The effect of ACE inhibitors and ARBs on outcomes in hospitalized patients with COVID-19.

BACKGROUND: Contradictory opinions exist regarding the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with hypertension, which is the most common comorbidity associated with COVID-19. Herein, the effects of ACEIs and ARBs on outcomes of COVID-19 patients were evaluated. METHODS: In this cross-sectional study, the outcomes of COVID-19 patients were compared between patients who received pretreatment ACEIs or ARBs and those who did not. RESULTS: The incidence of moderate and severe forms of COVID-19 was significantly higher in patients taking ACEI/ARB drugs (P-value = 0.012). Also, patients taking ACEI/ARB drugs (P-value = 0.034), patients with hypertension (P-value = 0.011), and patients with dyslipidemia (P-value = 0.011) experienced more severe forms of COVID-19. There was an association between increased length of hospital stay and dyslipidemia (P-value = 0.033) and the use of ACEI/ARB drugs (P-value = 0.041), while no correlation was found between other parameters in univariate linear regression analysis as well as multivariate linear regression. There was an association between increased mortality of patients with increasing age (P-value < 0.001), BMI greater than 30 kg/m2 (P-value = 0.02), asthma (P-value = 0.003), and dyslipidemia (P-value = 0.045). CONCLUSIONS: ACEI/ARB drugs put COVID-19 patients at high risk for moderate to severe forms of COVID-19 and higher length of hospital stay. Although, it is notable that these drugs did not significantly affect specific adverse outcomes of COVID-19, such as the need for admission to the intensive care unit (ICU), length of ICU stay, ventilation, and mortality.

An umbrella review and meta-analysis of renin-angiotensin system drugs use and COVID-19 outcomes.

BACKGROUND: Despite the availability of extensive literature on the effect of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) on COVID-19 outcomes, the evidence is still controversial. We aimed to provide a comprehensive assessment of the effect of ACEIs/ARBs on COVID-19-related outcomes by summarising the currently available evidence. METHODS: An umbrella review was conducted using Medline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 1 February 2021. Systematic reviews with meta-analysis that evaluated the effect of ACEIs/ARBs on COVID-19-related clinical outcomes were eligible. Studies' quality was appraised using the AMSTAR 2 Critical Appraisal Tool. Data were analysed using the random-effects modelling including several subgroup analyses. Heterogenicity was assessed using I2 statistic. The study protocol was registered in PROSPERO (CRD42021233398) and reported using PRISMA guidelines. RESULTS: Overall, 47 reviews were eligible for inclusion. Out of the nine COVID-19 outcomes evaluated, there was significant associations between ACEIs/ARBs use and each of death (OR = 0.80, 95%CI = 0.75-0.86; I2  = 51.9%), death/ICU admission as composite outcome (OR = 0.86, 95%CI = 0.80-0.92; I2  = 43.9%), severe COVID-19 (OR = 0.86, 95%CI = 0.78-0.95; I2  = 68%) and hospitalisation (OR = 1.23, 95%CI = 1.04-1.46; I2  = 76.4%). The significant reduction in death/ICU admission, however, was higher among studies which presented adjusted measure of effects (OR = 0.63, 95%CI = 0.47-0.84) and were of moderate quality (OR = 0.74, 95%CI = 0.63-0.85). CONCLUSIONS: Collective evidence from observational studies indicate a good quality evidence on the significant association between ACEIs/ARBs use and reduction in death and death/ICU admission, but poor-quality evidence on both reducing severe COVID-19 and increasing hospitalisation. Our findings further support the current recommendations of not discontinuing ACEIs/ARBs therapy in patients with COVID-19.

The divergent protective effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on clinical outcomes of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis.

BACKGROUND: Some studies have speculated that patients on angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are more susceptible to adverse outcomes of coronavirus disease 2019 (COVID-19). Here, we performed a systematic review and meta-analysis to evaluate the safety and efficacy of administering ACEIs and ARBs to patients with COVID-19. METHODS: Studies of COVID-19 were collected from the PubMed, Embase, medRxiv and BioRxiv databases. The pooled relative risk odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Subgroup analyses were conducted by medication (ACEIs and ARBs) and geographical location (China and outside China). Inter-study heterogeneity was assessed using meta-regression. Begg's test, Egger's test and funnel plots were adopted to evaluate possible publication bias. RESULTS: Thirty studies containing 10,434 adult patients were included in our meta-analysis. The pooled result indicated that the administration of ACEIs or ARBs reduced the risk of severe/death outcomes for COVID-19 patients. Meanwhile, a significant reduction in the risk of severe/death outcomes was observed to be associated with the administration of ACEIs or ARBs among COVID-19 patients in China, but this association was weaker for studies outside China. Furthermore, ACEI therapy was found to carry a significantly lower risk of an adverse clinical outcome. DISCUSSION: Our systematic review and meta-analysis found that neither ACEIs nor ARBs worsen the clinical outcomes of COVID-19 patients. On the contrary, we found that patients treated with ACEIs or ARBs have a reduced risk of severe/death outcomes, especially in Asia. Furthermore, ACEIs may reduce the risk of severe/death outcomes. Therefore, treatment interruption of ACEI or ARB therapy during COVID-19 infection is not recommended.

Effects of renin-angiotensin-aldosterone system inhibitors on disease severity and mortality in patients with COVID-19: A meta-analysis.

To investigate the effects of renin-angiotensin-aldosterone system (RAAS) inhibitors on the prognosis in patients with coronavirus disease 2019 (COVID-19). A meta-analysis was performed. We systematically searched PubMed, the Cochrane Library, the Web of Science, EMBASE, medRxiv, and bioRxiv database through October 30, 2020. The primary and secondary outcomes were mortality and severe COVID-19, respectively. We included 25 studies with 22,734 COVID-19 patients, and we compared the outcomes between patients who did and did not receive angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs). The use of ACEIs/ARBs was not associated with higher risks of severe disease (odds ratio [OR] = 0.89; 95% confidence interval [CI]: 0.63, 1.15; I2 = 38.55%), mechanical ventilation (OR = 0.89; 95% CI: 0.61, 1.16; I2 = 3.19%), dialysis (OR = 1.24; 95% CI: 0.09, 2.39; I2 = 0.00%), or the length of hospital stay (SMD = 0.05; 95% CI: -0.16, 0.26; I2 = 84.43%) in COVID-19 patients. The effect estimates showed an overall protective effect of ACEIs/ARBs against mortality (OR = 0.65; 95% CI: 0.46, 0.85; I2 = 73.37%), severity/mortality (OR = 0.69; 95% CI: 0.43, 0.95; I2 = 22.90%), transfer to the intensive care unit among COVID-19 patients with hypertension (OR = 0.36, 95% CI: 0.19, 0.53, I2 = 0.00%), hospitalization (OR = 0.79; 95% CI: 0.60, 0.98; I2 = 0.00%), and acute respiratory distress syndrome (OR = 0.71; 95% CI: 0.46, 0.95; I2 = 0.00%). The use of RAAS inhibitor was not associated with increased mortality or disease severity in COVID-19 patients. This study supports the current guidelines that discourage the discontinuation of RAAS inhibitors in COVID-19 patients.

Association of Hypertension with All-Cause Mortality among Hospitalized Patients with COVID-19.

It is unclear to which extent the higher mortality associated with hypertension in the coronavirus disease (COVID-19) is due to its increased prevalence among older patients or to specific mechanisms. Cross-sectional, observational, retrospective multicenter study, analyzing 12226 patients who required hospital admission in 150 Spanish centers included in the nationwide SEMI-COVID-19 Network. We compared the clinical characteristics of survivors versus non-survivors. The mean age of the study population was 67.5 ± 16.1 years, 42.6% were women. Overall, 2630 (21.5%) subjects died. The most common comorbidity was hypertension (50.9%) followed by diabetes (19.1%), and atrial fibrillation (11.2%). Multivariate analysis showed that after adjusting for gender (males, OR: 1.5, p = 0.0001), age tertiles (second and third tertiles, OR: 2.0 and 4.7, p = 0.0001), and Charlson Comorbidity Index scores (second and third tertiles, OR: 4.7 and 8.1, p = 0.0001), hypertension was significantly predictive of all-cause mortality when this comorbidity was treated with angiotensin-converting enzyme inhibitors (ACEIs) (OR: 1.6, p = 0.002) or other than renin-angiotensin-aldosterone blockers (OR: 1.3, p = 0.001) or angiotensin II receptor blockers (ARBs) (OR: 1.2, p = 0.035). The preexisting condition of hypertension had an independent prognostic value for all-cause mortality in patients with COVID-19 who required hospitalization. ARBs showed a lower risk of lethality in hypertensive patients than other antihypertensive drugs.

Angiotensin enzyme inhibitors and angiotensin receptor blockers as protective factors in COVID-19 mortality: a retrospective cohort study.

Targeting the renin-angiotensin system is proposed to affect mortality due to coronavirus disease 2019 (COVID-19). We aimed to compare the mortality rates in COVID-19 patients who received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) and those who did not. In this retrospective cohort study, mortality was considered as the main outcome measure. All underlying diseases were assessed by the chronic use of medications related to each condition. We defined two main groups based on the ACEIs/ARBs administration. A logistic regression model was designed to define independent predictors of mortality as well as a Cox regression analysis. In total, 2553 patients were included in this study. The mortality frequency was higher in patients with a history of underlying diseases (22.4% vs 12.7%, P value < 0.001). The mortality rate in patients who received ACEIs/ARBs were higher than non-receivers (29.3% vs. 19.5%, P value = 0.013, OR = 1.3, 95% CI 1.1, 1.7) in the univariate analysis. However, the use of ACEIs/ARBs was a protective factor against mortality in the model when adjusted for underlying conditions, length of stay, age, gender, and ICU admission (P value < 0.001, OR = 0.5, 95% CI 0.3, 0.7). The Kaplan-Meier curve showed an overall survival of approximately 85.7% after a 120-day follow-up. ACEIs/ARBs are protective factors against mortality in COVID-19 patients with HTN, and these agents can be considered potential therapeutic options in this disease. The survival probability is higher in ACEIs/ARBs receivers than non-receivers.

Impact of Treatment with Renin-Angiotensin System Inhibitors on Clinical Outcomes in Hypertensive Patients Hospitalized with COVID-19.

INTRODUCTION: Concerns have been raised about the possible harmfulness of angiotensin-converter enzyme inhibitors (ACEi) and aldosterone receptor blockers (ARB) in patients with COVID-19. However, few data from a European population have been published, especially from hypertensive patients. AIM: To study the association between ACEi or ARB treatments and major adverse outcomes during hospitalisation in COVID-19 patients. METHODS: We studied 545 consecutive hypertensive patients admitted to our institution due to COVID-19 with respiratory involvement. We analysed the incidence of combined event (death or mechanical ventilatory support) during hospitalisation, as well as the time to independent events. RESULTS: 188 (34.5%) patients presented the combined endpoint. 182 (33.4%) patients died, and 21 (3.9%) needed mechanical ventilatory support. Patients with previous treatment with ACEi or ARB presented similar incidence of the combined endpoint during hospitalisation (31.6% vs. 41.8%; p = 0.08), with a lower all-cause mortality rate (30.4% vs. 41.2%; p = 0.03) compared with those without prior treatment. Use of ACEi or ARB was not independently associated with lower incidence of the combined endpoint [Adjusted OR 0.675 (95% CI 0.298-1.528; p = 0.146)], but it was associated with lower mortality [Adjusted OR 0.550 (95% CI 0.304-0.930; p = 0.047)]. CONCLUSIONS: The use of ACEi or ARB was associated with less incidence of all-cause death during hospitalisation among hypertensive patients admitted with COVID-19 respiratory infection.

Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study.

AIMS: It remains unknown whether the treatment of hypertension influences the mortality of patients diagnosed with coronavirus disease 2019 (COVID-19). METHODS AND RESULTS: This is a retrospective observational study of all patients admitted with COVID-19 to Huo Shen Shan Hospital. The hospital was dedicated solely to the treatment of COVID-19 in Wuhan, China. Hypertension and the treatments were stratified according to the medical history or medications administrated prior to the infection. Among 2877 hospitalized patients, 29.5% (850/2877) had a history of hypertension. After adjustment for confounders, patients with hypertension had a two-fold increase in the relative risk of mortality as compared with patients without hypertension [4.0% vs. 1.1%, adjusted hazard ratio (HR) 2.12, 95% confidence interval (CI) 1.17-3.82, P = 0.013]. Patients with a history of hypertension but without antihypertensive treatment (n = 140) were associated with a significantly higher risk of mortality compared with those with antihypertensive treatments (n = 730) (7.9% vs. 3.2%, adjusted HR 2.17, 95% CI 1.03-4.57, P = 0.041). The mortality rates were similar between the renin-angiotensin-aldosterone system (RAAS) inhibitor (4/183) and non-RAAS inhibitor (19/527) cohorts (2.2% vs. 3.6%, adjusted HR 0.85, 95% CI 0.28-2.58, P = 0.774). However, in a study-level meta-analysis of four studies, the result showed that patients with RAAS inhibitor use tend to have a lower risk of mortality (relative risk 0.65, 95% CI 0.45-0.94, P = 0.20). CONCLUSION: While hypertension and the discontinuation of antihypertensive treatment are suspected to be related to increased risk of mortality, in this retrospective observational analysis, we did not detect any harm of RAAS inhibitors in patients infected with COVID-19. However, the results should be considered as exploratory and interpreted cautiously.