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06 april 2020

Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19 - NEJM

30-3-2020; 10.1056/NEJMsr2005760
By: Vaduganathan et al. 

Review evidence on RAAS inhibitors and SARS-CoV-2


  • ACE2 (an enzyme in RAAS) is the functional receptor to SARS-CoV-2.
  • Preclinical studies raised concerns on the safety of RAAS-inhibitors in covid-19
  • However; data is insufficient to draw clear conclusions. RAAS-inhibitors might even positively affect prognosis of covid-19
  • Clinical trials are under way to test the safety and efficacy of RAAS modulators,  and the ARB losartan in Covid-19
  • Withdrawal of RAAS-inhibitors has downsides and is not advisable in otherwise stable patients


  • The RAAS is a cascade of vasoactive peptides necessary for key physiological processes. 
  • The SARS-CoV-2 interfaces with RAAS through the ACE2 enzyme which functions as a receptor for the virus.
  • ACE-inhibitors and ARBs (angiotensin receptor blockers) are used commonly. 
  • Initial clinical COVID-19 reports have called attention to the potential overrepresentation of hypertension among (severely ill) covid-19 patients. There are concerns that medical management of hypertension (e.g. raas inhibitors) contribute to these adverse outcomes. However:
    • hypertension correlates with advancing age which is the strongest predictor of covid-19 related death
    • Reports have not corrected for age
    • In many other viral diseases comorbidities (like  hypertension) correlate negatively with prognosis
      • Properly conducted studies identifying the link between raas inhibitor use and worse covid-19 outcomes are unavailable.
  • Tissue-specific and circulating components of the RAAS make up a very complex intersecting network of regulatory and counterregulatory peptides. The direct effect of RAAS inhibition on (lung-specific) ACE2 expression remains unclear. 
    • This indicates the complexity of the RAAS-pathway and contradicting evidence (in animal models) it is impossible to say that the use of RAAS-inhibitors leads to a greater Sars-CoV-2 spread in lung tissue
  • There might even be potential benefit rather than harm of RAAS-inhibtors in covid-19 patients. 
    • SARS-CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently down-regulate ACE2 expression such that the enzyme is unable to exert protective effects in organs.
    • In experimental mouse models, exposure to SARS-CoV-1 spike protein induced acute lung injury, is limited by RAAS blockade.
    • RAAS-inhibitors also work cardioprotective. Covid-19 is known to lead to myocardial injury. 
  • Despite these theoretical uncertainties regarding whether pharmacologic regulation of ACE2 may influence the infectivity of SARS-CoV-2, there is clear potential for harm related to the withdrawal of RAAS inhibitors in patients in otherwise stable condition.
    • Withdrawal might lead to decompensation in stable patients while cardiopulmonary comorbidity negatively affects covid-19 prognosis.
  • On the basis of the available evidence, we think that, despite the theoretical concerns and uncertainty regarding the effect of RAAS inhibitors on ACE2 and the way in which these drugs might affect the propensity for or severity of Covid-19, RAAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, are being evaluated for, or have Covid-19.