What is the rationale for continuing or discontinuing ACEi/ARB?

Posted on April 24, 2020 by Raymond Cho

Summary

There is a lack of evidence to support that ACEi/ARBs truly increase infectivity of COVID-19 despite the theoretical physiological mechanism. Most groups including Hypertension Canada, CCS, AHA, HFSA, ACC recommend not switching patients on ACEi/ARBs at this time.

I.   THEORETICAL EFFECTS OF ACEI/ARB ON COVID-19 INFECTIVITY AND PROTECTION

    • Role of ACE2: ACE2 is a transmembrane protein (homologous to ACE1) which converts angiotensin II to angiotensin 1-7. This induces a counterregulatory effect of the traditional RAAS system, promoting cardioprotection and mild-moderate vasodilation (Figure 1) (1).

 

  • Effect of ACEi/ARB on ACE2: animal studies have shown that ACEis/ARBs upregulate ACE2 expression in addition to their main effect of inhibiting ACE1 to block the RAAS system (2). 
  • ACEi/ARB on Infectivity of COVID-19: unfortunately, SARS-CoV-2 uses the ACE2 protein to gain entry into cells and enable viral replication. Therefore, Sommerstein et. al. hypothesized that increased expression of ACE2 due to ACEi/ARBs could play a role in COVID-19 infectivity (3). However, there currently is no clinical-epidemiological data to support this hypothesis. 
  • ACEi/ARB on Cardioprotection in COVID-19: RAAS activation has been shown to play a role in acute lung injury in ARDS, the most common cause of critical illness in COVID-19. ACE2 was shown to reduce inflammation and increase oxygenation in mice with ARDS (4). Angiotensin II levels were also higher in patients who died from ARDS compared to those who survived (5).
  • Consequently, ACEis/ARBs may play a dual role in COVID-19, on one hand potentially increasing the infectivity of SARS-CoV-2 and on the other, reducing potential for lung injury and mortality in those already infected.

 

 

Figure 1: SARS-CoV-2 Infection could influence the balance between Ang II and Ang 1-7 (1).

II.   CLINICAL TRIALS TO DATE

  • We were only able to find one clinical trial determining the association between in-hospital use of ACEi/ARB and all-cause mortality in COVID-19 patients.
  • Zhang et. al. studied 1128 patients with hypertension and COVID-19 with 188 taking ACEis/ARBs and 940 not. They determined that unadjusted mortality was significantly lower in the ACEi/ARB group (3.7% vs. 9.8%, P = 0.01) and that ACEi/ARB was associated with decreased mortality compared to other antihypertensives (HR 0.3, P = 0.01) (6)
  • It should be noted that this is observational (not randomized) and there are confounding variables; several editorials note that this study is “hypothesis generating and worth further exploration” but not definitive (7).

III.   ARGUMENTS FOR AND AGAINST SWITCHING FROM ACEi/ARB

 

  • Against: 

 

      • ACEis/ARBs may potentially reduce the likelihood of severe acute lung injury in patients with ARDS by increasing expression of ACE2 (4,5).
      • In the frail, elderly population, switching between antihypertensive drugs may put patients at risk of adverse cardiovascular events. Given the robust evidence for ACEIs/ARBs in cardiovascular disease, discontinuation can lead to further negative outcomes unrelated to the COVID-19 infection (8).
      • ACEIs/ARBs are approved for treatment of hypertension, heart failure and cardioprotection following an acute MI, whereas CCBs may not be (8).

 

  • For:

 

    • Fang et. al. suggests that calcium channel blockers (CCB) may be a more suitable antihypertensive as it has no effect on ACE2 activity. However, there is no sound evidence that switching from ACEis/ARBs to CCBs is associated with beneficial effects on the prevention or prognosis of infected patients (9).
    • Ciulla in a commentary states that the use of ACEis/ARBs are documented in 52% of deaths in patients with COVID-19 from the Italian Health Institute (10). However, data from China PEACE Million Person’s Project show less than only 21.7% of hypertensive patients receive ARBs and 9.1% receive ACEis (11). Therefore, the evidence for ACEi/ARB association with mortality in COVID-19 is unclear.

IV.   POSITION STATEMENTS BY GROUPS

 

  • Canadian Cardiovascular Society and Canadian Heart Failure Society (March 15, 2020): Strongly discourages discontinuation of ACEi, ARB and ARNi in hypertensive or heart failure patients as a result of the COVID-19 pandemic (12).
  • Hypertension Canada (March 13, 2020): There is no evidence that patients treated with ACEis/ARBs are at higher risk of adverse outcomes from COVID-19 infection and endorse patients with hypertension to continue with their current blood pressure treatment (13). 
  • Heart Failure Society of America, American College of Cardiology, American Health Association (March 17, 2020): “The HFSA, ACC, and AHA recommend 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.” (14)
  • European Society of Cardiology (March 13, 2020): Highlights the lack of evidence supporting harmful effects of ACEi and ARB in context of COVID-19 outbreak. Strongly recommends continuing treatment with usual anti-hypertensive therapies (15).

 

 

Questions? Comments? Does this need to be updated? Do you have valuable points to add ? Please email ask.reakt@ubc.ca.

References

  1. Guo J, Huang Z, Lin L, Lv J. Coronavirus Disease 2019 (COVID‐19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin‐Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Journal of the American Heart Association [Internet]. 2020Apr1;9(7). Available from: https://www.ahajournals.org/doi/10.1161/JAHA.120.016219
  2. Sommerstein R, Kochen MM, Messerli FH, Gräni C. Coronavirus Disease 2019 (COVID‐19): Do Angiotensin‐Converting Enzyme Inhibitors/Angiotensin Receptor Blockers Have a Biphasic Effect? Journal of the American Heart Association [Internet]. 2020Apr1;9(7). Available from: https://www.ahajournals.org/doi/10.1161/JAHA.120.016509
  3. Sommerstein R. Preventing a covid-19 pandemic. BMJ [Internet]. 2020Mar3;368:m810. Available from: https://www.bmj.com/content/368/bmj.m810/rr-2
  4. Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Critical Care [Internet]. 2017Dec13;21(1). Available from: https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1882-z
  5. Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Critical Care [Internet]. 2017Sep7;21(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588692/
  6. Zhang P, Zhu L, Cai J, Lei F, Qin J-J, 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. Circulation Research [Internet]. 2020Apr17; Available from: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.317134
  7. ACEI/ARBs Linked With Survival in Hypertensive, Chinese COVID-19 Patients [Internet]. Medscape. 2020. Available from: https://www.medscape.com/viewarticle/929189#vp_2
  8. Trifirò G, Crisafulli S, Andò G, Racagni G, Drago F. Should Patients Receiving ACE Inhibitors or Angiotensin Receptor Blockers be Switched to Other Antihypertensive Drugs to Prevent or Improve Prognosis of Novel Coronavirus Disease 2019 (COVID-19)? Drug Safety [Internet]. 2020Apr17; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164333/
  9. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet Respiratory Medicine [Internet]. 2020Mar11;8(4). Available from: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext
  10. Ciulla MM. Switching to another antihypertensive effective drug when using ACEIs/ARBs to treat arterial hypertension during COVID-19. European Heart Journal [Internet]. 2020Apr23; Available from: https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa331/5824223
  11. Kuster GM, Osswald S. Switching antihypertensive therapy in times of COVID-19: why we should wait for the evidence. European Heart Journal [Internet]. 2020Apr23; Available from: https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa335/5824224
  12. Krahn A, Zieroth S. COVID-19 and concerns regarding use of ACEi/ARB/ARNi medications for heart failure or hypertension [Internet]. Canadian Cardiovascular Society. 2020. Available from: https://www.ccs.ca/images/Images_2020/CCS_CHFS_statement_regarding_COVID_EN.pdf
  13. Khan N. Hypertension Canada’s Statement on: Hypertension, ACE-Inhibitors and Angiotensin Receptor Blockers and COVID-19 [Internet]. Hypertension Canada. 2020. Available from: https://hypertension.ca/wp-content/uploads/2020/03/2020-30-15-Hypertension-Canada-Statement-on-COVID-19-ACEi-ARB.pdf
  14. Bozkurt B, Kovacs R, Harrington B. HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19 [Internet]. American College of Cardiology. 2020. 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
  15. de Simone G. Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers [Internet]. European Society of Cardiology. 2020. 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

Disclaimer

The above is intended to serve as a rapidly-created, accessible source of information curated by medical students and healthcare professionals. It is for educational purposes only and is not a complete reference resource. It is not professional medical advice, and is not a substitute for the discretion, judgment, and duties of healthcare professionals. You are solely responsible for evaluating the information above.