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By Christian Hoffmann &
Bernd S. Kamps
Top Ten Special on
ACE inhibitors/ARBs – continue them (or start them up again)!
There has hardly been a topic in the last weeks of this pandemic that has kept doctors (mainly internists) and their patients as busy as the question of whether ACE inhibitors or angiotensin-receptor blockers (ARBs) can cause harm to patients. Early observations of an increased risk for mortality or severe COVID-19 in patients with hypertension, cardiovascular diseases and diabetes (Guan 2020) raised concerns. These diseases share underlying renin-angiotensin-aldosterone system pathophysiology that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated (increased) in cardiovascular disease (Vaduganathan 2020). As SARS-CoV-2 cell entry depends on ACE2 (Hoffmann 2020), increased ACE2 levels may increase the virulence of the virus within the lung and heart. ACE inhibitors or ARBs which are frequently used to treat cardiovascular diseases may alter ACE2 and variation in ACE2 expression may in part be responsible for disease virulence.
Although a recent review of 12 animal studies and 12 human studies overwhelmingly implies that administration of both drug classes does not increase ACE2 expression (Sriram 2020), some concerns on deleterious effects remain and some media sources and health systems have called for the discontinuation of these drugs.
However, some small retrospective studies from China have shown no negative effect (Meng 2020). In the largest study, 188 patients taking ACEIs/ARBs were compared with 940 patients who did not use them. Of note, unadjusted mortality rate was lower in the ACEI/ARB group (3.7% vs. 9.8%) and a lower risk was also found in a multivariate Cox model (Zhang 2020).
Last week, three studies were published in the NEJM that will hopefully put an end to this discussion. Although all three were observational studies with the possibility of confounding, their message was consistent — none of the three studies showed any evidence of harm (Jarcho 2020).
The first study analyzed a total of 8,910 COVID-19 patients (from 169 hospitals located in 11 countries) for whom discharge status was availably by March 29 (Mehra 2020). A total of 515 (5.8%) died in the hospital. Factors independently associated with an increased risk of in-hospital death were an age greater than 65 years (odds ratio, 1.93), coronary artery disease (2.70), heart failure (2.48; 95% CI, 1.62 to 3.79), cardiac arrhythmia (1.95; 95% CI, 1.33 to 2.86), chronic obstructive pulmonary disease (2.96; 95% CI, 2.00 to 4.40), and current smoking (1.79; 95% CI, 1.29 to 2.47). No increased risk was found for the use of ACE inhibitors (0.33; 95% CI, 0.20 to 0.54) or the use of ARBs (1.23; 95% CI, 0.87 to 1.74). Of note, use of either ACE inhibitors or statins was associated with better survival. However, these associations should be considered with extreme caution as the study design cannot exclude the possibility of confounding.
The second study analyzed 2,573 COVID-19 patients with hypertension from New York City (Reynolds 2020). In total, 634 (24.6%) had severe disease, as indicated by ICU admission, mechanical ventilation, or death by April 15, 2020. After looking at different classes of antihypertensive medication — ACE inhibitors, ARBs, beta-blockers, calcium-channel blockers, and thiazide diuretics, the authors ruled out any substantial difference in the likelihood of severe COVID-19, with at least 97.5% certainty for all medication classes.
The third study looked at a possible independent relationship between RAAS blockers and the susceptibility to COVID-19 (Mancia 2020). The authors matched 6,272 Italian cases (positive for SARS-CoV-2) with 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. There was no evidence that ACE inhibitors or ARBs modify susceptibility to COVID-19. The results applied to both sexes as well as to younger and older persons.
We think that’s it. Take your ACE inhibitors or ARBs. We do not agree with the NEJM editorial that “one or more randomized trials will be needed to answer definitively the question of whether ACE inhibitors or ARBs pose a harm to patients with COVID-19” (Jarcho 2020). Let’s not waste time and/or resources. We have bigger fish to fry.
Top 10 references on this topic
Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28. PubMed: https://pubmed.gov/32109013. Full-text: https://doi.org/10.1056/NEJMoa2002032
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Mar 4. pii: S0092-8674(20)30229-4. PubMed: https://pubmed.gov/32142651. Full-text: https://doi.org/10.1016/j.cell.2020.02.052
Jarcho JA, Ingelfinger JR, Hamel MB, D´Agostino RB Sr, Harrington DP. Inhibitors of the Renin-Angiotensin-Aldosterone System and Covid-19. N Engl J Med. 2020 May 1. PubMed: https://pubmed.gov/32356625. Full-text: https://doi.org/10.1056/NEJMe2012924
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. PubMed: https://pubmed.gov/32356627. Full-text: https://doi.org/10.1056/NEJMoa2006923
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. PubMed: https://pubmed.gov/32356626. Full-text: https://doi.org/10.1056/NEJMoa2007621
Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020 Dec;9(1):757-760. PubMed: https://pubmed.gov/32228222. Full-text: https://doi.org/10.1080/22221751.2020.1746200
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. PubMed: https://pubmed.gov/32356628. Full-text: https://doi.org/10.1056/NEJMoa2008975
Sriram K, Insel PA. Risks of ACE inhibitor and ARB usage in COVID-19: evaluating the evidence. Clin Pharmacol Ther. 2020 Apr 22. PubMed: https://pubmed.gov/32320478. Full-text: https://doi.org/10.1002/cpt.1863
Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020 Mar 30. PubMed: https://pubmed.gov/32227760. Full-text: https://doi.org/10.1056/NEJMsr2005760
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 Apr 17. PubMed: https://pubmed.gov/32302265. Full-text: https://doi.org/10.1161/CIRCRESAHA.120.317134