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MARCH 27, 2020 -- The controversy about whether angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may increase susceptibility to the COVID-19 virus infection continues unabated, with new commentaries about this appearing almost daily.
The issue has been widely covered in the consumer press, leading to patient anxiety and uncertainty about whether to keep taking these medications. Doctors report being inundated with calls from panicked patients who want to discontinue treatment.
Cardiovascular societies are appealing for calm and have issued statements stressing there is no sound evidence to support the idea that ACE inhibitors or ARBs can increase risk of infection with COVID-19 and urging patients not to discontinue their medications.
Meanwhile, other information has surfaced suggesting that ACE inhibitors and ARBs may actually be beneficial in patients with COVID-19 infection by reducing the risk or severity of viralpneumonia, with some authors even suggesting that that these drugs may have potential as treatments for patients with the infection.
So what are clinicians supposed to do with all these conflicting hypotheses and patient anxiety? Here, Medscape Medical News reviews the available evidence supporting both suggestions of possible harm and benefit with ACE inhibitors and ARBs with regard to COVID-19, and discusses the evidence with several leading cardiovascular experts.
Many recent papers and commentaries have been published on this issue of possible harm with ACE inhibitors and ARBs in recent weeks.
First, several studies from China are reporting a high incidence of cardiovascular comorbidities, including hypertension and diabetes, in patients with severe cases or deaths from coronavirus, and ACE inhibitors and ARBs are agents very commonly used in these conditions. However, this could be accounted for by confounding, as patients with cardiovascular conditions will be older and likely to have other comorbidities as well.
It has been shown that COVID-19 uses the ACE2 receptor to gain access into cells. A key study by Zhou et al describing this was published in the journal Nature in February. In that study, the authors write: "We show that 2019-nCoV (COVID-19) is able to use ACE2 proteins as an entry receptor to enter ACE2-expressing cells, but not cells that did not express ACE2, indicating that ACE2 is probably the cell receptor through which 2019-nCoV enters cells."
The crux of the controversy is data suggesting that use of ACE inhibitors and ARBs may increase expression of ACE2, which leads to the hypothesis that these drugs may increase patient susceptibility to the virus. Several commentaries suggesting that ACE inhibitors and ARBs may increase susceptibility in this way have now appeared.
In one prominent report published as a letter to The Lancet Respiratory Medicine on March 11, Lei Feng, MD, PhD, University Hospital Basel, Switzerland, and colleagues write: "The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. ACE2 can also be increased by thiazolidinediones and ibuprofen.
"Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesize that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19," they conclude.
Writing in a Viewpoint in JAMA published online yesterday, Ankit Patel, MD, and Ashish Verma, MBBS, both from Brigham and Women's Hospital, Boston, Massachusetts, give more detailed information on ACE2 expression with ACE inhibitors and ARBs.
"There has been considerable evidence in animal models as well as some evidence in humans showing increased expression of ACE2 in the heart, brain, and even in urine after treatment with ARBs; however, there is limited evidence showing changes in serum or pulmonary ACE2 levels," they write. "More relevant, the significance of ACE2 expression on COVID-19 pathogenesis and mortality is not specifically known."
But even if ACE inhibitors and ARBs do increase ACE2 expression, this does not necessarily mean they increase infectivity of the virus, experts emphasize, and there are also suggestions that an increase in ACE2 may be a positive effect.
In a detailed scientific study in the journal Nephron published March 23, Luca Perico, PhD, Ariela Benigni, PhD, and Guiseppe Remuzzi, MD, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy, say the answer to the question of whether ACE inhibitors and ARBs could predispose patients to increased COVID-19 infection and more severe illness "is not as simple as it seems, at least based on current knowledge."
They state that COVID-19 entry into target cells "is a tightly regulated multi-step process, of which binding to ACE2 is merely the first."
They also note that ARBs enable the increase of available angiotensin II by competing with the same receptor and suggest that increased binding of angiotensin II to the catalytic domain of ACE2 could induce a structural change in ACE2 that is unfavorable for COVID-19 binding and internalization.
Then there are several studies suggesting that ACE inhibitors and ARBs could have a beneficial effect on COVID-19 patients by reducing lung damage.
The Italian authors report that preclinical studies have shown ACE2 is significantly downregulated in different animal models of severe lung injury, and that the ARB losartan attenuated severe acute lung injury in mice injected with the spike glycoprotein of SARS-CoV (which has a very similar structure to COVID-19). They also note that in experimental models ACE2 blockade resulted in exacerbated lung damage and reduced animal survival after respiratory syncytial virus infection.
"Altogether, the above complementary approaches suggest that ACE2 is protective in lung injury during coronavirus infection," the authors state.
ARBs: Possible COVID-19 Therapeutic?
This view is shared by David Gurwitz, PhD, Tel Aviv University, Israel, who actually proposes that ARBs could be used as a treatment for patients with COVID-19 infection to reduce the risk or severity of viral pneumonia.
In a commentary published online March 4 in Drug Development Research, Gurwitz explains that the binding of the coronavirus spike protein to ACE2 leads to ACE2 downregulation, which in turn results in excessive production of angiotensin II and less ACE2 to convert it the vasodilator angiotensin 1–7.
This in turn contributes to lung injury, as angiotensin increases pulmonary vascular permeability, thereby mediating increased lung pathology. Therefore, higher ACE2 expression with ARBs, "while seemingly paradoxical, may protect patients against acute lung injury," he writes.
So what do cardiovascular experts make of these conflicting ideas, and what do they recommend doctors advise patients to do?
Hypertension expert Franz Messerli, MD, told Medscape Medical News that ACE2 could be upregulated with ACE inhibitors/ARBs and there is speculation that this could increase infectivity with COVID-19, "but we don't know that for a fact."
"ACE2 is upregulated with many other situations too — with exercise or with dehydration, he noted. "No one has shown that patients on ACE inhibitors/ARBs have increased infection rates with this virus, so this remains purely speculative."
Messerli, who is professor of medicine at the University of Berne, Switzerland, and the Icahn School of Medicine at Mount Sinai, New York City, adds that there are also several animal studies and some human data to suggest ACE inhibitors/ARBs may have a benefit in viral pneumonia.
"Animals exposed to these drugs have a lower risk or milder form of pneumonia, and a previous meta-analysis and review pointed toward a putative protective role of ACE inhibitors and ARBs in human patients with community-acquired pneumonia compared with control treatment, with both drug classes associated with a decrease in pneumonia related mortality. But there are no data available specifically for COVID-19-infected patients," Messerli said.
"So there is suggestion of both harm and benefit with regards to COVID-19 and ACE inhibitors/ARBs, but no real clinical data to support these hypotheses. In this situation it is best to just leave everything the same. Do not change medication based on no evidence. And that is what I recommend."
"But I can see that some patients may be frightened with these ideas being hyped up in the press, and we really don't want patients stopping their medications. If hypertension patients are really anxious and insist upon coming off an ACE inhibitors or ARB then they can switch to a calcium antagonist which won't cause them any harm," he added.
Michael Weber, MD, professor of medicine at State University of New York Downstate in New York City, gave a similar opinion.
"There are two hypotheses on how ACE inhibitors/ARBs may affect COVID-19 infection — one harmful and one helpful. While both these mechanisms have some animal data to support them, there is no clinical data so they both remain largely speculation," he told Medscape Medical News.
"Of course, all this information is interesting and even encouraging, but unfortunately it doesn't tell clinicians what to prescribe or avoid for their vulnerable patients at the present time," Weber conceded. "So I don't know where were are left."
"The party line is definitely to stay on your medication as there is no credible evidence of harm in human experience. But I know many patients taking these drugs are worried," Weber acknowledged. "In this situation I would try and persuade patients to stay on ACE inhibitors/ARBs especially if they have heart failure or a recent MI, as these drugs have shown unique mortality benefits in these conditions.
"For patients with hypertension alone who really don't want to continue on ACE inhibitors/ARBs then there are alternatives available — they could switch to amlodipine alone or in combination with a beta-locker or a thiazide for similar blood pressure lowering," Weber suggested.
Two other experts were even more adamant that these hypotheses should not be influencing clinical practice in any way at the present time.
George Bakris, MD, director of the Comprehensive Hypertension Center at University of Chicago Medicine in Illinois, said: "This a huge controversial issue, but there is no clinical data that supports the hypothesis that individuals taking ACE inhibitors/ARBs are more likely to be infected with the COVID-19 virus. This is just a hypothesis based on limited animal data and a lot of speculation. We do not need sensational journalism on this matter. We need stability."
The ACE2 receptor does seem to be involved in entry of the virus into the cell, he added, "but we don't know how ACE inhibitors/ARBs affect ACE2 in humans. There are some studies in animals suggesting an upregulation and some a downregulation. And if there are changes to ACE2 with these drugs, we still don't know what difference this would make regarding COVID-19.
"But we do know what will happen if patients stop taking these medications," Bakris said. "There was a paper recently showing that patients with advanced kidney disease who stopped taking ARB/ACE inhibitors had a 39% increase in mortality over 2 years."
"All the cardiovascular societies have issued statements urging patients to stay on their ACE inhibitors/ARB medication. There is a uniform consensus from all cardiology and hypertension societies on this, and this is what needs to happen," Bakris stressed.
Murray Epstein, MD, professor of medicine, division of nephrology and hypertension, University of Miami Miller School of Medicine in Florida, also feels strongly on this controversy and has coauthored an editorial on the subject published today in Hypertension.
"I can't tell you how many calls I've taken on this since this first blew up a couple of weeks ago. Patients are clearly discontinuing their medication despite firm advice not to do so. Many primary care doctors are also unclear about what to do," he told Medscape Medical News.
"The evidence that ARBs increase ACE2 is not consistent — the data come from animal studies and varies between agents and organs. It is not possible to make a blanket statement on this. And there is no evidence at all that ARBs increase coronavirus entry by increasing ACE2 expression. This is pure speculation," Epstein said.
"And there is also is evidence from animal studies that ACE inhibitors/ARBs are protective in pulmonary infections. Putting it all together we conclude that ACE inhibitors/ARBs should not be discontinued based on current available evidence.
"This is not just relevant to hypertension patients. ACE inhibitors/ARBs are also the mainstay of treatment in heart failure, chronic kidney disease, and diabetic nephropathy. If these patients stop taking these drugs this will cause huge harm.
"Because we don't have any data that these drugs enhance infectivity, we see no reason to discontinue them. We do not change a beneficial treatment regimen based on speculation from an animal model. The data is just not there to change treatment patterns, period," he stressed.
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