A review of the literature was performed to answer the following question: What is the effect of using medications that influence ACE2 expression (ACEIs, ARBs, NSAIDs and thiazolidinediones) on the outcomes in patients with COVID-19? This question was structured in a PICO format.
Search and select
The databases Medline (via Ovid) and Embase (via Embase.com) were searched with relevant search terms until 24 June 2020. The systematic literature search resulted in 567 hits (see Table S1 of the Electronic Supplementary Material for details). A total of 64 studies were initially selected based on the title and abstract screening. After reading the full text, 56 studies were excluded (see Table S2 of the Electronic Supplementary Material for the reasons for exclusion). Nine studies were included in the analysis of the literature. Important study characteristics and results are summarised in the evidence tables (Tables S3, S4, S5 of the Electronic Supplementary Material). The assessment of the risk of bias is summarised in Table S6 of the Electronic Supplementary Material.
Description of studies
Zhang [
1] assessed the relationship between ACEI/ARB use and COVID-19 infection in a systematic review. A comprehensive search of the PubMed, Embase and Cochrane Library databases was performed to identify all relevant articles published between 1 January 2020 and 9 May 2020. Observational studies that met all the following criteria were included: (1) Study design: case-control, case-crossover, self-controlled case series or cohort study; (2) Antihypertensive treatment: ACEI/ARB use versus non-ACEI/ARB use; (3) Outcomes: the incidence of COVID-19, critical cases or death; (4) Adequate data were used to extract the risk estimates if the adjusted data were not provided in the publication. Editorials, correspondence, conference abstracts and commentary articles were excluded. Twelve articles (case-control and cohort studies) involving more than 19,000 COVID-19 cases were included. Information was not given for the duration of follow-up and the number of patients for whom complete outcome data were not available.
Mackey [
2] evaluated whether the use of ACEIs or ARBs either increased the risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or was associated with worse COVID-19 disease outcomes, and the efficacy of these medications for COVID-19 treatment in a systematic review. Medline (OVID) and the Cochrane Database of Systematic Reviews were searched from 2003 to 4 May 2020, with planned ongoing surveillance for one year; the World Health Organisation database of COVID-19 publications and medRxiv.org through to 17 April 2020; and ClinicalTrials.gov to 24 April 2020, with planned ongoing surveillance. Observational studies and trials in adults that examined associations and effects of ACEIs or ARBs on the risk of SARS-CoV‑2 infection and COVID-19 disease severity and mortality were included. Nineteen studies were included. Some of the included studies describe a composite outcome measure ‘severe COVID-19’.
Felice [
3] investigated the association between chronic use of ACEIs or ARBs and COVID-19-related outcomes in hypertensive patients. A single-centre study was conducted on 133 consecutive hypertensive subjects presenting to the emergency department with acute respiratory symptoms and/or fever, who were diagnosed with COVID-19 infection between 9 and 31 March 2020. All patients were grouped according to their chronic antihypertensive medications (ACEIs,
n = 40; ARBs,
n = 42; not on renin-angiotensin-aldosterone system (RAAS) inhibitors,
n = 51).
Gao [
4] investigated whether treatment of hypertension, especially with RAAS inhibitors, had an impact on the mortality of patients with COVID-19. Consecutive patients admitted to Huo Shen Shan Hospital in Wuhan, China (solely for the treatment of COVID-19) from 5 February to 15 March 2020 were included. In total, 2877 consecutive hospitalised patients with confirmed COVID-19 were enrolled in the study. The median time from symptom onset to discharge (last follow-up) was 39 (30–50) days. There were 710/850 (83.5%) patients with hypertension taking antihypertensive medications. A total of 183 (25.7%) patients were treated with RAAS inhibitors and 527 (74.2%) treated with beta-blockers, calcium channel blockers or diuretics (non-RAAS inhibitors). For the outcome measures of interest, the group of 710 patients was used, meaning that hypertensive patients treated with RAAS inhibitors were compared with hypertensive patients taking antihypertensive medications other than RAAS inhibitors. The medical history and blood pressure at admission did not differ significantly between the RAAS inhibitor-treated [RAASi (+)] and non-RAAS inhibitor-treated [RAASi (–)]patients. Fourteen patients reported shivering at admission in the RAASi (–) cohort, compared with none in the RAASi (+) cohort.
Jung [
5] aimed to assess the associations between prior use of RAAS inhibitors and clinical outcomes among Korean patients with COVID-19. Among 5179 confirmed COVID-19 cases, 762 patients were RAAS inhibitor users and 4417 patients were non-users. Relative to non-users, RAAS inhibitor users were more likely to be older, male and have comorbidities. Among 1954 hospitalised patients with COVID-19, 377 patients were on RAAS inhibitors and 1577 patients were non-users.
López-Otero [
6] performed a single-centre, retrospective, observational cohort study on 965 patients diagnosed with COVID-19 from 10 March to 6 April 2020. In total, 210 patients were under ACEI or ARB treatment at the time of diagnosis; 165 (78.57%) had been taking these medications for more than 1 year. During the study period, 38 patients died (3.94%), 35 (3.6%) of whom had heart failure. The cohort of patients receiving ACEI/ARB treatment was older (72.1 ± 13.2 vs 56.0 ± 20.5,
p < 0.01) and had more cardiovascular risk factors (hypertension, diabetes, smoking and dyslipidaemia) and cardiovascular comorbidities (coronary artery diseases and ventricular dysfunction) than the cohort without ACEIs/ARBs. There were fewer women in the ACEI/ARB group (43.8% vs 59.5%,
p < 0.01). Renal impairment and peripheral vasculopathy were also more prevalent in patients taking ACEIs/ARBs.
Selçuk [
7] aimed to determine the relation between the use of ACEIs and ARBs and in-hospital mortality of hypertensive patients diagnosed with COVID-19 pneumonia. All patients were on ACEIs/ARBs or other antihypertensive therapy. In total, 113 hypertensive COVID-19 patients were included, 74 of whom were receiving ACEIs/ARBs. During in-hospital follow-up, 30.9% (
n = 35) of the patients died.
Imam [
8] evaluated mortality predictors of COVID-19 in a large cohort of hospitalised patients in the US. A retrospective, multicentre cohort study of inpatients diagnosed with COVID-19 by reverse transcription-polymerase chain reaction from 1 March to 1 April 2020 was performed, and outcome data were evaluated from 1 March to 17 April 2020. Measures included demographics, comorbidities, clinical presentation, laboratory values and imaging on admission. The primary outcome was mortality. Secondary outcomes included length of stay, time to death and development of acute kidney injury in the first 48 h. A total of 1305 patients were hospitalised during the evaluation period. Mean age was 61.0 ± 16.3, 53.8% were male and 66.1% were African-American. Mean body mass index (BMI) was 33.2 ± 8.8 kg/m
2. The median Charlson Comorbidity Index was 2 (1–4), 72.6% of the patients had at least one comorbidity, with hypertension (56.2%) and diabetes mellitus (30.1%) being the most prevalent. ACEI/ARB use and NSAID use were widely prevalent (43.3% and 35.7%, respectively). Mortality occurred in 200 (15.3%) of the patients with a median time of 10 (6–14) days.
Zhou [
9] aimed to explore the clinical characteristics of COVID-19 complicated by hypertension. A retrospective, single-centre study was conducted in which 110 discharged patients with COVID-19 at Wuhan Fourth Hospital in Wuhan, China, from 25 January to 20 February 2020, were included. All study cases were grouped according to whether they had a history of hypertension. Then, a subgroup analysis for all hypertensive patients was carried out based on whether or not they were taking ACEI or ARB medication. The mean age of these 110 patients was 57.7 years (range 25–86 years), 60 (54.5%) were males. The main underlying diseases included hypertension (36 (32.7%)) and diabetes (11 (10.0%)).
Table
1 shows the characteristics of the included studies.