Association of renin-angiotensin system inhibitors with severity and outcomes of COVID-19 infection in hospitalized patients with hypertension

by
Lucrecia M. Burgos

Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are not associated with severity and outcomes of coronavirus disease 2019 (COVID-19) infection in hospitalized patients with hypertension  in Wuhan, China according to a recent study in JAMA Cardiology1.

In this retrospective single-centre analysis, the authors analysed hospitalized patients with COVID-19 at the Central Hospital of Wuhan China from January 15, 2020, to March 15, 2020. There were 1178 patients hospitalized with COVID-19 (mean age 55.5 years; 46.3% men). Among them, 30,7% had hypertension. Patients with hypertension were older and had greater prevalence of chronic diseases; they also had more severe manifestations of COVID-19, including higher rates of acute respiratory distress syndrome and greater in-hospital mortality (21.3% vs 6.5%; P < .001). Around one-third were taking an ACEI or ARB.

Patients with and without ACEI/ARB treatment had similar comorbidities, with the exception of higher prevalence of coronary artery disease in those taking ACEIs/ARBs (23.5% vs 14.2%).  They also presented similar laboratory profile results including blood cell counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers.  The frequency of severity of illness and acute respiratory distress syndrome did not differ with respect to ACEI/ARB therapy.  ACEIs/ARBs use was similar for those who died and those who survived (27.3% vs 33.0%; P = 0.34).

In this study, the authors report data demonstrating that there was no difference in the disease progression and risk of death during hospitalization for COVID-19 with respect to various antihypertensive drugs and in the use of ACEIs/ARBs. They also confirm that patients with hypertension had more severe illness and higher mortality rates than those without hypertension, however, these previous reports did not indicate how many patients were taking ACEIs or ARBs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) use the ACE2 receptor to enter the host cells, and ACE2 negatively regulates the renin-angiotensin system by inactivating angiotensin II and likely plays a protective role against the development and progression of acute lung failure 2,3.  Animal studies have shown that expression of ACE2 is substantially increased in patients treated with ACEIs/ARBs4.  In contrast to available animal models, there are few studies in humans regarding the effects of RAAS inhibition on ACE2 expression. In a study circulating ACE2 levels were increased in patients with diabetes treated with ACEIs5. Based on these observations, some experts have speculated that use of ACEIs/ARBs leading to increased expression of ACE2 could potentially facilitate infection with COVID-19. A recent study showed that serum angiotensin II levels in patients with COVID-19 pneumonia was significantly higher compared with healthy individuals and were linearly associated with viral load and lung injury6.  Based on this, it can be postulated that SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity, skewing the ACE/ACE2 balance to a state of heightened angiotensin II activity leading to pulmonary vasoconstriction and inflammatory and oxidative organ damage, which increases the risk for acute lung injury7.

The clinical role of this pathway in COVID-19 complications and any effect from possible modulation of this receptor is not yet fully known and going to be tested in upcoming clinical trials. A multicenter, double-blind, placebo-controlled phase 2 randomized clinical trial of starting losartan in patients with COVID-19 in outpatient settings (ClinicalTrials.gov identifier: NCT04311177) and in in-patient settings (ClinicalTrials.gov identifier: NCT04312009) is currently being planned7.

Presently, there are no data regarding a favorable effect of RAS blockade on pulmonary outcome in SARS-CoV-2-infected patients. Whether or not infectivity to viral infection is increased in patients treated with RAS blockers remains unknown8. There are no peer-reviewed experimental or clinical data demonstrating a specific benefit or risk from using ACE inhibitors, ARBs, or renin-angiotensin-aldosterone system antagonists in COVID-19 9. However, recent news media coverage of this issue have provoked concern and unfortunately even motivated some patients to discontinue RAS blockers all together.

Several professional societies have put forward their guidance regarding the use of ACEIs/ARBs in patients with COVID-19. A joint statement by the Heart Failure Society of America, American College of Cardiology, and American Heart Association recommends that these medications can be continued in patients with COVID-19 without interruption in compliance with available clinical guidelines10.

Study authors mention as a limitation that the current findings may not be generalizable to all patients with hypertension, and it is possible that ACEIs/ARBs could affect the chance of hospitalization. In addition, it is not certain whether the ACEI/ARB treatment at baseline was maintained throughout the hospitalization for all patients. Furthermore, the authors did not mention whether the inclusion of patients was consecutive. In China most patients are on ARB as opposed to an ACE inhibitor, because  the prevalence of cough requiring discontinuation of ACE inhibitor therapy was found to be significantly higher among subjects with Chinese ethnicity11,12.

To conclude, renin–angiotensin system blockade treatment should be continued.  Present evidence is insufficient to recommend use of RAS blockade prophylactically in subjects at risk or therapeutically in those infected with SARS-CoV-2. In this preliminary assessment ACEI/ARB was not associated with severity and worse outcomes of COVID-19 infection in hospitalized patients with hypertension.

Further epidemiological studies and prospective trials are urgently needed to investigate if use of ACEIs/ARBs can reduce the incidence, severity and or mortality associated with COVID-19.

References

1. Li J, Wang X, Chen J, et al. Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China. JAMA Cardiol. 2020 Apr 23. doi: 10.1001/jamacardio.2020.1624.

2. Li  F.  Structure, function, and evolution of coronavirus spike proteins.  Annu Rev Virol. 2016;3:237-261. doi:10.1146/annurev-virology-110615-042301

3. Imai  Y, Kuba  K, Rao  S,  et al.  Angiotensin-converting enzyme 2 protects from severe acute lung failure.  Nature. 2005;436:112-116. doi:10.1038/nature03712

4. Klimas  J , Olvedy  M , Ochodnicka-Mackovicova  K ,  et al.  Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats.   J Cell Mol Med. 2015;19:1965-1974. doi:10.1111/jcmm.12573

5. Soro-Paavonen  A , Gordin  D , Forsblom  C ,  et al; FinnDiane Study Group.  Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications.   J Hypertens. 2012;30:375-383. doi:10.1097/HJH.0b013e32834f04b6

6. Liu  Y , Yang  Y , Zhang  C ,  et al.  Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.   Sci China Life Sci. 2020;63:364-374. doi:10.1007/s11427-020-1643-8

7. Bavishi C, Maddox TM, Messerli FH. Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers. JAMA Cardiol. 2020 Apr 3. doi: 10.1001/jamacardio.2020.1282. 

8. Messerli FH, Siontis GCM2, Rexhaj E. COVID-19 and Renin Angiotensin Blockers: Current Evidence and Recommendations. Circulation. 2020 Apr 13. doi: 10.1161/CIRCULATIONAHA.120.047022.

9. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the Cardiovascular System: A Review. JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1286

10. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. Accessed March 19, 2020.

https://professional.heart.org/professional/ScienceNews/UCM_505836_HFSAACCAHA-statement-addresses-concerns-re-using-RAAS-antagonists-in-COVID-19.jsp

11. Woo KS, Nicholls MG. High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese. Br J Clin Pharmacol. 1995;40:141–4.

12. Tseng DS, Kwong J, Rezvani F, Coates AO. Angiotensin-converting enzyme-related cough among Chinese-Americans. Am J Med. 2010;123:183, e11–5


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