Renin-Angiotensin-Aldosterone System Inhibitors in COVID-19: A Review

Ferrari, Filipe; Martins, Vítor Magnus; Fuchs, Flávio Danni; Stein, Ricardo

doi:10.6061/clinics/2021/e2342

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REVIEW ARTICLE • Clinics 76 • 2021 • https://doi.org/10.6061/clinics/2021/e2342 copy

Renin-Angiotensin-Aldosterone System Inhibitors in COVID-19: A Review

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Among the multiple uncertainties surrounding the novel coronavirus disease (COVID-19) pandemic, a research letter published in The Lancet implicated drugs that antagonize the renin-angiotensin-aldosterone system (RAAS) in an unfavorable prognosis of COVID-19. This report prompted investigations to identify mechanisms by which blocking angiotensin-converting enzyme 2 (ACE2) could lead to serious consequences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The possible association between RAAS inhibitors use and unfavorable prognosis in this disease may have been biased by the presence of underlying cardiovascular diseases. As the number of COVID-19 cases has increased worldwide, it has now become possible to investigate the association between RAAS inhibitors and unfavorable prognosis in larger cohorts. Observational studies and one randomized clinical trial failed to identify any consistent association between the use of these drugs and unfavorable prognosis in COVID-19. In view of the accumulated clinical evidence, several scientific societies recommend that treatment with RAAS inhibitors should not be discontinued in patients diagnosed with COVID-19 (unless contraindicated). This recommendation should be followed by clinicians and patients.

Pandemic; Infection; SARS-CoV-2; Hypertension; Heart Failure

Study	Country	Patients	Mean age (y)	% Male	% Hypertension	% Chronic cardiac disease	% Cerebrovascular disease
Arentz et al. (68)	United States	Critically ill (N=21)	70	52	NA	43	NA
Bean et al. (31)	United Kingdom	All (N=1,200)	68	57	54	22	NA
Borba et al. (79)	Brazil	All (N=81)	51	75	46	9	NA
Cao et al. (49)	China	Critically ill (N=199)	58 (49-68)^* * Median age (interquartile range).	60	NA	NA	7
Chen et al. (51)	China	All (N=99)	55	68	NA	20	20
Chen et al. (50)	China	Dead (N=38)	70 (65-81)^* * Median age (interquartile range).	71	40	11	8
Docherty et al. (82)	United Kingdom	All ( N=20,133)	73 (58-82)^* * Median age (interquartile range).	60	NA	31	NA
Geleris et al. (69)	United States	All (N=1,376)	NA	57	32	NA	NA
Goldman et al. (81)	Multicenter	All (N=397)	NA	64	50	NA	NA
Goyal et al. (70)	United States	All (N=393)	62	61	50	14	NA
Grasseli et al. (76)	Italy	Critically ill (N=1,591)	63	82	49	21	NA
Grein et al. (80)	Multicenter	Critically ill (N=53)	68 (48-71)^* * Median age (interquartile range).	75	25	NA	NA
Guan et al. (47)	China	All (N=1,099)	47	58	15	3	1
Guo et al. (52)	China	All (N=187)	59	49	33	11	NA
Hou et al. (53)	China	All (N=101)	51	44	21	11	3
Huang et al. (54)	China	All (N=41)	49	73	15	15	NA
Itelman et al. (77)	Israel	All (N=162)	52	65	30	7	NA
Ji et al. (55)	China	All (N=101)	51	48	20	7	7
Li et al. (56)	China	Dead (N=25)	73	40	64	32	16
Li et al. (57)	China	All (N=103)	70 (62-78)^* * Median age (interquartile range).	58	54	25	17
Liang et al. (58)	China	Critically ill (N=131) Noncritically ill (N=1,459)	62 48	NA NA	41 15	10 3	8 1
Mao et al. (59)	China	All (N=214)	53	41	24	7	7
Mercuro et al. (71)	United States	All ( N=90)	60	51	53	21	NA
Mi et al. (60)	China	(All=10)	68	20	4	NA	NA
Myers et al. (72)	United States	All (N =377)	61 (50-73)^* * Median age (interquartile range).	56	44	6	NA
Nahum et al. (78)	France	Critically ill (N=34)	62	78	38	9	NA
Price-Haywood et al. (73)	United States	All (N=3,481)	54	40	31	8	NA
Richardson et al. (74)	United States	All (N=5,700)	63	60	57	18	NA
Shi et al. (61)	China	All (N=416)	64	49	31	15	5
Singh & Khan (75)	United States	All (N=2,530)	52	38	40	9	NA
Sun et al. (62)	China	Discharged (N=123) Dead (N=121)	67 (64-72)^* * Median age (interquartile range). 72 (66-78)^* * Median age (interquartile range).	42 68	50 63	12 17	NA NA
Xie et al. (63)	China	Dead (N=168)	70 (64-78)^* * Median age (interquartile range).	NA	50	23	4
Yang et al. (64)	China	Critically ill (N=52)	59.7	67	NA	10	13.5
Yu et al. (65)	China	All (N=421)	47	53	17	3	1
Wang et al. (46)	China	All (N=138)	56	54	31	15	5
Wu et al. (66)	China	All (N=201)	51 (43-60)^* * Median age (interquartile range).	64	19	4	NA
Zhang et al. (67)	China	All (N=140)	57	51	30	5	2.1

Study	Country	Design	Participants (N)	Men / Women (N)	Comparison	Endpoint	Results
Adrish et al. (12)	United States	Observational	469	279 / 190	ACEi / ARB vs. non-ACEi / ARB	Survival time from admission to disposition	ACEi / ABR: ↑15 days (95% CI, 11-17) vs. 12 days (95% CI, 11-13); p=0.0062.
Bae et al. (15)	South Korea	Observational	610	230 / 280	ACEi / ARB vs. other drug	Risk of mortality	No differenceOR 1.00; 95% CI, 0.46 to 2.16).
Bean et al. (32)	United Kindgom	Observational	1,200	686 / 514	ACEi / ARB vs. non-ACEi / ARB	Death or transfer to a ICU for organ support within 21-days of symptom onset	ACEi / ABR: ↓Adjusted OR 0.63; 95% CI, 0.47 to 0.84; p<0.01^† † After adjustment for age, sex, and comorbidities .
Bravi et al. (33)	Italy	Retrospective case-control	1,603	758 / 844	ACEi / ARBs vs. non- ACEi / ARBs	Very severe/lethal COVID-19	ACEi or ABR: No differenceOR 0.87; 95% CI, 0.50 to 1.49; p=0.6.ACEi: No differenceOR 0.82; 95% CI, 0.49 to 1.36; p=0.4.ARB: No differenceOR 0.83; 95% CI, 0.50 to 1.40; p=0.5.
Cannata et al. (34)	Italy	Observational	397	NA	ACEi/ARB discontinuation vs. no therapyACEi/ARB continuation vs. discontinuationACEi/ARB continuation vs. no therapyACEi/ARB continuation vs. discontinuation / no therapy	All-cause mortality	ACEi/ARB discontinuation vs. no therapy: No differenceAdjusted OR 1.11; 95% CI, 0.36 to 3.45.ACEi/ARB continuation vs. discontinuation: No differenceAdjusted OR 0.17; 95% CI, 0.03 to 1.00.ACEi/ARB continuation vs. no therapy: ↓Adjusted OR 0.05; 95% CI, 0.01 to 0.54.ACEi/ARB continuation vs. discontinuation / no therapy: ↓Adjusted OR 0.14; 95% CI, 0.03 to 0.66.
Conversano et al. (7)	Italy	Observational	191	131 / 60	ACEi / ARB vs. non-ACEi / ARB	All-cause mortality	No differenceHR 0.50 (95% CI, 0.20 to 1.20; p=0.13).
Covino et al. (8)	Italy	Observational	166	109 / 57	ACEi / ARB vs. non-ACEi / ARB	Death, and combined of death/admission to ICU	No differenceDeath: 18% vs. 16.3%; p=0.79.Combined of death/admission to ICU: 34.2% vs. 23.6%; p=0.16.
de Abajo et al. (35)	Spain	Observational	12,529	7,645 / 4,884	ACEi / ARB vs. other antihypertensive drugs	COVID-19 requiring admission to hospital	ACEi: No differenceAdjusted OR 0.80; 95% CI, 0.64 to 1.00.ARB: No differenceAdjusted OR 1.10; 95% CI, 0.88 to 1.37.
De Spiegeleer et al. (36)	Belgium	Observational	154	51 / 103	ACEi / ARBs vs. non- ACEi / ARBs	Asymptomatic status, and serious clinical outcome	No differenceAsymptomatic status:OR 2.72; 95% CI, 0.59 to 25.1; p=0.24.Serious clinical outcome: OR 0.48; 95% CI, 0.10 to 1.97; p=0.31.
Felice et al. (37)	Italy	Observational	133	86 / 47	ACEi / ARB vs. other antihypertensive drugs	Hospital admission, oxygen therapy, admission to ICU/sICU, non-invasive ventilation, and death	No differenceHospital admission: adjusted OR 0.39; 95% CI, 0,05 to 2.94; p=0.36.Oxygen therapy: adjusted OR 0.51; 95% CI, 0.15 to 1.78; p=0.29.Non-invasive ventilation: adjusted OR 0.58; 95% CI, 0.21 to 1.60; p=0.29.Death: adjusted OR 0.56; 95% CI, 0.17 to 1.83; p=0.34.ACEi / ARB: ↓ Admission to ICU/sICUAdjusted OR 0.25; 95% CI, 0.09 to 0.66; p=0.006.
Fosbøl et al. (27)	Denmark	Observational	4,480		ACEi / ARB vs. non-ACEi / ARB	Composite outcome of death or severe COVID-19	No differenceAdjusted HR 1.04; 95% CI, 0.89 to 1.23.
Gao et al. (38)	China	Observational	850	443 / 407	ACEi / ARB vs. other antihypertensive drugs	Mortality rates	No differenceAdjusted HR 0.85; 95% CI, 0.28 to 2.58; p=0.77.
Hakeam et al. (20)	Saudi Arabia	Observational	338	201 / 137	ACEi / ARB vs. non-ACEi / ARB	ICU admission, ICU admission within 24 hours of hospitalization, ICU stay (days), and ICU death	No differenceICU admission: 28.2% vs. 35.5%; p=0.19.ICU admission within 24 hours of hospitalization: 63.8% vs. 51.5%; p=0.23.ICU stay (days): 10.5 vs. 7; p=0.13.ICU death: 21.7% vs. 21.2%; p=0.58.
Hippisley-Cox et al. (39)	England	Observational	19,486	9,376 / 10,110	ACEi / ARBs vs. non- ACEi / ARBs	Risk of COVID-19, risk of ICU care	ACEi/ARBsRisk of COVID-19: ↓Adjusted HR 0.71; 95% CI, 0.67 to 0.74.Risk of ICU care: No differenceAdjusted HR 0.89; 95% CI, 0.75 to 1.06.
Huang et al. (6)	China	Observational	50	27 / 23	RAAS inhibitors vs. non-RAAS inhibitors	In hospital mortality	No difference0% vs. 6.67%; p=0.51
Jung et al. (17)	Korea	Observational	5,179	2,295 / 2,884	ACEi / ARB vs. non-ACEi / ARB	Risk of mortality	No differenceAdjusted OR 0.88; 95% CI, 0.53 to 1.44; p=0.60).
Khan et al. (24)	Scotland	Observational	88	50 / 38	ACEi / ARB vs. non-ACEi / ARB	Critical care admission, intubated and ventilated, and in-patient mortality	No differenceCritical care admission: 33.3% vs. 14.7%; p=0.08.Intubated and ventilated: 18.5% vs. 11.5%; p=0.58.In-patient mortality: 18.5% vs. 22.9%; p=0.85.
Kim et al. (18)	Korea	Observational	1,378,052	649,153 / 728,899	ARB vs. non-ARB	Risk of COVID-19	ARB: ↓Adjusted RR 0.75; 95% CI, 0.59 to 0.96).
Kocayigit et al. (25)	Turkey	Observational	169	79 / 90	ACEi / ARB vs. other antihypertensive drugs	In-hospital mortality	No differenceOR 0.53; 95% CI, 0.13 to 2.14; p=0.37.
Lam et al. (13)	United States	Observational	614	338 / 276	ACEi/ARB continuation in the hospital vs. discontinuation	Mortality, and ICU admission	ACEi/ARB continuation: ↓Mortality: OR 0.21; 95% CI, 0.10 to 0.45; adjusted p=0.001.ICU admission: OR 0.35; 95% CI, 0.19 to 0.64; p=0.001.
Li et al. (2)	China	Observational	362	173 / 189	ACEi / ARB vs. non-ACEi / ARB	Severe and non-severe infections, non-survivors and survivors	No differenceSevere and non-severe infections: 32.9% vs. 30.7%; p=0.65.Non-survivors and survivors: 27.3% vs. 33.0%; p=0.34.
Liu et al. (3)	China	Observational	157	73 / 84	ACEi / ARBs vs. CCBs	Chest computed tomography time, and hospitalization time	No differenceChest computed tomography time:HR 0.73; 95% CI, 0.45 to 1.2; p=0.87.Hospitalization time: HR 1.06; 95% CI, 0.44 to 1.1, p=0.83.
Lopes et al. (28)	Brazil	Randomized clinical trial	659	389 / 270	ACEi/ARB continuation in the hospital vs. discontinuation	Primary outcome: number of days alive and out of the hospital; secondary outcome: all-cause death	Primary outcome: No difference22.9 vs. 21.9; p=0.09.Secondary outcome: No difference2.8% vs. 2.7%; p=0.95.
Mancia et al. (10)	Italy	Observational	6,272	3,969 / 2,303	ACEi / ARBs vs. non- ACEi / ARBs	Association with COVID-19, and severe or fatal course of the disease	ARB: No differenceAssociation with COVID-19: adjusted OR 0.95; 95% CI, 0.86 to 1.05.Severe or fatal course of the disease: adjusted OR 0.83; 95% CI, 0.63 to 1.10.ACEi: No differenceAssociation with COVID-19: adjusted OR 0.96; 95% CI, 0.87 to 1.07.Severe or fatal course of the disease: adjusted OR 0.91; 95% CI, 0.69 to 1.21.
Mehta et al. (40)	United States	Observational	3,470	1,718 / 1,752	ACEi / ARB vs. non-ACEi / ARB	Admitted to hospital, admitted to ICU, and use of ventilator	ACEi:↑ Admitted to hospital: OR 1.84; 95% CI, 1.22 to 2.79.↑ Admitted to ICU: OR 1.77; 95% CI, 1.07 to 2.92.Use of ventilator: OR 1.35; 95% CI, 0.74 to 2.47.ARB:↑ Admitted to hospital: OR 1.61; 95% CI, 1.04 to 2.50.Admitted to ICU: OR 1.16; 95% CI, 0.67 to 2.02.Use of ventilator: OR 1.12; 95% CI, 0.59 to 2.12.
Pan et al. (41)	China	Observational	282	143 / 139	ACEi / ARB vs. other antihypertensive drugs	All-cause mortality, and proportion of critically ill	ACEi / ABR: ↓ All-cause mortality9.8% vs. 26.1%; p=0.03Proportion of critically ill: No difference31.7% vs. 43.2%; p=0.16.
Reynolds et al. (14)	United States	Observational	4,357	2,214 / 2,143	ACEi / ARB vs. non-ACEi / ARB	Severe COVID-19^* * Admission to the ICU, requirement of noninvasive mechanical ventilation, or death.	ACEi: No differenceMedian difference -3.3; 95% CI, -8.2 to 1.7.ARB: No differenceMedian difference 0.1; 95% CI, -4.8 to 4.9.
Sardu et al. (11)	Italy	Observational	62	41 / 21	ACEi / ARBs vs. CCBs	Hospital admission at ICU, mechanical ventilation, cardiac injury, and death	No difference
Savarese et al. (21)	Sweden	Observational	1,387,746	722,900 / 664,846	ACEi / ARB vs. non-ACEi / ARB	Risk of hospitalization/death for Covid-19 in the overall population, and risk of all-cause death in patients with COVID-19	ACEi/ARB: ↓Risk of hospitalization/death for COVID-19 in the overall population: Adjusted OR 0.86; 95% CI, 0.82 to 0.91.Risk of all-cause death in patients with COVID-19: Adjusted HR 0.90; 95% CI, 0.83 to 0.97).
Şenkal et al. (26)	Turkey	Observational	611	363 / 248	ACEi / ARB vs. other antihypertensive drugs	Severe disease	ACEi: ↓OR 0.37, 95% CI, 0.15 to 0.87; p=0.03.ARB: No differenceOR 0.60, 95% CI, 0.27 to 1.36; p=0.31.
Seo et al. (16)	South Korea	Observational	4,932	2,142 / 2,790	ACEi / ARB vs. non-ACEi / ARB	COVID-19 infection, and death	No differenceCOVID-19 infection: Adjusted OR 0.98; 95% CI, 0.85 to 1.13.Death: Adjusted OR 0.87; 95% CI, 0.55 to 1.40.
Son et al. (19)	South Korea	Observational	2,847	1,449 / 1.398	ACEi / ARB vs. non-ACEi / ARB	COVID-19 infection, long-term hospitalization, ICU admission, high-flow oxygen therapy, and death	No differenceCOVID-19 infection: Adjusted OR 1.16; 95% CI, 0.96 to 1.41.Long-term hospitalization: Adjusted OR 0.86; 95% CI, 0.53 to 1.40.ICU admission: Adjusted OR 1.51; 95% CI, 0.40 to 5.70; p>0.05.High-flow oxygen therapy: Adjusted OR 0.66; 95% CI, 0.28 to 1.62; p>0.05.Death: Adjusted OR 1.36; 95% CI, 0.51 to 3.66; p>0.05.
Tetlow et al. (23)	London	Observational	557	320 / 237	ACEi / ARB vs. non-ACEi / ARB	Macrovascular thrombus, acute kidney injury, and in-hospital mortality	No differenceMacrovascular thrombus: Overlap propensity score - RR 1.05; 95% CI, 0.48 to 2.31.Acute kidney injury: Overlap propensity score - RR 1.04; 95% CI, 0.71 to 1.52.In-hospital mortality: Overlap propensity score - RR 1.04; 95% CI, 0.80 to 1.36.
COVID-19 RISk and Treatments Collaboration (9)	Italy	Observational	4,069	1,560 / 2,509	ACEi / ARB vs. non-ACEi / ARB	In-hospital death	ACEi: No differenceAdjusted HR 0.96; 95% CI, 0.77 to 1.20.ARB: No differenceAdjusted HR 0.89; 95% CI, 0.67 to 1.19.
Vila-Corcoles et al. (22)	Spain	Observational	34,936	16,805 / 18,131	ACEi / ARB vs. non-ACEi / ARB	Risk of COVID-19	ACEi: No differenceHR 0.83; 95% CI, 0.61 to 1.13/ p=0.24.ARB: No differenceHR 0.67; 95% CI, 0.44 to 1.01; p=0.05.
Wang et al. (4)	China	Observational	210	100 / 110	ACEi / ARB vs. non-ACEi / ARB	Death during hospitalization, days of hospital stay, adverse events	No differenceDeath during hospitalization: 8.64% vs. 3.88%; p=0.15.Days of hospital stay: 17.00 vs. 17.00; p=0.82.Adverse events: 5.24% vs. 6.17%; p=0.63.
Xu et al. (42)	China	Observational	101	53 / 48	ACEi / ARB vs. other antihypertensive drugs	In-hospital mortality, ICU admission, or invasive mechanical ventilation	No differenceIn-hospital mortality: 28% vs. 34%; p=0.46.ICU admission: 20% vs. 28%; p=0.37.Invasive mechanical ventilation: 18% vs. 26%; p=0.31.
Yang et al. (5)	China	Observational	126	62 / 64	ACEi / ARB vs. non-ACEi / ARB	Proportion of critical patients, and death rate	No differenceProportion of critical patients: 9.3% vs. 22.9%; p=0.06.Death rate: 4.7% vs. 13.3%; p=0.21.
Zhang et al. (43)	China	Observational	1,128	603 / 525	ACEi / ARB vs. non-ACEi / ARB	Risk for all-cause mortality, and COVID-19 mortality	ACE / ARB: ↓Risk for all-cause mortality: Adjusted HR 0.42; 95% CI, 0.19 to 0.92; p=0.03.COVID-19 mortality: Adjusted HR 0.37; 95% CI, 0.15 to 0.89; p=0.03.
Zhou et al. (44)	China	Observational	3,572	NA	ACEi / ARB vs. other antihypertensive drugs	28-day all-cause death of COVID-19	ACEi / ARB: ↓Adjusted HR 0.39; 95% CI, 0.26 to 0.58; p<0.001.

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[1] *Corresponding author. E-mail: rstein@cardiol.br