anti‐hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID‐19 patients’. medRxiv. 2020:2020.2003.2020.20039586; (7) Yang G, Tan Z, Zhou L, et al. ‘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’. medRxiv. 2020:2020.2003.2031.20038935; (8) Bean D, Kraljevic Z, Searle T, et al. ‘ACE‐inhibitors and angiotensin‐2 receptor blockers are not associated with severe SARS‐COVID19 infection in a multi‐site UK acute Hospital Trust’. Eur J Heart Fail 2020. doi: https://doi.org/10.1002/ejhf.1924.

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 on this important research topic and provided preliminary data for subsequent evaluations. Furthermore, their findings are corroborated by two retrospective studies that used US databases, ⁶ , ⁷ showing the absence of significant difference between ACEI/ARB use and COVID‐19 test positivity. These include a recent study that used data from the Cleveland Clinic Health System in Ohio and Florida, ⁶ where a significant association between use of ACEI and/or ARB and COVID‐19 test positivity was absent among 18 472 patients tested for COVID‐19 [overlap propensity score–weighted odds ratio, 0.97; 95% confidence interval (CI) 0.81–1.15]—although ACEI/ARB use was associated with worse clinical outcomes in terms of hospitalization and admission to the intensive care unit. Also, a study using the New York University (NYU) Langone Health electronic health record involving 12 594 individuals tested for COVID‐19 was compared with respect to their medication history. ⁷ No significant association between ACEI/ARB use and development of COVID‐19 and severe COVID‐19, respectively, was reported.

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‐19‐related 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.

Conflict of interest

None declared.

Wong, M. C. S. , Wong, S. , Huang, J. , and Yan, B. (2020) Relating angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers with incidence or mortality of COVID‐19. ESC Heart Failure, 7: 3119–3123. 10.1002/ehf2.12952.