Impact of in-hospital discontinuation with angiotensin receptor blockers or converting enzyme inhibitors on mortality of COVID-19 patients: a retrospective cohort study

Abstract

Background: In the first wave of the COVID-19 pandemic, the hypothesis that angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) increased the risk and/or severity of the disease was widely spread. Consequently, in many hospitals, these drugs were discontinued as a "precautionary measure". We aimed to assess whether the in-hospital discontinuation of ARBs or ACEIs, in real-life conditions, was associated with a reduced risk of death as compared to their continuation and also to compare head-to-head the continuation of ARBs with the continuation of ACEIs.

Methods: Adult patients with a PCR-confirmed diagnosis of COVID-19 requiring admission during March 2020 were consecutively selected from 7 hospitals in Madrid, Spain. Among them, we identified outpatient users of ACEIs/ARBs and divided them in two cohorts depending on treatment discontinuation/continuation at admission. Then, they were followed-up until discharge or in-hospital death. An intention-to-treat survival analysis was carried out and hazard ratios (HRs), and their 95%CIs were computed through a Cox regression model adjusted for propensity scores of discontinuation and controlled by potential mediators.

Results: Out of 625 ACEI/ARB users, 340 (54.4%) discontinued treatment. The in-hospital mortality rates were 27.6% and 27.7% in discontinuation and continuation cohorts, respectively (HR=1.01; 95%CI 0.70-1.46). No difference in mortality was observed between ARB and ACEI discontinuation (28.6% vs. 27.1%, respectively), while a significantly lower mortality rate was found among patients who continued with ARBs (20.8%, N=125) as compared to those who continued with ACEIs (33.1%, N=136; p=0.03). The head-to-head comparison (ARB vs. ACEI continuation) yielded an adjusted HR of 0.52 (95%CI 0.29-0.93), being especially notorious among males (HR=0.34; 95%CI 0.12-0.93), subjects older than 74 years (HR=0.46; 95%CI 0.25-0.85), and patients with obesity (HR=0.22; 95%CI 0.05-0.94), diabetes (HR=0.36; 95%CI 0.13-0.97), and heart failure (HR=0.12; 95%CI 0.03-0.97).

Conclusions: The discontinuation of ACEIs/ARBs at admission did not improve the in-hospital survival. On the contrary, the continuation with ARBs was associated with a trend to a reduced mortality as compared to their discontinuation and to a significantly lower mortality risk as compared to the continuation with ACEIs, particularly in high-risk patients.

Keywords: Angiotensin receptor blockers; Angiotensin-converting enzyme inhibitors; COVID-19; In-hospital treatment; Mortality; Renin-angiotensin system inhibitors.

Fig. 1

Study design and patient selection. Abbreviations: ED emergency department, ICU intensive care unit, Non-RASIs other antihypertensive drugs different from RASIs, RASIs renin-angiotensin system inhibitors

Fig. 2

Switching from RASIs to CCBs, other antihypertensive drugs (OADs), or no antihypertensive treatment during the first 3 days since hospital admission (patients with uncertain discontinuation were excluded). Of all outpatient RASI users, 45.6% continued with RASIs (alone or combined with CCBs or OADs), 29.2% were switched to CCBs or OADs, and 25.3% were left without any antihypertensive treatment. Dynamic visualization available in: https://public.flourish.studio/visualisation/4808393/. Abbreviations: CCBs calcium-channel blockers, OADs other antihypertensive drugs (different from RASIs or CCBs), RASIs renin-angiotensin system inhibitors. RASIs+CCB combined use with OADs allowed, RASIs+OADs use of CCBs excluded, CCBs alone or combined with OADs and RASIs excluded, OADs use of RASIs and CCBs excluded

Fig. 3

Kaplan-Meier survival curves of in-hospital death among patients in whom treatment with ARBs was continued as compared to those in whom ACEIs was continued (defined in the first 3-day window). Abbreviations: ACEIs angiotensin-converting enzyme inhibitors, ARBs angiotensin receptor blockers. *Log-rank test

Fig. 4

Head-to-head comparison of continuation with angiotensin receptor blockers vs. continuation with angiotensin-converting enzyme inhibitors, by different subgroups. Abbreviations: ACEIs angiotensin-converting enzyme inhibitors, ARBs angiotensin receptor blockers, CV cardiovascular. *Mediator-controlled hazard ratio (controlled direct effect): including systemic corticosteroids (excepting stratification by corticosteroids), anticoagulants, and immunomodulators