Trifirò G, Berrino L, Del Re M et al. (2020) 1:1-3

https://doi.org/10.36118/pharmadvances.01.2020.01

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© 2020 The Italian Society of Pharmacology (SIF)

Published by EDRA SPA. All rights reserved

Official statement of the section of Clinical

Pharmacology of the Italian Society of

Pharmacology on the use of ACE- inhibitors or

angiotensin receptor blockers in COVID-19 infection

G. Trifirò1,2, L. Berrino3, M. Del Re4, R. Bernardini5, C. Chiamulera6, A. D’Avolio7, F. Scaglione8, A. Capuano9,

E. Clementi10, R. Danesi4 , L. Pani11, A. Catapano12 , G. Racagni12, on behalf of the Section of Clinical

Pharmacology of Italian Society of Pharmacology

1 Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina,

Messina, Italy 2 Unit of Clinical Pharmacology, A.O.U. “G. Martino”, Messina, Italy 3 Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy 4 Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental

Medicine, University of Pisa, Pisa, Italy 5 Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania,

Catania, Italy 6 Neuropsychopharmacology Lab, Section Pharmacology, Department Diagnostic & Public Health,

University of Verona, Verona, Italy 7 Department of Medical Sciences, University of Turin, ASL “Città di Torino” Laboratory of Clinical

Pharmacology and Pharmacogenetics, Amedeo di Savoia Hospital, Turin, Italy 8 Department of Oncology and Onco-Hematology, University of Milan, Milan, Italy, Clinical

Pharmacology Unit, ASST-GOM Niguarda Hospital, Milan, Italy 9 Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Regional Centre of

Pharmacovigilance, Campania Region, Naples, Italy 10 Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, University

Hospital “Luigi Sacco”, University of Milan, Milan, Italy 11 Section of Pharmacology, Department of Biomedical, Metabolic and Neural Sciences, University of

Modena and Reggio Emilia, Modena, Italy 12 Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

E-mail: trifirog@unime.it

The coronavirus 2019 (SARS-CoV-2) pandemic is

spreading around the world and is a matter of great

concern. In this situation, it is more important than ever

to make evidence-based decisions concerning

pharmacological treatment. Some editorials (Gurwitz D,

2020; Zheng YY et al, 2020; Watkins J, 2020) have re-

LETTER TO THE EDITOR Open Access

Pharmadvances (2020) 1:1-3 Trifirò G., Berrino L., Del Re M.

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ported conflicting hypotheses on the potential

benefit/risk profile of anti- hypertensive drugs acting on

the renin-angiotensin system. The relevance of these

drugs is related to the involvement of the angiotensin

converting enzyme 2 (ACE2) in the invasion process of

SARS-COV-2 in the host lung cells.

It is therefore critical to clarify the potential impact of

these drugs in SARS-CoV-2 infection and to promote a

clear understanding of the assumptions in favor of or

against switching patients treated with ACE-inhibitors

or angiotensin II receptor blockers (ARBs) to other anti-

hypertensive agents or vice-versa, in order to prevent

potentially inappropriate thera-peutic regimens.

ACE2 and ACE-inhibitors/ARBs

The angiotensin-converting enzyme 2 (ACE2) is an

aminopeptidase membrane protein that plays an

important role in the regulation of the cardiovascular and

immune systems. It is involved in the regulation of

cardiac activity and in the development of chronic

illness, such as hypertension and diabetes mellitus

(Turner AJ et al, 2004). ACE2 is highly expressed on the

surface of cardiac and pulmonary cells, and it is used by

coronaviruses, such as SARS-CoV and SARS- CoV-2,

to enter host cells (Hoffmann M et al, 2020).

Specifically, the interaction between the “spike” protein

of coronaviruses and ACE2 has been identified as a key

factor for the virus transmission.

SARS-CoV-2 mainly infects the epithelial cells of the

alveoli, leading to significant respiratory symptoms that

are particularly severe in patients affected by

cardiovascular diseases.

In vitro studies have demonstrated that both the ACE-

inhibitor lisinopril and the ARB losartan can

significantly in-crease the expression of cardiac ACE2

(by 5- and 3-fold, respectively) (Ferrario CM et al,

2005).

For these reasons, some authors suggested carefully

evaluating the potential risks and benefits of us-ing

ACE-inhibitors or ARBs in patients infected by SARS-

CoV-2 (Zheng YY et al, 2020; Watkins J, 2020).

However, several studies conducted on SARS-CoV,

which are generalizable to SARS-CoV-2, have

suggested the opposite to be true (Gurwitz D, 2020). It

has been demonstrated that the bond be-tween the spike

protein and ACE2 stimulates a down-regulation of

ACE2 that leads to an excessive production of the

angiotensin II.

This excessive production is mainly due to the absence

of the con-version of the angiotensin II into the

angiotensin 1-7 (a vasodilator peptide) by ACE2. This

phe-nomenon contributes to lung damage as the

stimulation of angiotensin receptors causes an increase

in pulmonary vascular permeability (Imai et al, 2005;

Kuba et al, 2005).

As a result, there is a para-doxical increase in the

expression of ACE2 induced by chronic treatment with

ARBs which may protect patients infected by SARS-

CoV-2 from more severe pulmonary symptoms. This

might be related to two complementary mechanisms: 1)

ARBs can block the effect of angiotensin receptors; 2)

ARBs can induce upregulation of ACE2 and

consequently increase the level of angiotensin 1-7

(Gurwitz D, 2020, de Wit et al, 2016).

Clinical evidence on the switch from or to ACE-

inhibitors and ARBs

ACE-inhibitors and ARBs are currently approved (with

some differences among single drugs) for the treatment

of high-impact chronic illnesses such as hypertension,

heart failure and diabetic glo-merular nephropathy, as

well as for the secondary prevention of acute myocardial

infarction.

To date, there is no scientific evidence from clinical

studies, nor is there any approved indication to support

the substitution of an ACE-inhibitor or an ARB with

other anti- hypertensive agents (or vice-versa) in patients

with SARS-CoV-2 infection whose hypertension is

adequately controlled with their current antihypertensive

medication/s. The Chongqing Medical University is

conducting a retrospective observational study to

evaluate clinical differences among adult hypertensive

pa-tients affected by COVID-19, who are treated or not

treated with ACE-inhibitors. This study will be

concluded on April 30th, 2020 (clinicaltrials.gov,

NCT04272710).

Moreover, the aforementioned editorials suggested that

“Whether patients with COVID-19 and hypertension

who are taking an ACE inhibitor or angiotensin-receptor

blocker should switch to another antihypertensive drug

re-mains controversial, and further evidence is required”

(Zheng YY et al, 2020) and “The tentative suggestion to

Pharmadvances (2020) 1:1-3 Trifirò G., Berrino L., Del Re M.

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apply [angiotensin receptor 1] antagonists such as

losartan and telmisartan as SARS‐CoV‐2 therapeutics

for treating patients prior to the development of acute

respiratory syndrome re-mains unproven until tried”

(Gurwitz, 2020).

In conclusion, therapeutic switching between different

anti-hypertensive classes which are known to be

effective in the treatment of chronic diseases such as

hypertension, heart failure, diabetes, and renal failure, is

unjustified as it exposes frail patients to an increased risk

of cardiovascular events or a worsening of the

aforementioned clinical conditions, considering that

existing evidence is derived from molecular hypotheses

or in vitro experiments.

The conduction of pharmacoepidemiology stud-ies and,

where possible, clinical trials, which evaluate the role of

ACE-inhibitors/ARBs in patients infected by SARS-

COV-2, are needed.

With regards to the hypothesis that ACE-inhibitors and

ARBs can be used in healthy people to pre-vent SARS-

CoV-2 infection, it is worth reminding clinicians that

these drugs should just be used to manage the conditions

for which they are indicated.

Furthermore, there is no biological or clinical evidence

in favor of their protective effect in COVID-19.

No regulatory authority in the world has, to date,

recommended any kind of therapeutic switch from or to

ACE- inhibitors/ARBs.

Many Sci-entific Societies have also expressed their

opinion in this regard (see the position statement of the

Italian Society of Hypertension, 2020; the clinical

guidelines of the Italian Society of Cardiology, 2020; the

position statement of the European Society of

Cardiology – Hypertension Council).

References 1. De Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS

and MERS: Recent insights into emerging coronaviruses.

Nature Reviews. Microbiology 2016, 14: 523–534.

2. Farmaci anti-ipertensivi e rischio di COVID-19. Il comunicato

della Società Italiana dell’Ipertensione Arteriosa (SIIA), 13

Marzo 2020: https://siia.it/notizie- siia/farmaci-antiipertensivi-

e-rischio-di-covid-19-il-comunicato-della-siia/ .

3. Ferrario CM, Jessup J, Chappell MC, et al. Effect of

angiotensin-converting enzyme inhibition and angiotensin II

receptor blockers on cardiac angiotensin- converting enzyme 2.

Circulation 2005; 111: 2605-10.

4. Guida clinica COVID-19 per cardiologi, Società Italiana di

Cardiologia, 11 marzo 2020:

https://www.sicardiologia.it/public/Documento-SIC-COVID-

19.pdf. Gurwitz D. Angiotensin re-ceptor blockers as tentative

SARS-CoV-2 therapeutics. Drug Dev Res. 2020; 1–4.

5. Hoffmann M, Kleine-Weber H, Kruger N, Muller M, Drosten

C, Pohlmann S. The novel corona-virus 2019 (2019-nCoV) uses

the SARS-coronavirus receptor ACE2 and the cellular protease

TMPRSS2 for entry into target cells. bioRxiv

2020:2020.01.31.929042.

6. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Penninger JM.

Angiotensin- converting enzyme 2 protects from severe acute

lung failure. Nature2005; 436: 112–116.

7. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Penninger JM.

A crucial role of angiotensin con-verting enzyme 2 (ACE2) in

SARS coronavirus-induced lung injury.

Nature Medicine 2005; 11: 875–879.

8. Position Statement of the ESC Council on Hypertension on

ACE-Inhibitors and Angiotensin Re-ceptor Blockers:

https://www.escardio.org/Councils/Council-on- Hypertension-

(CHT)/News/position-statement-of-the-esc-council-on-hyper–

tension-on-ace-inhibitors-and-ang.

9. Turner AJ, Hiscox JA, Hooper NM. ACE2: from vasopeptidase

to SARS virus receptor. Trends Pharmacol. Sci. 2004, 25, 291–

294.

10. Watkins J. Preventing a covid-19 pandemic. BMJ. 2020 Feb

28;368:m810.

11. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the

cardiovascular system. Nat Rev Cardiol. 2020 Mar 5. doi:

10.1038/s41569-020-0360-5.

Vincenzi M, Corsini A, Ruscica M (2020) 1: 4-5

https://doi.org/10.36118/pharmadvances.01.2020.02

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© 2020 The Italian Society of Pharmacology (SIF)

Published by EDRA SPA. All rights reserved

Commentary on: “Official statement of the section

of Clinical Pharmacology of the Italian Society of

Pharmacology on the use of ACE-

inhibitors or

angiotensin receptor blockers in COVID-19

infection”

M. Vicenzi1,2, A. Corsini3,4, M. Ruscica3

1IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Internal Medicine Department,

Cardiovascular Disease Unit, Milan, Italy 2Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy 3Department of Pharmaceutical and Biomolecular Sciences, University of Milan, Milan, Italy4IRCCS Multimedica Hospital, Milan, Italy

E-mail: alberto.corsini@unimi.it

The uncertainties whether pharmacologic regulation of

angiotensin-converting enzyme 2 (ACE2) may worsen

the infectivity of SARS-CoV-2 is gaining a large inte–

rest among the medical community.

As pointed out by Trifirò et al. although there could be a

paradoxical increase in the expression of ACE2 upon

chronic treatment, at least in animal models, with

angiotensin II receptor blockers (ARBs) (2,3),

therapeutic switching among different anti-hypertensive

classes in the treatment of chronic diseases (e.g.

hypertension) is unjustified (1).

In light of data in China, where 30 to 40% of patients

with hypertension are treated with an antihypertensive

therapy, with RAAS inhibitors prescribed to 25 to 30%

of these patients (4), evidence is not enough either to

confirm or deny concerns that, in Covid-19 patients with

hypertension, the use of renin–angiotensin–aldosterone

system (RAAS) inhibitors may contribute to the adverse

COMMENTARY Open Access

(G. Trifirò, L. Berrino, M. Del Re, R. Bernardini, C. Chiamulera, A. D’Avolio, F. Scaglione, A. Capuano, E.

Clementi, R. Danesi , L. Pani, A. Catapano , G. Racagni, on behalf of the Section of Clinical Pharmacology of

Italian Society of Pharmacology)

Pharmadvances (2020) 1:4-5 Vicenzi M.,Corsini A., Ruscica M.

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health outcomes (3). On top of this, there might be

further concerns because ACE inhibitors are confused

with ACE2 inhibitors (5).

Thus, it is a priority to focus on unraveling whether the

morbidities SARS-CoV-2 related are influenced by

current ACE-i/ARBs treatment. As again pointed out by

Trifirò et al., we need to await the data of the

retrospective observational study NCT04272710

evaluating the clinical differences among adult

hypertensive patients affected by COVID-19 who have

been treated or not treated with ACE-inhibitors (1). All-

in-all, we agree with the Authors that ARBs and RAAS

inhibitors should be used only to manage the conditions

for which they are indicated, i.e. high blood pressure,

heart failure, or other medical indications; while drug

discontinuation should be discouraged unless not

suggested by physician or healthcare (5).

References

1. Trifirò G., Berrino L., Del Re M., Bernardini R., Chiamulera C., D’Avolio A., Scaglione F., Capuano A., Clementi E., Danesi R., Pani L., Catapano A., Racagni G., on behalf of the Section of clinical pharmacology of Italian Society of Pharmacology, Official statement of the section of Clinical Pharmacology of the Italian Society of Pharmacology on the use of ACE-inhibitors or angiotensin receptor blockers in COVID-19 infection. Pharmadvances, 2020, 1(1): p.1-3.

Doi: 10.36118/pharmadvances.01.2020.01

2. Vaduganathan, M., et al., Renin–Angiotensin–Aldosterone

System Inhibitors in Patients with Covid-19. The New England

Journal of Medicine, 2020.

3. Wang, Z., et al., Status of Hypertension in China: Results From

the China Hypertension Survey, 2012-2015. Circulation, 2018.

137(22): p. 2344-2356.

4. Danser, A.H.J., M. Epstein, and D. Batlle, Renin-Angiotensin

System Blockers and the COVID-19 Pandemic:At Present

There Is No Evidence to Abandon Renin-Angiotensin System

Blockers.Hypertension,2020:p.HYPERTENSIONAHS120158

2.