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The Renin Angiotensin System as a potential treatment target for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major health concern and leading cause of death and disability in young adults in the UK and worldwide, however, there is a paucity of disease modifying therapies for the treatment of TBI. This review investigates the potential of the renin-angiotensin system (RAS) as a treatment pathway for traumatic brain injury (TBI) in adults. Relevant electronic databases were searched on 18 December 2019, updated 16 May 2021. All English language articles with adult human or animal populations investigating RAS drugs as an intervention for TBI or reporting genetic evidence relevant to the RAS and TBI were screened. Eighteen preclinical RCTs (n=2269) and 2 clinical cohort studies (n=771) were included. Meta-analyses of 6 preclinical randomised-controlled trials (n=99) indicated candesartan improved neurological function short-term (<7 days: standardised mean difference (SMD) 0.61, 95% confidence interval (CI) 0.19 - 1.03, I2=0%) and long-term (≥7 days: SMD 1.06, 95% CI 0.38; 1.73, I2=0%) post-TBI. Findings were similar for most secondary outcomes. There was a suggestion of benefit from other RAS-targeting drugs, although evidence was limited due to few small studies. There was insufficient evidence to enable strong assessment of these drugs on mortality post-TBI. We conclude that angiotensin-receptor blockers, especially candesartan, show positive outcomes post-TBI in preclinical studies with moderate quality of evidence (GRADE). More research into the effect of regulatory-RAS targeting drugs is needed. Clinical trials of candesartan following TBI are recommended, due to strong and consistent evidence of neuroprotection shown by these preclinical studies.