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International Journal of Cardiology. Heart & Vasculature logoLink to International Journal of Cardiology. Heart & Vasculature
. 2020 Aug 27;31:100627. doi: 10.1016/j.ijcha.2020.100627

Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis

Daniel Caldeira a,b,c,, Mariana Alves c,d,e, Ryan Gouveia e Melo a,f, Pedro Silvério António a,b, Nélson Cunha a,b, Afonso Nunes-Ferreira a,b, Luisa Prada c, João Costa c,e, Fausto J Pinto a,b
PMCID: PMC7451091  PMID: 32875060

Abstract

Objective

Animal studies suggested that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) facilitate the inoculation of potentially leading to a higher risk of infection and/or disease severity. We aimed to systematically evaluate the risk of COVID-19 infection and the risk of severe COVID-19 disease associated with previous exposure to (ACEi) and/or ARB).

Methods

MEDLINE, CENTRAL, PsycINFO, Web of Science Core Collection were searched in June 2020 for controlled studies. Eligible studies were included and random-effects meta-analyses were performed. The estimates were expressed as odds ratios (OR) and 95% confidence intervals (95%CI). Heterogeneity was assessed with I2 test. The confidence in the pooled evidence was appraised using the GRADE framework.

Results

Twenty-seven studies were included in the review. ACEi/ARB exposure did not increase the risk of having a positive test for COVID-19 infection (OR 0.99, 95%CI 0.89–1.11; I2 = 36%; 5 studies, GRADE confidence moderate). The exposure to ACEi/ARB did not increase the risk of all-cause mortality among patients with COVID-19 (OR 0.91, 95%CI 0.74–1.11; I2 = 20%; 17 studies; GRADE confidence low) nor severe/critical COVID-19 disease (OR 0.90, 95%CI 0.74–1.11; I2 = 55%; 17 studies; GRADE confidence very low). Exploratory analyses in studies enrolling hypertensive patients showed a association of ACEi/ARB with a significant decrease of mortality risk.

Conclusions

ACEi/ARB exposure does not seem to increase the risk of having the SARS-CoV-2 infection or developing severe stages of the disease including mortality. The potential benefits observed in mortality of hypertensive patients reassure safety, but robust studies are required to increase the confidence in the results.

Keywords: Coronavirus, SARS-CoV-2, Angiotensin-converting enzyme inhibitor, Angiotensin-receptor blocker, Acute respiratory distress syndrome, Acute lung injury

1. Introduction

The novel acute respiratory syndrome coronavirus 2 (SARS-CoV-2) firstly identified in Wuhan China lead to a world-wide outbreak pandemic situation with more than 350,000 related deaths [1]. The SARS-CoV-2 goes into the host cells through the angiotensin-converting enzyme (ACE) 2 (ACE2) receptor [2]. Some animal studies showed that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) increase the ACE2, creating the hypothesis that these drugs could facilitate the inoculation of SARS-CoV-2 potentially leading to a higher risk of infection and/or disease severity [3]. The fragility of these assumptions led several medical societies to issue a recommendation for not withdrawing these drugs because the evidence was not compelling and due to the potential harms, as these drugs are effective treatments in the management of hypertension, diabetes mellitus, coronary heart disease, cerebrovascular disease and/or chronic kidney disease for many people. In this systematic review we aimed to assess the risk of infection by SARS-CoV-2 and the risk of mortality or respiratory complications in patients with symptomatic disease of SARS-CoV-2 (COVID-19) related to previous use of ACEi or ARBs.

2. Methods

This systematic review followed the reporting principles of MOOSE and PRISMA [4], [5]. The protocol is available at https://osf.io/6vf2w. Patients and public were not involved in this review.

2.1. Eligibility criteria

We included all controlled studies with information about risk of infection or the risk of disease complications associated with ACEi and/or ARBs.

For randomized controlled trials or cohort/nested case-control studies that evaluated the risk of infection (positive test), studies had to enrol a population submitted to tests and to report the risk of having a positive test associated with ACEi and/or ARB, or having raw data that enables these calculations.

Regarding the risk of disease complications, studies had to evaluate the risk of mortality/severe disease associated with ACEi and/or ARB use compared with patients not treated with these drugs, both from a population perspective or among population infected with SARS-CoV-2. ACEi or ARBs had to be reported by the investigators as a group (ACEi/ARB) or individually. We accepted controls treated with other antihypertensive drugs or without any antihypertensive drug.

In case-control studies, cases were patients with COVID-19 infection (positive test) irrespective of disease severity, and controls were matched individuals without the referred outcomes. Data about ACEi and/or ARB risks should be available.

The outcomes of interest were:

  • 1)

    COVID-19 infection documented by nasophaygeal or oropharyngeal swab tests or reported by authors as having COVID-19;

  • 2)

    All-cause Mortality;

  • 3)

    Severe/Critical Disease according with the World Health Organization and Chinese Centre of Disease Control [6], [7].

Whenever possible, if adequate, adjusted measures were retrieved particularly for observational studies, giving preference to propensity score matching or weighting.

2.2. Search methods for study identification

The reviewers performed an electronic database search through MEDLINE, CENTRAL, PsycINFO and Web of Science Core Collection databases for relevant studies (Search strategy at Supplementary Table 1). The database medRxiv was also searched for unpublished pre-print manuscripts for an exploratory analysis. Relevant reviews obtained in the searching process as well as the references of potentially included studies were analysed in order to search for potential eligible studies. There were no restrictions on language or publication date. The search lastly performed at 8th June 2020.

2.3. Study selection and data collection process

The title and abstract screening phase of records yielded by the search was performed independently by clusters of 2 reviewers. Disagreements were resolved through consensus or by a third reviewer (DC). The studies that were not excluded went to the full-text assessment phase.

The reasons for exclusion were recorded at this stage.

The reviewers extracted study data following a pre-established data collection form. When studies presented different estimates of the outcome of interest, we extracted the most precise or adjusted measures.

Risk of bias was independently evaluated by three authors (DC, MA, ANF) using the Cochrane Risk of Bias Tool for randomized controlled trials and ROBINS-I tool for observational studies [8], [9]. The studies were qualitatively classified as at critical, serious, moderate, or low risk of bias. Risk of bias graphs were derived from these tools.

2.4. Statistical analysis and pooled data evaluation

We used Review Manager for statistical analysis and to derive forest plots. We used the inverse variance method and random-effects model to pool data. We reported pooled dichotomous data using odds ratios (OR) with their 95% confidence intervals (95% CIs). Heterogeneity was assessed using I2 [10]. We present effect estimates as OR because relative estimates are more similar across studies with different designs, populations and lengths of follow-up than absolute effects [11]. We used the hazard ratio (HR) when OR was not available nor possible to calculate. Publication bias assessment was performed through funnel plot examination and Egger test providing that a sufficient number of studies were included [12].

Exploratory analyses were performed with adjusted estimates, and only those with data of hypertensive patients. We further performed an additional exploratory analysis including unpublished (Preprint) studies found in medRxiv.

We used the Grading of Recommendations, Assessment, and Evaluation (GRADE) framework to report the overall quality of evidence. The certainty in the evidence for each outcome was graded as high, moderate, low, or very low [13].

3. Results

3.1. Included studies

The search returned 528 records, resulting in 27 study records after the deduplication, title and abstract screening and full-text screening (Fig. 1; details of excluded studies at Supplementary Table 2) [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40]. There was one randomized controlled trial (a non-prespecified interim analysis of an open-label trial), 4 case-control studies (two of them – Gnavi et al – were reported in the same article) and the remaining were cohort/nested case-control studies.

Fig. 1.

Fig. 1

Flowchart of studies selection process.

The main characteristics of the included studies are depicted in Table 1. The median sample size was 522 [interquartile range 113–4051] and overall, there were 119,656 participants evaluated.

Table 1.

Main characteristics of included studies.

Study Year Design Region Population Total/ ACEi/ARB Control Mean-median age / % female Comorbidities Outcome adjustments
RANDOMIZED CONTROLLED TRIAL
Amat-Santos 2020 Non-planned interim analysis of an open-label RCT Spain Patients with aortic stenosis successfully treated with transcatheter aortic valve
replacement
ACEi (ramipril): 52 Placebo: 50 83

47%
HTN: 54%
CAD: 26%
DM: 20%
CKD: 33%



CASE-CONTROL STUDIES
de Abajo 2020 Case-control study Madrid, Spain Case: ≥ 18 years with PCR-confirmed COVID-19 requiring hospital admission (n = 1139)

Control: from database Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database (n = 11390)

Matching 1:10 by sex and age
COVID-19 positive

Total: 497
ACEi: 240
ARB: 244
Aldosterone antagonists: 38
Renin inhibitors: 1
COVID-19 negative

Total: 3822
ACEi: 2192
ARB: 1616
Aldosterone antagonists:218
Renin inhibitors: 8
69

61%
HTN: 54% COVID-19+
50% COVID-19 -
CAD: 11% COVID-19+
8% COVID-19 -
DM: 27% COVID-19+
20% COVID-19 -
CKD: 8% COVID-19+
5% COVID-19 -
HF: 7% COVID-19+
4% COVID-19 -
Age, sex, diabetes, dyslipidemia, ischemic heart disease, heart failure, atrial fibrillation, thromboembolic disease, cerebrovascular accident, chronic obstructive pulmonary disease, asthma, cancer, and chronic kidney disease
Gnavi 2020 Nested case-control study in 2 cohorts Piedmont, Italy Case: Discharged patients with confirmed COVID-19 infection (RT-PCR) in
- Hypertensive patients (N = 316)
- Cardiovasular disease* patients (N = 171)

Control: Discharged patients without COVID-19 infection

Matching 1:5 by sex and age
COVID-19 positive

Total: 215
ACEi: NR
ARB: NR

Total: 93
ACEi: NR
ARB: NR
COVID-19 negative

Total: 1153
ACEi: NR
ARB: NR

Total: 475
ACEi: NR
ARB: NR
71 (hypertension cohort);
75 (cardiovascular disease cohort)


31% (hypertension cohort);
22% (cardiovascular disease cohort)
HTN: 100% Age, sex, and disease type (hypertension or cardiovascular disease)
Mancia 2020 Population-based case–control study Lombardy Italy Case: Positive COVID-19 patients (≥40 years old)
N = 6272

Control: beneficiaries of the Regional Health Service
N = 30759

Matched 1:5 by sex, age at index date, and municipality of residence
COVID-19 positive

Total: 2896
ACEi: 1502
ARB: 1394
COVID-19 negative

Total: 27863
ACEi: 6569
ARB: 5910
68

37%
NR Cardiovascular disease, respiratory disease, kidney disease, cancer, antihypertensive agents, lipid lowering agents, oral hypoglycemic agents, insulin, antiplatelet agents, antiarrhythmic agents, anticoagulant agents, digitalis, nitrates, inhaled glucocorticoids, nonsteroidal antiinflamatory drugs, immunosuppressive agents, beta agonists, other drugs for respiratory disease
COHORT/NESTED CASE-CONTROL STUDIES
Argenziano 2020 Single-center retrospective cohort study New York, USA Patients with hypertension and diabetes admitted in the emergency department or in the hospital for COVID-19 infection
N = 1000
Total: 284
ACEI: NR
ARB: NR
Non-ACEi/ARB: 716
63

40%
HTN: 60%
CAD: 13%
DM: 37%
CKD: 14%
HF: 10%
Bean 2020 Retrospective cohort study London, UK

Adult COVID 19 symptomatic patients
N = 1200
Total: 399
ACEi: 260
ARB: 147
Non-ACEi/ARB: 801
68

43%
HTN: 54%
DM: 35%
CKD: 17%
HF: 9%
Age, sex, hypertension, diabetes mellitus, chronic
kidney disease, ischaemic heart disease, heart failure
Chen 2020 Retrospective cohort study Wuhan, China Patients with hypertension and diabetes admitted in the hospital for symptomatic COVID-19 infection
N = 71
Total: 31
ACEi: NR
ARB: NR
Non-ACEi/ARB: 39 67

NR
HTN: 100%
DM: 100%
Chodik 2020 Cross sectional Cohort Tel Aviv, Israel individuals tested for SARS-COV-2 (RT-PCR)
N = 1317 positive
N = 13203 negative
Total: 991
ARB 603
ACEI 388
Non-ACEi/ARB: 13,529 41 COVID-19+
37 COVID-19–


40% COVID-19 + /
46% COVID-19 -
HTN: 14% COVID-19+
11% COVID-19 -
DM: 9% COVID-19+
5% COVID-19 -
CKD: 8% COVID-19+
6% COVID-19 -
HF: 0.2% COVID-19+
0.6% COVID-19 -
Age, sex, SES, BMI, and co-morbidities
Yan, 2020 Multicentre retrospective case-control study Zhejiang, China Case:
Consecutive patients presenting to hospital with confirmed diagnosis of Covid-19 infection
N = 610

Control:
Population-based control group
N = 48667
COVID-19+
Total: 58
ACEi: 5
ARB: 53
COVID.19 -
Total: 8040
ACEi: 555
ARB: 7485
49

49%
HTN: 22%
DM: 10%
CVD/cerebrovascular disease: 3%
Age, sex, BMI
Felice 2020 Single-centre retrospective cohort study Treviso, Italy Symptomatic COVID-19 hypertensive patients presenting to the emergency department
N = 133
Total: 82
ACEI: 40
ARB: 42
Non-ACEi/ARB: 51
73

35%
HTN: 100%
DM: 26%
HF: 24%
Feng 2020 Multi-center retrospective cohort study Wuhan, Shangai, Tongling
China
Subgroup of hypertensive COVID 19 symptomatic patients admitted in 3 hospitals
N = 113
Total: 33
ACEi: NR
ARB: NR
Non-ACEi/ARB: 62 53

45%
HTN: 100%
Gao 2020 Single-centre retrospective cohort study Wuhan, China Subgroup of hypertensive COVID 19 symptomatic patients admitted in the hospital
N = 710
Total: 183
ACEi: NR
ARB: NR
Non-ACEi/ARB: 527 64

48%
HTN: 100%
DM: 28%
HF: 3%
CKD: 2%
MI: 1%
Propensity-matched score for mortality
Age, sex, medical history of diabetes, insulin-treated diabetes, myocardial infarction, PCI/CABG, renal failure, stroke, heart failure, and COPD
Hu 2020 Retrospective single-centre cohort Zhejiang, China
Subgroup of hypertensive COVID 19 symptomatic patients admitted in the hospital
N = 149
Total: 65
ACEi: NR
ARB: NR
Non-ACEi/ARB: 84 57

41%
HTN 100%
DM: 20%
CKD: 4%
Huang 2020 Retrospective single-centre cohort Wuhan, China Hypertensive COVID 19 symptomatic patients admitted in the hospital
N = 50
Total: 20
ACEi: NR
ARB: NR
Non-ACEi/ARB: 30
62

45%
HTN: 100%
DM: 8%
CAD: 2%
Imam 2020 Retrospective multicentre cohort Detroit, USA COVID-19 symptomatic patients
N = 1305
Total: 565
ACEi: NR
ARB: NR
Non-ACEi/ARB: 740 61

46%
HTN: 56%
DM: 30%
HF: 6%
Vascular Disease: 16%
Age, comorbidities, NSAID, ACEi/ARB
Jung 2020 Cohort study Seoul, Korea Adult COVID 19 patients
N = 5179
Total: 762
ACEI: 32
ARB: 730
Non-ACEi/ARB: 1577
45

56%
HTN: 22%
DM: 17%
HF: 4%
CAD: 1%
CKD: 5%
Age, sex, Charlson Comorbidity Index, immunosuppression, and hospital type.
Li 2020 Retrospective, single-center cohort Wuhan, China Hypertensive COVID 19 symptomatic hospitalized patients
N = 362
Total: 115
ACEi: NR
ARB: NR
Non-ACEI/ARB: 247 66

41-51%
HTN: 100%
DM 35%
Cerebrovascular disease: 23%
CHD: 18%
HF 3%
Mehra, 2020 Cohort/Nested case-control 169 hospitals in Asia, Europe, and North
America
Hospitalized patients from Surgical
Outcomes Collaborative (Surgisphere), an international registry
N = 8910
Total: 1326
ACEi: 770
ARB: 556
Non-ACEi/ARB: 7584 49

40%
HTN: 26%
CAD: 11%
DM: 14%
HF: 2%
Dyslipidemia: 31%
COPD: 3%
Age, sex, hypertension
Mehta, 2020 Retrospective cohort study Ohio and Florida, USA Patients tested for COVID-19 N = 18472 N positive = 1735 N negative = 16737 Total: 2285
ACEi: 1322
ARB: 982
Non-ACEi/ARB: 16187


49

60%
HTN: 93%
DM: 46%
CAD: 22%
HF: 17%
COPD: 14%
Propensity score: Age, sex, and presence of hypertension, diabetes, coronary artery disease, heart failure, and COPD
Meng, 2020 Retrospective single center case control Shenzhen, China Hospitalized patients with COVID-19 and receiving anti-hypertensive therapy
N = 42
Total: 17
ACEi: NR
ARB: NR
Non-ACEi/ARB: 25 65

43%
HTN: 100%
DM: 24% ACEi/ARB
8% Non-ACEi/ARB
CHD: 35% ACEi/ARB
8% Non-ACEi/ARB
Million, 2020 Retrospective cohort study Marseille, France COVID-19 positive tested patients
N = 1061
ARB: 40 Non-ARB: 1021 44

54%
HTN: 14%
DM: 7%
CAD: 4%
Obesity: 6%
Chronic Respiratory Disease: 11%
Age, comedications, COVID-19 severity score
Montastruc 2020 Retrospective cohort study Toulouse, France Adult patients positive for COVID-19 admitted in the intensive care unit
N = 96
Total: 35
ACEI: 12
ARB: 23
Non-ACEi/ARB: 61 63

21%
HTN: 45%
DM: 28%
CKD: 10%
Arrythmia: 6%
Peng 2020 Retrospective cohort study Wuhan, China Hospitalized COVID-19 patients with Cardiovascular disease
N = 112
Total: 22
ACEi: NR
ARB: NR
Non-ACEi/ARB: 90 61

53%
DM: 33%
HTN: 82%
Reynolds 2020 Retrospective cohort study New York, USA Patients tested for COVID-19 N = 12594 N positive = 5894 N negative = 6700 Risk of infection (PSM):
Total 1909
ACEi: 1137
ARB: 1044

Risk of severe infection (PSM):
Total 1110
ACEi: 627
ARB: 664
Risk of infection (PSM):
Non-ACEi/ARB: 4344




Risk of severe infection (PSM):
Non-ACEi/ARB: 2453
49

59%
HTN: 35%
DM: 18%
HF: 6%
MI: 4%
CKD: 18%
COPD: 15%
Current smoker: 5%
Former smoker: 18%
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)
Tan, 2020 Retrospective cohort study Wuhan, China Subgroup of symptomatic COVID-19 patients with hypertension
N = 100
Total: 31
ACEi: NR
ARB: NR
Non-ACEi/ARB: 69 67

NR
HTN: 100%
DM: 26% ACEi/ARB
29% Non-ACEi/ARB
GI: 19% ACEi/ARB
25% Non-ACEi/ARB
CKD: 7% ACEi/ARB
13% Non-ACEi/ARB
CHD: 10% ACEi/ARB
16% Non-ACEi/ARB
COPD: 7% ACEi/ARB
10% Non-ACEi/ARB
Tumor: 3% ACEi/ARB
6% Non-ACEi/ARB
Tedeschi, 2020 Prospective cohort study Bologna,
Italy
Hypertensive adult COVID 19 patients hospitalized
N = 311
Total: 175
ACEI: 99
ARB: 76
Non-ACEi/ARB: 136 76

28%
HTN: 100%
CAD: 42%
DM: 24%
Age, gender, presence of CV comorbidities and COPD
Yang, 2020 Retrospective, single-center study Wuhan, China
Subgroup of hypertensive patients with COVID-19 hospitalized
N = 126
Total: 43
ACEi: NR
ARB: NR
Non-ACEi/ARB: 83 Median 67

51%
HTN: 100%
DM: 30%
Respiratory disease: 5%
Kidney disease: 3%
Hepatic disease: 6%
Cardiopathy: 18%
Neurological disease: 8%
Zhang, 2020 Retrospective cohort/nested case-control Hubei, China Hypertensive patients with COVID-19 hospitalized
N = 522

matching 1:2
Total: 174
ACEi: NR
ARB: NR
Non-ACEi/ARB: 348 median 64

47%
HTN: 100%
DM: 24%
CAD: 12%
CKD 3%
CVD: 3%
COPD: 1%
Age, gender, fever, cough, dyspnea, comorbidities (diabetes, coronary heart disease, and chronic renal disease), CT-diagnosed bilateral lung lesions, and incidence of increased CRP and creatinine.
Zhou 2020 Retrospective, single-center study Wuhan, China
Subgroup of hypertensive patients with symptomatic COVID-19 hospitalized
N = 36
Total: 15
ACEi: NR
ARB: NR
Non-ACEi/ARB: 21 65

47%
HTN:100%
DM: 25%
CVD: 19%
Age, sex, hospitalization time, time from onset to hospital admission, and whether to take ACEi or ARB



UNPUBLISHED
Rossi 2020 Population-based prospective cohort study on archive data Reggio Emilia,
Italy
COVID-19 symptomatic patients
N = 2653
Total: 818
ACEi: 450
ARB: 368
Non-ACEi/ARB: 1835 63

50%
HTN: 18%
DM: 12%
MI: 7%
HF: 6%
CKD: 3%
COPD: 5%
Vascular disease: 3%
Age, sex and analysis restricted to subjects with ischemic heart disease, hypertension, or heart failure
Ip 2020 Retrospective, Cohort, multicenter study New Jersey, USA Subgroup of hypertensive COVID 19 symptomatic hospitalized patients
N = 1584
Total: 1231
ACEi: 688
ARB: 543
Non-ACEi/ARB: NR NR HTN: 100%
Liu 2020 Multicentre retrospective cohort study Shenzhen, Wuhan, and Beijing, China Hypertensive COVID 19 symptomatic hospitalized elderly pts (greater than65 years-old)
N = 78
Total: 12
ACEi: 2
ARB: 10
Non-ACEi/ARB: 8 NR HTN 100% Gender
Rentsch 2020 Retrospective cohort study Connecticut, USA Patients from National Veterans Affairs Healthcare System tested for COVID-19 N = 3789 Total: 1532
ACEi: NR
ARB: NR
Non-ACEi/ARB: 2257 66

10%
HTN: 65%
DM: 38%
Vascular disease: 29%
COPD: 26%
Alcohol use disorder: 14%
Age, sex, race, medication, residence type, comorbidities
Zeng 2020 Retrospective, single-center study Wuhan,
China
Subgroup of hypertensive patients with clinically confirmed COVID-19 hospitalized
N = 75
Total: 28
ACEi: NR
ARB: NR
Non-ACEi/ARB: 47 67

53%
HTN: 100%
DM: 31%
CVD: 21%
CKD: 5%
Khera 2020 Retrospective Cohort Connecticut, USA Hypertension patients hospitalized for COVID-19 N = 7933 Total: 4587
ACEi: 2361
ARB: 2226
Non-ACEI/ARB: 3346 Median 69

53%
HTN 100%
DM: 68%
MI 4%
HF 14%
Propensity score: age, gender, race, insurance type, conditions that may lead to selective use of ACE inhibitors and ARBs each of the comorbidities in the Charlson Comorbidity Index, and the number of anti-hypertensive agents used for the patient

*with a diagnosis of ischaemic heart disease (ICD9CM at discharge 410–414), cerebrovascular disease (430–438), or heart failure (428), and persons registered in the regional register of persons with diabetes.

Legend: RT-CPR reverse transcriptase-polymerase chain reaction; ACEi Angiotensin-converting-enzyme inhibitors; ARB angiotensin receptor blocker; RAAS renin-angiotensin-aldosterone system; SES socioeconomic status; BMI body mass index; HTN hypertension; CAD coronary artery disease; HF heart failure; DM diabetes mellitus; CKD chronic kidney disease; MI myocardial infarction; COPD Chronic obstructive pulmonary disease; CHD chronic heart disease; PCI percutaneous coronary intervention; PSM: Propensity-score matching CABG coronary artery bypass graft; NSAID Nonsteroidal anti-inflammatory drugs; GI gastrointestinal; CT computed tomography; CRP c-reactive protein; pts patients.

3.2. Risk of bias

The risk of bias in the included studies was moderate for studies evaluating the risk of infection, while those assessing the infection severity/mortality were classified as serious. The only randomized controlled trial had an open-label design, a small sample size (n = 102) and was not designed to assess COVID-19 outcomes as the reported results were from a non-prespecified interim analysis. The lack of outcome adjustments for important clinical factors was the main source of risk of bias. Supplementary Table 3 details the risk of bias for each study according with the outcome. Supplementary Fig. 1 overviews the proportions of risk of bias categories.

3.3. Risk of COVID-19 infection (positive test) associated with ACEi/ARB

Six cohorts had information about COVID-19 infection (positive test) and ACEi and/or ARB. In the meta-analysis the ACEi/ARB group was not associated with increased risk of having a positive test for COVID-19 infection (OR 0.99, 95%CI 0.91–1.11; I2 = 36%; 6 studies; Fig. 2), nor ACEi (OR 0.94, 95%CI 0.87–1.02; I2 = 0%; 7 studies) or ARB (OR 1.01, 95%CI 0.93–1.10; I2 = 11%; 6 studies) (Supplementary Figs. 2 and 3), individually.

Fig. 2.

Fig. 2

Forest plots of ACEi/ARB association with the risk of COVID-19 infection and disease severity.

3.4. Mortality risk associated with ACEi/ARB among patients with COVID-19 infection

Regarding all-cause mortality, ACEi or ARB were associated with neither an increased nor reduction in the risk this outcome: ACEi/ARB, OR 0.91, 95%CI 0.74–1.11, I2 = 20%, 17 studies, Fig. 2); ACEi, OR 0.85, 95%CI 0.40–1.78, I2 = 0%, 4 studies; and ARB OR 0.80, 95%CI 0.47–1.35, I2 = 0%, 3 studies (Fig. 3; Supplementary Figs. 2 and 3).

Fig. 3.

Fig. 3

Forest plots of ACEi or ARB association with the risk of COVID-19 infection and disease severity, and the results of subanalyses of ACEi/ARB.

3.5. Risk of severe disease associated with ACEi/ARB among patients with COVID-19 infection

The risk of severe COVID-19 disease associated with ACEi/ARB (OR 0.90, 95%CI 0.74–1.11; I2 = 55%; 17 studies; Fig. 2), ACEi (OR 1.05, 95%CI 0.64–1.70; I2 = 63%; 4 studies) or ARB (OR 1.32, 95%CI 0.75–2.30; I2 = 86%; 6 studies) individually was not significantly increased nor decreased (Fig. 3; Supplementary Figs. 2 and 3).

3.6. Risk of severe disease associated with ACEi/ARB compared with populational controls

Two case-control studies evaluated the risk of severe COVID-19 associated with ACEi/ARB using populational controls as reference [17], [27]. One only study had data about a grouped estimate of ACEi/ARB and the results did not support the hypothesis that ACEi/ARB was associated with severe COVID-19 (OR 1.08, 95%CI 0.79–1.47; 1 study) [27]. Two studies supplied data for ACEi and ARB individually [17], [27], and the pooled estimates for both evaluations showed no significant effects (ACEi: OR 0.91, 95% 0.72–1-14; I2 = 0%, 2 studies; ARB: 1.01, 95%CI 0.67–1.50; I2 = 69%; 2 studies; Fig. 3; Supplementary Figs. 2 and 3).

3.7. Publication bias risk assessment

We performed the Egger test in the evaluations of ACEi/ARB with more than 10 studies to determine whether publication bias exists. The Egger test was not statistically significant in the risk of having COVID-19 infection (p-value 0.64), risk of mortality among those symptomatic COVID-19 (p-value 0.09), and risk of severe disease among those with COVID (p-value 0.42). The funnel plots are depicted in Supplementary Figure 4.

3.8. Sub-analyses

We performed sub-analyses of ACEi/ARB association including only studies with adjusted estimates, hypertensive patients, and including unpublished data (Fig. 3).

The analysis of studies with adjusted estimates did not find any significant association between ACEi/ARB and risk of infection (OR 0.99, 95%CI 0.89–1.11, I2 = 35%, 5 studies), mortality (OR 0.90, 95%CI 0.68–1.18, I2 = 27%) and severe/critical disease (OR 0.88, 95%CI 0.63–1.22, I2 = 68%) among patients with COVID-19 (Fig. 3, Supplementary Figure 5).

Analysing only the data from hypertensive patients, the risk of developing the infection in patients treated with ACEi/ARB was not significantly increased (OR 0.97, 95%CI 0.85–1.11; I2 = 38%) (Fig. 3, Supplementary Figure 6). The mortality risk (OR 0.76, 95%CI 0.59–0.98; I2 = 0%) was significantly decreased in this population while the risk of developing severe disease (OR 0.91, 95%CI 0.69–1.21; I2 = 64%) was not statistically significant (Fig. 3, Supplementary Figure 6).

Considering both published and unpublished data retrieved from 7 additional studies (supplementary Table 4), there was a non-statistically significant association between ACEi/ARB and decreased mortality risk among COVID-19 patients (OR 0.79, 95%CI 0.62–1.00, I2 = 0%) (Fig. 3, Supplementary Figure 5). The risk of infection (OR 0.99, 95%CI 0.91–1.09, I2 = 20%) and the risk of severe/critical disease (OR 0.89, 95%CI 0.70–1.14, I2 = 59%) were neither significantly increased nor decreased (Fig. 3, Supplementary Figure 7).

3.8.1. Assessment of confidence in cumulative evidence

Table 2 presents a summary of findings table which summarizes the results obtained only for the associations found for grouped ACEi/ARB exposure, according to certainty of the evidence (GRADE). The current evidence is that ACEi/ARB use is not associated with increased clinically significant risk of having a positive test with moderate confidence. Mortality risk among COVID-19 patients was significantly decreased, but the confidence of these data was graded as low (Table 2). The confidence concerning the association of ACEi/ARB and risk severe/critical disease among COVID-19 patients was very low (Table 2).

Table 2.

Summary of finding table with the GRADE approach.

Outcomes № of studies Certainty of the evidence (GRADE) for the lack of effect* Relative effect (95% CI)
ACEi/ARB and COVID-19
Positive test 5 observational studies graphic file with name fx1.gif 0.99
(0.89–1.11)
Mortality among COVID-19 patients 17 observational studies graphic file with name fx2.gif OR 0.91
(0.74–1.11)
Severe or critical disease 17 observational studies graphic file with name fx3.gif OR 0.90
(0.74–1.11)

*The threshold for clinically significant effect (harm) was arbitrarily established as an increase of 25% in the odds of the outcome (a measure suggested by GRADE [43]).

CI: Confidence interval; OR: Odds ratio.

4. Discussion

The main finding of this systematic review was that ACEi/ARB were not associated with increased risk of being infected (moderate confidence), and among patients with COVID-19 the exposure to ACEi/ARB did not increase the risk of severe disease (very low confidence) or mortality (low confidence). In our exploratory analysis that only included hypertensive patients, ACEi/ARB were associated with a decreased mortality risk among COVID-19 patients however the data quality/risk of bias and the fragility of this exploratory analysis precludes definite and robust conclusions about the potential benefit. The other exploratory analyses also did not suggest harm, assuring the safety for the use of these drugs.

The rationale for this research was mainly based on the correspondence publication of Lancet Respiratory Medicine where Lei Fang and colleagues found that a significant number of patients with severe infection or death from SARS-CoV-2 were hypertensive, diabetic or had cardio-cerebrovascular disease and that these conditions are often treated with ACEi or ARB [3]. They hypothesized that the risk of infection or death might be increased in this group of patients due to an increase in the expression of ACE2 which can facilitate the entrance of SARS-CoV-2 into the cells [3]. The publication gained prominence in the scientific community and led to alarmism in the non-scientific community, given the high number of patients taking these drugs.

Given that the suspension of ACEI or ARBs can lead to decompensation of the underlying pathologies and there were no robust studies to corroborate the aforementioned hypothesis (data from only small preclinical studies), this led to some of the main scientific societies such as the American Heart Association, the American College of Cardiology, the Council on Hypertension of the European Society of Cardiology, and European Society of Hypertension, to publish recommendations to warn against discontinuing these drugs in the absence of clear clinical evidence of harm [41]. Our data are important because they validate these recommendations.

Despite ACEi and ARB having pharmacodynamic effects in the same pathway, the specific site of drug action may hypothetically lead to different effects, particularly in the risk of infectious diseases. Previous systematic review evaluating the potential role of ACEi in the prevention of pneumonia [42]. At that time the putative protective mechanism was thought to be related with enhanced cough reflex related to bradykinin and substance P, both derived from the inhibition of ACE [42]. Nowadays, the mechanisms are still speculative but hypothetically both ACEi and ARB may provide lung protection through the activation of angiotensin II-receptors type 2 (AT2R) and Mas receptors. The potential role of ACE2 in the case of SARS-CoV-2 infection is still ambiguous. While its increase may supply pathways for SARS-CoV-2 entrance into the cells [2], it is known that cleaved and shedded ACE2 leads to the breakdown of Angiotensin II to Angiotensin 1-7 (directly or indirectly increased with ARB or ACEi, respectively) have anti-inflammatory and anti-fibrotic effect through Mas receptors [41], [43]. The SARS-CoV-2 infection also leads to a downregulation of ACE2, that was associated with increased lung injury in animal models [44], [45]. Despite these ambiguous roles of ACE2, it is important to mention that relationship of serum/urinary ACE2 and tissue concentrations and use of ACEi/ARB is not well established, particularly in humans [46], [47], [48], and the clinical relevance of such relationships point towards a neutral effect according to our data. In order to further explore the potential role ACE2 and ACEi/ARB in the Influenza A infection, which share the same lung injury pathway as SARS-CoV-2, Chung et al analyzed the data of more than 5 million people in the UK followed for a median of 8.7 years and they found that ACEi and ARB exposure were associated with a decreased risk of Influenza A infection [49].

The data of this review are also important to reassure the safety of ACEi/ARB after the retraction of a large observational study that supported the safety of ACEi/ARB and showed a potential association of ACEi with lower COVID-19 mortality (Mehra MR et al N Eng J Med 2020). The authors asked for paper retraction after some concerns about the study and the impossibility of having a third party review on their data and analyses. Therefore, and despite the retraction, considering our data (without the retracted study), it seems reasonable to claim that ACEi/ARB are not harmful, despite the limitations reflected in the GRADE confidence. This supports the recommendations for not stopping the therapeutic use of ACEi/ARB. For potential benefit assessment, as seen in the hypertensive subgroup, further studies, such as the Elimination or prolongation of ACE inhibitors and ARB in Coronavirus Disease 2019 (REPLACECOVID) or Stopping ACE-inhibitors in COVID-19 (ACEI-COVID), Coronavirus ACEi/ARB Investigation (CORONACION) will provide more insights.

Our data are limited by the studies risk of bias which includes their observational nature for most of them. Pooling data of studies with different designs that evaluated different populations should also be considered as a potential limitation. Nevertheless, it increases the power and external validity of obtained data. In some studies, the risk of severe/critical disease was retrieved from specific outcomes such as the need of mechanical invasive ventilation or acute respiratory distress syndrome. This could explain the heterogeneity found in this outcome, but exclusion of these studies did not decrease the statistical heterogeneity and it remained substantial in the sub-analyses (data not shown). Lastly in these results only reflect the impact of ACEi and/or ARB. Other modulators of the renin-angiotensin-aldosterone system such renin inhibitors (aliskiren), mineralocorticoid receptor antagonists (spironolactone or epleronone), or even sacubitril were not evaluated in this review. In fact these drugs are residual considering the prescription of ACEi or ARB that in the de Abajo study we used the odds ratio of renin-angiotensin-aldosterone inhibitors as ACEi and ARB represented more than 90% of patients treated with the drugs of this group [27].

5. Conclusions

Our systematic review with meta-analysis did not suggest that the exposure to ACEi/ARB increases the risk of having the SARS-CoV-2 infection or developing severe stages of the disease, which supports the position papers of several medical associations recommending for not withholding these drugs in people already treated with them. Our data also showed a statistically significant association between ACEi/ARB exposure and reduction in COVID-19 mortality in hypertensive patients, but the frailty of the data and analysis precludes definite conclusions and emphasizes the need of further robust data.

Declaration of Competing Interest

DC in the last 3 years has participated in educational conferences/congresses (including travel, accommodation, and/or hospitality) and has received speaker/consultant fees from Daiichi Sankyo, Menarini, Roche and Merck-Serono. FJP that has received speaker and consultant fees from Bayer, Boehringer Ingelheim, Daiichi, Sankyo and Astra Zeneca.

Acknowledgments

Acknowledgments

None.

Funding

This review was an academic project and was not supported by any funding.

Contributorship

DC is the guarantor and contributed for concept and design. MA, RGM, PSA, NC, ANF and LP searched the articles and retrieved the data. DC coordinated the data search and retrieval. DC, MA, ANF performed the risk of bias assessment. DC performed the statistical analysis and wrote the first draft. DA, MA, RGM, PSA, NC, ANF and LP were involved in the result interpretation, discussion and text writing. JC and FJP were involved in the analysis and interpretation of the data, critically revised the manuscript for important intellectual content. All the authors approved the version of the manuscript.

Ethics committee approval

Not required as this was a systematic review of publicly available studies.

Statement

Daniel Caldeira MD PhD is the guarantor and This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijcha.2020.100627.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Supplementary data 1
mmc1.pdf (1.8MB, pdf)

References

  • 1.WHO. Coronavirus disease 2019 (COVID-19): situation report, vol. 129, 2020.
  • 2.Hoffmann M., Kleine-Weber H., Schroeder S., Krüger N., Herrler T., Erichsen S., Schiergens T.S., Herrler G., Wu N.-H., Nitsche A., Müller M.A., Drosten C., Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271–280.e8. doi: 10.1016/j.cell.2020.02.052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Fang L., Karakiulakis G., Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respiratory Med. 2020;8(4):e21. doi: 10.1016/S2213-2600(20)30116-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Stroup D.F., Berlin J.A., Morton S.C., Olkin I., Williamson G.D., Rennie D. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–2012. doi: 10.1001/jama.283.15.2008. [DOI] [PubMed] [Google Scholar]
  • 5.Liberati A., Altman D.G., Tetzlaff J., Mulrow C., Gotzsche P.C., Ioannidis J.P.A., Clarke M., Devereaux P.J., Kleijnen J., Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ (Clinical research ed) 2009;339:b2700. doi: 10.1136/bmj.b2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Organization WH. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance, 13 March 2020. World Health Organization, 2020.
  • 7.Wu Z., McGoogan J.M. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239. doi: 10.1001/jama.2020.2648. [DOI] [PubMed] [Google Scholar]
  • 8.Sterne J.A., Hernán M.A., Reeves B.C., Savović J., Berkman N.D., Viswanathan M. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ (Clinical research ed) 2016;355 doi: 10.1136/bmj.i4919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.J.P.T. Higgins, D.G. Altman, J.A.C. Sterne, Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 510 (updated March 2011), The Cochrane Collaboration, 2011.
  • 10.Higgins J.P.T., Thompson S.G. Quantifying heterogeneity in a meta-analysis. Statist. Med. 2002;21(11):1539–1558. doi: 10.1002/sim.1186. [DOI] [PubMed] [Google Scholar]
  • 11.Deeks J.J. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Statist. Med. 2002;21(11):1575–1600. doi: 10.1002/sim.1188. [DOI] [PubMed] [Google Scholar]
  • 12.J.A.C.E.M. Sterne, D. Moher, I. Boutron (Eds.), Chapter 10: Addressing reporting biases, Cochrane Handbook for Systematic Reviews of Interventions version 520 (updated June 2017), Cochrane, 2017. Available from: www.training.cochrane.org/handbook.
  • 13.H.J.O.A. Schünemann, J.P.T. Higgins, G.E. Vist, P. Glasziou, E. Akl, G.H. Guyatt, on behalf of the Cochrane GRADEing Methods Group and the Cochrane Statistical Methods Group. Chapter 11: Completing ‘Summary of findings’ tables and grading the confidence in or quality of the evidence, in: J.P.T.C.R. Higgins, J. Chandler, M.S. Cumpston (Eds.), Cochrane Handbook for Systematic Reviews of Interventions version 520 (updated June 2017), Cochrane; 2017. Available from: www.training.cochrane.org/handbook.
  • 14.Feng Y., Ling Y., Bai T., Xie Y., Huang J., Li J. COVID-19 with Different Severity: A Multi-center Study of Clinical Features. Am. J. Respir. Crit. Care Med. 2020 doi: 10.1164/rccm.202002-0445OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Huang Z., Cao J., Yao Y., Jin X., Luo Z., Xue Y., Zhu C., Song Y., Wang Y., Zou Y., Qian J., Yu K., Gong H., Ge J. The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension. Ann. Transl. Med. 2020;8(7):430. doi: 10.21037/atm.2020.03.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Li J., Wang X., Chen J., Zhang H., Deng A. Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China. JAMA Cardiol. 2020;5(7):825. doi: 10.1001/jamacardio.2020.1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Mancia G., Rea F., Ludergnani M., Apolone G., Corrao G. Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19. N. Engl. J. Med. 2020;382(25):2431–2440. doi: 10.1056/NEJMoa2006923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Mehta N., Kalra A., Nowacki A.S., Anjewierden S., Han Z., Bhat P. Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19) JAMA Cardiol. 2020 doi: 10.1001/jamacardio.2020.1855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Menon A., Klein E.J., Kollars K., Kleinhenz A.L.W. Medical Students Are Not Essential Workers: Examining Institutional Responsibility During the COVID-19 Pandemic. Academic Med.: J. Assoc. American Med. Colleges. 2020 doi: 10.1097/ACM.0000000000003478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Reynolds H.R., Adhikari S., Pulgarin C., Troxel A.B., Iturrate E., Johnson S.B., Hausvater A., Newman J.D., Berger J.S., Bangalore S., Katz S.D., Fishman G.I., Kunichoff D., Chen Y.u., Ogedegbe G., Hochman J.S. Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19. N. Engl. J. Med. 2020;382(25):2441–2448. doi: 10.1056/NEJMoa2008975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.G. Yang, Z. Tan, L. Zhou, M. Yang, L. Peng, J. Liu, et al., Effects Of ARBs And ACEIs On Virus Infection, Inflammatory Status And Clinical Outcomes In COVID-19 Patients With Hypertension: A Single Center Retrospective Study, Hypertension (Dallas, Tex : 1979). 2020. [DOI] [PubMed]
  • 22.Zhang P., Zhu L., Cai J., Lei F., Qin J.-J., Xie J. 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 doi: 10.1161/CIRCRESAHA.120.317134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.S. Tedeschi, M. Giannella, M. Bartoletti, F. Trapani, M. Tadolini, C. Borghi, et al., Clinical impact of renin-angiotensin system inhibitors on in-hospital mortality of patients with hypertension hospitalized for COVID-19, Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 2020. [DOI] [PMC free article] [PubMed]
  • 24.Million M., Lagier J.-C., Gautret P., Colson P., Fournier P.-E., Amrane S., Hocquart M., Mailhe M., Esteves-Vieira V., Doudier B., Aubry C., Correard F., Giraud-Gatineau A., Roussel Y., Berenger C., Cassir N., Seng P., Zandotti C., Dhiver C., Ravaux I., Tomei C., Eldin C., Tissot-Dupont H., Honoré S., Stein A., Jacquier A., Deharo J.-C., Chabrière E., Levasseur A., Fenollar F., Rolain J.-M., Obadia Y., Brouqui P., Drancourt M., La Scola B., Parola P., Raoult D. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France. Travel Med. Infect. Dis. 2020;35:101738. doi: 10.1016/j.tmaid.2020.101738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Chodick G., Nutman A., Yiekutiel N., Shalev V. Angiotension-converting enzyme inhibitors and angiotensin-receptor blockers are not associated with increased risk of SARS-CoV-2 infection. J. Travel Med. 2020 doi: 10.1093/jtm/taaa069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Zhou X., Zhu J., Xu T. Clinical characteristics of coronavirus disease 2019 (COVID-19) patients with hypertension on renin–angiotensin system inhibitors. Clin. Exp. Hypertens. 2020;42(7):656–660. doi: 10.1080/10641963.2020.1764018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.F.J. de Abajo, S. Rodriguez-Martin, V. Lerma, G. Mejia-Abril, M. Aguilar, A. Garcia-Luque, et al., Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study, Lancet (London, England), 2020. [DOI] [PMC free article] [PubMed]
  • 28.R. Gnavi, M. Demaria, R. Picariello, M. Dalmasso, F. Ricceri, G. Costa, Therapy with agents acting on the renin-angiotensin system and risk of SARS-CoV-2 infection, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020. [DOI] [PMC free article] [PubMed]
  • 29.S.Y. Jung, J.C. Choi, S.H. You, W.Y. Kim, Association of renin-angiotensin-aldosterone system inhibitors with COVID-19-related outcomes in Korea: a nationwide population-based cohort study, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020. [DOI] [PMC free article] [PubMed]
  • 30.Montastruc F., Romano C., Montastruc J.-L., Silva S., Seguin T., Minville V., Georges B., Riu-Poulenc B., Fourcade O. Pharmacological characteristics of patients infected with SARS-Cov-2 admitted to Intensive Care Unit in South of France. Therapies. 2020;75(4):381–384. doi: 10.1016/j.therap.2020.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Peng Y.D., Meng K., Guan H.Q., Leng L., Zhu R.R., Wang B.Y. Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV. Zhonghua xin xue guan bing za zhi. 2020;48:E004. doi: 10.3760/cma.j.cn112148-20200220-00105. [DOI] [PubMed] [Google Scholar]
  • 32.Tan N.-D., Qiu Y., Xing X.-B., Ghosh S., Chen M.-H., Mao R. Associations Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blocker Use, Gastrointestinal Symptoms, and Mortality Among Patients With COVID-19. Gastroenterology. 2020 doi: 10.1053/j.gastro.2020.05.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Chen Y., Yang D., Cheng B., Chen J., Peng A., Yang C., Liu C., Xiong M., Deng A., Zhang Y.u., Zheng L., Huang K. Clinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication. Dia Care. 2020;43(7):1399–1407. doi: 10.2337/dc20-0660. [DOI] [PubMed] [Google Scholar]
  • 34.Bean D.M., Kraljevic Z., Searle T., Bendayan R., Kevin O.G., Pickles A. 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: 10.1002/ejhf.1924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Amat-Santos I.J., Santos-Martinez S., López-Otero D., Nombela-Franco L., Gutiérrez-Ibanes E., Del Valle R. Ramipril in High Risk Patients with COVID-19. J. Am. Coll. Cardiol. 2020 doi: 10.1016/j.jacc.2020.05.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Hu J., Zhang X., Zhang X., Zhao H., Lian J., Hao S., Jia H., Yang M., Lu Y., Xiang D., Cai H., Zhang S., Gu J., Ye C., Yu G., Jin C., Zheng L., Yang Y., Sheng J. COVID-19 patients with hypertension have more severity condition, and ACEI/ARB treatment have no infulence on the clinical severity and outcome. J. Infect. 2020 doi: 10.1016/j.jinf.2020.05.056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Imam Z., Odish F., Gill I., O'Connor D., Armstrong J., Vanood A. Older age and comorbidity are independent mortality predictors in a large cohort of 1305 COVID-19 patients in Michigan, United States. J. Internal Med. 2020 doi: 10.1111/joim.13119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Gao C, Cai Y, Zhang K, Zhou L, Zhang Y, Zhang X, et al. Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study. European heart journal. 2020;41:2058-66. [DOI] [PMC free article] [PubMed]
  • 39.Felice C, Nardin C, Di Tanna GL, Grossi U, Bernardi E, Scaldaferri L, et al. Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives. American journal of hypertension. 2020. [DOI] [PMC free article] [PubMed]
  • 40.Argenziano MG, Bruce SL, Slater CL, Tiao JR, Baldwin MR, Barr RG, et al. Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series. 2020;369:m1996. [DOI] [PMC free article] [PubMed]
  • 41.Kreutz R, Algharably EAE, Azizi M, Dobrowolski P, Guzik T, Januszewicz A, et al. Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19. Cardiovascular research. 2020. [DOI] [PMC free article] [PubMed]
  • 42.Caldeira D., Alarcao J., Vaz-Carneiro A., Costa J. Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis. BMJ. 2012;345(jul11 1):e4260. doi: 10.1136/bmj.e4260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Lumbers E.R., Delforce S.J., Pringle K.G., Smith G.R. The Lung, the Heart, the Novel Coronavirus, and the Renin-Angiotensin System; The Need for Clinical Trials. Frontiers in medicine. 2020;7:248. doi: 10.3389/fmed.2020.00248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Imai Y., Kuba K., Rao S., Huan Y.i., Guo F., Guan B., Yang P., Sarao R., Wada T., Leong-Poi H., Crackower M.A., Fukamizu A., Hui C.-C., Hein L., Uhlig S., Slutsky A.S., Jiang C., Penninger J.M. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112–116. doi: 10.1038/nature03712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Ye R., Liu Z. ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway. Exp. Mol. Pathol. 2020;113:104350. doi: 10.1016/j.yexmp.2019.104350. [DOI] [PubMed] [Google Scholar]
  • 46.Sama IE, Ravera A, Santema BT, van Goor H, Ter Maaten JM, Cleland JGF, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. European heart journal. 2020;41:1810-7. [DOI] [PMC free article] [PubMed]
  • 47.Ramchand J, Patel SK, Srivastava PM, Farouque O, Burrell LM. Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease. 2018;13:e0198144. [DOI] [PMC free article] [PubMed]
  • 48.Furuhashi M., Moniwa N., Mita T., Fuseya T., Ishimura S., Ohno K., Shibata S., Tanaka M., Watanabe Y., Akasaka H., Ohnishi H., Yoshida H., Takizawa H., Saitoh S., Ura N., Shimamoto K., Miura T. Urinary Angiotensin-Converting Enzyme 2 in Hypertensive Patients May Be Increased by Olmesartan, an Angiotensin II Receptor Blocker. Am. J. Hypertens. 2015;28(1):15–21. doi: 10.1093/ajh/hpu086. [DOI] [PubMed] [Google Scholar]
  • 49.Chung S.-C., Providencia R., Sofat R. Association between Angiotensin Blockade and Incidence of Influenza in the United Kingdom. N. Engl. J. Med. 2020;383(4):397–400. doi: 10.1056/NEJMc2005396. [DOI] [PMC free article] [PubMed] [Google Scholar]

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Supplementary data 1
mmc1.pdf (1.8MB, pdf)

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