Effect of losartan on hospitalized patients with COVID-19-induced lung injury: A randomized clinical trial

Abstract

Background: SARS-CoV-2 viral entry may disrupt angiotensin II (Ang II) homeostasis in part via ACE2 downregulation, potentially contributing to COVID-19 induced lung injury. Preclinical models of viral pneumonias that utilize ACE2 demonstrate Ang II type 1 receptor (AT1R) blockade mitigates lung injury, though observational COVID-19 data addressing the effect of AT1R blockade remain mixed. Methods: Multicenter, blinded, placebo-controlled randomized trial of losartan (50 mg PO twice daily for 10 days) versus placebo. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already taking a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible. The primary outcome was the imputed partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity, oxygen, ventilator, and vasopressor-free days, and mortality. Losartan pharmacokinetics (PK) and RAAS components [Ang II, angiotensin-(1-7) (Ang-(1-7)), ACE, ACE2] were measured in a subgroup of participants. Findings: From April 2020 - February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO2/FiO2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0.12)]. Losartan did not improve any secondary clinical outcome, but worsened vasopressor-free days. PK data were consistent with appropriate steady-state concentrations, but we observed no significant effect of losartan on RAAS components. Interpretation: Initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury does not improve PaO2 / FiO2 ratio at 7 days. These data may have implications for ongoing clinical trials.

Cardiovascular drugs and COVID‐19 clinical outcomes: a systematic review and meta‐analysis of randomized controlled trials

“…Ten studies 33 , 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 57 investigated ACEIs/ARBs, with only 1 study (102 patients) 33 investigating COVID‐19 infectivity. Compared to standard of care, the ACEI ramipril (initial dose 2.5 mg/d, titrated up to 10 mg/d), when newly initiated, was reported to have no effect on COVID‐19 infectivity (hazard ratio 1.15, 95% CI 0.35 to 3.77).…”

“…The effect of ACEI/ARB exposure (in both treatment‐experienced and ‐naïve patients) on severity (varying definitions based on oxygen supplementation, intensive care unit [ICU] admission, World Health Organization ordinal scale among 43 others, Table 1 ) was investigated by 9 studies 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 57 (1661 patients) with ACEIs/ARBs not having an effect on disease severity (pooled RR 0.90, 95% CI 0.71 to 1.15, I 2 = 24%, Figure 2 ). When only the 6 estimates 36 , 37 , 38 , 39 , 40 , 57 (1320 patients) with low risk of bias (RR 0.85, 95% CI 0.60 to 1.20, I 2 = 38%) or 4 studies 34 , 40 , 42 , 57 (948 patients) that included only hypertensive patients (RR 0.86, 95% CI 0.71 to 1.04, I 2 = 0%) were pooled, the results were unchanged.…”

“…The effect of ACEI/ARB exposure (in both treatment‐experienced and ‐naïve patients) on severity (varying definitions based on oxygen supplementation, intensive care unit [ICU] admission, World Health Organization ordinal scale among 43 others, Table 1 ) was investigated by 9 studies 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 57 (1661 patients) with ACEIs/ARBs not having an effect on disease severity (pooled RR 0.90, 95% CI 0.71 to 1.15, I 2 = 24%, Figure 2 ). When only the 6 estimates 36 , 37 , 38 , 39 , 40 , 57 (1320 patients) with low risk of bias (RR 0.85, 95% CI 0.60 to 1.20, I 2 = 38%) or 4 studies 34 , 40 , 42 , 57 (948 patients) that included only hypertensive patients (RR 0.86, 95% CI 0.71 to 1.04, I 2 = 0%) were pooled, the results were unchanged. Five 34 , 36 , 37 , 38 , 39 of the 9 studies (589 patients) investigated ARBs alone in patients not taking ACEIs/ARBs—the analysis showed that, compared to amlodipine, 34 placebo 37 , 39 or standard of care, 36 , 38 ARBs had no effect on disease severity (RR 0.75, 95% CI 0.42 to 1.35, I 2 = 42%, Figure 2 ), even after 1 estimate 34 with a high risk of bias was removed (RR 0.71, 95% CI 0.30 to 1.64, I 2 = 57%, 509 patients).…”

“…When only the 6 estimates 36 , 37 , 38 , 39 , 40 , 57 (1320 patients) with low risk of bias (RR 0.85, 95% CI 0.60 to 1.20, I 2 = 38%) or 4 studies 34 , 40 , 42 , 57 (948 patients) that included only hypertensive patients (RR 0.86, 95% CI 0.71 to 1.04, I 2 = 0%) were pooled, the results were unchanged. Five 34 , 36 , 37 , 38 , 39 of the 9 studies (589 patients) investigated ARBs alone in patients not taking ACEIs/ARBs—the analysis showed that, compared to amlodipine, 34 placebo 37 , 39 or standard of care, 36 , 38 ARBs had no effect on disease severity (RR 0.75, 95% CI 0.42 to 1.35, I 2 = 42%, Figure 2 ), even after 1 estimate 34 with a high risk of bias was removed (RR 0.71, 95% CI 0.30 to 1.64, I 2 = 57%, 509 patients). Based on 4 studies 40 , 41 , 42 , 57 (1072 patients) that investigated ACEI/ARB continuation vs .…”

“…Nine trials 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 57 (1646 patients) investigated the association between ACEI/ARB exposure (both treatment‐experienced and ‐naïve patients) and mortality, although 1 study had 0 events. 37 The results were not statistically significant (pooled RR 0.92, 95% CI 0.58 to 1.47, I 2 = 33%, Figure 2 ) even after considering only the 5 estimates 36 , 37 , 39 , 40 , 57 with a low risk of bias (RR 1.13, 95% CI 0.70 to 1.83, I 2 = 0%, 1164 patients). When only hypertensive patients were analysed (4 studies, 34 , 40 , 42 , 57 948 patients), the results were similar (RR 1.00, 95% CI 0.60 to 1.67, I 2 = 0%).…”