Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors in COVID-19: Meta-analysis/Meta-regression Adjusted for Confounding Factors

Abstract

BACKGROUND Angiotensin receptor blockers (ARBs) and/or angiotensin converting enzyme (ACE) inhibitors could alter mortality of COVID-19, but existing meta-analyses which combined crude and adjusted results may be confounded by comorbidities being more common in ARBs/ACE inhibitors users. METHODS We searched PubMed/MEDLINE/Embase for cohort studies and meta-analysis reporting mortality by pre-existing ARB/ACE inhibitor treatment in hospitalized COVID-19 patients. Random effects meta-regression was used to compute pooled odds ratios for mortality adjusted for imbalance in age, sex and prevalence of cardiovascular disease, hypertension, diabetes mellitus and chronic kidney disease between users and non-users of ARBs/ACE inhibitors at the study-level during data synthesis. RESULTS In 30 included studies of 17,281 patients, 22%, 68%, 25%, and 11% had cardiovascular disease, hypertension, diabetes mellitus and chronic kidney disease. ARBs/ACE inhibitors use was associated with significantly lower mortality after controlling for potential confounding factors (OR 0.77 (95% CI: 0.62, 0.96)). In contrast, meta-analysis of ARBs/ACE inhibitors use was not significantly associated with mortality when all studies were combined with no confounder adjustment performed (0.87 (95% CI: 0.71, 1.08)). CONCLUSIONS ARBs/ACE inhibitors use was associated with decreased mortality in cohorts of COVID-19 patients after adjusting for age, sex, cardiovascular disease, hypertension, diabetes and chronic kidney disease. Unadjusted meta-analyses may not be appropriate for determining whether ARBs/ACE inhibitors are associated with mortality of COVID-19 because of indication bias.

Renin‐Angiotensin Aldosterone System Inhibitors and COVID‐19: A Systematic Review and Meta‐Analysis Revealing Critical Bias Across a Body of Observational Research

“…This study was not the first systematic review and meta‐analysis to assess the associations between RAAS inhibitor use and COVID‐19 outcomes. As of December 2021, at least 52 meta‐analyses had been conducted, 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 each of which pooled studies that have a critical risk of bias. Critical biases limit confidence in the evidence produced by these meta‐analyses as much as they do in each of the studies that t...…”

“… 6 At least 52 meta‐analyses have assessed associations between RAAS inhibitor use and COVID‐19 risk by collating parts of that body of research. 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 However, little attention has been paid to selection bias, or other biases for that matter, which may distort the interaction between RAAS inhibitor use and COVID‐19.…”

Biomarkers of Volume Overload and Edema in Heart Failure With Reduced Ejection Fraction

“…Comorbidities such as HF and coronary artery disease express elevated levels of ACE2, thus leading to an increased susceptibility and disease severity in SARS-CoV-2 infection. Also, the binding of the virus to ACE2 receptors determines endothelial dysfunction through hyperinflammation, elevated plasma levels of prothrombin, and as a consequence the risk of arterial and venous thrombosis increases (46)(47)(48).…”

“…Additionally, a meta-regression analyses shows that ARBs/ACEi use, correlates with a significant drop in mortality in COVID-19 patients, after sex, age, cardiovascular disease, high blood pressure and chronic kidney disease adjusting. Moreover, treatment management of COVID-19 patients from current guidelines also recommend continuation with these pharmacological agents in patients with cardiovascular comorbidities (46).…”

Pronóstico de los pacientes hospitalizados por Covid-19 que utilizaban inhibidores de la enzima convertidora de angiotensina o antagonistas del receptor de angiotensina II

“…22 Por último, en un análisis de metarregresión realizado entre 30 estudios, el uso de iECA o ARA II se asoció con una disminución significativa de la mortalidad en pacientes hospitalizados por COVID-19 después de controlar los posibles factores de confusión al nivel del estudio durante la síntesis de datos (OR de 0.77 con IC del 95% de 0.62 -0.96), sin dicho ajuste el resultado no obtuvo significancia estadística (OR de 0.87 con IC del 95% de 0.71 -1.08). 23 Reconocemos como limitaciones del presente estudio que los pacientes procedían de hospitales de cuarto nivel de atención, lo que puede inducir a un sesgo de selección al tratarse de casos con una severidad mayor de base. Las variables fueron evaluadas solo al momento de su ingreso a hospitalización lo que podría tener implicaciones en el desempeño presentado.…”