Use of RAAS Blockers During COVID – 19 Infection: Friend or

Foe?

Barry Greenberg, MDDistinguished Professor of Medicine

Director, Advanced Heart Failure Treatment ProgramUniversity of California, San Diego

26th Annual San Diego Heart Failure SymposiumLa Jolla, California

September 26, 2020

Evolving Insights into the Renin Angiotensin System (RAS)

The Renin Angiotensin System (RAS)

Iwata M, Greenberg B. J Mol Cell Cardiol 2011;51:542-547.

The Role of ACE2 in Controlling the RAS and in Coronavirus Infection

Eur Heart J, 2020;41:1818–1820.

• Ang I and Ang IIare substratesfor ACE2

• ACE2 is cleaved from the cell surface by ADAM-17

Iwata M, Greenberg B. J Mol Cell Cardiol 2011;51:542-547.

• Coronavirus binding to ACE2 leads tointernalization of the virus and infection

ACE2 Expression and Coronavirus Binding

Gheblawi M, Oudit G. Circ Res 2020

Does ACEI/ARB Use Increase Risk of COVID-19 and Severity of Infection?• ACEI/ARBs have been shown to upregulate ACE2 and increase enzyme

activity in a variety of tissues in animal models.

• Early studies reported high prevalence of HTN and use of ACEIs/ARBs in patients infected with COVID-19.

• Since ACE2 controls entry of COVID-19 into cells, are patients who are being treated with ACEIs or ARBs:

- more susceptible to infection?

- more likely experience more severe infection or death?

No Association Between Positive COVID-19 Test and Anti-Hypertensive Therapy

HR Reynolds et al. NEJM 2020

From: Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and MortalityJAMA. 2020;324(2):168-177. doi:10.1001/jama.2020.11301

Standardized 30-Day Absolute Risks for Death, Composite of Death or Severe COVID-19, and Severe COVID-19

No Significant Association Between ACEI/ARBs and Outcomes in Hypertensive Patients in Wuhan

JAMA Cardiology 2020

No Association Between Anti-hypertensive Agents and Severe COVID-19 Infection

There was no substantial increase in the likelihood of either a positive test for Covid-19 or in the risk of severe Covid-19 infection among patients who tested positive in association with five common classes of antihypertensive medications.

HR Reynolds et al. NEJM 2020

Association Between HTN and COVID-19 Lethality• Studied 1591 COVID-19 patients hospitalized in Italy.• At least 1 comorbidity in 73.4%, with HTN being the most common (54.9%). • There were 181 deaths (11.8%; mean age, 79.6±0.9 years). • Non-survivors were older, more likely to have HTN, DM, COPD, CKD, CAD, and

had higher Charlson Comorbidity Index than survivors. • ACEIs, diuretics, and β-blockers more frequently used in non-survivors than in

survivors. • After correction by multivariate analysis, only age (P=0.0001), DM (P=0.004), COPD

(P=0.011), and CKD (P=0.004) but not HTN predicted mortality. • Charlson Comorbidity Index, which cumulates age and comorbidities, predicts

mortality with an exponential increase in the odds ratio by each point of score. • Concluded that mortality predicted by age and presence of comorbidities; no

significant interaction between HTN and antihypertensive therapy and COVID-19 lethality.

Iaccarino G. Hypertension: 76: 366-372;2020

Forest Plot of ACEI/ARB Exposure and Mortality Risk in COVID-19 Patients

Zhang X et al. Pharmacol Res;158:2020

Meta-analysis of 12 studies including more than 19,000 patients

Professional Society Recommend Continuing Use of ACEIs and ARBs in COVID-19 Patients

ACE2 Inhibition with C16 Has Adverse Effects in the Post-MI Heart

Kim M, Greenberg B et al. JCF 16:777-785, 2010

Could ACEI/ARB Therapy Improve COVID-19Outcomes?• ACE2-Ang1-7-Mas receptor pathway is protective.• Depletion of ACE2 during COVID-19 infection shifts balance between

Ang II (deleterious) and Ang1-7 (beneficial).• Lower ACE2 levels may increase the likelihood of tissue injury.• Diseases such as HTN and T2DM where ACE2 levels are reduced are

associated with worse outcomes from COVID-19.• ACE2 activity is increased by ACEIs/ARBs.• Could these drugs protect the heart and other organs during COVID-

19 infection?

Outcomes in COVID-19 Patients Taking ACEI/ARBs

Zhang P et al, Circ Res;126:1671-1681. 2020

Use of sACE2 to Bind Coronaviruses and Prevent Uptake Mediated by Cell Based ACE2

From: Battle D et al. Clin Sci (London) 2020

Use of RAAS Blockers During COVID – 19 Infection: Friend or Foe?• Most studies failed to demonstrate an adverse effects of ACEIs or

ARBs on either COVID-19 infection or outcomes.• Professional societies recommend not discontinuing these agents.• The possibility that ACEIs/ARBs may improve outcomes is currently

under investigation.• Possible treatment with sACE2 to bind COVID-19 in the circulation

and prevent virus uptake into cells.