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 with commentary

COMPLIANCE WITH ETHICAL STANDARDS 
Fundings: There were no institutional or private fundings for this article.
Conflict of interests: The authors declare that they have no conflict of interests.
Authors’ contributions: The authors contributed equally to the realization of the manuscript.
Availability of data and materials: The data underlying this manuscript are available in the article.
Ethical approval: N/A.

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 reported 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 antihypertensive 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 ACEinhibitor 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 SARSCoV-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 SARSCoV-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 ACEinhibitors 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 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 SARSCOV-2, are needed. With regards to the hypothesis that ACE-inhibitors and ARBs can be used in healthy people to pre-vent SARSCoV-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-antiipertensivie-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-COVID19.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, Krüger N, Müller M, Drosten C, Pöhlmann 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-hypertension-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.

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. Vicenzi ^1,2, A. Corsini ^3,4, M. Ruscica ³

¹ IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Internal Medicine Department, Cardiovascular Disease Unit, Milan, Italy
² Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
³ Department of Pharmaceutical and Biomolecular Sciences, University of Milan, Milan, Italy
⁴ IRCCS Multimedica Hospital, Milan, Italy

The uncertainties whether pharmacologic regulation of angiotensin-converting enzyme 2 (ACE2) may worsen the infectivity of SARS-CoV-2 is gaining a large interest 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 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.