Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on in-hospital mortality among patients with COVID-19: a systematic review and meta-analysis

Cai, Xinzhe James; Tay, Julian Cheong Kiat; Kui, Swee Leng; Tin, Aung Soe; Tan, Vern Hsen

doi:10.11622/smedj.2020159

Cited by 9 publications

(21 citation statements)

References 26 publications

(67 reference statements)

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“…Retrospective observational studies are marked by bias and other methodologic concerns so the overall neutral findings are of limited value [ 14 – 21 ]. Two recent meta-analyses have shown no benefit or harm of ARBs in COVID-19 [ 22 , 23 ]. Interestingly, however, ACE-I and ARBs have been documented to be lung protective, suggesting possible benefit in renin angiotensin system blockade in pneumonia [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Randomized Prospective Open Label Study Shows No Impact on Clinical Outcome of Adding Losartan to Hospitalized COVID-19 Patients with Mild Hypoxemia

Geriak

Haddad

Kullar³

et al. 2021

Infect Dis Ther

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Introduction Despite considerable scientific debate, there have been no prospective clinical studies on the effects of angiotensin II receptor blockers (ARBs) on the course of COVID-19 infection. Losartan is the ARB that was chosen to be tested in this study. Methods Patients with COVID-19 and mild hypoxia (receipt of ≤ 3 L/min O 2 by nasal cannula) admitted to three hospitals were randomized in a 1:1 ratio within 72 h of SARS-CoV-2 nucleic acid testing confirmation to prospectively receive standard of care (SOC) alone or SOC plus losartan 12.5 mg orally every 12 h for 10 days or until hospital discharge, with the option to titrate upward dependent on blood pressure tolerability. Primary composite endpoint was receipt of mechanical ventilation or death before receiving ventilation. Subjects were followed until discharge to home or until an endpoint was met in the hospital. Results Sixteen subjects received an ARB plus SOC and 15 subjects received SOC alone. The median age was 53 years for both groups. Median time from hospital admission to study enrollment was 2 days (range 1–6) for the ARB group and 2 days (range 1–4) for the SOC group. Mean Charlson comorbidity index was 2 for both groups. One subject in each group achieved the composite endpoint. Conclusion This small prospective randomized open-label study showed no clinically significant impacts of ARB therapy in mildly hypoxemic patients hospitalized with COVID-19 early in the pandemic. A larger prospective randomized placebo-controlled trial would be needed to confirm these findings or capture less pronounced effects and probably should focus on outpatients earlier in disease course. Trial Registration clinicaltrials.gov; March 27, 2020; NCT04340557.

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Section: Discussionmentioning

confidence: 99%

Randomized Prospective Open Label Study Shows No Impact on Clinical Outcome of Adding Losartan to Hospitalized COVID-19 Patients with Mild Hypoxemia

Geriak

Haddad

Kullar³

et al. 2021

Infect Dis Ther

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“… 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.…”

mentioning

confidence: 99%

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

Loader

Taylor

Lampa

et al. 2022

JAHA

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Background Renin‐angiotensin aldosterone system (RAAS) inhibitor—COVID‐19 studies, observational in design, appear to use biased methods that can distort the interaction between RAAS inhibitor use and COVID‐19 risk. This study assessed the extent of bias in that research and reevaluated RAAS inhibitor—COVID‐19 associations in studies without critical risk of bias. Methods and Results Searches were performed in MEDLINE, EMBASE, and CINAHL databases (December 1, 2019 to October 21, 2021) identifying studies that compared the risk of infection and/or severe COVID‐19 outcomes between those using or not using RAAS inhibitors (ie, angiotensin‐converting enzyme inhibitors or angiotensin II type‐I receptor blockers). Weighted hazard ratios (HR) and 95% CIs were extracted and pooled in fixed‐effects meta‐analyses, only from studies without critical risk of bias that assessed severe COVID‐19 outcomes. Of 169 relevant studies, 164 had critical risks of bias and were excluded. Ultimately, only two studies presented data relevant to the meta‐analysis. In 1 351 633 people with uncomplicated hypertension using a RAAS inhibitor, calcium channel blocker, or thiazide diuretic in monotherapy, the risk of hospitalization (angiotensin‐converting enzyme inhibitor: HR, 0.76; 95% CI, 0.66–0.87; P <0.001; angiotensin II type‐I receptor blockers: HR, 0.86; 95% CI, 0.77–0.97; P =0.015) and intubation or death (angiotensin‐converting enzyme inhibitor: HR, 0.64; 95% CI, 0.48–0.85; P =0.002; angiotensin II type‐I receptor blockers: HR, 0.74; 95% CI, 0.58–0.95; P =0.019) with COVID‐19 was lower in those using a RAAS inhibitor. However, these protective effects are probably not clinically relevant. Conclusions This study reveals the critical risk of bias that exists across almost an entire body of COVID‐19 research, raising an important question: Were research methods and/or peer‐review processes temporarily weakened during the surge of COVID‐19 research or is this lack of rigor a systemic problem that also exists outside pandemic‐based research? Registration URL: www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42021237859.

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“…In terms of number of COVID-19 related outcomes reported in each review, one outcome was reported by 13 reviews (27.7%) (18, 20, 21, 23, 24, 28, 29, 38, 39, 47, 52, 53, 61), two outcomes by 15 reviews (31.9%) (4, 17, 26, 31, 32, 34-37, 40, 42, 49, 54, 55, 58), three outcomes by 11 reviews (23.4%) (6, 22, 25, 27, 33, 44-46, 50, 56, 60) and 4-9 outcomes by eight reviews (17%) (19, 30, 41, 43, 48, 51, 57, 59). Overall, the 47 eligible reviews reported data on 18 unique pooled outcome estimates including death in 36 reviews, reviews (4, 6, 17-19, 22, 24, 25, 27, 30-39, 41-49, 54-56, 58-60), ICU admission in nine reviews (27, 28, 30, 41, 43, 48, 51, 56, 59), death/ICU admission as a composite outcome in 16 reviews (4, 20, 21, 23, 26, 29, 31, 32, 40, 41, 43, 45, 51, 55, 59), risk of acquiring COVID-19 infection in 15 reviews (19, 25, 27, 40<...>…”

Section: Resultsmentioning

confidence: 99%

“…were published in a pre-print database) (17-19, 21-23, 30, 32-34, 36, 46, 50, 54, 60). The time the searches were conducted ranged from April 2020 to October 2020, with 21 (44.7%) review searches conducted in the month of May 2020 (4-6, 17, 21, 23, 24, 28, 30-32, 35, 36, 40-42, 44, 46, 48, 50, 54) Pre-print articles were included in 28 (59.6%) reviews (4, 17, 19-22, 25, 26, 30, 33, 37, 41-45, 47-53, 55, 56, 59, 60), and 10 (21.3%) reviews adjusted for retracted studies (4, 18, 31, 40, 45, 47-50, 56). Full details of the 47 reviews are presented in Supplementary file 3 .…”

Section: Resultsmentioning

confidence: 99%

“…Overall confidence in the results was ‘moderate’ for 10 (21.3%) reviews (19, 25, 26, 30, 37, 41-43, 56, 59), ‘low’ for 15 (30.6%) reviews (4, 5, 20-22, 27, 28, 31, 34, 45, 49-51, 55, 60), and ‘critically low’ for 22 (44.9%) reviews (6, 17, 18, 23, 24, 29, 32, 33, 35, 36, 38-40, 44, 46-48, 52-54, 57, 58) (Supplementary file 5 ). Considering the critical domains, most reviews were considered to have had a satisfactory technique for the statistical combination of results (n=45, 95.7%) (4-6, 17-22, 24-57, 59, 60) and for assessing risk of bias (n=38, 80.1%) (4-6, 17, 19-23, 25-28, 30, 31, 34-38, 40-46, 48-53, 55-57, 59, 60). Less reviews were favourably considered in terms of accounting for risk of bias when interpreting and discussing the results (n=32, 68.1%), with appropriate conduct of publication bias (n=33) (4-6, 17, 19-21, 23-27, 30-33, 37, 38, 41-45, 47, 49-51, 53, 56, 57...…”

Section: Resultsmentioning

confidence: 99%

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An umbrella review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 outcomes: what do we know so far?

Kurdi

Weir

Mueller

2022

Preprint

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BackgroundsEvidence from several meta-analyses are still controversial about the effects of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) on COVID-19 outcomes.PurposeUmbrella review of systematic reviews/meta-analysis to provide comprehensive assessment of the effect of ACEIs/ARBs on COVID-19 related outcomes by summarising the currently available evidence.Data SourceMedline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 1st February 2021.Study SelectionSystematic reviews with meta-analysis that evaluated the effect of ACEIs/ARBs on COVID-19 related clinical outcomesData ExtractionTwo reviewers independently extracted the data and assessed studies’ risk of bias using AMSTAR 2 Critical Appraisal Tool.Data SynthesisPooled estimates were combined using the random-effects meta-analyses model including several sub-group analyses. 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).LimitationsThe effect of unmeasured confounding could not be ruled out. Only 21.3% (n=10) of the studies were of ‘moderate’ quality.ConclusionCollective 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.RegistrationThe study protocol was registered in PROSPERO (CRD42021233398).Funding SourceNone

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Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on in-hospital mortality among patients with COVID-19: a systematic review and meta-analysis

Cited by 9 publications

References 26 publications

Randomized Prospective Open Label Study Shows No Impact on Clinical Outcome of Adding Losartan to Hospitalized COVID-19 Patients with Mild Hypoxemia

Randomized Prospective Open Label Study Shows No Impact on Clinical Outcome of Adding Losartan to Hospitalized COVID-19 Patients with Mild Hypoxemia

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

An umbrella review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 outcomes: what do we know so far?

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