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- Page navigation anchor for RE: Update on Developments in the LiteratureRE: Update on Developments in the Literature
An international cohort study of 8910 patients (1) that found no association between use of RAAS inhibitors and risk of in-hospital death has been retracted over concerns of the validity of its data sources (2). We had included this article in our update of the evolving evidence on the risk of potential harm associated with use of Renin–Angiotensin–Aldosterone System (RAAS) inhibitors in patients with COVID-19 (3) but not in our original CMAJ article (4).
Therefore, we reviewed the sources of data from all studies cited in our articles. To the best of our knowledge no other concerns exist.
As a further update, a recently published matched case-population study of over 1100 hospitalized adults admitted with COVID-19 found no association between use of RAAS inhibitors and risk of admission to hospital, intensive care unit or death (5).
Given the evidence to date, we continue to support our original conclusion and the recommendations from multiple professional societies that “patients prescribed RAAS inhibitors should remain on them during the COVID-19 pandemic, pending release of high-quality and replicable data to the contrary” (3,4).Competing Interests: None declared.References
- Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. 2020 May 1.
- Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Retraction: Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. 2020 June 4.
- Quinn KL, Fralick M, Zipursky JS, Stall NM. Good things come in threes (and sometimes fours). CMAJ. 2020 May 11.
- Quinn KL, Fralick M, Zipursky JS, Stall NM. Renin-angiotensin-aldosterone system inhibitors and COVID-19. CMAJ. 2020 Apr 24.
- de Abajo FJ, Rodríguez-Martín S, Lerma V, Mejía-Abril G, Aguilar M, García-Luque A, et al. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet. 2020 May 30;395(10238)
- Page navigation anchor for RE: Renin-angiotensin-aldosterone system inhibitors to treat COVID-19?RE: Renin-angiotensin-aldosterone system inhibitors to treat COVID-19?
I would like to respond to two statements in this Commentary.
1. “ACE inhibitors and ARBs exert opposite effects on angiotensin II”.
Angiotensinogen (AGT) is produced mainly in the liver and fat cells, in response to poor perfusion, and acts as a pro-signal in the complex downstream renin-angiotensin-aldosterone (RAAS) system. AGT is cleaved to angiotensin I (Ang-1-10) by renin, which is found mostly in the juxtaglomerular apparatus of the kidney, and is also considered a pro-signal peptide. Angiotensin I can be cleaved by one of two membrane proteases expressed by angiotensin-targeted cells: i) angiotensin converting enzyme (ACE) to form angiotensin II, or ii) angiotensin converting enzyme-2 to form Ang(1-9). Angiotensin II is the main RAAS agonist and binds to angiotensin receptors (AR) expressed on the same targeted cells.
Thus, both ACE inhibitors and AR blockers (ARBs) exert downregulating effects on angiotensin II activity. In essence, they complement the effect of ACE2, which is a naturally occurring protease that counters angiotensin II activity.
2. Improved outcomes during COVID-19 with ACE inhibitors and ARBs “are unlikely to be causal”.
It is generally accepted that increased expression of ACE2 is advantageous for an ACE2-targetting virus such as SARS-CoV-2, which cycles through cells with membrane ACE2 proteases until those proteases are depleted. Higher ACE2 expression enables more viral cycling and thus a higher viral...
Show MoreCompeting Interests: Provisional patent filed: Use of Mineralocorticoid Blockers in the Treatment of COVID-19.References
- Kieran L. Quinn, Michael Fralick, Jonathan S. Zipursky, et al. Renin–angiotensin–aldosterone system inhibitors and COVID-19. CMAJ 2020;192:E553-E554.
- Zhang P, Zhu L, Cai 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. Circ Res 2020;126:1671–1681.
- Page navigation anchor for RE: Association between angiotensin blockade and COVID-19 severity in Hong Kong: a territory-wide studyRE: Association between angiotensin blockade and COVID-19 severity in Hong Kong: a territory-wide study
We read this commentary(1) with interest on the role of angiotensin converting enzymes inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are in COVID-19 incidence and severity. Recent observational studies did not show increased risk of disease severity with ACEI/ARB use,(2,3) and an observational study(4) even reported a lower mortality risk with ACEIs (adjusted odds ratio [aOR]:0.33). However, all these studies did not adjust for laboratory parameters, which may confound the observed association.
We conducted a territory-wide retrospective cohort study by retrieving data from territory-wide electronic healthcare database ing Hong Kong Hospital Authority. We identified all patients aged ≥18 years diagnosed with COVID-19 between 1 January 2020 and 27 April 2020. The primary outcome was severe disease including (1)severe pneumonia, (2)critical complication (respiratory failure, septic shock and/or multiple organ dysfunction), (3)ventilatory support (invasive or non-invasive), (4)intensive care unit admission or (5)death. Drug exposure including ACEIs and ARBs was defined as ever exposure within 5 years before admission. Multivariable logistic regression model was performed by adjusting for other covariates including age, sex, comorbidities (diabetes mellitus, hypertension, ischemic heart disease, stroke and atrial fibrillation), other medications (aspirin, statins, proton pump inhibitors), and laboratory parameters (leukocyte, platelet, C-reactive protein...
Show MoreCompeting Interests: None declared.References
- Kieran L. Quinn, Michael Fralick, Jonathan S. Zipursky, et al. Renin–angiotensin–aldosterone system inhibitors and COVID-19. CMAJ 2020;192:E553-E554.
- Mancia G, Rea F. Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19. 2020.
- Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med 2020.
- Mehra MR, Desai SS. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. 2020.
- Page navigation anchor for Good things come in threes (and sometimes fours)Good things come in threes (and sometimes fours)
Since the publication of our article in CMAJ,(1) there have been significant developments in the literature regarding the role of Renin–Angiotensin–Aldosterone System (RAAS) inhibitors in patients with COVID-19. We wish to summarize them here to support our recommendations on prescribing practices for these drugs.
Three large observational studies of over 20,000 patients with COVID-19 found no association between the use of RAAS inhibitors and increased risk of infection, development of severe disease, or death.(2-4) The three studies used different methodological approaches, and all came to similar conclusions.
A separate cohort study of 18,472 patients who were tested for SARS-CoV-2 also found no association between RAAS inhibitor use and testing positive for COVID-19. However, a secondary analysis of 1,735 patients in the study with confirmed COVID-19 demonstrated an increased risk of severe disease requiring ICU admission.(5)
All observational studies are at risk of unmeasured confounding. However, based on the consistent results across these studies, RAAS inhibitors are unlikely to cause harm in patients with COVID-19.
In our original article we reinforced recommendations from multiple professional societies that “the totality of current clinical and experimental evidence for RAAS inhibitors to facilitate infection by SARS-CoV-2 or increase the risk of harm in patients with COVID-19 is insufficient to suggest altering current use.”(1) We co...
Show MoreCompeting Interests: None declared.References
- 1. Quinn KL, Fralick M, Zipursky JS, Stall NM. Renin-angiotensin-aldosterone system inhibitors and COVID-19. CMAJ. 2020 Apr 24.
- 2. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. 2020 May 1.
- 3. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. 2020 May 1.
- 4. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med. 2020 May 1.
- 5. Mehta N, Kalra A, Nowacki AS, et al. Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020 May 5.
- Page navigation anchor for ACE2 is on the X chromosomeACE2 is on the X chromosome
There is a good discussion of this issue in Online Mendelian Inheritance in Man at
https://omim.org/entry/300335 It seems likely that ARBs and ACE inhibitors are protective in COVID-19.ACE 2 is located on the X chromosome, and men are more severely affected than women by COVID-19 [2]. An issue that is not discussed, but interesting to consider, is whether a reason why women are relatively protected is that women have two copies of that gene, and men have only one.
Competing Interests: None declared.References
- Kieran L. Quinn, Michael Fralick, Jonathan S. Zipursky, et al. Renin–angiotensin–aldosterone system inhibitors and COVID-19. CMAJ 2020;10.1503/cmaj.200619.
- 2. Sharma G, Volgman AS, Michos ED. Sex Differences in Mortality from COVID-19 Pandemic: Are Men Vulnerable and Women Protected? JACC Case Rep. 2020 May 4. doi: 10.1016/j.jaccas.2020.04.027. [Epub ahead of print]