This Is the Way: Randomized Clinical Trial Shows ACEis and ARBs Can Safely Be Continued in Patients with COVID-19

Severe acute respiratory coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2) to enter host cells. Early in the pandemic, several basic science studies were often cited and suggested that ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) may have an effect to increase the abundance of ACE2 (1). Thus, logic would prevail that if anyone on ACEis or ARBs is at risk of infection, becomes infected, or develops coronavirus infectious disease 2019 (COVID-19), then these should be discontinued. However, the science of the renin angiotensin system (RAS) is far more intricate and interesting. The correct answer is that continuing ACEis or ARBs might indeed be harmful—or perhaps even beneficial. Thus, we and others (2) argued that empirical studies were needed to establish this rather than rely on biological plausibility and vacuous theorizing.

While much of the world was pontificating, some groups went on to design and conduct randomized clinical trials. REPLACE COVID is one such trial, recently published in The Lancet Respiratory Medicine (3). This trial began on March 31, 2020, within a few months of COVID-19 hitting North America and in the thick of the first wave. Over a period of 5 months, the required 152 patients were enrolled with global participation (20 hospitals representing 7 countries). Patients hospitalized with COVID-19, already on chronic ACEi or ARB, in whom equipoise was possible (e.g., excluding patients with hypo- or hypertension, hyperkalemia, severe acute kidney injury [AKI], or a compelling indication for ACEi/ARB), were randomized to either continue or stop their ACEi or ARB. Such an intervention is inherently open label, but the endpoints—primarily a global rank score, with secondary data on hospitalization, intensive care unit (ICU) length of stay, and mortality—were adjudicated by a blinded clinical panel.

In terms of the results, there was absolutely no difference in any of the outcomes, i.e., the primary global rank scores, nor all-cause death (10 in the continuation arm and 11 in the discontinuation arm), nor length of ICU or hospital stay. There was also no difference in the exploratory outcomes of ICU admission, ventilation, or hypotension requiring hemodynamics support. These results also question the oft-mentioned “sick day rules” for ACEis and ARBs, showing that patients hospitalized with a severe respiratory infection did not have an untoward effect. However, the debate on sick day rules is still ongoing (4). Thus, the REPLACE COVID trial does answer the question of whether ACEis or ARBs should be stopped in hospitalized patients with COVID-19 in the absence of classical clinical indications (e.g., hypotension). They should not be stopped!

These findings are also bolstered by the similar findings from the BRACE CORONA trial in a slightly less sick cohort of 659 patients. BRACE CORONA was conducted in Brazil and reported at the European Society of Cardiology but is not yet published (5). Some other questions in this area still remain: is infection with SARS-CoV-2 or the development of COVID-19 affected by being on ACEi or ARB, or can the addition of an ACEi or ARB to a RAS-naive patient be of benefit with COVID-19? The ongoing trials’ list is available on the NephJC page (http://www.nephjc.com/news/covidace2) on the topic.

For now, let’s celebrate the fact that nephrologists, cardiologists, infectious disease specialists, and other specialties came together and demonstrated that clinical trials are possible even at the height of a pandemic. This is the way!

Visual Abstract by Divya Bajpai Dr. Divya Bajpai is associate professor, Department of Nephrology, Seth GSMC and KEM Hospital Mumbai

/kidneynews/13_2/12/graphic/12f1.jpg

Notes

[1] Conflicts of interest The authors report no conflict of interest.

References

1. Fang L, et al Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020; 8:e21. doi: 10.1016/S2213-2600(20)30116-8. Erratum in: Lancet Respir Med 2020; 88:e54. doi: 10.1016/S2213-2600(20)30235-6

2. Sparks MA, et al Sound science before quick judgement regarding RAS blockade in COVID-19. Clin J Am Soc Nephrol 2020; 15:714−716. doi: 10.2215/CJN.03530320

3. Cohen JB, et al Continuation versus discontinuation of renin–angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial. Lancet Respir Med [published online ahead of print January 7, 2021]. doi: 10.1016/S2213-2600(20)30558-0; https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30558-0/fulltext#seccestitle160

4. Whiting P, et al What are the risks and benefits of temporarily discontinuing medications to prevent acute kidney injury? A systematic review and meta-analysis. BMJ Open 2017; 7:e012674. doi: 10.1136/bmjopen-2016-012674

5. Lopes RD, et al Effect of discontinuing vs continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19: A randomized clinical trial. JAMA 2021; 325:254-264. doi:10.1001/jama.2020.25864

February 2021 (Vol. 13, Number 2)