We thank Alberto Palazzuoli et al. for their interest in our article1 and providing insightful comments on the use of renin-aldosterone system inhibitors (RASi) in patients with COVID-19. We would like to highlight some salient updates with regards to our understanding on the use of RASi, particularly angiotensin-converting-enzyme inhibitors or AT1 blockers (ACEI/ARBs), in COVID-19.
At present, there is an abundance of evidence that the use of RASi has no detrimental effect in patients with COVID-19 and should not be discontinued, unless clinically indicated. We now have results from 2 randomized controlled trials that have tested this hypothesis. The BRACE CORONA trial2 included 659 patients on ACEI/ARBs who were hospitalized with mild to moderate COVID-19 and randomized them to discontinuation or continuation groups. There was no significant difference in the primary endpoint of the number of days alive and out of the hospital in the discontinuation versus the continuation group (mean 21.9 versus 22.9 days). Moreover, there was no difference in in-hospital or 30-day mortality between the two groups. In the REPLACE COVID trial3, 152 patients on ACEI/ARBS were randomly assigned to either continue or discontinue groups. The primary outcome was global rank score across four hierarchies of clinical outcomes during hospitalization. There was no difference in global rank score between discontinuation or continuation groups (73 vs 81, p=0.61). The in-hospital all-cause mortality was also similar between the two groups. Undertaken in the midst of the pandemic, these trials certainly have some limitations, however they provided high-quality data supporting the use of RASi in COVID-19 patients. Whether there is a differential effect between ACEIs and ARBs in COVID-19 is an intriguing question. Our meta-analysis showed that neither ACEIs nor ARBs were associated with mortality compared to controls. Other randomized trials are on-going and should provide further insights on this topic.
The link between RASi and COVID-19 was initially postulated based on the earlier experimental data4,5 that showed that RASi substantially increases the expression of the angiotensin-converting enzyme (ACE) 2 receptors which also serves as entry receptors for SARS-CoV-2. However, recent experimental studies6,7 using human tissues failed to show any significant association between RASi and upregulation of ACE2. To the contrary, RASi may play a role in mitigating the hyperinflammatory response to SARS-CoV-2, thereby potentially reducing target organ injury in acute phase in addition to their well-known long-term cardio-renal benefits.
Footnotes
Conflict of Interests/Disclosures: Dr. Mancia reports personal fees from Bayer, Boehringer Ingelheim, CVRx, Daiichi Sankyo, Ferrer, Medtronic, Menarini Int., Merck, Novartis, Recordati, Servier, outside the submitted work. Dr. Corrao reports grants from European Community, grants from Italian Medicines Agency (AIFA), Italian Ministry of Education, University and Research (MIUR), Novartis, GSK, other from Roche, AMGEN, BMS, outside the submitted work. Dr. Messerli reports consulting fees from Medtronic, Daiichi Sankyo and Menarini Int. Drs. Bavishi, and Whelton report no conflicts of interest.
References
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