A Meta-analysis of the Relationship Between Renin-Angiotensin-Aldosterone System Inhibitors and COVID-19.

The angiotensin converting enzyme (ACE) 2 is a cell surface protein used for entry into type II pneumocytes and other tissues by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the infective agent of COVID-19. It has been demonstrated that ACE2 is upregulated on tissues by renin-angiotensin-aldosterone system (RAAS) inhibitors. This raised concerns that RAAS inhibitors may increase susceptibility and worsen prognosis in COVID-19. In contrast, ACE2 facilitates degradation of angiotensin II and has an anti-inflammatory function and may actually protect the lungs and other tissues from injury. Thus, the effect of RAAS inhibitors on susceptibility and prognosis of COVID-19 continues to be the subject of much debate. Individual observational studies in the area have yielded equivocal results; hence, we sought to conduct a meta-analysis of all available data to provide greater insight.

For this study, PubMed and Scopus were searched in May 2020 using the following keywords and their MeSH terms: “COVID-19,” “hypertension,” “ACE inhibitors (ACEIs),” and “Angiotensin receptor blockers (ARBs).” Studies were included if they: they reported the risk of testing positive for COVID-19 and/or the risk of mortality in COVID-positive patients; and compared hypertensive patients prescribed RAAS inhibitors to those not using these drugs. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) from each study were pooled using a random-effects model. A p-value <0.05 was considered significant.

Our initial search yielded 950 potential studies. After exclusions, eight studies2, 3, 4, 5, 6, 7, 8, 9 with a total of 62,706 patients (n = 20,316 ACEI/ARB users and n = 42,390 nonusers) remained for analysis. Study and baseline characteristics are provided in Table 1 . Pooled analysis revealed no significant association between the likelihood of testing positive for COVID-19 and the use of ACEIs (OR 0.96 [0.88 to 1.04]; p = 0.29; I2 = 0%) (Figure 1 ) or ARBs (OR 0.99 [0.91 to 1.08]; p = 0.90; I2 = 5%) (Figure 1). Similarly, no significant difference was observed in mortality rate among hypertensive patients prescribed RAAS inhibitors compared with hypertensive patients not prescribed these medications (OR 0.74 [0.34 to 1.58]; p = 0.43; I2 = 65%) (Figure 1).

Table 1

Baseline and study characteristics

Study	Design	Country	Total patients	COVID-19 positive (%)	RAAS inhibitor group (Total, ACEi, ARB)	Non-RAAS inhibitor group (Total, non-ACEI, non-ARB)	Age	Male (%)	Adjustment
Studies reporting mortality
Meng et al.	Cross-sectional	China	42	-	17, -, -	25, -, -	64.5 (55.80 - 69.00)	57.1	-
Richardson et al.	Retrospective	USA	2411	-	-, 140, 194	2077, -, -	63 (52 - 75)	60.3	-
Yang et al.	Retrospective	China	126	-	43, -, -	83, -, -	66 (61 - 73)	49.2	-
Yudong et al.	Retrospective	China	112	-	22, -, -	90, -, -	62	-	-
Zhang et al.	Retrospective	China	1128	-	188, -, -	940, -, -	-	ACEIARB - 53.2	-
Studies reporting risk of testing positive for COVID-19
Mancia et al.	Case-control	Italy	37,031	16.9	15,375, 8071, 7304	21,656, -, -	68 ± 13	63	Multivariable adjustment for severity, sex, municipality, age at diagnosis, a number of treatment-related covariates and markers of patient clinical status
Mehta et al.	Cross-sectional	USA	18472	9.4	2285, 1322, 982	16187, 17150, 17490	ACEI - 63, ARB -64	ACEI - 49, ARB - 59	Propensity matched for age, sex, diabetes, coronary artery disease, hypertension, chronic obstructive pulmonary disease and heart failure
Reynolds et al.	Cross-sectional	USA	3384	46.8	1692, 954, 1057	1692, 954, 1057	ACEI - 64.7, ARB - 66	ACEI - 56, ARB - 50	Propensity matched for age; sex; race; ethnic group; body-mass index; smoking history; history of hypertension, myocardial infarction, heart failure, diabetes, chronic kidney disease, and obstructive lung disease (e.g., asthma and obstructive pulmonary diseases); and other classes of medication.

RAAS inhibitor = Renin-angiotensin-aldosterone system inhibitor; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker.

Figure 1

Forest plots displaying the odds of (A) testing positive for COVID-19 amongst patients using ACEI, compared to those not using ACEI; (B) testing positive for COVID-19 amongst patients using ARBs, compared to those not using ARBs; (C) mortality in COVID-19 patients using RAAS inhibitors, compared to those not using RAAS inhibitors.

The results of the current meta-analysis suggest that neither ACEI nor ARB use is significantly associated with the odds of testing positive with COVID-19. This result can be considered robust, as it was derived from 3 large-scale studies , , which adjusted for multiple potential confounding factors, including age, sex and co-morbidities. Our findings also show no significant association between RAAS inhibitor use and mortality in COVID-19 patients; however, this result must be viewed with caution as – due to the lack of data – we were unable to analyze ACEI users and ARB users separately, and adjusted data was reported by only one study. In this context, specific aspects of our analysis are notable. COVID-19 patients using RAAS inhibitors are older and have a higher burden of comorbidities, and this may have confounded our results. Adjustment for these factors could potentially shift the results in favor of RAAS inhibitors. Thus, our results support the consensus by multiple specialty societies, which recommend continued usage of RAAS inhibitors in COVID-19 patients and among the general public who have been prescribed these medications.

Disclosures

Javed Butler: is a consultant for Abbott, Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Relypsa, Vifor. Stephen J Greene: has received a Heart Failure Society of America/ Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; has received research support from Amgen, Bristol-Myers Squibb and Novartis; has served on advisory boards for Amgen and Cytokinetics; and serves as a consultant for Amgen and Merck. Richard A Krasuski: is a consultant and receives research funding from Actelion Pharmaceuticals. He is also an investigator for Edwards Lifesciences and is an unpaid member of the scientific advisory board for Ventripoint.