Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol

Abstract

Clinical Trial Registration Number: clinicaltrials.gov NCT04338009 | 1781 COHEN Et al. 1 | INTRODUC TI ON Since its emergence in December 2019, the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a devastating global health impact. 1 COVID-19 is associated with a high incidence of multiorgan dysfunction and mortality. 2,3 Accordingly, there has been an extraordinary response by the international research community to quickly develop trials to evaluate potential disease-modifying interventions in COVID-19. Early in the COVID-19 pandemic, several reports described hypertension as a risk factor for SARS-CoV-2 infection and severity. 4 Angiotensin-converting enzyme 2 (ACE2), a key counterregulatory component of the renin-angiotensin system (Figure 1), plays an important role in hypertension pathophysiology and also facilitates SARS-CoV-2 host cell entry. 5 ACE2 activity and expression have been implicated as potential contributors to SARS-CoV-2 infection and severity. 4 Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two of the most commonly used antihypertensive classes, 6 may increase ACE2 expression. 4 Consequently, it was speculated that ACEIs and ARBs could worsen the risk of COVID-19 and COVID-19-related adverse outcomes, 7-10 resulting in widespread media coverage and possibly in empiric discontinuation of these medications. However, there is also evidence suggesting that ACE2 overexpression ameliorates lung injury associated with COVID-19, 11,12 and thus, ACEIs and ARBs could reduce adverse outcomes in patients with this infection. 4 Thus, it remains

Does taking an angiotensin inhibitor increase the risk for COVID-19? – a systematic review and meta-analysis

“…The results showed that ramipril had no impact on the incidence or severity of COVID-19, which is in line with our results. Additional protocols from RCTs have also been published, and their results deserve attention [ 40 – 42 ]. Thus, our systematic review based on currently available large cohort studies will have clinical value until the results of additional well-designed RCTs with large sample sizes become available.…”

Continuation versus discontinuation of renin–angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial

“…An independent data safety monitoring board was assembled to provide independent oversight of the trial. Details of the rationale and trial design have been previously described 17 and additional details are included in appendix 2 (pp 2–6 ).…”

Inpatient Omission of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Is Associated With Morbidity and Mortality in Coronavirus Disease 2019

“…The first randomised control trials concerning this topic are currently ongoing, the results of which will be the next important step in clarifying the role of ACEi/ARBs in acute COVID-19 illness. [23][24][25][26][27] Regular ACEi/ARB use in our study was associated with worsened indicators of morbidity. It is possible that this is attributable to the large number of our cohort that had their ACEi/ARBs omitted during admission, an intervention that we find to be strongly associated with poorer outcomes.…”