NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date

SUMMARY:

Coronavirus disease 2019 (COVID-19) is an infection caused by the SARS-CoV-2 virus. The virus is known to target the angiotensin converting enzyme 2 (ACE-2) co-receptor. Therefore, concern has been raised whether the use of common medications that impact ACE and the renin angiotensin system may also result in increased COVID-19 infection risk. Papers have been now been published demonstrating no increased risk with use of ACE inhibitors or angiotensin receptor blockers (ARBs).

• High Risk Groups for COVID-19 infection
• ACE Enzymes
• ACE Inhibitors and ARBs
• What We Currently Know about SARS-CoV-2 Infectivity
• Do ACE Inhibitors and ARBs Increase Risk for COVID-19
• Recommendations

High Risk Groups for COVID-19 infection

• Patients at higher risk for significant morbidity and mortality from COVID-19 infection include older patients, especially those with chronic medical conditions such as the following
  • Pulmonary disease
  • Cardiac disease
  • Kidney disease
  • Diabetes
  • Hypertension
• It is unclear whether the above associations are independently related to pathogenesis, other associated comorbidities, or even treatment
  • These disorders themselves are not necessarily independent and often appear together in patients, particularly in the context of the metabolic syndrome
• ACE inhibitors, ARBs and other renin angiotensin aldosterone system (RAAS) inhibitors are commonly used in patients who would be considered ‘at risk’ for COVID-19

Angiotensin Converting Enzymes

• ACE-1 and ACE-2 are two major enzymes found in the renin-angiotensin system
  • ACE enzymes play a critical role in the balance of peptides in the angiotensin family
  • ACE-2 is found on
    • Epithelial cells in both respiratory and GI tracts
    • Cardiac and kidney cells

ACE Inhibitors and ARBs

• ACE inhibitors and ARBs
  • Strongly influence angiotensin peptides
  • Increase ACE-2 activity in cardiac tissue

What We Currently Know about SARS-CoV-2 Infectivity

• SARS-CoV-2 is covered with crown-like glycoprotein spikes (hence ‘corona’) comprised of 2 subunits
  • Subunit S1: Binds to ACE-2 on the cell surface
  • Subunit S2: Fuses with the cell membrane
  • TMPRSS2 (host enzyme): Promotes cellular entry of the virus

Do ACE Inhibitors and ARBs Increase Risk for COVID-19?

• ACE inhibitors, ARBs and other renin angiotensin aldosterone system (RAAS) inhibitors are commonly used in patients who would be considered ‘at risk’ for COVID-19
• Theoretical risk raised
  • Because ACE inhibitors and ARBs ‘may’ increase expression of ACE-2 leading to greater risk for virus to enter and infect cells, could these medication lead to increased risk for COVID-19 morbidity and/or mortality?
• Possible benefit
  • Study from China showed that while hypertension is a risk factor for COVID-19 mortality, patients on ACE inhibitors and ARBs did better (see review in ‘Learn More – Primary Sources’ below)
  • Underlying mechanism is unclear, but there may be a biphasic pattern: (1) In phase 1, these medications could increase infectivity (2) In phase 2, ACE-2 downregulation by the virus may be the “hallmark” of COVID-19 progression and therefore medications that upregulate in the second phase may be of benefit
  • In addition, there is a hypothesis that ACE-2 also stimulates one of the angiotensin peptides (angiotensin-(1-7)) that has positive anti-inflammatory effects | Therefore, medications that stimulate ACE-2 could have a beneficial effect

Current Evidence

• Zhang et al. (Circ Res, 2020)
  • Retrospective, multi-centered study | 1128 hospitalized patients with COVID-19 | ACE Inhibitors/ARB group: 188
  • After adjustment, detected risk for all-cause mortality was lower in the ACE Inhibitors/ARB group compared to the non-ACE Inhibitors/ARB group
  • Adjusted hazard ratio: 0.42 (95% CI, 0.19 to 0.92; p = 0.03)
  • These medications may be associated with a lower risk of all-cause mortality in the setting of COVID-19 compared to non-users
• Reynolds et al. (NEJM, 2020)
  • 12,594 tested | 5894 patients positive for COVID-19 | Severe in 17%
  • Hypertension history: 34.6% of tested patients | 59.1% were COVID-19 positive had a positive test | Severe in 24.6%
  • Authors conclude that there was no association with likelihood of a positive test or severity of illness
• Mancia et al. (NEJM, 2020)
  • Population-based case–control study | 6272 patients with confirmed SARS-CoV-2 infection
  • Use of ARBs or ACE inhibitors did not show any association with Covid-19 overall or those with severe or fatal disease
• Editorial (Jarcho et al. NEJM, 2020)
  • The accompanying editorial recognizes limitations inherent in observational data
  • However, these studies support professional guidance that recommend against altering these medications when indicated
  • Furthermore, the editorial authors state

Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe Covid-19 among those infected, or the risk of in-hospital death among those with a positive test. 

KEY POINTS:

Recommendations

• Guidance is based on the current lack of evidence that ACE inhibitors or ARBs increase risk of infection or result in a more severe course of COVID-19 disease
  • It is acknowledged that new data may result in a future update to these guidelines
• Professional recommendations do not support stopping or changing medications for patients who are currently being treated with ACE inhibitors or ARBs
• In addition, cessation is associated potential for significant harms including
  • Medical risk: Exacerbation of underlying medical conditions
  • Infection risk: Due to increased pharmacy encounters, visits for blood work etc.
• The HFSA/ACC/AHA recommends

…continuation of RAAS antagonists for those patients who are currently prescribed such agents for indications for which these agents are known to be beneficial, such as heart failure, hypertension, or ischemic heart disease

In the event patients with cardiovascular disease are diagnosed with COVID-19, individualized treatment decisions should be made according to each patient’s hemodynamic status and clinical presentation

Therefore, be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice

Learn More – Primary Sources:

Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19 (Vaduganathan et al., NEJM)

Drugs and the renin-angiotensin system in covid-19 (BMJ)

HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19

COVID-19: An ACP Physician’s Guide and Resources

European Medicines Agency: EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic

British Society for Heart Failure (BHF) and British Cardiology Society (BCS): Statement on ACI Inhibitors and ARBs in COVID-19

Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19 (Zhang et al. Circ Res, 2020)

Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19 (Reynolds et al. NEJM, 2020)

Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19 (Mancia et al. NEJM, 2020)

Inhibitors of the Renin–Angiotensin–Aldosterone System and Covid-19 (Editorial. NEJM 2020)

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