Discussion:
Among patients who were hospitalized for COVID-19, this study showed no significant association between prior use of ACEI/ARBs and COVID-19 mortality or severity as evident by ICU admission rate after adjusting for baseline characteristics, comorbidities, and steroid use, using the adjusted logistic regression model and Cox-proportional hazard model.
The mean BMI in our study population was high (32). Eighty percent of the patients had BMI equal or higher than 25. This finding correlates with the findings of other studies on the association between BMI and COVID-19 hospitalization rates.
Some studies have suggested that ACEI/ARB may increase viral entry, with concerns that these drugs could increase the risk of developing severe outcome with COVID-19
However, to date, there is insufficient data the association between prior use of ACEI/ARBs associated and an increased risk of COVID-19 severity. A retrospective cohort study was conducted in two Saudi public specialty hospitals, included 354 patients with COVID-19 (in which 146 were ACEI/ARB users and 208 were non-ACEI/ARB users) after controlling for confounders, using multivariate logistic regression and sensitivity analyses using propensity score matching (PSM) and inverse propensity score weighting (IPSW) for high-risk patient subsets. The ACEI/ARB group had an eight-fold higher risk of developing critical or severe COVID-19 (OR = 8.25, 95%CI = 3.32–20.53); a nearly 7-fold higher risk of intensive care unit (ICU) admission (OR = 6.76, 95%CI = 2.88–15.89) and a nearly 5-fold higher risk of requiring noninvasive ventilation (OR = 4.77,95%CI = 2.15–10.55). Concluding that ACEI/ARBs use was associated with a higher risk of severe COVID-19 disease. However, this study had a small sample size, some variables were overlooked including the use of steroids, and the results showed a wide confidence interval.
On the other hand, a prospective cohort study in England involving 8.28 million participants showed reduced risk of COVID-19 positive disease requiring hospitalization. This study is limited by unavailability of standard systematic strategy for COVID-19 testing in the UK and restricting the COVID-19 testing to only hospitalized patients by UK health policy during the period of the study.
Despite that, a meta-analysis including 13 studies conducted in 2020 showed that ACEI/ARB use was not associated with an increased risk of all-cause mortality or severe disease due to COVID-19. Among these 13 studies, 11 studies that reported odds ratio showed the thebACEI/ARB group had a significantly lower risk of all-cause mortality than non-ACEI/ARB group regardless of confounders of adjustment for confounders. This meta-analysis was limited by inconsistencies in the definition of severe diseases and in inclusion criteria that were inconsistent across the studies.
In addition to this meta-analysis, an open randomized controlled trial in Brazil including 659 hospitalized patients with mild to moderate COVID-19 showed no effect of discontinuation of ACEIs or ARBs on COVID-19 mortality. However, this study explored a different question than our study. The two proposed two conflicting hypotheses state that ARBs and ACEIs either increase ACE2 expression, allowing virus entry into the cell and, therefore, increasing SARS-COV2 infectivity and severity or coronavirus downregulates ACE2 receptors causing an elevation of angiotensin II, which may lead to lung injury. Based on this, prior use of ACEI/ARB would affect the COVID-19 infectivity, severity or mortality or than the use of ACEIs/ARBs after establishment COVID-19.
Another study conducted in New York in the March of 2020 showed a reduced length of hospital stay in patients admitted with COVID-19 who used ACEI/ARB in the hospital, most of whom belonged to ethnic minorities. This limitations of this study include the disproportionate size of the control vs. treatment group and the fact that study only considered the ACEIARB during the hospitalization. The results were not significant for the other primary outcome or the secondary outcomes.
We have a large high-quality database of hospitalized COVID-19 patients at our hospitals. Our study is observational and we were able to reduce the confounding effect by adjusting a wide range of confounders recorded in electronic medical records including age, race, BMI, and other comorbidities. Our sample was representative and was restricted to a group of patients with hypertensive. Another great strength of our study is the inclusion of a diverse group of patients as the eight hospitals are spread out over the Southeast Michigan region where a majority of Michigan’s population resides and comprises of Caucasians, African Americans, and Arabs. The limitations of our study include, the retrospective nature of the study, the inability to specify the chronicity of ACEI/ARB use based on the available data, overlooking of unknown confounders and finally, and performing the study during the early months of COVID-19 pandemic where little information about the treatment and disease was available.
At this stage, there is insufficient clinical evidence for either, thus we still need further studies. Until further data are available, we should continue using ACEI and ARB to treat cardiovascular disease in patients with COVID-19 given the significant cardiovascular benefits of ACEI/ARBs. In addition, the sudden withdrawal of ACEI/ARBs in those patients may result in adverse outcomes.