Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicentre, phase 3, randomised controlled trial

Abstract

Objective To determine whether disrupting the renin angiotensin system with angiotensin receptor blockers will improve clinical outcomes in people with covid-19. Design CLARITY was a pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. Setting 17 hospital sites in India and Australia. Participants Participants were at least 18 years old, previously untreated with angiotensin receptor blockers, with a laboratory confirmed diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection who had been admitted to hospital for management of covid-19. Intervention Oral angiotensin receptor blockers (telmisartan in India) or placebo (1:1) for 28 days. Main outcome measures The primary endpoint was covid-19 disease severity using a modified World Health Organization Clinical Progression Scale (WHO scale) at day 14. Secondary outcomes were WHO scale scores at day 28, mortality, intensive care unit admission, and respiratory failure. Analyses were evaluated on an ordinal scale in the intention-to-treat population. Results Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomised: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met. Conclusions In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan. Trial registration ClinicalTrials.gov NCT04394117 .

Renin-angiotensin blocker use is associated with improved cardiovascular mortality in Indian patients with mild-moderate chronic kidney disease—findings from the ICKD study

“…During the COVID pandemic, there has been a debate on the ability of ARBs to protect against development of severe disease. Our data, however, was collected mostly before the pandemic ( 36 ).…”

Human Coronavirus Cell Receptors Provide Challenging Therapeutic Targets

“…Additionally, the ACE2 Receptor Blockers (ARB) impede the signaling through AT1R; therefore, Ang (1-7) is produced and accumulates, inducing anti inflammation [ 151 ]. The ARB telmisartan was tested in a Phase III clinical trial to moderate COVID-19 patients; it was concluded that there was not an effective reduction in the disease severity, but ongoing trials might assess its effectivity in more severe patients [ 142 ]. All these molecules are used for reducing blood pressure because they can modulate the balance between Ang (1-7) and Ang II, favoring the first one; nonetheless, the effectiveness for treating COVID-19 is uncertain [ 135 ].…”

Telmisartan and losartan: The marked differences between their chemical and pharmacological properties may explain the difference in therapeutic efficacy in hospitalized patients with COVID‐19

“…4 Conversely, losartan did not show oral efficacy at a dose of 50 mg twice daily for 10 days in hospitalized patients with COVID-19. 5 On the contrary, a recent article 6 reported the results of an RCT of telmisartan treatment in COVID-19 patients. This study was conducted largely in India (99% of all subjects) during the period from May 3, 2020, to November 13 when the delta variant of SARS-CoV-2 was present.…”