Argument for RAAS Inhibitorsí» Safety During COVID-19 Pandemic Solidifies Despite Controversy

Various Research Indicates ACE Inhibitors, Arbs Do Not Increase Risk of Infection or More Severe Illness

Despite the controversy, renin-angiotensin-aldosterone system (RAAS) inhibitors such as angiotensin receptor blockers (ARBs) and angiotensin-converting-enzyme (ACE) inhibitors are being proven safe to use during the COVID-19 pandemic by independent studies.

The safety of RAAS inhibitors, which are used to control high blood pressure, came under scrutiny during the epidemic after reports out of China showed many COVID-19 patients had underlying comorbidities such as hypertension, and that these hypertensive COVID-19 patients fared poorly compared to those without high blood pressure.

The issue was further aggravated when an influential Lancet paper raised theoretical concerns of antihypertensive medication raising risk of COVID-19 infection.

As more researchers began weighing in on the issue with respective clinical findings, evidence is climbing towards RAAS inhibitors as being safe, compounded by medical societies urging hypertensive patients to continue taking the drugs.

RAAS Inhibitor Controversy Ignites Over Conflicting Theoretical Concerns

As early as February, researchers from Wuhan Institute of Virology, China unraveled in Nature1 how SARS-CoV-2 uses the ACE2 protein to enter cells, which is the same cell entry receptor as SARS-CoV. This finding was backed up by researchers from the German Primate Center2 who on April 16 outlined how SARS-CoV-2 uses the SARS-CoV receptor ACE2 to enter a host cell and the serine protease TMPRSS2 for spike protein priming.

Researchers from the University Hospital Basel in Switzerland3 on March 11 raised concerns in The Lancet Respiratory Medicine that since treatment with ACE inhibitors and ARBs lead to an upregulation of ACE2, it would theoretically facilitate infection with COVID-19.

According to the Swiss team, the concern with ACE inhibitors and ARBs is two-fold: one is that ACE inhibitors directly inhibit ACE2, and the second is that ACE inhibitors and ARBs increase expression of ACE2, thereby increasing patient vulnerability to the virus.

Through this logic, the research team hypothesized that "diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19" and suggested that if patients with underlying conditions such as cardiac diseases, hypertension, or diabetes, are treated with ACE2-increasing drugs, it raises the risk for severe COVID-19 infection.

Several animal studies in the pursuing week, however, suggested the exact opposite - hypertensive drugs might slow or stop inflammation in the lungs and have a protective effect in COVID-19 patients.

As controversy and public confusion grew, researchers from Brigham and Women's Hospital in Boston, Massachusetts4 on March 4 pulled in the reigns on these two hypotheses, saying that "the significance of ACE2 expression on COVID-19 pathogenesis and mortality is not specifically known," adding that there is currently no evidence that proves ACE inhibitors and ARBs worsens or improves clinical outcomes in COVID-19.

Medical societies then began uniformly releasing statements that recommended the continuation of RAAS inhibitor treatment for disease where its efficacy is proven.

The European Society of Hypertension kicked off the statements on March 12 by making a strong recommendation for continuing treatment with antihypertensive therapy "because there is no clinical or scientific evidence to suggest that treatment with ACE inhibitors or ARBs should be discontinued because of the COVID-19 infection."5

The statement was followed by others from the Council on Hypertension of the European Society of Cardiology, Hypertension Canada, Canadian Cardiovascular Society, The Renal Association (U.K.), International Society of Hypertensive, American College of Physicians, Spanish Society of Hypertension, the Korean Society of Hypertension, and the British and Irish Hypertension Society, among others.

Shortly after on March 17, the Heart Failure Society of America (HFSA), American College of Cardiology (ACC) and the American Heart Association (AHA)6 released a joint statement that stressed the controversy around hypertension drugs hinges upon an unproven theoretical concern and urged continuation of RAAS inhibitors for patients to effectively treat heart failure, hypertension, or ischemic heart disease until more clinical evidence was available.

"Currently there are no experimental or clinical data demonstrating beneficial or adverse outcomes with background use of ACE inhibitors, ARBs or other RAAS antagonists in COVID-19 or among COVID-19 patients with a history of cardiovascular disease treated with such agents," the statement reads. "Therefore, be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice."

Major Studies Highlight Safety of RAAS Inhibitors

As called for, researchers began rolling out studies that examined the safety of RAAS inhibitors in the COVID-19 landscape, heavily favoring the argument that patients should continue taking prescribed ACE inhibitors and ARBs for conditions such as hypertension.

The first heavily cited NEJM paper7 conducted by Brigham and Women's University Hospital found that there was no harmful association of ACE inhibitors or ARBs and mortality. Although NEJM recently retracted the paper, experts still say that at least four other reputable papers from NEJM, The Lancet, and JAMA point towards the safety of RAAS inhibitors.

NYU Langone cardiologist Harmony R. Reynolds' team8 found no association between any single antihypertensive medication class and an increased likelihood of a positive COVID-19 test in a NEJM paper published May 1, dispelling the notion that RAAS inhibitors increase the risk of infection.

Likewise, Alcalá University's Francisco J de Abajo from Span concluded in The Lancet9 that "RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19."

University of Milano-Bicocca's Giuseppe Mancia in Italy also reported that they did not see any associations between COVID-19 and ARBs (aOR 0.95, 95% CI 0.86~1.05) or ACE inhibitors (0.96, 95% CI 0.87~1.07).

Additionally, Cleveland Clinic's Neil Mehta10 in JAMA Cardiology published data from a cohort study on 18,472 patients of whom 7.2 percent were taking ACE inhibitors and 5.3 percent were taking ARBs. Statistical analysis showed no association between ACE inhibitors or ARB use and testing for COVID-19 (OR 0.97, 95% CI 0.81~1.15).

Mehta's team said the results backed "the various society guidelines to continue current treatment of chronic disease conditions with either ACE inhibitors or ARB during the COVID-19 pandemic."

Now the latest data published in the European Heart Journal by Chinese researchers solidifies the argument for RAAS inhibitors during the COVID-19 crisis.

According to Xijing Hospital's Chao Gao in China, hypertension patients were more likely to die during COVID-19 hospitalization (4.0% vs. 1.1% without hypertension, aHR 2.12, 95% CI 1.17~3.82). However, people with a history of hypertension who were not taking hypertensive medication were also more likely to die during hospitalization (7.9% vs. 3.2% on medications, aHR 2.17, 95% CI 1.03~4.57).

When looking at medication class, RAAS inhibitors versus other antihypertensives produced similar mortality, although it was not statistically significant (2.2% vs. 3.6%, aHR 0.85, 95% CI 0.28~2.58).

When the data was pooled with three other groups in China in a meta-analysis, RAAS inhibitors were associated with a significantly lower risk of mortality compared to other hypertensive drugs (RR 0.65, 95% CI 0.45~0.94).

"While hypertension and the discontinuation of antihypertensive treatment are suspected to be related to increased risk of mortality, in this retrospective observational analysis, we did not detect any harm of RAAS inhibitors in patients infected with COVID-19," said Gao. "However, the results should be considered as exploratory and interpreted cautiously."

Taken together, the evidence largely dispels the notion that RAAS inhibitors increase the risk of COVID-19 infection or worsens clinical outcomes of those affected.

The deputy editor of the NEJM John Jarcho, MD and several coauthors drove the message home in an editorial,11 citing that there is not enough "evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among the infected, or the risk of in-hospital death among those with a positive test."

Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19.

John Jarcho, MD


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