Effects of Renin–Angiotensin–Aldosterone Inhibitors on Early Outcomes of Hypertensive COVID-19 Patients: A Randomized Triple-Blind Clinical Trial

Abstract

Background The role of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) has been addressed in some studies related to the current coronavirus disease-2019 (COVID-19) pandemic with possible higher severity and mortality in patients with hypertension. A triple-blind randomized controlled trial was designed to evaluate the effects of these medications on the COVID-19 progression. Methods Patients were enrolled in this trial between April and September 2020. They were randomized in two groups. The former dosage of ACEis/ARBs was continued in one group while in another group, the ACEis/ARBs were replaced by amlodipine ± carvedilol according to the dose equivalents. The primary outcomes were length of stay in hospitals and intensive care units. Other outcomes include mechanical ventilation, non-invasive ventilation, readmission, and COVID-19 symptoms after discharge. Results We randomized 64 patients with COVID-19 into two groups. Most patients were aged 66-80 and 46-65 years-old, 33 (51.6%) and 27 (42.2%), respectively. The study groups were nearly similar in baseline vital signs and characteristics. In addition, there was no significant difference in terms of recorded systolic and diastolic blood pressure measurements between groups. Furthermore, we did not find a significant difference between the days of intensive care unit or ward admission, the discharge rate, or readmission rates between the two groups. Conclusions This randomized triple-blind multi-centric clinical trial did not show any deleterious effects of ACEi/ARB medications in hypertensive COVID-19 patients.

Cardiovascular drugs and COVID‐19 clinical outcomes: a systematic review and meta‐analysis of randomized controlled trials

“…Ten studies 33 , 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 57 investigated ACEIs/ARBs, with only 1 study (102 patients) 33 investigating COVID‐19 infectivity. Compared to standard of care, the ACEI ramipril (initial dose 2.5 mg/d, titrated up to 10 mg/d), when newly initiated, was reported to have no effect on COVID‐19 infectivity (hazard ratio 1.15, 95% CI 0.35 to 3.77).…”

“…Seven studies 34 , 36 , 38 , 40 , 41 , 42 , 57 investigated whether ACEI/ARB exposure (both treatment‐experienced and ‐naïve patients) affected length of hospitalization. One study, 38 reported only medians and a hazard ratio and could therefore not be included in the primary meta‐analysis.…”

“…The effect of ACEI/ARB exposure (in both treatment‐experienced and ‐naïve patients) on severity (varying definitions based on oxygen supplementation, intensive care unit [ICU] admission, World Health Organization ordinal scale among 43 others, Table 1 ) was investigated by 9 studies 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 57 (1661 patients) with ACEIs/ARBs not having an effect on disease severity (pooled RR 0.90, 95% CI 0.71 to 1.15, I 2 = 24%, Figure 2 ). When only the 6 estimates 36 , 37 , 38 , 39 , 40 , 57 (1320 patients) with low risk of bias (RR 0.85, 95% CI 0.60 to 1.20, I 2 = 38%) or 4 studies 34 , 40 , 42 , 57 (948 patients) that included only hypertensive patients (RR 0.86, 95% CI 0.71 to 1.04, I 2 = 0%) were pooled, the results were unchanged.…”

“…The effect of ACEI/ARB exposure (in both treatment‐experienced and ‐naïve patients) on severity (varying definitions based on oxygen supplementation, intensive care unit [ICU] admission, World Health Organization ordinal scale among 43 others, Table 1 ) was investigated by 9 studies 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 57 (1661 patients) with ACEIs/ARBs not having an effect on disease severity (pooled RR 0.90, 95% CI 0.71 to 1.15, I 2 = 24%, Figure 2 ). When only the 6 estimates 36 , 37 , 38 , 39 , 40 , 57 (1320 patients) with low risk of bias (RR 0.85, 95% CI 0.60 to 1.20, I 2 = 38%) or 4 studies 34 , 40 , 42 , 57 (948 patients) that included only hypertensive patients (RR 0.86, 95% CI 0.71 to 1.04, I 2 = 0%) were pooled, the results were unchanged. Five 34 , 36 , 37 , 38 , 39 of the 9 studies (589 patients) investigated ARBs alone in patients not taking ACEIs/ARBs—the analysis showed that, compared to amlodipine, 34 placebo 37 , 39 or standard of care, 36 , 38 ARBs had no effect on disease severity (RR 0.75, 95% CI 0.42 to 1.35, I 2 = 42%, Figure 2 ), even after 1 estimate 34 with a high risk of bias was removed (RR 0.71, 95% CI 0.30 to 1.64, I 2 = 57%, 509 patients).…”

Impact of renin–angiotensin–aldosterone system inhibitors on COVID-19

“…AUC, mean of SOFA were significantly lower in the discontinuation group. Najmeddin, 2021 [ 27 ] Iran Patients on ACEI or ARB therapy 64 Triple blind RCT Continuation or Discontinuation (1:1) ACEI or ARB No effect on the days of ICU or ward admission, the discharge rate, and readmission rates. Puskarich, 2021 [ 28 ] USA Outpatients with not already taking ACEI or ARB 117 Double-blind RCT Losartan or placebo (1:1) ARB (Losartan 25 mg twice daily) No effect on hospitalization, functional status, dyspnea, temperature, and viral load.…”