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Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. 2020 May 1. doi: 10.1056/NEJMoa2008975. (Original study)

BACKGROUND: There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2).

METHODS: We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference.

RESULTS: Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive.

CONCLUSIONS: We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 7 / 7
General Internal Medicine-Primary Care(US) 7 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Public Health 6 / 7
Infectious Disease 6 / 7
Intensivist/Critical Care 6 / 7
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

Good paper that is of general interest. Some limitations in terms of the diagnosis of COVID-19 and the nature of the chart review.

Family Medicine (FM)/General Practice (GP) rater

Nicely reassuring.

General Internal Medicine-Primary Care(US) rater

This article reviewed 12,594 patients in NY who were tested for coronavirus and found that 56% were positive. It looked at the likelihood of being positive and having a severe or lethal infection, and found that taking an ACE or ARB did not increase the probability of infection or its severity. In fact taking a beta-blocker may slightly decrease the risks for infection.

Hospital Doctor/Hospitalists rater

It's good to know this information as there was much speculation that this was otherwise.

Hospital Doctor/Hospitalists rater

Very important information considering the frequency of RAAS inhibitor use and the concern that this class of medication may enhance the risk for infection.

Infectious Disease rater

Since it is difficult to "prove" a negative (in this case a lack of association between certain classes of antihypertensive drugs and some bad outcome from COVID-19), this kind of study is needed. The usual provisos apply: this is not a controlled study, there might be confounders, etc. Having said that, this study shows that IF there is a deleterious (or beneficial) effect from RAAS medications, it does not show up in a reasonably large sample. This is important because there is some biologic plausibility that ACE inhibitors might worsen COVID-19, and some authorities were suggesting (with little evidence) that it might be helpful to switch to another drug class for hypertension. Such a switch might be harmless, but it might also require titration, looking for side effects, etc. All of these things are harder in a "telemedicine only" environment. So, for now, we can continue our high BP treatment in our patients and await other kinds of studies to fill in the gaps in our knowledge.

Intensivist/Critical Care rater

This is an important observational study that arose as a response from early observations that many COVID patients had hypertension as a comorbidity and that COVID binds to the ACE2 receptor. It was speculated that there was a cause-and-effect relation behind this association. This study is important because the large number of patients taking antihypertensives would possibly require widespread changes in prescribing if there was a cause-and-effect relation. The authors examined patients who were tested for COVID for a relation between both the likelihood of developing a positive test and also developing severe disease depending on the status of their antihypertensive medication use. They found there was no association. Although not definitive, it does not support the speculation that there is increased risk for developing COVID or developing severe disease if taking an antihypertensive.

Intensivist/Critical Care rater

Not sure how helpful this report is. Although it gives a little bit of data on medications in the RAAS system, it is clearly underpowered for detecting the effect. So, I think the results are interesting but certainly not definitive.

Internal Medicine rater

This ACE/ARB result is already old news, since the initial concern that ACE/ARB use was a risk factor for severe disease has quieted down. I think no one here is any longer considering moving patients to a different agent.

Public Health rater

Renin/angiotensin blockade and implications for antihypertensive therapy in the Covid era. This well powered and statistically strong analysis provides additional reassurance that patients with hypertension do not need therapeutic substitution for safety. The authors set a 10% corridor to expedite publication, so there may be small differences yet to be defined; however, the benefits of ACE/ARB agents outweigh any potential small increased risk.

Public Health rater

Timely and needed information that will help many practitioners and patients alike.
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