High Blood Pressure & Cardiovascular Prevention (2023) 30:265–279

https://doi.org/10.1007/s40292-023-00579-0

ORIGINAL ARTICLE

Discontinuation of Antihypertensive Drug Use Compared

to Continuation in COVID‑19 Patients: A Systematic Review
with Meta‑analysis and Trial Sequential Analysis
Diego Chambergo‑Michilot1,5 · Fernando M. Runzer‑Colmenares1 · Pedro A. Segura‑Saldaña2,3,4

Received: 16 January 2023 / Accepted: 4 May 2023 / Published online: 12 May 2023
© Italian Society of Hypertension 2023

Abstract
Introduction COVID-19 related mortality is about 2%, and it increases with comorbidities, like hypertension. Regarding
management, there is debatable evidence about the benefits of continuation vs. discontinuation of angiotensin-converting
enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB).
Aim We performed a systematic review to assess the effects and safety of in-hospital discontinuation compared to continu-
ation of ACEI/ARB in COVID-19 patients.
Methods We systematically searched on PubMed, Scopus, and EMBASE from inception to June 19, 2021. We included
observational studies and trials that compared the effects and safety of continuing ACEI/ARB compared to discontinuing
it in COVID-19 patients. Effects sizes for dichotomous variables were expressed as risk ratios (RR) and 95% confidence
intervals. For continuous variables, effects were expressed as mean difference (MD). We used random effect models with
the inverse variance method. We assessed certainty of evidence using the GRADE approach.
Results We included three open-label randomized controlled trials and five cohort studies. We found that the continua-
tion group had lower risk of death compared with the discontinuation group only in the cohort group (RR: 0.46, 95% CI:
0.24–0.90), but not in the RCT group (RR: 1.22, 95% CI: 0.75–2.00). The ICU admission rate was significantly lower in the
continuation group (RR: 0.46, 95% CI: 0.31–0.68) in the cohort group, but not in RCT group (RR: 1.03, 95% CI: 0.67–1.59).
We did not find significant differences between groups regarding hospitalization length, hypotension, AKI needing renal
replacement therapy, mechanical ventilation, new or worsening heart failure, myocarditis, renal replacement therapy, arrhyth-
mias, thromboembolic events and SOFA AUC. The GRADE approach revealed that the certainty ranged from moderate to
high level.
Conclusions There is no significant difference in mortality and other outcomes between continuation and discontinuation
groups.

Keywords COVID-19 · Hypertension · Angiotensin-converting enzyme inhibitors · Angiotensin receptor antagonists ·

Systematic review (Source: MeSH NLM)

3
* Diego Chambergo‑Michilot Ingeniería Biomédica, Facultad de Ciencias y Filosofía,
diegochambergomichilot@hotmail.com Universidad Peruana Cayetano Heredia, Lima, Peru
4
Fernando M. Runzer‑Colmenares Departamento de Cardiología, Hospital Nacional Edgardo
frunzer@cientifica.edu.pe Rebagliati Martins, Lima, Peru
5
Pedro A. Segura‑Saldaña CHANGE Research Working Group, Carrera de Medicina
pedro.segura.s@upch.pe Humana, Universidad Científica del Sur, Lima, Peru
1
Universidad Científica del Sur, Lima, Peru
2
Department of Cardiology Research, Torres de Salud
National Research Center, Lima, Peru

Vol.:(0123456789)
266
1 Introduction
Coronavirus disease (COVID-19) has affected approxi-
mately 200 million people worldwide, and global mortality
is around 2% [1]. This elevated mortality is not only due to
the pathogen SARS-CoV-2, but comorbidities, like hyper-
tension, that reduces lifespan in general population [2].
Angiotensin converting enzyme 2 (ACE2) cleaves angi-
otensin I into angiotensin 1–9, and some of them (I–VII)
has vasodilation, anti-inflammatory and anti-proliferation
(vessel smooth muscle) properties [3]. SARS-CoV-2 pro-
tein spike interacts with the ACE2 to entry the human
system (Supplementary material 1) [4], resulting in down-
regulation of ACE2 [5]. Therefore, infection may be asso-
ciated with endothelial dysfunction [6]. A role between
angiotensin converting enzyme inhibitors and angiotensin
receptor blockers (ACEI / ARB) drugs and COVID-19 evo-
lution has been settled, however there are heterogeneous
opinions on the directness of the effect of those drugs.
On one side, inhibition of renin–angiotensin–aldoster-
one system may lead to compensatory increase of ACE2
[7], and increase the risk of SARS-CoV-2 infectivity [8].
There is overproduction of bradykinin and its metabolites
in severe COVID-19, so ACEI drugs could worsen inflam-
mation and the acute respiratory distress syndrome [9].
ACEI may cause hyperkalemia, especially when combin-
ing with spironolactone [10], which worsens the prognosis
of a patient with severe COVID-19. Therefore, it is advis-
able to stop ACEI/ARB in acute illness setting (shock,
AKI, hypotension, hyperkalemia) [11]. Indeed, a French
cohort of severe COVID-19 patients revealed that ACEI/
ARB chronic therapy was associated with AKI and altered
kidney markers [12]. In another cohort, ACEI/ARB was
associated with higher risk of severe COVID-19, intensive
care unit (ICU) admission, and needing of noninvasive
ventilation, nevertheless the confidence intervals were
very robust [13].
On the other hand, the risk of discontinuing ACEI/
ARB is worrying since may decompensate patients with
hypertension, chronic heart failure, chronic kidney dis-
ease and CAD. Furthermore, an analysis of a multicenter
cohort showed that chronic ACEI/ARB use was associ-
ated with significantly lower mortality in patients with
ST-elevation myocardial infarction during the COVID-19
pandemic [14]. Evidence of ACEI/ARB benefits is consist-
ent [15] and could be superior to the risk of continuing it
in COVID-19 acute setting.
Taking this debate into account, several meta-analyses
have been published. Some of them found that there is
not association between ACEI/ARB use (vs non-use) and
severe disease and mortality [16–18]. Nevertheless, a key
issue of methodology is that most of analyzed primary
D. Chambergo‑Michilot et al.
studies compared chronic use of ACEI/ARB vs other anti-
hypertensive agents or just not being treated with those
drugs, which may bias the result. The latter could happen
because if the comparator is the “non-use” of ACEI/ARB,
it may involve patients without hypertension, heart failure
and other diseases treated with these drugs. Therefore,
the best way to elucidate the debate is to see if there is an
effect of discontinuing ACEI/ARB compared with con-
tinuing ACEI/ARB in COVID-19 patients. Both groups
would be composed of diseased patients being treated with
ACEI/ARB, so evidence would be accurate for them. In
this context, we performed a systematic review to assess
the effects and safety of continuation compared with dis-
continuation of ACEI/ARB in COVID-19 patients.
2 Methods
This systematic review follows the recommendations of the
Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) statement, and the Cochrane Handbook
for Systematic Reviews of Interventions [19, 20]. The proto-
col of this systematic review was published in Figshare [21].
2.1 Search Strategy
We searched evidence up to January 28, 2021 in the follow-
ing databases: PubMed, Scopus, and EMBASE. We updated
the search on December 6, 2022. The strategies included
related terms to COVID-19 and ACEI/ARB are available in
Supplementary material 2. We did not limit the search by
publication date.
2.2 Inclusion Criteria
We included randomized controlled trials (RCT) and cohorts
that assessed the effects or safety of continuation of ACEI/
ARB therapy compared with discontinuation in patients with
COVID-19. We excluded case reports, case series, cross-
sectional studies, case–control studies, reviews, congress or
conference abstracts, editorials, interviews, comments, and
newspaper articles.
2.3 Study Selection
One author (D.C.M.) downloaded all references to an End-
Note document to eliminate duplicates. The author exported
those references to the Rayyan QCRI webpage (https://​
rayyan.​qcri.​org/). Two reviewers (D.C.M., P.A.S.S.) inde-
pendently screened titles and abstracts. Then, those review-
ers assessed the full-text version of selected articles to
determine eligibility. This selection was performed using
COVID-19 and Antihypertensive Drugs
a pre-piloted Microsoft Excel sheet. Any disagreement was
resolved by consensus.
2.4 Data Extraction
Two reviewers (D.C.M., P.A.S.S.) independently extracted
data of interest. For dichotomous outcomes, we extracted
absolute and relative frequencies. For continuous outcomes,
we extracted mean, standard deviation, median and range
of the outcomes in each group (continuation vs discontinu-
ation). The extraction was performed using a pre-piloted
Microsoft Excel sheet. Any disagreement was resolved by
consensus.
2.5 Primary and Secondary Outcomes
The primary outcome of our systematic review was all-cause
mortality. Our secondary outcomes were the global rank
score [composed of (1) days to death, (2) days on invasive
mechanical ventilation or extracorporeal membrane oxygen-
ation, (3) days on renal replacement therapy or inotropic or
vasopressor therapy, (4) area under the curve of a modified
SOFA score], intensive care unit (ICU) admission, length of
hospitalization, and adverse events.
2.6 Methodological Assessment
We assessed the risk of bias using the version 2 of the
Cochrane risk-of-bias tool for randomized trials (RoB 2).
This tool has five domains (randomization process, devia-
tions from intended interventions, missing outcome data,
measurement of the outcome, and selection of the reported
results) and the overall score. Each domain can be judged
as follows: low risk of bias, some concerns, and high risk
of bias [20].
New Castle–Ottawa tool was used to assess methodo-
logical issues in cohorts [22]. It has the following domains:
selection (representativeness, ascertainment of exposure,
demonstration that outcomes were not present at the begin-
ning), comparability, and outcome. The maximum score is 9.
2.7 Synthesis
Meta-analyses were performed using random-effect model
with the inverse variance method. We used the Paule–Man-
del estimator and Hartung–Knapp–Sidik–Jonkman method
for τ2 and 95% confidence intervals (95% CIs) calculation,
respectively [23, 24].
For dichotomous outcomes, we used relative risks (RR)
with their 95% CI. For continuous outcomes, we calculated
the mean difference (MD) by subtracting the mean in the dis-
continuation group from the mean in the continuation group.
267
Heterogeneity was described with the I2 statistic [25]. An
I < 30%, I2 30–60%, and I2 > 60% defined low, moderate and
2
high heterogeneity, respectively. We pooled outcomes only if
occurring in at least two studies. If one or more outcomes
could not be extracted from a study, it was removed from the
analysis. Two-sided p-values ≤ 0.05 were considered statisti-
cally significant for all tests. Funnel plots and the Egger’s test
were performed to assess publication bias and asymmetry
of plots, respectively, in case of 10 or more studies included
[26]. We conducted the analyses using metabin, metacount and
metareg functions of the meta library of R 3.5.1 (R Foundation
for Statistical Computing, Vienna, Austria; http://​www.r-​proje​
ct.​org).
Meta-analyses may result in non-reliable significant results
due to repeated testing of significance. Therefore, it is impor-
tant to reduce the risk of false-positive or false-negative infer-
ence. We used the trial sequential analysis (TSA) to calculate
the required information size (sample size) to confirm or reject
an outcome at a relative risk reduction (RRR). We used a type
1 error of 5%, a power of 90%, a RRR of 20% for calculating
information size. This RRR was chosen because it may be
clinically meaningful and realistic for outcomes like mortal-
ity, furthermore, it had been used in prior meta-analyses with
TSA [27, 28]. A model variance-based estimate was used
to correct for heterogeneity. The later was used to perform
monitoring boundaries according to the O’Brien–Fleming type
alpha-spending function for the cumulative z-scores [29]. This
boundaries are meant to determine if sufficient data is reached
or not. We used the TSA software (Copenhagen Trial Unit,
Centre for Clinical Intervention Research; https://​ctu.​dk/​tsa/).
2.8 Recommendations Grading
We used the GRADE approach (Grading of Recommendations
Assessment, Development and Evaluation) to rate the quality
of evidence of the pooled primary outcomes. The domains
of assessment are risk of bias, publication bias, imprecision,
inconsistency, indirectness, and magnitude of effect. The qual-
ity ratings are very low, low, moderate or high [30].
2.9 Ethics
The protocol of this study was approved by the committee of
the Universidad Científica del Sur (Peru, registration code:
267-2021-PRE15).
3 Results
3.1 Eligible Studies
We identified 5294 studies through the systematic search.
We assessed 11 studies for full-text eligibility. Finally, we
268
included eight studies in the systematic review (Supplemen-
tary material 3).
3.2 Characteristics of Included Studies
We included three open-label RCT [31–33] and five cohorts
[34–38]. The range of publication year was 2020–2021.
Inclusion criteria consisted in either adults with confirmed
COVID-19 taking ACEI/ARB prior to hospitalization, or
adults hospitalized with COVID-19. In case of the latter
criteria, we only considered data from those who contin-
ued or discontinued ACEI or ARB during hospitalization.
Regarding important exclusion criteria, one RCT excluded
patients with recent acute coronary syndrome or severe heart
failure [33]; another RCT excluded patients with heart fail-
ure with reduced ejection fraction, and patients with AKI
with ≥ 100 % increase in creatinine [31]; and one cohort
excluded patients with prior solid organ transplant or taking
chronic immunosuppressive medication [38]. The sample
size ranged from 80 to 3897. The trials reported that the
follow-up was until approximately one month. The most
frequent primary outcome was mortality. Other primary
outcomes were the Sequential Organ Failure Assessment
(SOFA) score, number of days alive and out of the hospital,
the global rank score, and other composite outcome (need
of invasive mechanical ventilation, need of non-invasive
mechanical ventilation, ICU, and mortality) (Table 1).
3.3 Characteristics of Studies’ Population
Sample size of the continuation group ranged from 49 to
1860. Sample size of the discontinuation group ranged from
31 to 2037. In the majority of studies, mean/median age
was higher than 60 years, and there were not significant dif-
ferences between groups (continuation vs discontinuation).
Male proportion accounted for more than a half along the
studies, but there were no significant differences between
groups. The most frequent indication of ACEI/ARB was
hypertension. Regarding other diseases, in some studies we
found considerable differences between groups in propor-
tion of diabetes [32, 33], heart failure [31, 33], and kid-
ney disease [33, 38]. We did not find important differences
between groups in creatinine levels, COVID-19 progression,
C-reactive protein or potassium level (Table 2).
We reported the use of drugs to treat COVID. Anticoagu-
lation, azithromycin, antiviral drugs and hydroxychloroquine
were frequently used. We found considerable differences in
the proportion of Tocilizumab use between the groups in
two studies [31, 36]. We also reported the antihypertensive
drugs used instead of ACEI/ARB in the discontinuation
group. Calcium channel blockers and beta-blockers were
the most frequently used, however there were no significant
differences between groups. Regarding the cross-over rate,
D. Chambergo‑Michilot et al.
in studies that reported it, we found that this rate was more
frequent in the continuation group rather than in the discon-
tinuation group (Table 3).
3.4 Risk of Bias
Overall risk of bias was low in all RCT (Fig. 1). Quality
score of cohorts was high (all: 8 points) (Supplementary
material 4).
3.5 Meta‑analyses
We found that the continuation group had lower risk of death
compared with the discontinuation group only in the cohort
group (RR: 0.46, 95 % CI: 0.24–0.90), but not in the RCT
group (RR: 1.22, 95% CI: 0.75–2.00). The heterogeneity
was high in the cohort group (I2: 87%) (Fig. 2A). The TSA
showed that there was no enough data to confirm or reject
the result in the RCT group with a RRR of 20 % (Supple-
mentary material 6 A).
The global rank score was significantly lower in the
continuation group (2 RCT, MD: −10.49, 95% CI: −17.18,
−3.79) (Fig. 2C). The ICU admission rate was signifi-
cantly lower in the continuation group (RR: 0.46, 95% CI:
0.31–0.68) in the cohort group, but not in RCT group (RR:
1.03, 95 % CI: 0.67–1.59). The heterogeneity was low in the
cohort group (I2: 0%) (Fig. 2D). The TSA showed that there
was no enough data to confirm or reject the result in the RCT
group with a RRR of 20% (Supplementary material 6B). The
area under the curve of SOFA score was significantly lower
in the discontinuation group (2 RCT: MD: 4.76, 95% CI:
1.88–7.64) (Supplementary material 5E).
We did not find significant differences between groups
regarding hospitalization length, hypotension, AKI need-
ing renal replacement therapy, mechanical ventilation, new
or worsening heart failure, myocarditis, renal replacement
therapy, arrhythmias, thromboembolic events and SOFA
AUC. We reported that TSA of meta-analyses of only RCT
in the Supplementary material 6.
We performed an exploratory meta-analysis regarding
the ARB use vs ACEI use during hospitalization along. We
pooled adjusted hazard ratios, and found that those taking
ARB drugs were less likely to die compared with those tak-
ing ACEI drugs (HR: 0.73, 95% CI: 0.59–0.92) (Supplemen-
tary material 5F).
3.6 Non Meta‑analyzed Results
In ACEI-COVID trial, the maximum median SOFA score
did not significantly differ between groups (continuation vs
discontinuation) ­(pWMW = 0.12), however mean SOFA score
decreased more rapidly and reached lower levels in the dis-
continuation group. There were significant interactions with
Table 1  Characteristics of included studies
Study Year Design Main inclusion criteria Main exclusion criteria Sample ­sizeb Follow – up Primary outcome Main results

ACEI- COVID 2021 Open-label RCT​ Adults with confirmed
COVID-19 taking
ACEI/ARB prior to
hospitalization
ACS (last 3 months), 204 30 days SOFA and mortality No significant difference in
≥ 4 antihyperten- the maximum severity of
sive drugs, NYHA COVID-19, but discon-
III–IV, LVEF < 30 %, tinuation may lead to a
NTproBNP ≥ 600 pg/ faster and better recovery
mL, impossibility to
substitute ACEI or
ARB
COVID-19 and Antihypertensive Drugs

BRACE CORONA 2021 Open- label RCT​ Adults with confirmed Patients taking: ≥ 3 anti- 659 30 days Number of days No significant difference
COVID-19 taking hypertensive agents, alive and out of in the primary outcome
ACEI/ARB prior to sacubitril/valsartan, or the hospital between the groups
hospitalization those hospitalized for
HF within the last year
REPLACE COVID 2021 Open- label RCT​ Adults with confirmed Contraindications to con- 152 28 days Global rank s­ corea No significant difference
COVID-19 taking tinuing or discontinuing in the primary outcome
ACEI/ARB prior to ACEI/ARB, SBP < 100 between the groups
hospitalization or > 180 mmHg,
DBP > 110 mmHg,
HFrEF, potas-
sium > 5 mmol/L, AKI
with ≥ 100% increase
in creatinine, severe
proteinuria, taking
aliskiren or sacubitril–
valsartan, imprisoned
or incarcerated
De Abajo 2021 Cohort Adults hospitalized Patients in whom the 625 At in-hospital death or Mortality Continuation with ARBs
patients with COVID- continuation or discon- discharge was associated with
19b tinuation could not be a trend to a reduced
properly assessed at mortality compared to
admission, patients who ARB discontinuation and
presented the outcome ACEI continuation
or were discharged
within the first 3 days of
hospital admission
Roy-Vallejo 2021 Cohort Adults hospitalized Patients who remained 3897 NI Composite: need for Continuation of ACEI/
patients with COVID- hospitalized as of 4 IMV, NIMV, ICU, ARB lead to a lower
19b June 2020, those who mortality incidence of the compos-
did not have data on ite outcome compared to
ACEI or ARB, or the discontinuation
date of first positive
RT-PCR recorded
269
Table 1  (continued)
270

Study Year Design Main inclusion criteria Main exclusion criteria Sample ­sizeb Follow – up Primary outcome Main results

Cannata 2020 Cohort Adults hospitalized NI 173 At death or discharge Mortality Patients who continue
patients with COVID- ACEI/ARB have a lower
19b risk of mortality com-
pared with those discon-
tinuing it or not taking
these drugs at home
Lam 2020 Cohort Adults hospitalized Discharged from emer- 335 NI Mortality Patients who continue
patients with COVID- gency department, ACE/ARB had lower
19 and hypertension transferred to other mortality and ICU
regardless of prior hospitals, unknown admission rate compared
ACE/ARB therapy discharge status as of to patients who discon-
23 May 2020 tinued
Chaudhri 2020 Cohort Adults hospitalized Prior solid organ trans- 80 NI Mortality Therapeutic benefits of
patients with COVID- plant, chronic immuno- continuing ACEI or
19b suppressive medication ARB was not offset by
and patients without a adverse outcomes
disposition (death or
discharged alive)

RCT​ randomized clinical trial; HF heart failure; SBP systolic blood pressure; DBP diastolic blood pressure; HFrEF heart failure with reduced ejection fraction; AKI acute kidney injury;
ICU intensive care unit; ACEI angiotensin converting enzyme inhibitor; ARB angiotensin receptor blocker; ACS acute coronary syndrome; NYHA New York Heart Association class;
SOFA Sequential Organ Failure Assessment; IMV invasive mechanical ventilation; NIMV non-invasive mechanical ventilation; NI no information
a
Each participant was ranked across four hierarchies of outcomes: (1) days to death (lowest to highest), (2) days on invasive mechanical ventilation or extracorporeal membrane oxygenation
(highest to lowest), (3) days on renal replacement therapy or inotropic or vasopressor therapy (highest to lowest), (4) area under the curve of a modified SOFA score (it incorporated cardiac, res-
piratory, coagulation and renal domains of the SOFA score)
b
We considered data from only those who continued or discontinued ACEI or ARB during hospitalization
D. Chambergo‑Michilot et al.
Table 2  Characteristics of studies’ population
Study Year Study Sample Age Male, % Hospital HTN, % Diabetes, CAD, % HF, % Kidney Creatinine Scores of CRP Potassium
group size stay (days) % disease, COVID – 19
% severity

ACEI – COVID 2021 Continua- 100 75 (69–80) 64 11 (7–19) 99 37 23 6 21 NI SOFA: 4.5 NI

tion 0.8 ± 1 (1.6–8.3)
mg/dL
Discontin- 104 74 (63–80) 63 10 (6–15) 96 29 21 12 15 NI SOFA: 5.1 NI
uation 0.7 ± 1 (1.5–9.6)
mg/dL
COVID-19 and Antihypertensive Drugs

BRACE 2021 Continua- 325 56 (46.1– 60 6.7 ± 6.3 100 30.5 4.3 2.2 1.2 88.4 Moderate: 4.2 4 (3.7–4.4)
CORONA tion 66.1) (70.7– 43.7%a (1.4–7.4)
106.1) mg / dL
μmol/L
Discontin- 334 55 (46.1– 59.3 7.8 ± 7.4 100 33.2 4.8 0.6 1.5 88.4 Moderate: 4.3 4 (3.7–4.4)
uation 63.1) (70.7– 42.2%a (1.6–8.9)
97.2) mg/dL
μmol/L
REPLACE 2021 Continua- 75 62 ± 12 56 6 (3–11) 100 56 8 4 NI 0.8 mg/dL Moderate: 48 ± 68 mg/ 4 ± 0.5
COVID tion (mean) 37%b dL
Severe:
12 %b
Discontin- 77 62 ± 12 55 5 (3–10) 100 48 16 4 NI 0.9 mg/dL Moderate: 45 ± 77 mg/ 4 ± 0.5
uation (mean) 33 %b dL
Severe:
13 %b
De Abajo 2021 Continua- 285 75 (68–82) 58.3 10 (7–16) 97.2 38.9 17.2 14 11.9 NI Severity 271 ± 95.1 NI
tion score:
2.9 ± 1.2c
Discontin- 340 74 (65.5– 62.7 11 97.6 36.2 14.7 8.5 11.2 NI Severity 322 ± 94.7 NI
uation 82) (7.5–17) score:
3.1 ± 1.2c
Cannata 2020 Continua- 56 NI NI NI NI NI NI NI NI NI NI NI NI
tion
Discontin- 117 NI NI NI NI NI NI NI NI NI NI NI NI
uation
Lam d 2020 Continua- 164 68 (58–79) 56.4 7 (4–12) 100 45.4 24.6 11.3 9 1.1 NI 7 (3.1–13.6) 4.2
tion (0.8–1.5) (3.8–4.6)
Discontin- 171 mg/dL
uation
271
 272 D. Chambergo‑Michilot et al.

male sex and COPD regarding effect on the primary endpoint,

NI no information; HTN arterial hypertension; CAD coronary artery disease; HF heart failure; CRP C-reactive protein; HCQ hydroxychloroquine; SOFA Sequential Organ Failure Assessment
4.3 ± 0.0.6
Potassium favoring discontinuation [33].

4.1 ± 0.6
The BRACE CORONA trial [31] did not find significant
differences between the groups regarding the absolute dif-
ference in the mean of days alive and out of the hospital
(3.3–11.4)

(3.6–15.3)
(−1.10, 95 % CI: −2.30, 0.13). The on-treatment analysis

Defined as blood oxygen saturation less than 94% or lung infiltrates greater than 50%, or ratio of partial pressure of arterial oxygen to fraction of inspired oxygen less than 300
mg/dL

mg/dL
showed that the between group mean ratio of the proportion
CRP

Roy-Vallejo et al. [37] did not report the data of the group of interest [those who previously were taking ACEI/ARB, and continued (n = 1860) or discontinued (n = 2037)]
7.3

9.4 of 0 days alive and out of the hospital was 0.91 (95% CI:
0.84–0.96). Group analysis showed that interaction favors
COVID – 19

continuation of ACEI/ARB in those with < 94 % ­O2 satura-

Creatinine Scores of

severity

tion and greater disease severity at admission. There were

1 (0.8–1.3) NI

NI

not significant differences on the cardiovascular death and

COVID-19 progression.
(1 – 1.8)
mg/dL

mg/dL

The REPLACE trial reported no significant differences

between the groups regarding the length of ICU stay or inva-
1.4

sive mechanical ventilation [32].

disease,

ACEI-COVID trial [33] performed a prespecified per-pro-

CAD, % HF, % Kidney

This score ranges from 0 to 7, and is composed of hypoxemia, CRP, troponin, D-dimer, procalcitonin, NT-pro-BNP, and lymphopenia
16.3

22.6

tocol analysis censoring patients at times of crossover, and

%

it did not affect the main results. Similarly, the REPLACE

trial [32] performed a sensitivity analysis censoring those
30.6

25.8

patients, and there were no significant differences in study

endpoints.
28.6

35.5

Roy-Vallejo et al. [37] reported that there were no sig-

nificant differences between continuation and discontinua-
HTN, % Diabetes,

tion of ACEI/ARB in survival at 30 days (HR: 0.79, 95% CI:

0.60–1.05). The Cox regression showed an initial significant
44.9

48.4
%

difference in survival between groups, however the effect

diminished over time.
100

100

Data was only available for the whole group regardless of continuation or discontinuation

3.7 GRADE Summary of Findings

stay (days)

7 (4–14)

9 (5–15)
Male, % Hospital

The GRADE approach revealed that the certainty of the

evidence of all the outcomes ranged from moderate to high
level. There were no grading of level in results that were
pool of data from RCT and cohorts, however the primary
67.6 ± 11.4 53.1

69.9 ± 12.3 71

studies were classified as low risk of bias (Table 4).MD

4 Discussion
Age

According to the WHO COVID-19 disease severity

4.1 Main Findings
Sample

The take-to-home message is that there is not enough evi-

size

49

31

dence to recommend discontinuing ACEI/ARB during

COVID-19 hospitalization. These drugs are effective and
Discontin-
2020 Continua-

uation

safe in several diseases, like hypertension, heart failure and

group
Year Study

tion

CAD, and, if not treated, further consequences may happen

to the patient.
Table 2  (continued)

4.2 What is Known in Literature About our

Question?
Chaudhri

Some observational studies have reported that ACEI/ARB

Study

Score

use is associated with lower mortality and clinical severity in

b

d
a

c
COVID-19 and Antihypertensive Drugs 273

Table 3  Characteristics of therapy in studies

Study Year Study group COVID – 19 therapy, % Other antihypertensive drugs Crossover rate (%) to the
used during hospitalization, % other group for medical
reasons

ACEI–COVID 2021 Continuation NI NI 21

Discontinuation NI CCB: 50 16
BB: 1.9
AB: 1.9
Diuretics: 3.9
BRACE CORONA 2021 Continuation Azithromycin: 91.1 NI NI
Anticoagulation: 67.1
Antiviral: 41.5
Chloroquine or HCQ: 17.8
Tocilizumab: 2.2
Corticosteroid: 48.3
Discontinuation Azithromycin: 90.1 NI NI
Anticoagulation: 66.5
Antiviral: 42.5
Chloroquine or HCQ: 21.6
Tocilizumab: 5.1
Corticosteroid: 50.6
REPLACE COVID 2021 Continuation Anticoagulation: 15 CCBs: 27 22
Antiviral: 24 BB: 15
HCQ: 4 Diuretics: 33
Convalescent plasma: 3
Corticosteroid: 1
Discontinuation Anticoagulation: 10 CCBs: 34 9
Antiviral: 20.8 BB: 18
HCQ: 8 Diuretics: 27
Convalescent plasma: 1
Corticosteroid: 1
De Abajo 2021 Continuation Azithromycin: 40.7 CCBs: 24.6 Excluded from analysis
Anticoagulation:73 BB: 24.2
Antiviral: 83.9 AB: 3.2
HCQ: 85.6 Diuretics: 34
Tocilizumab: 20
Corticosteroid: 39.3
Discontinuation Azithromycin: 37.7 CCBs: 38.5 Excluded from analysis
Anticoagulation: 87.9 BB: 17.7
Antiviral: 86.5 AB: 3.2
HCQ: 90 Diuretics:20.3
Tocilizumab: 12.7
Corticosteroid: 49.1
Cannata 2020 Continuation NI NI NI
Discontinuation NI NI NI
Lam 2020 Continuation NI NI NI
Discontinuation
Chaudhri 2020 Continuation NI NI NI
Discontinuation NI NI NI

CCBs calcium channel blockers; BB beta-blockers; AB alpha-blockers; HCQ hydroxychloroquine; NI no information

Roy-Vallejo et al. [37] did not report the data of the group of interest (those who previously were taking ACEI/ARB, and continued or discontin-
ued, n = 3897)
274
Fig. 1  Risk of bias assessment
of included trials
Deviaons from intended
Randomizaon process
Study ID
ACEI-COVID, 2021
+ +
BRACE CORONA,
2021
+ +
REPLACE COVID,
2021
+ +
COVID-19 patients. Nevertheless, novel systematic reviews
have elucidated that ACEI/ARB has a non-clinically signifi-
cant role in COVID-19 prognosis. For instance, Zhang et al.
[39] reviewed studies from three large databases, and found
that ACEI/ARB were not associated with a higher risk of
COVID-19 infection, moreover, it was not associated with
severe infection or mortality. Further systematic reviews
were consistent with this conclusion [16, 17]. Another meta-
analyses showed that the non-significant effect was constant
in group analyses stratified by populations, drug exposures,
and other secondary outcomes [17]. However, the systematic
review of Baral et al. [40] reported that within the hyper-
tensive cohort there was a significant association between
ACEI/ARB use and mortality.
Interestingly, Patoulias et al. [41] assessed geographical
disparities in the association between renin–angiotensin sys-
tem inhibitors and COVID-19. Authors found that ACEI/
ARBs were associated with decreased odds for severe or
critical illness and mortality in studies carried out in Asian
countries, however they were associated with increased odds
for ICU admission in studies in North America and death in
Europe. About surrogate outcomes, the systematic review of
Xue et al. [42] found that ACEI/ARB were associated with
lower D-dimer, and the chances of getting fever was lower
in this group.
Mechanism of COVID-19 entry involves the renin–angio-
tensin system, specifically the ACE2, which is altered by
spike protein of SARS-CoV-2. It is associated with vaso-
constriction and endothelial dysfunction, which further dam-
age to organs. At the molecular level, hypertensive patients
present oxidative stress that leads to inadequate processing
D. Chambergo‑Michilot et al.
Measurement of the outcome
Selecon of the reported
Missing outcome data
Overall
Low risk
+ + + + +
Some concerns
+ + + + ?
High risk
+ + + + —
of proteins, resulting in inflammation and vascular remod-
eling [43]. Reactive oxygen species can increase inflamma-
tory response and reduce nitric oxide, which contributes to
endothelial dysfunction [43]. Blockage of renin-angiotensin
system have several benefits, for example, increased expres-
sion of angiotensin II type 2 receptor which contribute to
reduce endothelial dysfunction and arterial remodeling [43].
Hypotheses of ACEI / ARB benefit in COVID-19 are sup-
ported by the latter. Since ACEI/ARB are the first line of
treatment in hypertensive patients, the administration will
increase the lifespan of hypertensive COVID -19. And it can
be reflected in the general COVID-19 population because
hypertension is frequent. Indeed, a prior systematic review
reported that pooled prevalence was 30% (95% CI: 23–37%)
[44].
4.3 Comparability of Studies Included in our Review
We found that the effect of continuing ACEI/ARB on
mortality and ICU admission was significantly only in the
cohort group, but not in the RCT group. There are some
explanations to this result. First, meta-analyses were not
adjusted, therefore sociodemographic variables, like sex
and age, COVID-19 progression, other antihypertensive
used, in-hospital complications, among other confounders,
may be mediating the effect. Furthermore, exclusion crite-
ria in cohort was not as specific as in RCT. For instance,
some RCT excluded patients with recent acute coronary
syndrome (ACS), several antihypertensive agents or severe
heart failure. These populations benefit from ACEI/ARB, so
mortality could be higher on the continuation group if not
COVID-19 and Antihypertensive Drugs
A. Mortality
C. Global rank score
E. Hypotension needing support
G. Mechanical ventilation
Fig. 2  Meta-analyses of outcomes. Data from Roy-Vallejo et al.
was not included in the mortality outcome because its data was not
expressed in relative risk, but hazard ratio, and absolute frequency
was not available. In ACEI-COVID trial the range of global rank
excluded. Also, we did not know the crossover rate in the
majority of studies, and if authors performed a sensitivity
analysis by excluding this group.
Regarding trials, all of them were open-label phase III
RCT. However, they differed in exclusion criteria. While
ACEI-COVID’s authors [33] excluded patients with ACS
and severe HF, REPLACE COVID’s authors [32] excluded
patients with potassium > 5 mmol/L, AKI with ≥ 100%
increase in creatinine or severe proteinuria. Sample size
was significantly higher in BRACE CORONA (n = 659)
compared to the other trials. Also, ACEI-COVID and
275
B. Hospitalization length
D. Intensive care unit admission
F. Acute kidney injury needing renal replacement therapy
H. New or worsening heart failure
score median was between 10–90th percentile, therefore we used it
instead of 25–25th percentile to calculate mean and standard devia-
tion. We used the pulmonary embolism or deep vein thrombosis to
define the thromboembolic outcome in the REPLACE trial
BRACE CORONA trials’ primary outcome were mortality
and number of days alive and out of the hospital, respec-
tively, which directly defines survival, but the outcome in
the REPLACE COVID trial was a composite one (global
rank score). Despite the effect of ACEI/ARB continua-
tion was not significant on primary outcomes along all
the trials, there were some differences in the results. For
example, the 30-day mortality was significantly higher in
the ACEI-COVID trial compared with BRACE CORONA
trial. This may be due to age difference, hospital stay, and
heart failure and kidney disease proportion.
276 D. Chambergo‑Michilot et al.

Table 4  Summary of findings

Outcomes Anticipated absolute e­ ffects* (95 % CI) Relative effect No. of participants Certainty of the
(95% CI) (studies) evidence
Risk with [comparison] Risk with [intervention] (GRADE)

All-cause mortality (gen- 179 per 1000 122 per 1000 RR 0.68 2228 –
eral) assessed with: RR (72 to 207) (0.40 to 1.16) (7 studies)
All-cause mortality (RCTs) 52 per 1000 64 per 1000 RR 1.22 1015 ⊕⊕⊕⊕
assessed with: RR (39 to 105) (0.75 to 2.00) (3 RCTs) HIGH
All-cause mortality 278 per 1000 128 per 1000 RR 0.46 1213 ⊕⊕⊕◯
(cohorts) assessed with: (67 to 250) (0.24 to 0.90) (4 observational studies) MODERATE
RR
Days alive and out of the Absolute difference 1.1 – 659 ⊕⊕⊕⊕
hospital assessed with: lower (1 RCT) HIGH
RCT​ (2.3 lower to 0.13 higher)
Hospitalization length MD 0.01 higher – 1095 –
assessed with: MD (1.4 lower to 1.42 higher) (4 studies)
Global rank score assessed MD 10.49 lower – 356 ⊕⊕⊕⊕
with: MD (17.18 lower to 3.79 lower) (2 RCTs) HIGH
Intensive care unit admis- 188 per 1000 193 per 1000 RR 1.03 356 ⊕⊕⊕⊕
sion (RCTs) assessed (126 to 299) (0.67 to 1.59) (2 RCTs) HIGH
with: RR
Intensive care unit admis- 287 per 1000 132 per 1000 RR 0.46 415 ⊕⊕⊕◯
sion (cohorts) (89 to 195) (0.31 to 0.68) (2 observational studies) MODERATE
Hypotension needing sup- 88 per 1000 81 per 1000 RR 0.92 811 ⊕⊕⊕⊕
port assessed with: RR (51 to 126) (0.58 to 1.44) (2 RCTs) HIGH
Acute kidney injury needing 29 per 1000 27 per 1000 RR 0.93 811 ⊕⊕⊕⊕
renal replacement therapy (12 to 62) (0.41 to 2.11) (2 RCTs) HIGH
assessed with: RR
Mechanical ventilation 110 per 1000 89 per 1000 RR 0.81 1095 –
assessed with: RR (63 to 126) (0.57 to 1.15) (4 studies)
New or worsening heart 29 per 1000 36 per 1000 RR 1.23 1015 ⊕⊕⊕⊕
failure assessed with: RR (18 to 70) (0.63 to 2.41) (3 RCTs) HIGH
Myocarditis assessed with: 5 per 1000 2 per 1000 RR 0.51 811 ⊕⊕⊕⊕
RR (0 to 27) (0.05 to 5.54) (2 RCTs) HIGH
Renal replacement therapy 23 per 1000 24 per 1000 RR 1.01 1015 ⊕⊕⊕⊕
assessed with: RR (11 to 51) (0.46 to 2.21) (3 RCTs) HIGH
Arrhythmias assessed with: 27 per 1000 35 per 1000 RR 1.30 811 ⊕⊕⊕⊕
RR (16 to 76) (0.59 to 2.85) (2 RCTs) HIGH
Thromboembolic events 17 per 1000 23 per 1000 RR 1.34 811 ⊕⊕⊕⊕
assessed with: RR (4 to 124) (0.24 to 7.30) (2 RCTs) HIGH
SOFA AUC assessed with: MD 4.76 higher – 356 ⊕⊕⊕⊕
MD (1.88 higher to 7.64 higher) (2 RCTs) HIGH

GRADE Working Group grades of evidence

High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there
is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of
effect
CI confidence interval; RR risk ratio; mean difference
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect
of the intervention (and its 95% CI).

4.4 What our Study adds to Literature?
Several observational studies have shown heterogeneous
evidence about benefit of ACEI/ARB in COVID-19. In this
context, several physicians have questioned if discontinuing
ACEI/ARB may benefit the patient. Indeed, ACEI/ARB may
present interactions with other drugs, such as NSAIDs [45],
which can be used in COVID-19 [46]. Moreover, some stud-
ies in animals have revealed that ACEI/ARB increase ACE2,
which may amplify the capacity of SARS-CoV-2 entry [32].
In this context, this review assesses the importance of
continuation or discontinuation ACEI/ARB in COVID-19
COVID-19 and Antihypertensive Drugs
patients. Regarding mortality, ICU admission and life-threat-
ing adverse events, our meta-analysis did not find any differ-
ence between the groups. Other non-metaanalyzed outcomes
were consistent with these findings. We analyzed the results
using an integral methodological appraisal (GRADE), and
the findings were considered high-quality. Nevertheless,
TSA of the main meta-analyses showed that there was no
enough data to confirm or reject the result in the RCT group
at a clinically significant RRR (20%).
The National Institute for Health and Care Excellence
[47] mentions that the risk of ACE/ARB discontinuation,
such as worsened heart failure or hypertension, are under-
stood. Several associations have recommended that patients
should not discontinue ACEI/ARB during COVID-19 pan-
demic [11].
Considering the results of our systematic review, we rec-
ommend to continue the ACEI/ARB therapy in those who
were chronically taking these drugs, however the decision
must be individualized according to contraindications or
in-hospital complications of the treatment. We also recom-
mend further studies with higher sample size. In addition,
due to the COVID-19 context there has been interruption of
screening or follow-up programs, especially in cardiovascu-
lar diseases, so it may contribute to missed diagnoses and
delayed therapy. Therefore, we highly recommend to keep
the follow-up of hypertensive patients to ensure the continu-
ation of medications [48].
4.5 Limitations
To our knowledge, this is the first systematic review explor-
ing the effects of ACEI/ARB in-hospital discontinua-
tion compared to continuation in COVID-19 patients. We
selected several databases, and performed an integral sys-
tematic review by not only analyzing the quantitative results,
but the qualitative ones and bias. However, there are some
limitations. First, RCTs were open-label, so it might have
introduced a bias in results. Then, exclusion criteria was
slightly heterogeneous among the RCT. Two studies showed
a crossover group, however sensitivity analysis showed
no influence on the main outcome. We found that sam-
ple size was not large enough to demonstrate a clinically
significant difference on outcomes. We could not perform
adjusted meta-analyses in the cohort groups, so the differ-
ence between groups may be overestimated. Some studies
reported its continuous outcomes in median, and we con-
verted it to mean, but it reduces the quality of meta-analysis,
therefore authors should interpret those results with caution.
Especially the global rank score meta-analysis that resulted
significant, since one study reported only the 10–90th per-
centile range, and we used it instead of 25–25th percentile to
calculate mean and standard deviation.Finally, we performed
an exploratory meta-analysis by comparing ACEI with ARB
277
group, nevertheless this result should not be taken as fully
true because it was not our main goal. The latter could be
taken by researchers as an idea for further reviews.
Supplementary Information The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 40292-0​ 23-0​ 0579-0.
Funding None.
Data Availability Regarding data availability, we did not upload a data-
base since meta-analyses data is available in all the cited papers that
we included in the review.
Declarations
Conflict of interest None.
References
1. Coronavirus Resource Center, Johns Hopkins University Maps &
Trends [accessed on January 1 2022]. Available from https://w
​ ww.​
coron​avirus.​jhu.​edu/​map.​html.
2. Bepouka B, Situakibanza H, Sangare M, Mandina M, Mayasi N,
Longokolo M, et al. Mortality associated with COVID-19 and
hypertension in sub‐Saharan Africa. A systematic review and
meta‐analysis. J Clin Hypertens. 2022;24(2):99.
3. Gong J, Sun Y, Xie L. ACEI/ARB drug therapy in COVID-19
patients: yes or no? J Transl Int Med. 2021;9(1):8–11.
4. Robson B. COVID-19 coronavirus spike protein analysis for
synthetic vaccines, a peptidomimetic antagonist, and therapeutic
drugs, and analysis of a proposed achilles’ heel conserved region
to minimize probability of escape mutations and drug resistance.
Comput Biol Med. 2020;121:103749.
5. Onweni CL, Zhang YS, Caulfield T, Hopkins CE, Fairweather
DL, Freeman WD. ACEI/ARB therapy in COVID-19: the double-
edged sword of ACE2 and SARS-CoV-2 viral docking. Crit Care.
2020;24:475.
6. Gavriilaki E, Anyfanti P, Gavriilaki M, Lazaridis A, Douma S,
Gkaliagkousi E. Endothelial dysfunction in COVID-19: lessons
learned from coronaviruses. Curr Hypertens Rep. 2020;22(9):63.
7. Esler M, Esler D. Can angiotensin receptor-blocking drugs
perhaps be harmful in the COVID-19 pandemic? J Hypertens.
2020;38(5):781–2.
8. Harky A, Chor CYT, Nixon H, Jeilani M. The controversy of
using angiotensin-converting enzyme inhibitors and angiotensin
receptor blockers in COVID-19 patients. J Renin Angiotensin
Aldosterone Syst. 2021;22(1):1470320320987118.
9. Székács B, Várbíró S, Debreczeni L. High-dose ACEi might be
harmful in COVID-19 patients with serious respiratory distress
syndrome by leading to excessive bradykinin receptor activation.
Physiol Int. 2021;108(1):1–9.
10. Villa-Zapata L, Carhart BS, Horn JR, Hansten PD, Subbian V,
Gephart S et al. Serum potassium changes due to concomitant
ACEI/ARB and spironolactone therapy: a systematic review and
meta-analysis. Am J Health Syst Pharm. 2021;78(24):2245–55.
11. Barry St JMH. COVID-19 and the role of angiotensin-converting
enzyme inhibitors and angiotensin receptor blockers. Can Pharm
J (Ott). 2020;153(4):193–7.
12. Oussalah A, Gleye S, Clerc Urmes I, Laugel E, Callet J, Barbé F
et al. Long-term ACE inhibitor/ARB use is associated with severe
renal dysfunction and acute kidney injury in patients with severe
COVID-19: results from a referral center cohort in the Northeast
of France. Clin Infect Dis. 2020;71(9):2447–56.
278
13. Alrashed AA, Khan TM, Alhusseini NK, Asdaq SMB, Enani M,
Alosaimi B, et al. Severity of COVID-19 infection in ACEI/ARB
users in specialty hospitals: a retrospective cohort study. J Infect
Public Health. 2021;14(6):726–33.
14. De Luca G, Cercek M, Okkels Jensen L, Bushljetikj O, Calmac
L, Johnson T, et al. Impact of renin-angiotensin system inhibitors
on mortality during the COVID pandemic among STEMI patients
undergoing mechanical reperfusion: insight from an international
STEMI registry. Biomed Pharmacother. 2021;138:111469.
15. Goyal A, Cusick AS, Thielemier B. ACE inhibitors. En: Stat-
Pearls. Treasure Island (FL): StatPearls Publishing; 2021.
16. Grover A, Oberoi M. A systematic review and meta-analysis to
evaluate the clinical outcomes in COVID-19 patients on angioten-
sin-converting enzyme inhibitors or angiotensin receptor blockers.
Eur Heart J Cardiovasc Pharmacother. 2021;7(2):148–57.
17. Xu J, Teng Y, Shang L, Gu X, Fan G, Chen Y et al. The effect
of prior angiotensin-converting enzyme inhibitor and angiotensin
receptor blocker treatment on coronavirus disease 2019 (COVID-
19) susceptibility and outcome: a systematic review and meta-
analysis. Clin Infect Dis. 2021;72(11):e901–13.
18. Dai XC, An ZY, Wang ZY, Wang ZZ, Wang YR. Associations
between the use of renin-angiotensin system inhibitors and the
risks of severe COVID-19 and mortality in COVID -19 patients
with hypertension: a meta-analysis of observational studies. Front
Cardiovasc Med. 2021;8:609857.
19. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred report-
ing items for systematic reviews and meta-analyses: the PRISMA
statement. Int J Surg. 2010;8(5):336–41.
20. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page
MJ, Welch VA, eds. Cochrane handbook for systematic reviews
of interventions version 6.3 (updated February 2022). Cochrane,
2022 [accessed on January 1 2022]. Available from https://​www.​
train​ing.​cochr​ane.​org/​handb​ook.
21. Chambergo-Michilot D, Runzer-Colmenares FM, Saldaña PAS.
Proyecto de tesis: Descontinuación del uso de fármacos anti-
hipertensivos comparado a la continuación en pacientes con
COVID-19: una revisión sistemática con meta-análisis y análisis
secuencial de ensayos clínicos. May 2021. https://d​ oi.o​ rg/1​ 0.6​ 084/​
m9.​figsh​are.​14526​663.​v1.
22. Lo CKL, Mertz D, Loeb M. Newcastle-Ottawa Scale: compar-
ing reviewers’ to authors’ assessments. BMC Med Res Methodol.
2014;14:45.
23. Veroniki AA, Jackson D, Viechtbauer W, et al. Methods to esti-
mate the between-study 2 variance and its uncertainty in meta-
analysis. Res Synth Methods. 2016;7(1):55–79.
24. IntHout J, Ioannidis JPA, Borm GF. The Hartung–Knapp–Sidik–
Jonkman method for random effects meta-analysis is straightfor-
ward and considerably outperforms the standard DerSimonian-
Laird method. BMC Med Res Methodol. 2014;14:25.
25. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring
inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.
26. Egger M, Davey Smith G, Schneider M, Minder C. Bias in
meta-analysis detected by a simple, graphical test. BMJ.
1997;315(7109):629–34.
27. Yu CL, Carvalho AF, Thompson T, Tsai TC, Tseng PT, Hsu CW,
et al. Trial sequential analysis and updated meta-analysis of flu-
voxamine on clinical deterioration in adult patients with symp-
tomatic COVID-19 infection. Int J Environ Res Public Health.
2023;20(5):4088.
28. Bellaver P, Schaeffer AF, Leitao CB, Rech TH, Nedel WL. Asso-
ciation between neuromuscular blocking agents and the devel-
opment of intensive care unit-acquired weakness (ICU-AW): a
systematic review with meta-analysis and trial sequential analysis.
Anaesth Crit Care Pain Med. 2023;42(3):101202.
29. Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell
S, Hill SR, et al. Ivermectin for prevention and treatment of
D. Chambergo‑Michilot et al.
COVID-19 infection: a systematic review, meta-analysis, and
trial sequential analysis to inform clinical guidelines. Am J
Ther. 2021;28(4):e434.
30. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J,
et al. GRADE guidelines: 1. Introduction-GRADE evidence
profiles and summary of findings tables. J Clin Epidemiol.
2011;64(4):383–94.
31. Lopes RD, Macedo AVS, de Barros E, Silva PGM, Moll-Ber-
nardes RJ, dos Santos TM, Mazza L, et al. Effect of discontinu-
ing vs continuing angiotensin-converting enzyme inhibitors and
angiotensin II receptor blockers on days alive and out of the
hospital in patients admitted with COVID-19: a randomized
clinical trial. JAMA. 2021;325(3):254.
32. Cohen JB, Hanff TC, William P, Sweitzer N, Rosado-Santander
NR, Medina C et al. Continuation versus discontinuation of
renin–angiotensin system inhibitors in patients admitted to hos-
pital with COVID-19: a prospective, randomised, open-label
trial. Lancet Respir Med. 2021;9(3):275–84.
33. Bauer A, Schreinlechner M, Sappler N, Dolejsi T, Tilg H, Aul-
inger BA et al. Discontinuation versus continuation of renin-
angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a
prospective, parallel group, randomised, controlled, open-label
trial. Lancet Respir Med. 2021;9(8):863–72.
34. Cannata F, Chiarito M, Reimers B, Azzolini E, Ferrante G, My
I, et al. Continuation versus discontinuation of ACE inhibitors
or angiotensin II receptor blockers in COVID-19: effects on
blood pressure control and mortality. Eur Heart J Cardiovasc
Pharmacother. 2020;6(6):412–4.
35. Lam KW, Chow KW, Vo J, Hou W, Li H, Richman PS, et al.
Continued in-hospital angiotensin-converting enzyme inhibitor
and angiotensin II receptor blocker use in hypertensive COVID-
19 patients is associated with positive clinical outcome. J Infect
Dis. 2020;222(8):1256–64.
36. de Abajo FJ, Rodríguez-Miguel A, Rodríguez-Martín S, Lerma
V, García-Lledó A, de Abajo FJ, et al. Impact of in-hospital
discontinuation with angiotensin receptor blockers or convert-
ing enzyme inhibitors on mortality of COVID-19 patients: a
retrospective cohort study. BMC Med. 2021;19(1):118.
37. Roy-Vallejo E, Sánchez Purificación A, Torres Peña JD, Sánchez
Moreno B, Arnalich F, García Blanco MJ, et al. Angiotensin-
converting enzyme inhibitors and angiotensin receptor blockers
withdrawal is associated with higher mortality in hospitalized
patients with COVID-19. J Clin Med. 2021;10(12):2642.
38. Chaudhri I, Koraishy FM, Bolotova O, Yoo J, Marcos LA, Taub
E, et al. Outcomes associated with the use of renin-angioten-
sin-aldosterone system blockade in hospitalized patients with
SARS-CoV-2 infection. Kidney360. 2020;1(8):801–9.
39. Zhang X, Yu J, Pan L-Y, Jiang H-Y. ACEI/ARB use and risk of
infection or severity or mortality of COVID-19: a systematic
review and meta-analysis. Pharmacol Res. 2020;158:104927.
40. Baral R, White M, Vassiliou VS. Effect of renin-angiotensin-
aldosterone system inhibitors in patients with COVID-19: a
systematic review and meta-analysis of 28,872 patients. Curr
Atheroscler Rep. 2020;22(10):61.
41. Patoulias D, Katsimardou A, Stavropoulos K, Imprialos K,
Kalogirou MS, Doumas M. Renin-angiotensin system inhibi-
tors and COVID-19: a systematic review and meta-analysis.
Evidence for significant geographical disparities. Curr Hyper-
tens Rep. 2020;22(11):90.
42. Xue Y, Sun S, Cai J, Zeng L, Wang S, Wang S, et al. Effects of
ACEI and ARB on COVID-19 patients: a meta-analysis. J Renin
Angiotensin Aldosterone Syst. 2020;21(4):1470320320981321.
43. Gallo G, Volpe M, Savoia C. Endothelial Dysfunction in hyper-
tension: current concepts and clinical implications. Front Med.
2022;8:798958.
COVID-19 and Antihypertensive Drugs
44. Khateri S, Mohammadi H, Khateri R, Moradi Y. The prevalence
of underlying diseases and comorbidities in COVID-19 patients;
an updated systematic review and meta-analysis. Arch Acad
Emerg Med. 2020;8(1):e72.
45. Harężlak T, Religioni U, Szymański FM, Hering D, Barańska A,
Neumann-Podczaska A, et al. Drug interactions affecting kidney
function: beware of health threats from triple whammy. Adv Ther.
2022;39(1):140.
46. Abu Esba LC, Alqahtani RA, Thomas A, Shamas N, Alswaidan
L, Mardawi G. Ibuprofen and NSAID use in COVID-19 infected
patients is not associated with worse outcomes: a prospective
cohort study. Infect Dis Ther. 2021;10(1):253–68.
47. NICE. Factors for decision making: COVID-19 rapid evidence
summary: angiotensin-converting enzyme inhibitors (ACEIs) or
279
angiotensin receptor blockers (ARBs) in people with or at risk of
COVID-19: advice. https://w ​ ww.n​ ice.o​ rg.u​ k/a​ dvice/e​ s24/c​ hapte​ r/​
Facto​rs-​for-​decis​ion-​making.
48. Volpe M, Gallo G. COVID-19 and the forgotten majority. High
Blood Press Cardiovasc Prev. 2020;27(5):339.
Springer Nature or its licensor (e.g. a society or other partner) holds
exclusive rights to this article under a publishing agreement with the
author(s) or other rightsholder(s); author self-archiving of the accepted
manuscript version of this article is solely governed by the terms of
such publishing agreement and applicable law.