RAPID REVIEW

Use of Renin-Angiotensin System Antagonists in Patients with Hypertension and COVID-19 Infection: A Rapid Review and Meta-analysis

Rowena Natividad S. Flores-Genuino,1,2 Charissa Mia Salud-Gnilo3 and Evelyn Osio-Salido4,5

1Department of Anatomy, College of Medicine, University of the Philippines Manila, Manila, Philippines

2Department of Dermatology, Makati Medical Center, Makati, Philippines

3Asia-Pacific Center for Evidence-Based Healthcare

4Division of Rheumatology, Department of Medicine, College of Medicine and Philippine General Hospital, University of the Philippines Manila, Manila, Philippines

5Dela Salle University Medical Center

KEY FINDINGS

Among patients with confirmed COVID-19 infection and hypertension, there is insufficient evidence that RAS antagonists are associated with mortality or severe COVID-19 disease.

•There is uncertainty with regards to the safe use of renin-angiotensin system (RAS) antagonists, such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), for COVID-19 patients with hypertension and other comorbidities (heart failure, chronic kidney disease) because of two possible contradictory mechanisms 1) upregulation of ACE2 receptors that may facilitate the virus entry into the lung. and 2) control of unabated angiotensin II levels reducing acute lung injury.

•Based on very low-quality retrospective cohort studies, there is insufficient evidence that RAS antagonists are associated with increased mortality (6 studies) or severe disease (10 studies) among patients with confirmed COVID-19 infection and hypertension.

•There are 36 ongoing studies (21 RCTs, 1 single-arm trial, 4 prospective cohorts, 4 retrospective cohorts, 4 case- control, and 2 cross-sectional) on this topic.

•The European Society of Cardiology (ESC) Council on Hypertension, the International Society of Hypertension (ISH) and the joint statement by the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) all caution against discontinuing RAS-related treatments in patients with hypertension who become infected with COVID-19.

Disclaimer: The aim of these rapid reviews is to retrieve, appraise, summarize and update the available evidence on COVID-related health technology. The reviews have not been externally peer- reviewed; they should not replace individual clinical judgement and the sources cited should be checked. The views expressed represent the views of the authors and not necessarily those of their host institutions. The views are not a substitute for professional medical advice.

Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

When the COVID-19 pandemic broke out, concerns were raised as to the safety of renin-angiotensin system (RAS) antagonists, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which are commonly used as maintenance medications for hypertension, heart failure, and chronic kidney disease. The concern is based on the knowledge that the coronaviruses SARS-COV-1 and SARS-COV-2 gain entry into the cells by using the ACE2 receptors which may be upregulated by this group of antihypertensive drugs, possibly resulting in an increased risk of infection. With hypertension being recognized as common comorbidity among those with severe cases of COVID-19, calls were made to discontinue these classes of drugs in the high-risk groups to prevent infection.1

On the other hand, some argue that RAS antagonists may be protective for this high-risk group. ACE2 serves as a counter-regulatory enzyme by degrading angiotensin I and II to angiotensin-(1-9) and angiotensin-(1-7), respectively,

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thereby protecting different organs against the deleterious effects of these vasoconstrictors, such as acute lung injury and adverse myocardial remodeling. When the SARS- COV viruses enter the cells, they cause downregulation of ACE2 expression, which may cause unopposed activation of RAS. RAS antagonists, therefore, are deemed beneficial in this setting.2

A recent systematic review that searched up to April 21, 2020, included five observational studies (4 retrospective cohorts and 1 prospective cohort)(N=1480) and reported a 62% reduction in odds of death (OR 0.38; 95% CI: 0.19- 0.74, I2=0%). However, there was a nonsignificant association between severe COVID-19 and the use of RAS antagonists (OR 0.56; 95% CI: 0.34-1.89; I2=68%).3 In addition, the review noted many confounding factors due to the retrospective design of the included studies. However, there have been several studies published since their last search.

This rapid review summarizes the available evidence on whether RAS antagonists are associated with harmful or beneficial clinical outcomes among patients with hypertension diagnosed with COVID-19.


METHODS

See General Methods Section.

We searched the following databases and clinical trial registries (April 28 to May 1, 2020): MEDLINE (PubMed), CENTRAL, clinicaltrials.gov, Chinese clinical trial registry, EU Clinical Trials Register, Republic of Korea

-Clinical Research Information Service, Japan Primary Registries Network/ NIPH Clinical Trials Search, ICTRP, ChinaRXIV and MedRXIV (Appendix 1). We also searched UpToDate, WHO, and CDC websites.

Articles were selected based on the following inclusion criteria:

• Population: Patients with COVID-19 and hyper- tension, of any age, with any comorbidity, any severity

• Intervention: Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), any dose, any duration

• Comparator: Placebo, any active control, no intervention

• Outcomes: Severity of disease, death

• Study designs: Randomized controlled trials (RCTs), non-randomized studies, observational studies (e.g., cohort, case-control, cross-sectional, case report, case series)

The first reviewer extracted data and assessed the risk of bias while the 2nd reviewer checked for agreement. We assessed the risk of bias in the included studies using appraisal criteria for studies on harm (Painless Evidence- Based Medicine 2nd ed.).4 We discussed any disagreement and consulted a third reviewer, when necessary.

We combined studies in meta-analyses if they seemed clinically homogenous. We used RevMan 5.3 to compute

for odds ratios and 95% confidence intervals. We used the random effects method in meta-analysis to account for heterogeneity. We considered an I2 of >50% as significant heterogeneity and performed posthoc subgroup analyses to search for possible causes of heterogeneity.


RESULTS

Description of Included studies

We found 13 retrospective cohort studies in this review; 5 of them were preprinted (Appendix 2).5–9

Ten studies were done in various cities in China and three in the U.S. (California, New Jersey, New York). The median sample size was 109 (range 14 to 1,129).

Thirteen studies included data for patients with confirmed COVID-19 infection with hypertension. The comparator group was a non-RAS antihypertensive drug in 3 studies (Feng 2020a; Feng 2020b; Meng 2020), and a mix of non-RAS antihypertensive drugs and no drug in 4 studies (Liu 2020; Richardson 2020; Rubin 2020; Zhang 2020a). In six studies, it was not clear whether the comparator group was purely non-RAS antihypertensive drug or whether there also were patients without anti-HTN drugs who were included. Twelve of 13 studies recruited only hospitalized patients while one study in Stanford Hospital, USA (Rubin 2020) included both outpatients and inpatients. The average age was 50 years (3 studies) to 60 years (5 studies) in the majority of studies.

The types of ACE inhibitor and ARB were not specified in the studies. The other type of antihypertensive drugs were described as drug classes (calcium channel blockers, beta- blockers, and diuretics) in three studies (Feng 2020a; Liu 2020; Zhang 2020a) and as specific generic names (e.g., amlodipine, felodipine, lacidipine, metoprolol, bisoprolol, and spironolactone) in two studies (Liu 2020; Meng 2020). No details were given as to dose, route of administration, frequency, and duration of intake of the medications.

The severity of COVID disease was defined in different ways: seven Chinese studies followed the 5th version of guidelines from the National Health Commission but used different combinations of severity grades (ranging from mild, moderate, severe, critical). One US study reported ICU admission and disease progression to acute respiratory distress syndrome (Rubin 2020); while another US study reported the use of invasive mechanical ventilation (Richardson 2020). Seven studies reported on COVID deaths (Guo 2020; Ip 2020; Li 2020; Meng 2020; Richardson 2020; Yang 2020; Zhang 2020a), while one study reported all-cause mortality (Zhang 2020b). Two studies reported hospitalization rates (Rubin 2020; Zeng 2020).

Risk of Bias Assessment

The appraisal of the 13 studies included in our review showed high or unclear risk of bias mainly due to the following methodologic limitations 1) not all the important

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prognostic factors were considered, 2) inadequate follow- up period, and 3) exclusion of participants with incomplete data or outcomes (Feng 2020a; Guo 2020; Ip 2020; Richardson 2020; Zhang 2020a) (Appendix 3).


Effects of Use of RAS antagonists

We pooled the results of 10 studies that compared patients on RAS antagonists versus those on other antihypertensive drugs or no drugs.6,10 We described another 3 studies that did not provide raw data (Rubin 2020; Zhang 2020a; Zhang 2020b).7,9,11

Severe COVID-19 Among Patients with Hypertension on RAS Antagonists

Among patients with hypertension with confirmed COVID-19 infection, there was no statistically significant difference in odds of severe COVID-19 disease with the intake of RAS antagonists versus other antihypertensive drugs (10 pooled studies, N=3382; OR, 0.77 [0.50, 1.19, I2=77%) (Figure 1).5,6,10,12–18

Post-hoc subgroup analysis showed that the type of anti-hypertensive comparator was a significant factor. When the comparator was limited to non-RAS antihypertensive drugs, there was a significant reduction in odds for severe COVID-19 by 79% for those on RAS antagonists compared to non-RAS antihypertensive drugs (0.21 [0.09, 0.49]; I2=0%, p=0.0002). (Figure 2). However, since the included studies are all observational, there may be confounding factors such as the severity of hypertension, the presence of other comorbidities, and other patient characteristics, which are best explored in future RCTs. There were no significant differences based on country (P=0.42, I2=0%), the definition of severity (P=0.14, I2=54.7%), and inclusion only of patients with known outcomes (P=0.67, I2=0%) (Appendix 4 - Figures 1 to 3).

Mortality Among Patients with Hypertension on RAS Antagonists

We pooled the results from five studies to determine the association between COVID-19-related mortality and the use of RAS antagonists among patients with hypertension. There was no significant difference in the mortality rates among those on RAS antagonists compared to those on other antihypertensive drugs (6 studies, N=2032; OR, 0.95, 95% CI 0.67, 1.36; I2=20%) (Figure 3).

Three retrospective cohort studies were not pooled with the above studies due to a lack of raw data. These studies showed conflicting results. One study showed significantly lower mortality for patients on RAS antagonists (HR 0.37 [95% CI 0.15-0.89]; P=0.03) (Zhang 2020b). Another study that compared mixed groups (RAS antagonists and diuretics group versus calcium blockers or no drugs) showed unclear effects (HR 0.47 [95% CI, 0.06, 3.83]; P=0.48) (Zhang 2020a). One study showed no correlation between the use of ACEI and ARBs with disease progression to ARDS (ACEI, P=0.997; ARB, P=0.467) and ICU admission (ACEI, P=0.995; ARB, P=0.433 (Rubin 2020).

There are 36 ongoing studies (including 21 RCTs) on RAS antagonists in COVID-19. Details of each ongoing study are in Appendix 5.


Recommendations of Organizations and Medical Groups

The European Society of Cardiology (ESC) Council on Hypertension, the International Society of Hypertension (ISH) and the joint statement by the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) all caution against discontinuing RAS-related treatments in patients with hypertension who become infected with COVID-19.19–21

Figure 1. RAS antagonists vs Not on RAS antagonists: Severe COVID among patients with hypertension. (View in the PDF)

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Figure 2. RAS antagonists vs Not on RAS antagonists: Severe COVID among patients with hypertension (Subgroup analysis based on the type of comparator). (View in the PDF)

Figure 3. RAS antagonists vs Not on RAS antagonists: COVID-associated deaths among patients with hypertension.(View in the PDF)

CONCLUSION

Based on very low-quality evidence from 13 retro- spective cohort studies, there is insufficient evidence to conclude that RAS antagonists are associated with increased mortality (6 studies) or severe disease (10 studies) among patients with confirmed COVID-19 infection and hypertension.

Declaration of Conflict of Interest

No conflict of interest.

REFERENCES

1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80. doi:10.1016/j.cell.2020.02.052

2.Vaduganathan M, Vardeny O, Michel T, Mcmurray JJ V, Pfeffer MA, Solomon SD. Renin–angiotensin–aldosterone system inhibitors in patients with COVID-19. N Engl J Med. 2020; 382(17):1653-9.

3.Ghosal S, Mukherjee JJ, Sinha B, Gangopadhyay KK. The effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on death and severity of disease in patients with coronavirus disease 2019 ( COVID-19 ). MedRxiv Prepr. 2020 Apr 23. doi:10.1101/2020.04.23.20076661

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4.Loyola AB, Ibrahim I, Dans AL. Evaluation of Articles on Harm. In: Dans AL, Dans LF SM, ed. Painless Evidence-Based Medicine. Wiley; 2017. pp. 58-74.

5.Feng Z, Yu Q, Yao S, Luo L, Duan J, Yan Z, et al. Early prediction of disease progression in 2019 Novel Coronavirus pneumonia patients outside Wuhan with CT and clinical characteristics. MedRxiv Prepr. 2020 February 1(138). doi:10.1101/2020.02.19.20025296

6.Liu Y, Huang F, Xu J, Yang P, Qin Y, Cao M. Anti-hypertensive angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients. MedRxiv Prepr. 2020. doi:10.1101/2020.03.20.20039586.

7.Rubin SJS, Falkson SR, Degner N, Blish C. Clinical characteristics associated with COVID-19 severity in California. MedRxiv Prepr. 2020;1-11. doi:10.1101/2020.03.27.20043661

8.Yang G, Tan Z, Zhou L, Yang M, Peng L, Liu J, et al. Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors usage is associated with improved inflammatory status and clinical outcomes in COVID-19 patients with hypertension. MedRxiv Prepr. 2020.

9.Zhang L, Sun Y, Zeng HL, Peng Y, Jiang X, Shang WJ, et al. Calcium channel blocker amlodipine besylate is associated with reduced case fatality rate of COVID-19 patients with hypertension. MedRxiv Prepr. 2020 Apr 8; 1-34. doi:10.1101/2020.04.08.20047134

10.Richardson S, Hirsch JS, Narasimhan M, Crawford JM, Mcginn T, Davidson KW. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020; 323(20):2052-9. doi:10.1001/jama.2020.6775

11.Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, et al. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020; 126(12):1671-81. doi:10.1161/CIRCRESAHA.120.317134

12.Feng Y, Ling Y, Bai T, Xie Y, Huang J, Li, J, et al. COVID-19 with different severities: A multi-center study of clinical features. Am J Respir Crit Care Med. 2020; 201(11):1380-8. doi:10.1164/rccm.202002- 0445OC

13.Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020; 5(7):1-8. doi:10.1001/ jamacardio.2020.1017

14.Ip A, Parikh K, Parrillo JE, Mathura S, Hansen E, Sawczuk IS, et al. Hypertension and renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. MedRxiv Prepr. 2020 April 24. doi:10.1101/2020.04.24.20077388

15.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):1-6. doi:10.1001/jamacardio.2020.1624

16.Meng J, Xiao G, Zhang J, He X, Ou M, Bi J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020; 9(1):757-60. doi:10.1080/22221751.2020.1746200

17.Yang G, Tan Z, Zhou L, Yang M, Peng L, Liu J, et al. Effects of ARBs And ACEIs on virus infection, inflammatory status and clinical outcomes in patients with COVID-19 and hypertension: A single center retrospective study. Hypertension. 2020; 76(1):51-8. doi:10.1161/HYPERTENSIONAHA.120.15143

18.Zeng Z, Sha T, Zhang Y, Wu F, Hu H, Li H, et al. Hypertension in patients hospitalized with COVID-19 in Wuhan, China: A single-center retrospective observational study. medRxiv. 2020: 2020.04.06.20054825. doi:10.1101/2020.04.06.20054825

19.de Simone G. Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin receptor blockers [Internet]. European Society of Cardiology. [cited 2020 Apr 15]. Available  from:  https://www.escardio.org/Councils/Council-on- Hypertension-(CHT)/News/position-statement-of-the-esc-council- on-hypertension-on-ace-inhibitors-and-ang.

20.HFSA/ACC/AHA.HFSA/ACC/AHAStatementAddressesConcerns Re: Using RAAS Antagonists in COVID-19 [Internet]. American College of Cardiology. [cited 2020 Apr 15].  Available  from:  https:// www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa- acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in- covid-19.

21.International Society of Hypertension [Internet]. A statement from the International Society of Hypertension on COVID-19. [cited 2020 Apr 15]. Available from: https://ish-world.com/news/a/A-statement-from- the-International-Society-of-Hypertension-on-COVID-19/.

22.Feng Z, Li J, Yao S, Yu Q, Zhou W, Mao X, et al. The use of adjuvant therapy in preventing progression to severe pneumonia in patients with coronavirus disease 2019: A multicenter data analysis. MedRxiv Prepr. 2020; (138).

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Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

APPENDICES

Appendix 1. Literature search

 

Database

Search strategy / search terms

Medline

12 #1 and #11

 

11 #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10

 

10 (RAAS inhibitor) or (RAAS blocker) or (RAAS antagonist)

 

9

(RAS inhibitor) or (RAS blocker) or (RAS antagonist)

 

8

(angiotensin receptor inhibitor) or (angiotensin receptor

 

blocker) or (angiotensin receptor antagonist)

 

7

(angiotensin converting enzyme inhibitor) or (angiotensin

 

converting enzyme blocker) or (angiotensin converting

 

enzyme antagonist)

 

6

(Renin angiotensin system inhibitor) or (Renin angiotensin

 

system blocker) or (Renin angiotensin system antagonist)

 

5

(ACE blocker) or (ACE antagonist) or (ACE inhibitor)

 

4

“Angiotensin-Converting Enzyme Inhibitors”[Mesh]

 

3

“Angiotensin Receptor Antagonists”[Mesh]

 

2

“Renin-Angiotensin System”[Mesh]

 

1

“Coronavirus Infections”[Mesh] OR “Coronavirus”[Mesh] OR

 

coronavirus OR novel coronavirus OR NCOV OR “COVID-19

”[Supplementary Concept] OR covid19 OR covid 19 OR covid-19 OR “severe acute respiratory syndrome coronavirus 2” [Supplementary Concept] OR severe acute respiratory syndrome coronavirus 2 OR SARS2 OR SARS 2 OR

SARS COV2 OR SARS COV 2 OR SARS-COV-2

Date and time

 

Results

of search

Yield

Eligible

April 28, 2020

153

5

12:01:20

 

 

GMT+8

 

 

CENTRAL

1 coronavirus OR novel coronavirus OR NCOV OR covid19 OR

May 1 2020

16

6

 

covid 19 OR covid-19 OR severe acute respiratory syndrome

12:05:00

 

(duplicate of CTG)

 

coronavirus 2 OR SARS2 OR SARS 2 OR SARS COV2 OR

GMT+8

 

 

 

SARS COV 2 OR SARS-COV-2

 

 

 

 

2 angiotensin

 

 

 

 

3 #1 and #2

 

 

 

Trial Registries

 

 

 

 

ClinicalTrials.gov

COVID and angiotensin

April 28, 2020

37

24

 

 

20:00:00

 

 

 

 

GMT+8

 

 

Chinese Clinical Trial

COVID

April 29, 2020

15

1

Registry

 

10:20:00

 

 

 

 

GMT+8

 

 

EU Clinical Trials

COVID

April 29 ,2020

34

2

Register

 

10:21:30

 

 

 

 

GMT+8

 

 

Republic of Korea -

COVID

April 29, 2020

0

0

Clinical Research

 

10:23:00

 

 

Information Service

 

GMT+8

 

 

Japan Primary Registries

COVID

April 29, 2020

48

0

Network / NIPH Clinical

 

10:24:00

 

 

Trials Search

 

GMT+8

 

 

ICTRP Database

COVID

May 1, 2020

8

4

(COVID-19 trials)

 

10:00:00

 

(1, duplicate of

 

 

GMT+8

 

ChiCTR; 2, duplicate

 

 

 

 

of EUDRACT)

Other databases

 

 

 

 

Chinaxiv.org

COVID

April 28, 2020

19

0

 

 

16:20:00

 

 

 

 

GMT+*

 

 

Medrxiv.org

(covid or coronavirus) and (angiotensin)

April 29, 2020

425

7

 

 

10:26:00

 

 

 

 

GMT+8

 

 

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Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

Appendix 2. Characteristics of included studies

 

 

 

 

 

 

 

No.

Study ID/Title

Study design

Country

Population

Intervention Group(s)

Comparison Group(s)

Clinical Outcomes

Key Findings

RAS antagonists vs other antihypertensive drugs

 

 

 

 

 

 

 

1

Feng 2020a22 (preprint)

Retrospective

China, 9 hospitals in 7 cities

65 adult patients with confirmed

ACEI/ARB (n=16/65)

Non-ACEI/ARB drugs

Severe COVID

Fewer hypertensive patients on ACEI/

 

 

cohort

 

COVID-19 and hypertension on

 

(calcium blockers, beta-

 

ARB therapy developed severe pneumonia

 

The Use of Adjuvant Therapy in Preventing

 

Jan 17 to Feb 28, 2020

antihypertensive drugs

 

blockers, diuretics)

Discharge

in contrast with those on non-ACEI/ARB

 

Progression to Severe Pneumonia in

 

(final date of follow-up:

 

 

(n=49/65)

 

antihypertensive therapy (1 of 16 [6.3%] patients

 

Patients with Coronavirus Disease 2019:

 

Mar 15, 2020)

(17 were excluded due to lack of

 

 

Deaths (not reported)

and 16 of 49 [32.7%] patients, respectively

 

A Multicenter Data Analysis

 

 

data and were given amlodipine or

 

 

 

[difference, 26.4%; 95% CI, 1.5% to 41.3%])

 

 

 

 

nitrendipine as needed)

 

 

 

 

 

 

 

 

Of 564 consecutively hospitalized

 

 

 

 

 

 

 

 

patients: Median age = 47 years (IQR,

 

 

 

 

 

 

 

 

36-58; range, 19-84 years) (50.4%)

 

 

 

 

 

 

 

 

were men. 132 (23.4%) patients had

 

 

 

 

 

 

 

 

comorbidities, (including hypertension:

 

 

 

 

 

 

 

 

n = 82 [14.5%]; DM 8%; CVD 3.9%))

 

 

 

 

2

Feng 2020b12

Retrospective

China

95 patients w/ HTN and on

ACEI/ARB (n=33/95)

Other antiHTN drugs

Disease severity (Moderate,

Compared with severe and critical groups, there were

 

 

cohort

 

antiHTN drugs

 

(n=62/95)

severe, critical) (5th version of

more patients taking ACEI/ARB in moderate group.

 

COVID-19 with Different Severity:

 

Admitted to 3 hospitals in

 

 

 

the guidelines issued by the

There was a significant difference in angiotensin-

 

A Multi-center Study of Clinical Features

 

Wuhan, Shanghai and Anhui

476 patients with COVID-19; 113

 

 

National Health Commission

converting enzyme inhibitors/angiotensin II receptor

 

 

 

 

(24%) w/HTN; 205 patients (43.1%)

 

 

of China on Diagnosis and

blockers usage among patients with different severities.

 

 

 

Jan 1 to Feb 15, 2020 (End

w/ comorbidities; median age, 53

 

 

Treatment of COVID-19)

 

 

 

 

of data collection: Feb 15)

years [IQR, 40-64]; male, 56.9%)

 

 

 

 

3 Meng 202016

Retrospective

China (Shenzhen)

42 patients with COVID-19

 

cohort

 

with hypertension AND on anti-

Renin-angiotensin system inhibitors

 

Hospitalized

hypertensives; Median age = 64.5 yrs.

improve the clinical outcomes of

 

 

(range, 55.8-69.0 out of 51 with HTN

COVID-19 patients with hypertension.

 

Jan 11 to Feb 23, 2020

but 9 not on antiHTN drugs) (out of

 

 

 

417 admitted patients)

ACE inhibitors or ARB,

Non-ACEI/ ARB anti-HTN

diff doses (n=17/42)

drugs (e.g., amlodipine,

 

L-amlodipine, felodipine,

 

lacidipine, metoprolol,

 

bisoprolol, spironolactone)

 

(n=25/42)

Severe disease (National Health Commission of the People’s Republic of China)

Deaths

“We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases. This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension.”

RAS antagonists vs Not on RAS antagonists

4 Guo 202013

Retrospective

China (Wuhan)

61 COVID-19 treated patients with

 

cohort

Hospitalized at designated

hypertension (33%; out of 187);

Cardiovascular Implications of Fatal

 

COVID hospital;

Mean age (SD) = 58.5 yrs. (14.66)

Outcomes of Patients With Coronavirus

 

Jan 23 to Feb 23, 2020

Either discharged or died during

Disease 2019 (COVID-19)

 

 

 

 

 

hospitalization (NOT includes those

 

 

 

still admitted); Excluded 67 patients

 

 

 

who were not yet discharged or died)

ACEI/ARB (n=14/61) Non-ACEI/ARB drugs

COVID-19-associated death

(n=47/61)

Acute respiratory distress

 

 

syndrome (not reported)

 

Malignant arrhythmia

 

(not reported)

 

Acute myocardial injury

“The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers was 36.8% (7 of 19) and 25.6% (43 of 168).”

5

Ip 202014

Retrospective

US (NJ)

1129 w/ HTN and known outcomes

ACEI/ARB

Non-ACEI/ARB drugs

Discharged or died

The mortality rates were lower for hypertensive

 

 

cohort

 

 

(n=460/1129)

(n=669/1129)

 

patients prescribed ACE1 (27%, p=0.001) or ARBs

 

Hypertension and Renin-Angiotensin-

 

Admitted to hospitals

1584 w/ HTN (52.5% of 3017

 

 

 

(33%, p=0.12) compared to other anti-hypertensive

 

Aldosterone System Inhibitors in

 

within Hackensack

hospitalized COVID-19 patients)

 

 

 

agents (39%) in the unadjusted analyses. RAAS

 

Patients with COVID-19

 

Meridian Health network

 

 

 

 

inhibitor therapy appeared protective compared to

 

 

 

Convenience sampling

 

 

 

 

other anti-hypertensive agents (p=0.001).

 

 

 

 

 

 

 

 

 

 

 

Discharged or deceased

 

 

 

 

 

 

 

 

cohort with known outcomes

 

 

 

 

 

6

Li 202015

Retrospective

China (Hubei)

362 patients with HTN and COVID-19

ACEIs/ARBs

Non-ACEI/ARB drugs

Severe disease (diagnosis

The current findings did not identify an association

 

 

cohort

 

 

(n=115/362)

(n=247/362)

and treatment scheme

between treatment with ACEIs/ARBs and either

 

Association of Renin-Angiotensin System

 

Admitted to Central

259 (71.5%) were older than 60 years;

 

 

for COVID-19 of Chinese

severity or clinical outcomes of COVID-19

 

Inhibitors With Severity or Risk of Death in

 

Hospital of Wuhan

52.2% men

 

 

[5th edition])

hospitalizations in patients with hypertension.

 

Patients With Hypertension Hospitalized

 

 

 

 

 

 

 

 

for Coronavirus Disease 2019 (COVID-19)

 

Jan 15 to Mar 15, 2020

 

 

 

Deaths

 

 

Infection in Wuhan, China

 

(End of study not stated)

 

 

 

 

 

7 Yang 2020a17

Retrospective

China (Hubei)

126 COVID-19 patients with

ARBs/ACEIs

Non-ARBs/ACEI drugs

1. Severe COVID

 

cohort

 

preexisting hypertension

(n=43/126)

(n=83/126)

(5th Trial Version of the Chinese

Effects of ARBs And ACEIs On Virus Infection,

 

Hubei Provincial Hospital of

 

 

 

National Health Commission)

Inflammatory Status And Clinical Outcomes

 

Traditional Chinese Medicine

Median age, 66 (IQR, 61-73)

 

 

2. Deaths

In COVID-19 Patients With Hypertension:

 

 

 

 

 

A Single Center Retrospective Study

 

Jan 5 to Feb 22, 2020

 

 

 

 

“Furthermore, much lower proportion of critical patients (9.3% vs 22.9%; p=0.061), and a lower death rate (4.7% vs 13.3%; p=0.216) were observed in ARBs/ ACEIs group than non-ARBs/ACEIs group, although these differences failed to reach statistical significance.

Our findings thus support the use of ARBs/ACEIs in COVID-19 patients with preexisting hypertension.”

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Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

 

Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

No. Study ID/Title

Study design Country

Population

Intervention Group(s) Comparison Group(s)

Clinical Outcomes

Key Findings

8Zeng 202018

Hypertension in patients hospitalized with COVID-19 in Wuhan, China: A single-center retrospective observational study

Retrospective China (Wuhan) cohort

Admitted to Hankou Hospital

Jan 5 and Mar 8, 2020 (Minimum 14 days follow-up, even after discharge)

75 with hypertension

Mean age (SD), 67(11); 55% M)

(27%, out of 274 patients with clinically confirmed COVID-19; mean age 60 [SD 15]; 55% M)

ACEI/ARB (n=28/75)

Non-ACEI/ARB drugs

28-day mortality

On B-blockers

(n=47/75)

Severity of pneumonia

 

(n= 7/28, 25%)

On B-blockers

Length of hospital stay

On CCB

(n=12/47, 25%)

 

Discharge rate from hospital

(n= 8/28, 29%)

On CCB (n=41/47, 87%)

 

On diuretics

On diuretics (n=0)

Hospitalization

 

(n = 4/28, 14%)

 

 

Patients with hypertension who had previously taken ACEI/ARB drugs for antihypertensive treatment have an increased tendency to develop severe pneumonia after infection with SARS-COV-2 (P = 0.064).

9 Zhang 2020b11

Retrospective

China (Hubei province)

1128 adult patients with hypertension

ACEI/ARB group

Non-ACEI/ARB group

All-cause mortality

Among hospitalized COVID-19 patients with

 

cohort

 

diagnosed with COVID-19

(n=188/1128)

(n=940/1128)

 

hypertension, inpatient use of ACEI/ARB was

Association of Inpatient Use of Angiotensin

 

Admitted to 9 hospitals

 

 

 

Septic shock

associated with lower risk of all-cause mortality

Converting Enzyme Inhibitors and Angiotensin

 

 

 

Median age 64

Median age 64 [IQR 57-69];

 

compared with ACEI/ARB non-users. While study

II Receptor Blockers with Mortality Among

 

Dec 31, 2019 to Feb 20, 2020

 

[IQR 55-68] years;

53.5% men)

DIC

interpretation needs to consider the potential for

Patients With Hypertension Hospitalized

 

 

 

53.2% men)

 

 

residual confounders, it is unlikely that in-hospital

With COVID-19

 

Final date of follow-up:

 

 

 

*Only reported HR,

use of ACEI/ARB was associated with an increased

 

 

Mar 7, 2020

 

 

 

not raw data

mortality risk.

RAS antagonists vs other antihypertensive drugs or no drugs

 

 

 

 

 

 

 

10 Liu 2020a (preprint)6

Retrospective China (Shenzhen)

 

cohort

Antihypertensive Angiotensin II

Admitted to 3 hospitals

receptor blockers associated to mitigation of

 

disease severity in elderly COVID-19 patients

Jan 11 to Feb 5, 2020; Wuhan,

 

Jan 12 to Feb 9, 2020; Beijing,

 

Dec 27, 2019 to Feb 29, 2020

78 adult patients with COVID-19

ACEI or ARB

Non-ACEI/ARB drugs

and hypertension;

(n=22/78)

(CCB or Thiazide or BB)

Average age = 65.2 yrs. (10.7)

 

(n=39/78)

 

 

No drug (n=17/78)

Mild versus Severe COVID (New Coronavirus Pneumonia Prevention and Control Program published by the National Health Commission of China)

“No statistical difference in disease severity between any of the 5 different types of anti-hypertensive drugs (CCB, ARB, ACEI, Thiazide or BB) compared to no drugs taken by all COVID-19 patients with hypertension comorbidity in the study.”

11

Richardson 202010

 

USA (NY)

1366 patients with HTN (24%)

ACEI/ARB

Not on ACEI/ARB

Invasive mechanical

Mortality rates for patients

 

 

Retrospective

 

(out of 2411 with home medication

(n=413/1366)

(n =953/1366)

ventilation, kidney replacement

with hypertension not taking an ACEI or ARB, taking

 

Presenting Characteristics, Comorbidities,

cohort

Admitted to 12 hospitals in

information out of 2634 who were

 

*unspecified how many

therapy, and death.

an ACEI and taking an ARB were 26.7%, 32.7%, and

 

and Outcomes Among 5700 Patients

 

New York City, Long Island,

discharged or died; out of 5700

 

were on other antiHTN

 

30.6%, respectively.

 

Hospitalized With COVID-19 in the

 

and Westchester County, New

sequentially hospitalized patients

 

or no drugs

 

(...results are unadjusted for known confounders,

 

New York City Area

 

York, within the Northwell

with COVID-19)

 

 

 

including age, sex, race, ethnicity, socio-economic

 

 

 

Health system. Mar 1 and

 

 

 

 

status indicators, and comorbidities such as diabetes,

 

 

 

Apr 4, 2020

Median age, 63 years [IQR, 52-75;

 

 

 

chronic kidney disease, and heart failure).

 

 

 

Most patients in this study

range, 0-107 years]; 60.3% male)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

were still in hospital at the

HTN (56.6%), obesity (41.7%), and

 

 

 

 

 

 

 

study end point (3066, 53.8%). diabetes (33.8%)

 

 

 

 

 

 

 

 

Median no. of medications, 3

 

 

 

 

 

 

 

 

(IQR 0–7)

 

 

 

 

12

Rubin 2020 (preprint)7

Retrospective

USA (California)

14 w/ HTN (26%, out of 54

ACEI or ARB (n=9/14)

Non-ACEI/ARB drugs or

Progression to severe disease

“In our study, history of ACE-I or ARB use did not affect

 

 

cohort

 

COVID-19 patients who and w/

 

no drug use (?) (n=5/14)

1. Recommendation for further

diagnosis rate or predispose patients to worse disease

 

Clinical characteristics associated with

 

Stanford Hospital (OPD &

past medical history documentation;

 

 

hospital care

outcomes. However, our study is underpowered to

 

COVID-19 severity in California

 

inpatient)

18 inpatients, 36 outpatients)

 

 

2. Admission to ICU

draw definitive conclusions from such negative data.”

 

 

 

 

 

 

 

3. Diagnosis of pneumonia

 

 

 

 

by Mar 16, 2020

Median 53.5 yrs. [IQR, 32.75; range,

 

 

4. Progression to ARDS

 

 

 

 

 

20–91]); 50% M

 

 

No raw data; Reported only as

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

p-values using univariate and

 

 

 

 

 

 

 

 

multivariate analysis

 

13Zhang 2020a (Apr 8 preprint)14

Calcium channel blocker amlodipine besylate is associated 1 with reduced case 2 fatality rate of COVID-19 patients with hypertension

Retrospective

China

cohort

Admitted to 2 hospitals:

 

In vitro anti-

Tongji Hospital from Jan 17

viral testing

to Feb 14, 2020

 

Union Hospital from Jan 10

 

to Mar 30, 2020

90 patients, who only had hypertension as the comorbidity and were either discharged from the hospital or deceased (out of 487 adult COVID-19 patients with Hypertension)

Median 67 yrs. (59.5–72); 63% M (amlodipine group) to 65 (57–74) 40.9% M (non-amlodipine group)

Various

Amlodipine besylate

Deaths

Calcium channel blockers (CCB) can significantly inhibit

antihypertensive

(n=44/90)

 

the post-entry replication events of SARS-CoV-2

drugs (including ARBs,

 

*No raw data, only reported HR

in vitro. Comparison with two other major types of

ACEIs, β-blockers, and

Nifedipine (n=16/90),

 

anti-hypertension drugs, the angiotensin converting

thiazide) (n=17/90)

 

 

enzyme inhibitors (ACEI) and angiotensin II receptor

 

Other CCBs (n=4/90)

 

blockers (ARB), showed that only CCBs display

 

No antiHTN drug (n=9/90)

 

significant anti-SARS-CoV-2 efficacy.

 

 

 

COVID, Coronavirus disease; ACEI, Angiotensin converting enzyme inhibitor; ARB, Angiotensin receptor blocker; HTN, Hypertension; CCB, Calcium channel blocker; SARS-CoV-2, Severe acute respiratory distress-associated coronavirus 2

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Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

Appendix 3. Summary of Risk of Bias Appraisal for Studies on Harm

 

 

1. Did the

2. Were important prognostic

3. Were unbiased

4. Were unbiased

 

 

 

exposure in

factors balanced at the

criteria used

criteria used

5. Was the

 

Study ID

question precede

time of exposure? If not,

to determine

to detect the

follow-up rate

 

 

the undesirable

were statistical adjustments

exposure in

outcome in

adequate?

 

 

outcome?

made for these factors?

all patients?

all patients?

 

1

Feng 2020 Apr 8 preprint

Y

Y

Y

Y

N

2

Feng 2020 Apr 10

Y

N, No statistical adjustment

Y

Y

N

3

Guo 2020

Y

N, No statistical adjustment

Y

Y

N

4

Ip 2020 Apr 24 preprint

UC

N

Y

Y

N

5

Li 2020

Y

Y

UC

Y

UC

6

Liu 2020 Mar 20 preprint

Y

UC

Y

Y

N

7

Meng 2020

Y

Y

Y

Y

N

8

Richardson 2020

Y

N, no statistical adjustment

Y

Y

N

9

Rubin 2020 Mar 27 preprint

Y

Y

Y

N

N

10

Yang 2020

Y

UC

Y

Y

N

11

Zeng 2020 Apr 6 preprint

Y

N, No statistical adjustment

Y

Y

Y

12

Zhang 2020

Y

Y

Y

Y

Y

13

Zhang 2020 Apr8 preprint

Y

Y

N

Y

Y

Y, Yes; N, No; U, Unclear

Appendix 4. Subgroup and Sensitivity Analyses

Figure 1. RAS antagonist vs Not on RAS antagonist: Severe COVID (Subgroup analysis based on country).

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Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

Figure 2. RAS antagonist vs Not on RAS antagonist: Severe COVID (Subgroup analysis based on definition of severity).

Figure 3. RAS antagonist vs Not on RAS antagonist: Severe COVID (Subgroup analysis based on inclusion only of patients with known outcomes, i.e., discharged or died).

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Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

 

 

 

 

Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

Appendix 5. Characteristics of Ongoing Trials

 

 

 

 

 

 

 

 

 

 

 

 

Start and

 

 

 

 

Intervention

 

 

No.

Clinical Trial ID / Title

Status

estimated primary

Study design

Country

 

Population

Comparison Group(s)

Clinical Outcomes

 

Group(s)

 

 

 

completion date

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1

NCT04330300

Recruiting

Mar 30, 2020 to

RCT, open-label

Ireland

 

Men and non-pregnant women aged 60 or

Continue

Alternative anti-hypertensive medication

Primary: Death (All-cause

 

 

 

Jan 31, 2021

(N=2414)

 

 

over with known diagnosis of hypertension,

ACEi/ARB

Switch to an alternative BP medication

mortality)

 

CORONAvirus Angiotensin Converting Enzyme

 

 

 

 

 

currently using ACEi or ARB for the

antihypertensive

(specifically a Calcium channel blocker

Secondary: Intubation in

 

Inhibitors/Angiotensin Receptor Blockers InvestigatiON:

 

 

 

 

 

treatment of hypertension and COVID-19

 

[CCB] or Thiazide/Thiazide-like diuretic

ICU; Hospitalization for non-

 

A Randomized Clinical Trial (CORONACION)

 

 

 

 

 

naïve (i.e. not known to be infected)

 

at an equipotent blood pressure lowering

invasive ventilation (NIV)

 

 

 

 

 

 

 

 

 

dose). The choice of either CCB or

 

 

 

 

 

 

 

 

 

 

Thiazide/Thiazide-like anti-hypertensive

 

 

 

 

 

 

 

 

 

 

provided as alternative therapy will be at

 

 

 

 

 

 

 

 

 

 

the discretion of the physician

 

2

NCT04338009

Enrolling by

Mar 31 to

RCT (N=152)

Pennsylvania, USA

 

18 y/o hospitalized COVID-19 suspect,

Continuation

Discontinuation of ACEI/ARB

Primary: Global rank score

 

 

invitation

Dec 31, 2020

 

 

 

or confirmed with PCR on prior outpatient

of ACEI/ARB

 

based on (1) time to death,

 

Elimination or Prolongation of ACE Inhibitors and ARB

 

 

 

 

 

use of ACEI or ARB

 

 

(2) no. of days on IMV or

 

in Coronavirus Disease 2019 (REPLACECOVID)

 

 

 

 

 

 

 

 

ECMO, (3) no. of days on

 

 

 

 

 

 

 

 

 

 

renal replacement therapy

 

 

 

 

 

 

 

 

 

 

or pressor/inotropic therapy,

 

 

 

 

 

 

 

 

 

 

and (4) a modified sequential

 

 

 

 

 

 

 

 

 

 

Organ Failure Assessment

 

 

 

 

 

 

 

 

 

 

(SOFA) score.

 

 

 

 

 

 

 

 

 

 

Secondary: All-cause death;

 

 

 

 

 

 

 

 

 

 

Length of hospital stay; Length

 

 

 

 

 

 

 

 

 

 

of ICU stay; AUC SOFA

3

NCT04351581

Recruiting

Apr to Dec 2020

RCT (N=215)

Copenhagen,

 

Verified COVID-19; Hospital admitted;

Continuation

Discontinuation of ACEi/ARB

Primary: Days alive and out of

 

 

 

 

 

Denmark

 

Daily administration of RAS-inhibiting

of ACEi/ARB

 

hospital

 

Effects of Discontinuing Renin-angiotensin

 

 

 

 

 

therapy; Age 18 years and above

 

 

Secondary: Worsening of

 

System Inhibitors in Patients With COVID-19

 

 

 

 

 

 

 

 

COVID-19; Severe respiratory

 

 

 

 

 

 

 

 

 

 

insufficiency; Referral to ICU,

 

 

 

 

 

 

 

 

 

 

30-d mortality, etc.

 

 

 

 

 

 

 

 

 

 

 

4

NCT04353596

Recruiting

Apr 15 , 2020 to May

RCT (N=208)

Innsbruck, Austria

 

Proven and symptomatic SARS-CoV2

Continuation

Discontinuation of ACEi/ARB

Primary: Combination of

 

 

 

15, 2021

 

 

 

infection ≤ 5 days; Age ≥ 18 years;

of ACEi/ARB

 

maximum Sequential Organ

 

Stopping ACE-inhibitors in COVID-19

 

 

 

 

 

Chronic (≥ 1 month) ACEI/ARB therapy

 

 

Failure Assessment (SOFA)

 

 

 

 

 

 

 

for treatment of arterial hypertension,

 

 

Score and death

 

 

 

 

 

 

 

diabetes mellitus, heart failure or coronary

 

 

Secondary: Maximum SOFA,

 

 

 

 

 

 

 

artery disease; Stable hemodynamic

 

 

Non-invasive ventilation, Renal

 

 

 

 

 

 

 

conditions allowing to stop or continue

 

 

replacement therapy, etc.

 

 

 

 

 

 

 

treatment with ACEI/ARB (systolic

 

 

 

 

 

 

 

 

 

 

blood pressure ≤180mmHg)

 

 

 

5

NCT04360551

Not yet

Jul 1, 2020 to

RCT (N=40)

Hawaii, USA

 

Male or non-pregnant female adult

Telmisartan

Placebo

Primary: Maximum clinical

 

 

recruiting

Jun 30, 2021

 

 

 

≥18 y/o; Has laboratory-confirmed severe

 

 

severity of disease

 

Pilot Clinical Trial of the Safety and Efficacy of

 

 

 

 

 

acute respiratory syndrome corona virus 2

 

 

Secondary: treatment

 

Telmisartan for the Mitigation of Pulmonary and

 

 

 

 

 

(SARS-CoV-2) infection

 

 

emergent adverse events

 

Cardiac Complications in COVID-19 Patients

 

 

 

 

 

 

 

 

 

6

NCT04340557

Recruiting

Mar 27 to

RCT (N=200)

California, USA

 

Confirmed COVID-19 positive test result;

Standard of

Standard of care plus losartan

Primary: Mechanical

 

 

 

Oct 6 2020

 

 

 

Mild to moderate respiratory disease

Care plus an ARB

 

ventilation

 

Do Angiotensin Receptor Blockers Mitigate

 

 

 

 

 

defined by oxygen requirement of at least

 

 

Secondary: ICU transfer;

 

Progression to Acute Respiratory Distress Syndrome

 

 

 

 

 

2 L/min to maintain oxygen saturation level

 

 

Oxygen therapy

 

With SARS-CoV-2 Infection

 

 

 

 

 

≥92%; Systolic blood pressure ≥ 110 mmHg;

 

 

 

 

 

 

 

 

 

 

Age ≥18 years old

 

 

 

7

NCT04351724

Recruiting

Apr 16 to

RCT (N=500)

Vienna, Austria

 

Laboratory confirmed infection

Candesartan

Non-RAS blocking antihypertensives

Primary: Sustained

 

 

 

Dec 1, 2020

 

 

 

with SARS-CoV-2 ≤72 hours before

 

 

improvement (>48h) of one

 

Austrian CoronaVirus Adaptive Clinical Trial

 

 

 

 

 

randomization; Hospitalisation due to

 

Others:

point on the WHO Scale

 

(COVID-19) (ACOVACT)

 

 

 

 

 

SARS-CoV-2 infection (for anti-viral

 

Chloroquine or Hydroxychloroquine

Secondary: Time to

 

 

 

 

 

 

 

treatment arms); oxygen saturation <94%

 

Lopinavir/Ritonavir

improvement on the WHO

 

 

 

 

 

 

 

when breathing room air or >3% drop in

 

Best standard of care

scale, time to discharge or a

 

 

 

 

 

 

 

case of chronic obstructive lung disease

 

Clazakizumab

National Early Warning Score

 

 

 

 

 

 

 

 

 

Placebo for clazakizumab

(NEWS) ≤2, Oxygenation free

 

 

 

 

 

 

 

 

 

Rivaroxaban

days, etc

 

 

 

 

 

 

 

 

 

Thromboprophylaxis

 

8

NCT04355936

Recruiting

Apr 1 to

RCT (N=400)

Buenos Aires,

 

Aged 18 years or older w/ confirmed

Telmisartan +

Standard of care

Primary: Need for

 

Telmisartan for Treatment of COVID-19 Patients

 

Oct 2020

 

Argentina

 

diagnosis of COVID-19 by PCR test

Standard of care

 

supplementary oxygen

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

114

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Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

 

 

 

Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

 

 

 

Start and

 

 

 

Intervention

 

 

No.

Clinical Trial ID / Title

Status

estimated primary

Study design

Country

Population

Comparison Group(s)

Clinical Outcomes

Group(s)

 

 

 

completion date

 

 

 

 

 

 

 

 

 

 

 

 

 

 

9

NCT04345406

Not yet

Apr 15 to

RCT (N=60)

Tanta, Egypt

Patients infected with COVID 19

ACEIs

Conventional treatment

Primary: number of patients

 

Angiotensin Converting Enzyme Inhibitors in Treatment

recruiting

Dec 2020

 

 

 

 

 

with virological cure

 

 

 

 

 

 

 

 

 

 

of Covid 19

 

 

 

 

 

 

 

 

10

NCT04335786

Recruiting

Apr to Jul 2020

RCT (N=651)

's-Hertogenbosch,

Adult (age ≥ 18 years); admitted to the

Valsartan (Diovan)

Placebo oral tablet

Primary: ICU admission,

 

 

 

 

 

Arnhem,

hospital of any participating center;

 

 

mechanical ventilation or

 

Valsartan for Prevention of Acute Respiratory Distress

 

 

 

Netherlands

confirmed SARS-CoV-2 infection with

 

 

death

 

Syndrome in Hospitalized Patients With SARS-COV-2

 

 

 

 

either: positive laboratory test for SARS-

 

 

Secondary: Acute Kidney

 

(COVID-19) Infection Disease

 

 

 

 

CoV-2*; or positive CT thorax diagnostic

 

 

injury

 

 

 

 

 

 

for SARS-CoV-2

 

 

 

11

NCT04328012

Recruiting

Apr 2020 to

RCT (N=4000)

New York, USA

Hospitalized patient w/ laboratory

Losartan

Lopinavir/ritonavir

Primary: National Institute

 

 

 

Jan 2021

 

 

confirmation of SARS-CoV-2 infection

 

Hydroxychloroquine Sulfate

of Allergy and Infectious

 

COVID MED Trial - Comparison Of Therapeutics for

 

 

 

 

 

 

Placebo

Diseases COVID-19 Ordinal

 

Hospitalized Patients Infected With SARS-CoV-2

 

 

 

 

 

 

 

Severity Scale (NCOSS)

 

 

 

 

 

 

 

 

 

Secondary: Hospital length

 

 

 

 

 

 

 

 

 

of stay, ICU, Mechanical

 

 

 

 

 

 

 

 

 

ventilation, Survival

12

NCT04312009

Recruiting

Apr 2020 to

RCT (N=200)

Minnesota, USA

Presumptive positive laboratory test

Losartan

Placebo

Primary: Difference in

 

 

 

Apr 2021

 

 

for Covid-19 based on local laboratory

 

 

Estimated (PEEP adjusted)

 

Losartan for Patients With COVID-19 Requiring

 

 

 

 

standard; admission to the hospital

 

 

P/F Ratio at 7 days

 

Hospitalization

 

 

 

 

with a respiratory Sequential Organ

 

 

Secondary: Daily Hypotensive

 

 

 

 

 

 

Failure Assessment (SOFA) score ≥1 and

 

 

Episodes, Hypotension

 

 

 

 

 

 

increased oxygen requirement compared

 

 

Requiring Vasopressors,

 

 

 

 

 

 

to baseline among those on home O2

 

 

Acute Kidney Injury, etc.

13

NCT04311177

Recruiting

Apr 2020 to

RCT (N=580)

Minnesota, USA

Positive laboratory test for COVID-19

Losartan

Placebo

Primary: Hospital admission

 

 

 

Apr 2021

 

 

based on local laboratory standard; Upper

 

 

Secondary: PROMIS

 

Losartan for Patients With COVID-19 Not Requiring

 

 

 

 

respiratory symptoms (cough, rhinorrhea)

 

 

Dyspnea Functional

 

Hospitalization

 

 

 

 

or fever (>101.5)

 

 

Limitations, PROMIS

 

 

 

 

 

 

 

 

 

Dyspnea Severity, Daily

 

 

 

 

 

 

 

 

 

Maximum Temperature, etc.

14

NCT04359953

Not yet

Apr 2020 to

RCT (N=1600)

Strasbourg, France

Age ≥ 75, or ≥ 60 if dementia; infected with

Telmisartan

Drug: Hydroxychloroquine

Primary: Two-weeks survival

 

 

recruiting

Jun 2021

 

 

COVID 19 (confirmed by RT-PCR SARS-

 

Drug: Azithromycin

rate

 

Efficacy of Hydroxychloroquine, Telmisartan and

 

 

 

 

CoV-2 detectable less than 5 days old

 

 

Secondary: Rate of death,

 

Azithromycin on the Survival of Hospitalized Elderly

 

 

 

 

and clinical picture); clinical manifestation

 

 

Hypotension, Hypothermia

 

Patients With COVID-19 (COVID-Aging)

 

 

 

 

of COVID 19 requiring hospitalization:

 

 

or hyperthermia, Pneumonia

 

 

 

 

 

 

pneumopathy and/or upper airway

 

 

severity, etc.

 

 

 

 

 

 

infection and/or respiratory distress,

 

 

 

 

 

 

 

 

 

confusion and/or encephalopathy and/

 

 

 

 

 

 

 

 

 

or signs of encephalitis, walking disorders

 

 

 

 

 

 

 

 

 

with ataxia and/or falls, digestive problem

 

 

 

 

 

 

 

 

 

(diarrhea and/or vomiting); affiliated to a

 

 

 

 

 

 

 

 

 

social health insurance scheme

 

 

 

15

NCT04343001

Not yet

Apr 2020 to

RCT (N=10,000)

London, UK

Adults age 40 years and older; with

Losartan

Aspirin

Primary: Death

 

 

recruiting

Apr 2021

 

 

suspected or confirmed acute COVID-19

 

Simvastatin

Secondary: Myocardial

 

Coronavirus Response - Active Support for

 

 

 

 

infection. Acute COVID-19 infection

 

 

infarction, Congestive

 

Hospitalised Covid-19 Patients (CRASH-19)

 

 

 

 

is suspected in the presence of a fever

 

 

cardiac failure, Severe cardiac

 

 

 

 

 

 

and at least one symptom of respiratory

 

 

arrhythmia, etc.

 

 

 

 

 

 

disease e.g. cough, difficulty breathing,

 

 

 

 

 

 

 

 

 

signs of hypoxia. The clinician may suspect

 

 

 

 

 

 

 

 

 

COVID-19 infection if i) the patient lives

 

 

 

 

 

 

 

 

 

in or has recently travelled to an area with

 

 

 

COVID-19 transmission; ii) the patient had recent contact with a confirmed or probable COVID-19 case, or iii) no alternative diagnosis fully explains the clinical presentation; requiring hospitalisation

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Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

 

 

 

 

Use of RAS Antagonists in Patients with Hypertension and COVID-19 Infection

 

 

 

Start and

 

 

 

 

Intervention

 

 

No.

Clinical Trial ID / Title

Status

estimated primary

Study design

Country

Population

Comparison Group(s)

Clinical Outcomes

Group(s)

 

 

 

completion date

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

16

NCT04349410

Enrolling by

Apr to Oct 2020

RCT (N=500)

California, USA

COVID-19 infection

Drug: Losartan

Drug: Hydroxychloroquine, Azithromycin

Primary: Improvement in

 

 

invitation

 

 

 

 

 

 

Drug: Hydroxychloroquine, Doxycycline

FMTVDM Measurement with

 

The Fleming [FMTVDM] Directed CoVid-19

 

 

 

 

 

 

 

Drug: Hydroxychloroquine, Clindamycin

nuclear imaging

 

Treatment Protocol

 

 

 

 

 

 

 

Drug: Hydroxychloroquine, Clindamycin,

Secondary: Ventilator status,

 

 

 

 

 

 

 

 

 

Primaquine - low dose.

Survival status

 

 

 

 

 

 

 

 

 

Drug: Hydroxychloroquine, Clindamycin,

 

 

 

 

 

 

 

 

 

 

Primaquine - high dose.

 

 

 

 

 

 

 

 

 

 

Drug: Remdesivir

 

 

 

 

 

 

 

 

 

 

Drug: Tocilizumab

 

 

 

 

 

 

 

 

 

 

Drug: Methylprednisolone

 

 

 

 

 

 

 

 

 

 

Drug: Interferon-Alpha2B

 

 

 

 

 

 

 

 

 

 

Drug: Convalescent Serum

 

17

NCT04355429

Not yet

May to Jul 2020

RCT (N=230)

Paris, France

Hospitalization for acute respiratory failure

Captopril

Standard care

Primary: 14-day ventilation

 

 

recruiting

 

 

 

requiring oxygen administration ≥3L/mn;

 

 

free survival

 

Efficacy of Captopril in Covid-19 Patients With Severe

 

 

 

 

Age > 18 years or older; Presence of

 

 

 

 

Acute Respiratory Syndrome (SARS) CoV-2 Pneumonia

 

 

 

 

pneumonia; PCR SARS-CoV-2 positive in

 

 

 

 

(CAPTOCOVID)

 

 

 

 

any biological sample in the last 7 days;

 

 

 

 

 

 

 

 

 

Patient affiliated to social security regime

 

 

 

18

NCT04356495

Not yet

Apr to Jul 2020

RCT (N=1057)

Bordeaux, France

Positive SARS-CoV-2 infection virology

Telmisartan

Dietary Supplement: Vitamins

Primary: Hospitalization, Death

 

 

recruiting

 

 

 

test on nasopharyngeal swab; Onset

 

Hydroxychloroquine

Secondary: ICU, loss of

 

Treatments to Decrease the Risk of Hospitalization

 

 

 

 

of symptoms < 72 hours prior to naso-

 

Imatinib

autonomy evaluated by the

 

or Death in Elderly Outpatients With Symptomatic

 

 

 

 

pharyngeal swab sampling; Age ≥ 65 years;

 

Favipiravir

ADL and IADL scale

 

SARS-CoV-2 Infection (COVID-19) (COVERAGE)

 

 

 

 

Valid, ambulatory person, fully capable

 

 

 

 

 

 

 

 

 

of understanding the challenges of

 

 

 

 

 

 

 

 

 

the trial; No hospitalization criteria

 

 

 

19

EudraCT Number- 2020-001303-16

Ongoing

Registered

RCT (N=1600)

Strasbourg, France

Male or female age ≥ 75, or ≥ 60 if

Telmisartan

Azithromycin

Primary: 2-wk Survival

 

 

 

Mar 29, 2020

 

 

dementia; infected with COVID 19

 

Hydroxychloroquine,

Secondary: Serious adverse

 

Efficacy of Hydroxychloroquine, Telmisartan and

 

 

 

 

(confirmed by RT-PCR SARS-CoV-2

 

 

events rate; SARS RT-PCR-

 

Azithromycin on Survival in Elderly Hospitalized Patients

 

 

 

 

detectable less than 5 days old and clinical

 

 

Cov-2 at 7 and 14 days;

 

with VIDOC-19: A Randomized, Multi-Centre, Adaptive,

 

 

 

 

picture); Clinical manifestation of COVID 19

 

 

28-day death rate

 

Blinded Study

 

 

 

 

requiring hospitalization; Subject affiliated

 

 

 

 

 

 

 

 

 

to a social health insurance scheme

 

 

 

20

EudraCT Number- 2020-001320-34

Ongoing

Registered

RCT (N=641)

Nijmegen,

Adult (age ≥ 18 years)

Valsartan

Placebo

Primary: either:

 

 

 

Mar 30, 2020

 

Netherlands

•

Admitted to the hospital of any

 

 

1) ICU admission;

 

A double-blind, placebo-controlled randomized

 

 

 

 

 

participating center

 

 

2) Mechanical ventilation;

 

clinical trial with valsartan for PRevention of Acute

 

 

 

 

•

Confirmed SARS-CoV-2 infection with

 

 

3) Death, within 14 days

 

rEspiraTORy dIstress syndrome in hospitAlized patieNts

 

 

 

 

 

either: positive laboratory test for SARS-

 

 

Secondary: Death within

 

with SARS-COV-2 Infection Disease (COVID-19)

 

 

 

 

 

CoV-2* ; or positive CT thorax diagnostic

 

 

30 days, 90 days and 1 year

 

 

 

 

 

 

 

for SARS-CoV-2 infection

 

 

 

21

IRCT20151113025025N3

Recruiting

Apr to Sep 2020

RCT (N=60)

Tehran, Iran

Patients who have suggestive signs

Continuation

Discontinuation of RAAS inhibitors and

Primary: Death, ICU

 

 

 

 

 

 

of COVID-19 in their chest computed

of RAAS

shift to calcium blocker or beta-blocker

 

 

Clinical Trial of renin-angiotensin-aldosterone system

 

 

 

 

tomography scan, reported by a radiologist.

inhibitors

 

 

 

inhibitors with halting their administration and the

 

 

 

 

Patients consuming angiotensin-converting

 

 

 

 

effect on clinical outcomes of patients with corona virus

 

 

 

 

enzyme inhibitors or angiotensin

 

 

 

 

disease-2019 (COVID-19) referring to Sina Hospital

 

 

 

 

receptor blockers

 

 

 

 

in 2020

 

 

 

 

 

 

 

 

 

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