The role of RAAS blockers in COVID-19 remains to be fully elucidated, and this has led to significant discussions in the medical communities regarding the safety of these drugs. Whilst multiple national societies supported the continuous use of RAAS inhibitors, we have seen many patients unilaterally stopping them due to concerns after reading the initial reports [22,23,24]. The emerging outbreak means that there is a need for robust clinical data on these antihypertensives in COVID-19 patients .
Our meta-analysis, the largest and most detailed undertaken to date, showed a third of hypertensive and a quarter of overall COVID-19 patients were prescribed an ACEi/ARB, likely due to the increasing risk of infection in patients with comorbidities such as cardiovascular diseases, hypertension and diabetes . Although cardiovascular diseases in combination with COVID-19 portend increased risk of severity and mortality [8, 12], the use of ACEi/ARB is not the likely culprit. The use of ACEi/ARB did not show any association with severity of disease or even death among patients admitted with COVID-19.
On the contrary, this meta-analysis showed that death/critical events may even decrease with the use of ACEi/ARB across pathologies, although the analysis failed statistical significance (p = 0.071). This effect however was magnified and was significant among the hypertensive cohorts. Hypertensive patients with COVID-19 who were on ACEi/ARB were 0.67 times less likely to have a fatal/critical outcome than those not on ACEi/ARB (p = 0.01). ACEi/ARB was also associated with a significantly lower risk of death (p = 0.03) in hypertensive patients. Our results are comparable to another meta-analysis comprising of nine studies and 3936 hypertensive patients. This study demonstrated a lower mortality association of ACEi/ARB treatment in hypertensive COVID-19 patients compared to non-ACEi/ARB (OR 0.57, 95% CI 0.38–0.84, p 0.004) [25••]. The benefits of RAAS inhibitors were comparable in both ACEi and ARB. Whilst we did not see a significantly lower risk of death/critical outcomes in patients taking ACE vs non-ACEi and in ARB vs non-ARB, as only a few studies included these data, our analysis might have been underpowered.
Nevertheless, our study in addition to reassuring patients taking RAAS inhibitors begs an important question on whether ACEi/ARB therapy has an obscure beneficial role in patients admitted with COVID-19. Animal studies previously have shown a downregulated expression of ACE2 following SARS infection which results in increased activation of RAAS [13, 26]. This leads to a sequelae of events , notably acute lung injury and consequently, adult respiratory distress syndrome (ARDS) . Thus, the use of ACEi/ARB and deactivation of RAAS might be beneficial in preventing this sequence of events .
In addition to the benefits of ACEi/ARB in cardiovascular patients [28, 29], our study clearly demonstrates the beneficial effects of ACEi/ARB especially in hypertensive cohort with COVID-19. Whilst the meta-analysis does not modify the existing clinical practice, it provides essential information on the use of RAAS blockers in COVID-19 patients and supports the recommendations of the national medical societies to continue treatment with these drugs [22,23,24]. Withholding ACEi/ARB could lead to compromising cardiopulmonary reserve in patients who are already at increased risk of COVID-19 [30, 31] which is an important issue for future research and warrants a clinical trial.
Due to the emerging infection, there is insufficient data to compare these analyses to a control population. In order to undertake a comprehensive evaluation of all data on the usage of ACEi/ARB in COVID-19, the search strategy was inclusive. Pre-print data were included which could potentially introduce bias, but at this time of increasing COVID-19 disease, it was pertinent to review all relevant and essential data.
Furthermore, heterogeneity in the meta-analysis is likely due to the varied sample population or different definitions for severity of the disease. For instance, some studies only analysed hypertensive or cardiovascular patients or those of at least ‘moderate’ severity, whilst some are based on hospital inpatients which is likely to be of at least moderate in disease severity. Several steps were taken to decrease heterogeneity; a standard definition of ‘critical’, published by CDCC  was used and subgroup analysis of hypertensive patients was done. Additionally, those studies including clinically suspected/confirmed COVID-19 were excluded to keep a comparable group of patients.
Although our study sheds light on the association between RAAS blockers and mortality in COVID-19, it begs another question as to whether ACEi/ARB lowers the mortality in these patients. There are no clinical data currently on the effect of ACEi/ARB in COVID-19. In order to establish a viable association, future randomised controlled studies are required.