4.0 Discussion:
Speculation over the deleterious effects of ACEi/ARB in patients with COVID-19 stems from the fact that SARS-CoV-2 uses the ACE2 receptor to enter target human cells (5). A few preclinical studies have suggested that RAAS inhibitors increase ACE2 expression, raising concerns regarding their safety in patients with COVID-19 (9). This thought was seemingly further strengthened by a retrospective study on hospitalised patients with COVID-19 in Wuhan, China, which reported that hypertensive patients on ACEi/ARB had an increased tendency to develop severe pneumonia with SARS COV 2 infection compared to those not on ACEi/ARB (54% vs. 32% respectively; p = 0.055) (17). This created confusion amongst patients and their health care workers since ACEi/ARB are an essential component of treatment not only in many individuals with hypertension but also in those with diabetes, coronary artery disease, heart failure and chronic kidney disease; sudden withdrawal of these medications in these patients might cause harm (22). However, findings from the same study showed that hypertensive patients with COVID-19 who were on ACEi/ARB had lesser hospitalisation (18% vs. 28%), lesser number of deaths (7% vs. 11%), and a higher number of discharges (75% vs. 61%) when compared to those not on ACEi/ARB; however, these observations failed to reach statistical significance due to the small number of patients analysed (17). In another study from China on elderly hypertensive patients with COVID-19, treatment with ARB was associated with a significant reduction in the risk of disease severity (OR=0·343, 95% CI 0·128-0·916, p=0·025) (18). A study by Yang et al. reported that compared to patients on non-ACEi/ARB antihypertensives, those on ACEi/ARB had a significant reduction in inflammatory markers, namely C-reactive protein (11.5 [ACEi/ARB] [4.0-58.2] vs. 33.9 [non ACEi/ARB] [5.1-119.2]; p=0.049) and procalcitonin (0.061 [ACEi/ARB] [0.044-0.131] vs. 0.121 [non ACEi/ARB] [0.052-0.295]; p=0.008), (19) consistent with previously described anti-inflammatory properties of ACEi/ARB (23, 24). This study also revealed a much lower proportion of critical patients (9.3% vs.22.9%; p=0.061), and a lower death rate (4.7% vs. 13.3%; p=0.216) in those receiving ACEi/ARB compared to those not on ACEi/ARB; however, these differences failed to reach statistical significance (19).
In a study from the United Kingdom, Bean et al. reported that in patients with COVID-19, those treated with ACEi had a lower rate of death or transfer to a critical care unit [OR 0.29 CI 0.10-0.75 p <0.01], after adjusting for age, gender, and comorbidities (hypertension, diabetes mellitus, ischaemic heart disease and heart failure) compared to those who were not on ACEi/ARB (20). Recently, Zhang et al. reported a large multicentre retrospective study on 1128 hospitalised hypertensive patients with COVID-19; there was a significant reduction in all-cause mortality (adjusted HR, 0.30; 95%CI, 0.12-0.70; P = 0.01) in patients treated with ACEi/ARB compared to those treated with other anti-hypertensive medications, even after adjusting for a large number of variables (21). This study also demonstrated that use of ACEi/ARB was associated with lower risk of septic shock when compared to those not on ACEi/ARB (adjusted HR, 0.36; 95% CI, 0.16-0.84; P = 0.01) (21).
In a recently published retrospective analysis of hypertensive patients from China, Li J et al. have reported that there was no difference in severity of disease (32.9% vs 30.7%; P = 0.645) or mortality (27.3%vs 33.0%; P = 0.34) among the hypertensive patients on ACEIs/ARBs when compared to those who were not on ACEi/ARB. (22)
The six studies described above, which have individually reported on the effect of ACEi/ARB in patients with COVID-19, are limited by the small number of patients and varied outcomes reported that makes it difficult to ascertain the effect of ACEi/ARB in patients with COVID-19. Ours is the first meta-analysis reporting the effect of ACEi/ARB on death and severity of disease in patients with COVID-19. We noted that patients with COVID-19 who were on ACEi/ARB had a 38% non-significant reduction in the odds for risk of developing severe disease [OR 0.62 (95% CI: 0.31-1.23), I2=70.36] when compared to those not on ACEi/ARB. The odds for risk of hospitalisation was also reduced by 19% (95% CI: 0.42-1.55, I2: 0.000) among patients with COVID-19 on ACEi/ARB compared to those not on ACEi/ARB, which failed to reach statistical significance. Most importantly, our meta-analysis of the four studies that have reported on death, reveals a statistically significant 43% reduction [OR 0.57 (95% CI: 0.37-0.88, I2=0.000) p=0.01] in the odds of death among patients with COVID-19 on ACEi/ARB compared to those not on ACEi/ARB, with negligible heterogeneity of data. The statistically significant benefits seen in our meta-analysis in the odds of death with use of ACEi/ARB in patients with COVID-19, together with a trend in reduction of severity of disease and risk for hospitalization, strengthens the recommendations from European Societies of Cardiology (25), Heart Failure Society of America, American College of Cardiology, American Heart Association (26) and International Society of Hypertension (27) to continue ACEi/ARB in patients with COVID-19. The reduction in the odds of death and the trend in the risk of developing severe disease and hospitalization is not only reassuring concerning the safety of ACEi/ARB in patients with COVID-19 but also point towards the urgent need for an adequately powered RCT to confirm these benefits. Till such time, our meta-analysis adds to current knowledge confirming not only the safety of ACEi/ARB in patents with COVID-19 but also possible benefit in terms of reduction in death.
These findings are in keeping with the results of a meta-analysis of three studies with 70346 patients with non-COVID pneumonia, where use of ARB was associated with a significant reduction in the risk of pneumonia-related morbidity (OR=0·55, 95% CI; 0·43-0·70, p<0·01) and mortality (OR=0·55, 95% CI; 0·44-0·69, p<0·01) (18). In another retrospective study on 313 elderly patients, it was noted that the relative risk of developing a new pneumonia of mixed aetiology was higher in patients who were not on an ACEi when compared to those who were receiving ACE inhibitors [18% vs. 7%; RR 2·65 (95% CI 1·31–5·35, p=0·007)] (28). lt would appear that ACEi/ARB have a protective effect on pneumonia related pulmonary injury, which may be of benefit in patients with COVID-19 since the SARS-CoV-2 has a predilection for the lower respiratory tract.
Our meta-analysis has a few limitations. The six studies included for analysis used different primary and secondary end-points that led to a moderate degree of heterogeneity in the reported results; we circumvented this by restricting our meta-analysis to clinically relevant end-points of death, hospitalisation and severity of disease, which resulted in negligible heterogeneity in our analysis on hospitalisation and death. The number of patients in the individual studies were small and there were various confounders, which were partly addressed by pooling of the data from the individual studies. Last, but not the least, due to a very small number of patients in the studies that reported outcomes independently in patients with COVID-19 on an ACEi or ARB, we were unable to assess the independent effect of ACEi or ARB on death and severity of disease in patients with COVID-19.
The strength of our meta-analysis lies in the fact that in an evolving infectious disease pandemic with acute consequences, where generation of evidence at the earliest is crucial to guide management, the best way to increase the predictability of the question in focus is to perform pooled analysis, till results of a randomized controlled trial (RCT) becomes available. By pooling data from multiple small observational studies with multiple inherent confounding factors, and by performing a meta-analysis, we have largely circumvented the problems associated with the individual studies. This meta-analysis, highlighting the safety and possibly beneficial effects of ACEi/ARB, shall help physicians use ACEi/ARB in patients with COVID-19 till further information becomes available. Secondly, since, the parameters assessed and the outcomes analysed varied enormously between the six studies, we analysed clinically relevant end-points including death, risk of hospitalisation, and severity of illness.