The renin-angiotensin-aldosterone system (RAAS) is a physiological marvel. It regulates blood pressure and fluid balance. Targetting it with ACE-inhibitors, angiotensin-receptor blockers, and aldosterone antagonists has reduced mortality in heart failure, as well reducing cardiovascular risk in people with hypertension. And just when we thought we couldn’t exploit the RAAS anymore, two observations were made linking our buddy, the RAAS, to COVID-19.

First, the virus, SARS-CoV-2, uses the ACE2 receptor protein to enter human cells, and second, people with hypertension appear to do worse when they get COVID-19. The ACE2 receptor is found on multiple organ surfaces such as epithelial cells in the lungs, heart, kidney, liver, and gastrointestinal tract. There are some suggestions that ACE-inhibitors and angiotensin-receptor blockers may increase propagation of the SARS-COV-2 and others hypothesizing that there may be a protective effect. Naturally the link is worth exploring. Observational work around the impact of ACE-inhibitors and angiotensin-receptor blockers can be misleading, though.

Outrageous headlines

Take this headline, for example. “Coronavirus ‘could be treated by common blood pressure pills taken by millions’.” Sensationalising is one thing but this is downright incorrect. Treated by? How can anyone make such a claim. Using the word “could” doesn’t help matters. Anything could do anything but why waste anyone’s time with that unless there’s substantial reason to be hopeful. This headline would only be correct if a positive randomised trial had been published in which people with COVID-19 were randomised to receive the drugs or not. Whose responsibility is correctness? Everyone’s and noone’s, it seems.

This headline stems from a subgroup analysis within a meta-analysis of observational studies with a questionable combined endpoint of death and “critical events” (did the data for death alone not support the message the authors wanted to send?). The bottom line is that we shouldn’t decide treatments on the basis of observational data because the observed associations can be confounded. And we shouldn’t justify basing treatments on observational evidence by saying there is no randomised data or that it’s too hard to do a randomised trial because observational data actually may not be “better than nothing”. Nothing IS better than observational data sending people down the garden path. Nothing, in this context, means accepting uncertainty. Most of medicine and, indeed, life involves accepting uncertainty. This is safer than pretend certainty.

A bit more certainty

Bring on the BRACE CORONA trial. This randomised trial was presented at ESC over the weekend (with no publication as yet). Lopes et al randomised 740 patients with severe COVID-19 in Brazil who were already using an ACE-inhibitor or angiotensin-receptor blocker (usually the latter drug) to either continue or suspend the drug. They excluded people who were haemodynamically unstable presumably because these people had to stop the drugs anyway for the sake of their blood pressure. The primary endpoint was days alive and out of hospital at 30 days. There was no difference between the 2 groups. This is no way makes these drugs a treatment for COVID-19. It’s about whether a blood pressure treatment needs to be suspended or continued.

BRACE CORONA study flowchart shown at ESC 2020

Lopes very fairly said, “I think our results endorse, with reliable and more definitive data, what the societies have recommended, which is basically that you shouldn’t stop your ACE inhibitors or ARBs”.

This trial, like any good trial, addresses one specific question: If you already take an ACE-inhibitor or angiotensin receptor blocker and you get severe COVID-19, is it harmful to continue the drug? Answer: No, there is no evidence that continuing the drug was harmful.

What’s next?

It’s human, but wrong, to extrapolate the meaning of these results to anything else. This question is important for people who get admitted to hospital with COVID-19 and who take these drugs. The question that will impact far greater numbers of people worldwide,though, and that isn’t answered by a meta-analysis of observational data nor the BRACE CORONA trial, is whether taking these drugs increases or decreases (or makes no difference to) the risk of contracting COVID-19 and it being severe.

When you have a pandemic, you have lots of people trying to do their best to protect themselves and their families. They may wonder whether they should be starting these drugs even if they weren’t taking them before and don’t have high blood pressure. For them, there is no answer because there is no randomised evidence.

But it’s ok not to know. Medicine isn’t omniscient. The job of physicians is to guide you regardless of the lack of relevant high-quality evidence. They can offer their experience, their assessment of data, their knowledge of guidelines, and importantly, their understanding of your medical history, your values and your preferences to help you decide.

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