Risk or benefit of ACEs and ARBs still unclear

In the spring of 2020, SARS CoV-2 infections first surged, marking the initial “season” of the Covid-19 pandemic — and one of the first concerns in those early days was that use of ACE-inhibitors or angiotensin-receptor blockers (ARBs) could increase risk of initial infection or of worsening infection. This article, first published April 1, 2020, debunks that fear and explains the role of the ACE2 receptor in the disease. BreakingMED is republishing the article as part of its year-end clinical review series.

The internet is abuzz with reports linking use of ACE-inhibitors and angiotensin-receptor blockers (ARBs) with Covid-19 — but is this a real concern?

Both ACE-inhibitors and ARBs are used to treat hypertension and heart failure, so separating fact from speculation is a matter of some concern.

Stepping into the fray is Scott D. Solomon, MD, from the Cardiovascular Division, Brigham and Women’s Hospital, and Harvard Medical School, Boston, and colleagues, who attempted to unpack what is known so far.

“[S]ome media sources and health systems have recently called for the discontinuation of [angiotensin-converting enzyme] ACE inhibitors and angiotensin-receptor blockers (ARBs), both prophylactically and in the context of suspected Covid-19,” Solomon and colleagues wrote in the New England Journal of Medicine. “Given the common use of ACE inhibitors and ARBs worldwide, guidance on the use of these drugs in patients with Covid-19 is urgently needed. Here, we highlight that the data in humans are too limited to support or refute these hypotheses and concerns.”

In fact, Solomon and colleagues noted that stopping medication could be dangerous for high risk patients and, moreover, they “propose an alternative hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury.”

The exacerbation theory is enticing, because ACE2 and the renin-angiotensin-aldosterone system (RAAS) are linked in a cascade of processes to both SARS-CoV-1 and SARS-CoV-2.

“ACE2, an enzyme that physiologically counters RAAS activation, is the functional receptor to SARS-CoV- 2, the virus responsible for the Covid-19 pandemic,” Solomon and colleagues explained. This has led to speculation or suggestion in several preclinical studies that “RAAS inhibitors may increase ACE2 expression, raising concerns regarding their safety in patients with Covid-19.”

But as Solomon and colleagues noted, there is not a lot of detail on the use of background RAAS inhibitors in the studies, and, “[p]opulation-based studies have estimated that only 30 to 40% of patients in China who have hypertension are treated with any antihypertensive therapy; RAAS inhibitors are used alone or in combination in 25 to 30% of these treated patients.” This means only a fraction of the Covid-19 patients in China were likely to have previously been treated with the therapy. Therefore, they noted that to infer a connection between RAAS inhibitors and Covid-19 is limited due to a lack of data on the connection or whether the cited study results translate to humans.

And, moreover, “no studies have evaluated the effects of RAAS inhibitors in Covid-19,” they wrote.

They did note that there are clinical trials being conducted “to test the safety and efficacy of RAAS modulators, including recombinant human ACE2 and the ARB losartan in Covid-19.”

Of interest, however, is Solomon and colleagues’ hypothesis that RAAS blockers could actually benefit patients with Covid-19, as they might limit acute lung injury in these patients.

ACE2 could be the doorway letting SARS-CoV-2 in and, in turn, could be starting the cascade to organ injury. “It has been postulated but unproven that unabated angiotensin II activity may be in part responsible for organ injury in Covid-19…” because of the subsequent and continued down-regulation of ACE2.

“Down-regulation of ACE2 activity in the lungs facilitates the initial neutrophil infiltration in response to bacterial endotoxin and may result in unopposed angiotensin II accumulation and local RAAS activation,” they wrote. “Indeed, in experimental mouse models, exposure to SARS-CoV-1 spike protein induced acute lung injury, which is limited by RAAS blockade.”

“In a small study, patients with Covid-19 appeared to have elevated levels of plasma angiotensin II, which were in turn correlated with total viral load and degree of lung injury. Restoration of ACE2 through the administration of recombinant ACE2 appeared to reverse this devastating lung-injury process in preclinical models of other viral infections and safely reduced angiotensin II levels in a phase 2 trial evaluating acute respiratory distress syndrome in humans,” they wrote.

They also noted that another theory argues that if ACE2 is dysregulated, it could afford some cardioprotection in the face Covid-19 infection.

“In autopsies of patients who died from SARS, 35% of heart samples showed the presence of viral RNA, which in turn was associated with reduced ACE2 protein expression,” Solomon and colleagues wrote. “Administration of recombinant ACE2 normalizes angiotensin II levels in human explanted hearts with dilated cardiomyopathy. These hypotheses have prompted trials to test whether the provision of recombinant ACE2 protein may be beneficial in restoring balance to the RAAS network and potentially preventing organ injury.”

Nonetheless, whether of benefit or whether they cause harm, Solomon and colleagues noted that based on what is known and unknown, RAAS inhibitors should not be withdrawn in high-risk patients, “including those who have heart failure or have had myocardial infarction, [as doing so] may result in clinical instability and adverse health outcomes.”

What is known is that patients with underlying cardiovascular diseases are at greater risk for Covid-19 and have worsening outcomes with myocardial injury, myocardial stress, and cardiomyopathy developing over the course of the illness.

“RAAS inhibitors have established benefits in protecting the kidney and myocardium, and their withdrawal may risk clinical decompensation in high-risk patients,” they wrote.

They also caution that for patients on RAAS inhibitors for guideline-directed therapy, switching to another antihypertensive would “require careful follow-up to avoid rebound increases in blood pressure. “

Solomon and colleagues concluded: “Although additional data may further inform the treatment of high-risk patients with Covid-19, clinicians need to be cognizant of the unintended consequences of prematurely discontinuing proven therapies in response to hypothetical concerns that may be based on incomplete experimental evidence.”

Candace Hoffmann, Managing Editor, BreakingMED™

Solomon reports grants and/or personal fees from Alnylam, Amgen, AstraZeneca, Bellerophon, BMS, GSK, Ionis, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, Theracos, Akros, Bayer, Merck, Roche, Quantum Genomics, Janssen, Eidos, Cytokinetics, Tenaya, Daichi-Sankyo, Cardurion, NeuroTronik, Respicardia, outside the submitted work.

Cat ID: 914

Topic ID: 74,914,287,500,503,791,932,730,933,914,125,469,520,192,927,151,928,925,934