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

Abstract

Aims: To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs).

Methods: More than 500 databases were searched between 1 November 2020 and 2 October 2021 to identify RCTs that were published after our baseline review. One reviewer extracted data with other reviewers verifying the extracted data for accuracy and completeness.

Results: After screening 22 414 records, we included 24 and 21 RCTs in the qualitative and quantitative syntheses, respectively. The most investigated drug classes were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and anticoagulants, investigated by 10 and 11 studies respectively. In meta-analyses, ACEI/ARBs did not affect hospitalization length (mean difference -0.42, 95% confidence interval [CI] -1.83; 0.98 d, n = 1183), COVID-19 severity (risk ratio/RR 0.90, 95% CI 0.71; 1.15, n = 1661) or mortality (risk ratio [RR] 0.92, 95% CI 0.58; 1.47, n = 1646). Therapeutic anticoagulation also had no effect (hospitalization length mean difference -0.29, 95% CI -1.13 to 0.56 d, n = 1449; severity RR 0.86, 95% CI 0.70; 1.04, n = 2696; and, mortality RR 0.93, 95% CI 0.77; 1.13, n = 5689). Other investigated drug classes were antiplatelets (aspirin, 2 trials), antithrombotics (sulodexide, 1 trial), calcium channel blockers (amlodipine, 1 trial) and lipid-modifying drugs (atorvastatin, 1 trial).

Conclusion: Moderate- to high-certainty RCT evidence suggests that cardiovascular drugs such as ACEIs/ARBs are not associated with poor COVID-19 outcomes, and should therefore not be discontinued. These cardiovascular drugs should also not be initiated to treat or prevent COVID-19 unless they are needed for an underlying currently approved therapeutic indication.

Keywords: COVID-19; RCTs; cardiovascular drugs; living systematic review; meta-analysis.

FIGURE 1

PRISMA Flow Chart of Included Studies. Abbreviations: SSRN = Social Science Research Network, RCT = randomized controlled trial

FIGURE 2

Forest plots for associations between angiotensin‐converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and COVID‐19 outcomes. ^a Total admission days, reported as means (standard deviations), used. When the ‘length of hospital stay’, means (standard deviations) estimated from the reported medians (interquartile range), were used, the subgroup pooled mean difference was 0.41 (95% confidence interval [CI] −1.02 to 1.84, I ²  = 65%) days while the overall pooled mean difference was −0.06 (95% CI −1.36 to 1.24, I ²  = 57%) days. ^b Used intubations to define severity as this was more consistent with the rest of the studies. When severity was defined as the requirement for supplemental oxygen, the subgroup and overall pooled risk ratios were 0.74 (95% CI = 0.46 to 1.18, I ²  = 44%) and 0.91 (95% CI 0.78 to 1.07, I ²  = 23%) respectively. ^c Used admission to the intensive care unit and/or the requirement for mechanical ventilation to define severity as this was more consistent with the rest of the studies. When severity was defined based on the World Health Organisation COVID‐19 ordinal severity scale, the subgroup and overall pooled risk ratios were 0.93 (0.79 to 1.10, I ²  = 2%) and 0.93 (95% CI 0.75 to 1.14, I ²  = 24%) respectively. ^d Follow up of 30 days, which was preferred as this was more consistent with the rest of the studies. When 90‐day follow up was used, the subgroup and overall pooled risk ratios were 0.50 (95% CI 0.20 to 1.29, I ²  = 48%) and 0.89 (95% CI 0.57 to 1.40, I ²  = 31%) respectively. ^e14‐day follow up. Risk of bias domains: 1 = risk of bias arising from the randomization process; 2 = risk of bias due to deviations from the intended interventions (effect of adhering to intervention); 3 = risk of bias due to missing outcome data; 4 = risk of bias in measurement of the outcome; 5 = risk of bias in selection of the reported result; 6 = overall risk of bias. Colour codes: green = low risk; yellow = some concerns; red = high risk

FIGURE 3

Forest plots for associations between anticoagulants and COVID‐19 outcomes. ^a Results are based on those who initiated trial therapy. When the intention‐to‐treat populations are used, the pooled risk ratio becomes 0.55 (95% CI 0.26 to 1.18, I ²  = 0%). ^b Active arm is apixaban 2.5 mg or 5 mg orally twice daily. ^c Low molecular weight heparin or unfractionated heparin, unless otherwise indicated. ^d Therapeutic anticoagulation comprised oral rivaroxaban for stable patients. ^e When organ support or death is used as the severity outcome (instead of mechanical ventilation or death), the result becomes significant (risk ratio 0.83, 95% CI 0.72 to 0.95, I ²  = 0%). ^f Represents in‐hospital deaths (2 vs. 5 deaths). When all‐cause deaths (1 vs. 3 deaths) were used instead, the pooled risk ratio (0.94, 95% CI 0.78 to 1.14, I ²  = 51%) remained similar. ^g Preferred to Bikdeli et al.'s study that used the same dataset (90‐day follow‐up) since Sadeghipour et al.'s 30‐day follow‐up was consistent with the rest of the included studies (follow‐up range 21–45 d). Nevertheless, a sensitivity analysis in which the Bidkeli et al. study was included instead of the Sadeghipour et al. study produced a similar result (pooled risk ratio 0.94, 95% CI 0.77 to 1.14, I ²  = 54%). ^h Therapeutic‐dose apixaban (5 mg orally twice daily) vs. prophylactic‐dose apixaban (2.5 mg orally twice daily). ⁱ Results are based on those who initiated trial therapy. When the intention‐to‐treat populations are used, the pooled risk ratio becomes 0.94 (95% CI 0.78 to 1.14, I ²  = 48%). DOACS = direct oral anticoagulants. Risk of bias domains: 1 = risk of bias arising from the randomization process; 2 = risk of bias due to deviations from the intended interventions (effect of adhering to intervention); 3 = risk of bias due to missing outcome data; 4 = risk of bias in measurement of the outcome; 5 = risk of bias in selection of the reported result; 6 = overall risk of bias. Colour codes: green = low risk; yellow = some concerns; red = high risk