Abstract
BackgroundIn 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.MethodsAdult 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.ResultsOut 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).ConclusionsThe 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.
Highlights
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
In 141 of them, we were unable to assess the continuation of reninangiotensin system inhibitors (RASIs) (59 patients were directly admitted to the Intensive care unit (ICU): 47 from the emergency department (ED) and 12 from other hospitals; 44 were transferred from the ED to another hospital; 38 had the event—death or ICU admission—or were discharged within the first 3 days of admission); and in 53, the intention-to-discontinue was uncertain (22 presented a sole prescription in days 1 and 31 in days 2 or 3)
The baseline characteristics and in-hospital treatment of patients who continued with ARBs and ACEIs appeared to be evenly distributed with some exceptions (Additional file 1: Table S3), but the mortality rates were remarkably different (20.8% vs. 33.1% for ARBs and ACEIs, respectively; p= 0.03), yielding a head-to-head crude Propensity score adjusted hazard ratio (HR) of 0.57 (95%Confidence interval (CI) 0.35–0.93), which barely changed after adjustment for baseline covariates (PS-HR=0.56; 95%CI 0.32–0.99) and after controlling for mediators (MC-HR=0.52; 95%CI 0.29–0.93) (Table 4)
Summary
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. The ACE1-angiotensin II-AT1R axis (the classical RAS) is counter-regulated by the ACE2-Angiotensin (1-7)MasR axis When the latter weakens, angiotensin II is unopposed and its vasoconstrictor, pro-inflammatory, and pro-thrombotic actions may contribute to the pathophysiology of severe COVID-19 [13,14,15]. Two randomized clinical trials have been published [18, 19] reporting no difference in mortality between discontinuation and continuation arms These trials and most observational studies have pooled ACEIs and ARBs and analyzed in a unique group, overlooking that they have different pharmacological actions [20] that could lead to distinct clinical effects [20], in COVID-
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