DISCUSSION
This review of original studies aimed to examine the mortality and disease severity in hypertensive COVID-19 patients exposed and unexposed to ACEIs/ARBs. In our analysis, we found a protective effect of ACEI/ARB among hypertensive patients, having a lower risk of mortality. Though we observed no significant difference with regards to disease severity of COVID-19 by the use of ACEI/ARB, there still seems to be a significant protective effect. We believe these results still support the notion that the use of ACEI/ARB is not associated with increased risk of harm in COVID-19 patients but rather a potential protective effect from mortality.
When we look at the individual studies that we included, we found that a significant reduction in the risk of mortality was noted in a study by Zhang et al. [11] when confounders were extensively adjusted with no age difference between the two groups. Zhang et al. [11] included 1,128 patients with hypertension in their study, of which 188 patients were receiving ACEIs/ARBs. They reported that the use of ACEIs/ARBs significantly reduced the risk of all-cause mortality by 58%. The reduction in the mortality risk is even more significant in propensity score-matched analysis where the exposure to RAS Inhibitors was also associated with a 63% reduced risk of mortality.
Two of the largest studies included in this analysis were by Lee et al. [12] who analysed Korean COVID-19 patients (n=8,266) and Mehra et al. [22] who included COVID-19 patients from 11 countries in Asia, Europe, and North America (n=8,910). Lee et al. [12] did not show any statistical significance even after the adjustment of confounders as in Zhang et. al [11]. Mehra et al. [22] on the other hand, demonstrated a significant reduction in mortality among ACEI users but not ARB users after the adjustment of confounders. This could be due to patients included by Zhang et al. [11] were all hypertensive, compared to only 19.0% and 26.3% from Lee et al. [12] and Mehra et al. [22], respectively. Hypertensive patients may have diminished circulatory reserve to meet the excessive demands of COVID-19 on the cardiovascular system and thus a predilection towards cardiac injury and mortality [3]. In this sense, ACEIs/ARBs may have a cardioprotective effect in patients with COVID-19 and thus a reduced risk of mortality as demonstrated in our analysis. Besides, COVID-19 patients with cardiac injury are more likely to be complicated by the acute respiratory distress syndrome (ARDS), in which ACEIs/ARBs may have a protective effect on lung injury due to their effects on angiotensin II as explained above [9].
Likewise, we observed a significant protective effect from severe/critical COVID-19 in hypertensive patients after adjustment of confounders by Zhang et al. [11] where the use of ACEIs/ARBs significantly reduced the risk of severe/critical disease (septic shock) by 64% and even greater reduction of 68% in propensity score-matched analysis. However, no benefit was associated with ACEI/ARB use in the development of severe/critical disease in COVID-19 patients with or without hypertension by Feng et al. [15].
Other than a reduced incidence of septic shock, there is also a significant reduction in the risk of disseminated intravascular coagulation among hypertensive patients [11]. This is consistent with the anti-inflammatory potential of ACEIs/ARBs, as patients receiving ACEIs/ARBs had also significantly lower concentrations of C-reactive protein and procalcitonin [13]. ACEI/ARB may also protect against cardiac injury as significantly lower levels of cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and lactate dehydrogenase were found in ACEI/ARB users with or without hypertension [15,18]. Immunomodulatory function of ACEIs/ARBs have also been reported previously; a significantly higher CD3 and CD8 T-cell counts were found in peripheral blood of hypertensive patients receiving ACEIs/ARBs compared to their counterparts without RAS blockade [14]. There have also been reports of the significant reduction in peak viral load in hypertensive users of ACEI/ARB than the non-users, which to some extent, discredited the suggestion that elevated expression of ACE2 might increase the susceptibility to acquiring SARS-CoV-2 infection or could increase the viral load [14].
In conclusion, this review and analysis of early data demonstrated a protective effect of ACEI/ARB on mortality in COVID-19 patients with hypertension. Moreover, no significant difference was found between ACEI/ARB and non-ACEI/ARB groups in the risk of developing severe/critical COVID-19 disease. Therefore, our analysis with currently available studies should provide comfort to the clinicians who might ponder upon whether to continue the use of ACEI/ARB in hypertensive patients amid the COVID-19 pandemic.
Funding : This study was not funded.
Conflict of interest statement : The authors have no conflict of interest to declare.