Enalapril, losartan and other medications that act on the renin-angiotensin-aldosterone system: Should their users be particularly concerned about COVID-19?

 

(We recommend reading this post on the basics of evidence-based medicine and the findings on COVID-19.)

 

Based on: Preliminary evidence (preclinical studies and initial human studies).

 

The development of a new drug, from the discovery of its component to the regulatory agencies’ approval for use in humans, may take between twelve and fifteen years. So, when faced with a new healthcare challenge, the first thing scientists turn to is drugs that are already available. The current COVID-19 pandemic has not been the exception to this process.

 

The first hints of which drugs might be beneficial or harmful (i.e. preliminary evidence) comes from two major sources. The first one is formed by preclinical studies, such as those conducted in animals or cell cultures. The second source is formed by initial human studies, which allow us to identify statistical correlation, but do not demonstrate causality.

 

But as practical experience has proven, over and over again, translating preliminary findings to the decision-making process at population level rarely contributes to scientific progress. In fact, those types of research are most useful when used as a ‘hypothesis generator’ for researchers rather than a direct input for clinicians or policymakers.

 

Unfortunately, it is common for the media and social networks to present as definitive certain findings that, resulting from this type of evidence, are not. The phenomenon is exacerbated when it comes to a disease with no known cure that has already caused more than 30,000 deaths. 

 

A recent, widespread case of the phenomenon are the treatments that inhibit the renin-angiotensin-aldosterone system, such as enalapril —an inhibitor of the angiotensin-converting enzyme (ACE) inhibitor— or losartan, a blocker of the angiotensin receptor (ARB). Apparently, the event that ignited the controversy was a response to a BMJ editorial, published in the same journal on March 3, 2020, which warned that ACE inhibitors constituted a potential risk factor for fatal COVID-19 in hypertensive patients. Replies did not take long: ACE inhibitors are a well-known treatment for a number of chronic conditions, including several cardiovascular diseases. Arguments both in favour and against the suspension of these drugs mounted rapidly —all of them, however, based on preclinical evidence or plain speculation. Some of the justifications based on preclinical evidence are: 

 

• Against suspending these drugs: SARS-CoV-2 makes use of the angiotensin-converting enzyme 2 (ACE2) —a molecule widely available in our body— to enter host cells and unleash its pathogenicity in humans. It is possible, then, that blocking ACE2 —through an inhibitor or an antibody, for example— prevents the binding of the virus, therefore also preventing its entry into host cells. 
• In favour of suspending these drugs: Given that certain drugs that inhibit the action of ACE2 paradoxically generate an increase in the availability of this enzyme, these drugs might facilitate the development of serious forms of COVID-19.

 

Now, preclinical evidence and polemics aside, are there any relevant studies in humans?

 

With the help of the COVID-19 L·OVE Working Group we carried out an exhaustive search (systematic review) of scientific studies answering this question, yet we did not identify any study presenting conclusive results, be it in humans or not. In fact, we only identified one study in humans, which showed no effect (neither for nor against the suspension of the drugs). But this is preliminary evidence as well, so we can only conclude that it is not possible to clearly establish whether these drugs increase or decrease the risk, or if they have no effect in patients at either risk of contracting COVID-19 or already infected.

 

There are indeed some planned studies, which, we hope, will shed more light on the issue.

 

What should decision makers put in the balance today?

 

Putting aside the option of administering these drugs to patients who do not currently receive them —something no one has ventured to consider, apparently— the most important decision is whether, in patients who do receive them already, it is better to replace them with other alternatives or to keep calm and restrain from acting on it.

 

The answer to this question, like most of the time, is not black or white. According to the third principle of evidence-based medicine: 

 

Evidence alone is never sufficient to make a clinical decision. Decision makers must always trade off the benefits and risks, burden, and costs associated with alternative management strategies and, in doing so, consider their patients’ unique predicament and values and preferences.

In order to inform those who are making decisions at the global level as quickly as possible, pending the regular publication process of a scientific article, we will make available a preliminary report with the necessary data to analyse the benefits and risks of this treatment. Stay tuned!

Use this link to access the L·OVE platform and stay up to date on the new evidence on this question, either consulting it directly or receiving notifications by mail.