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No harm from angiotensin-converting enzyme inhibitors or angiotensin receptor inhibitors in patients with COVID-19. Results of a prospective study on a hospital-based cohort

This study aims to assess the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor inhibitors (ARBs) on the course of COVID-19. It is a prospective study on 221 (M/F ratio= 143/78, mean age 72±13) consecutive hypertensive patients with COVID-19: 76 (34.4%) treated with ACEIs, 63 (28.5%) with ARBs and 82 (37.1%) with antihypertensives OTHER than ACEIs or ARBs. They were all followed up until discharge or death. BAD outcome was defined as the need for invasive mechanical ventilation or death. The three classes of medication were well balanced for confounding variables. BAD outcome was overall recorded in 63/221 (28%) patients, in 20/76 (26%) of ACEI, in 17/63 (27%) of ARB and in 26/82 (32%) of OTHER users, with no statistically significant difference in any comparison. These findings refute the hypothesis that treatment with ACEIs or ARBs may negatively affect the course of COVID-19. Correspondence: Gian Paolo Anzola, Consultant Neurologist, San Camillo Hospital, via Turati 47, 25123 Brescia, Italy. Tel.: +39.030.2910311. E-mail: gpanzola@gmail.com

the Community Hospital of Gavardo for symptoms or signs suggestive of SARS-CoV-2 infection were considered for the study. However, only those confirmed by a real-time polymerase chain reaction in nasal or pharyngeal swab were included.
Following a pre-specified protocol, relevant clinical and laboratory variables were recorded on the field, focusing on the type of current anti-hypertensive treatment. In particular, a dichotomous categorization (yes/no) was employed for cardiovascular disease (CVD) (including the history of myocardial infarction, percutaneous transcatheter coronary angioplasty, coronary artery by-pass grafting, heart failure stroke and atrial fibrillation), chronic renal failure, chronic liver disease, diabetes mellitus, chronic obstructive pulmonary disease, history of or present neoplasm, history of or present autoimmune disease, hypertension, current use of ACEIs, current use of ARBs, current use of antihypertensives other than ACEIs or ARBs (OTHERs). Relevant laboratory tests were recorded at presentation: these included hemoglobin in g/L, platelet, leukocyte and lymphocyte count per microliter, serum creatinine in mg/dL, aspartate aminotransferase (AST), alanine aminotransferase in units per liter and C-reactive protein (CRP) in mg/L. In case of missing data, the electronic chart was reviewed on discharge to finalize ascertainment.
Endpoints were: GOOD outcome if during the hospital stay, the patient survived and did not need invasive mechanical ventilation and BAD outcome if he/she needed invasive mechanical ventilation or died. In non-hospitalized patients, a follow-up telephone call was done three weeks after the presentation.
Single comparisons were performed with Chisquare test or Fisher's exact test when appropriate on categorical variables and with independent sample T-test (if normally distributed) or with the Mann-Whitney U test on continuous variables. Variables that had proven significant on univariate analysis were included to multivariate binomial logistic regression analyses to identify independent predictors of BAD outcome. Statistical significance was set at P<0.05. SPSS 20 statistical package was used.
The Local Institutional Review Board approved the study.
Variables that turned significant in univariate analyses were included into a multivariate binomial logistic regression analysis with BAD outcome as the dependent variable. Only age, CRP, and creatinine remained independent predictors of BAD outcome ( Table 2). With regard to age, BAD outcome was recorded in 4% of subjects younger than 60, 18% of those in the 61-70 range, 35% of those between 71 and 80, and in 48% of those older than 80.
The case fatality rate was overall at 23% (51/221). Among ACEI users, it was 20% (15/61), among ARB 22% (14/49) and among OTHER users 27% (22/60) with no statistically significant difference in any comparison (Table 3).   Variables that on univariate analyses were significant in predicting a BAD outcome were evenly distributed across classes, as shown in Table 3. Likewise, age and gender were well balanced. Bad outcome was recorded in 26% of ACEI, 27% of ARB, and 32% of OTHER users, again with no statistically significant difference.

Discussion and Conclusions
The results of the present study show that in COVID-19 hypertensive patients presenting at the Emergency Unit the outlook is somewhat unfavorable, as the proportion of individuals who will progress to invasive mechanical ventilation or will eventually die is 28% on the average but with a steep rise to 35% in people older than 70 and to 48% in older than 80. This finding is in agreement with previous reports that have identified hypertension and age as main predictors of bad outcome or death in hospitalized patients. [2][3][4] Cardiovascular disease, which in univariate analysis appeared to double the risk of BAD outcome, was no longer significant when corrected by age, again in agreement with previously published findings, 4 whereas, creatinine and CRP remained independent predictors of bad outcome, most likely as markers of the systemic involvement of infection.
With regard to the main aim of the study, ACEIs and ARBs each accounted for 30% of the cohort of    hypertensive patients, the remaining drugs being represented for the vast majority by diuretics, betablockers, and calcium antagonists. These were put together under the heading of OTHER, for comparison with ACEIs and ARBs. From Table 3 it appears that most if not all confounders were equally balanced among classes, and the bad outcome was equally frequent in ACEI, ARB, and OTHER. The same holds for the case fatality rate. Concerning patients with a BAD outcome, there was a trend for an over-representation of OTHER (26/63, 41%) with respect to ACEI (20/63, 32%) and ARB (17/63, 27%) but the trend was not statistically significant. Finally, ACEIs/ARBs put together were excluded by logistic regression analysis as predictors of bad outcome. All together these findings refute the hypothesis that treatment with ACEIs or ARBs may negatively affect the course of COVID-19, in agreement with the results of three retrospective studies done in hospitalized patients in China. [5][6][7] However, essential differences with regard to these studies need to be noted: age was lower in one, 5 the proportion of ACEI/ARB users was much lower than ours in another 6 and, the most important thing, these studies were performed only on Asian patients, who are usually treated with lower doses of antihypertensive medication and are known to metabolize β-blockers differently from Caucasians. 8 Therefore, the results of these studies may not be entirely transferable to western patients. Nevertheless, our findings are quite similar and show substantial neutrality of ACEIs and ARBs on the outcome. We noted a non-significant trend for a worse outcome in users of OTHER antihypertensives, which compares with Zhang's finding of a protective effect of ACEI. 6 However, it is important to note that Zhang et al. compared the in-hospital use of ACA/ARBs with other medications and were unable to assess pre-hospital treatment. 6 This may, of course, have introduced a critical bias. Yet, a protective effect of ACEIs on death is suggested from the findings of a recently published study performed in 8910 hospitalized patients. 9 This study included subjects of different ethnicities from all over the world, and the proportion of patients taking ACEIs or ARBs was extremely low. Therefore, according to what the Authors themselves admitted, this conclusion must be taken very cautiously. 9 On the other hand, further support for the substantial safety of RAS inhibitors comes from two population-based studies that were unable to find any association between ACEI or ARB use and the susceptibility to COVID-19 or the likelihood of a worse outcome in affected subjects. 10,11 In summary, regardless of the study type, sample size, and outcome variables, the bulk of studies that have appeared in the last few weeks unanimously re-ject the hypothesis that taking ACEIs or ARBs adversely affects the course of COVID-19. This conclusion is confirmed by the results of the present study, which is the only one, to the authors' knowledge, to have assessed patients prospectively on the field from Emergency Unit to discharge or death.
The whole picture emerging from available data plays in favor of the safety of RAS inhibitors, with a hint for a possible protective effect from ACEIs, which, however, will have to be tested in future randomized controlled trials. For the time being, a conservative conclusion may suggest that there is no reason to withhold ACEIs and ARBs in patients with COVID-19.
Our study suffers from several limitations: it was based on a single-center experience, and the duration of treatment or the dosage of drugs could not be assessed. Furthermore, we are aware that the relatively small sample size might expose to a Type II error in erroneously accepting the null hypothesis. We did not perform a calculation of the required sample size, but with a prevalence of the outcome variable of 28%, the sample size needed to pick up a difference of 12% in its occurrence would have been 486. Finally, the three classes of medication were well balanced for confounding variables, and we believe that any minimal difference that could emerge from a more powerful study would probably be clinically meaningless.