key: cord-1024242-0v0mpqpv authors: Sablerolles, Roos S. G.; Hogenhuis, Freija E. F.; Lafeber, Melvin; van de Loo, Bob P. A.; Borgsteede, Sander D.; Boersma, Eric; Versmissen, Jorie; van der Kuy, Hugo title: No association between use of angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers prior to hospital admission and clinical course of COVID‐19 in the COvid MEdicaTion (COMET) study date: 2021-02-18 journal: Br J Clin Pharmacol DOI: 10.1111/bcp.14751 sha: ec5d0055acd132d94c1e831ea326d24c1d834a22 doc_id: 1024242 cord_uid: 0v0mpqpv Since the outbreak of SARS‐CoV‐2, also known as COVID‐19, conflicting theories have circulated on the influence of angiotensin‐converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) on incidence and clinical course of COVID‐19, but data are scarce. The COvid MEdicaTion (COMET) study is an observational, multinational study that focused on the clinical course of COVID‐19 (i.e. hospital mortality and intensive care unit [ICU] admission), and included COVID‐19 patients who were registered at the emergency department or admitted to clinical wards of 63 participating hospitals. Pharmacists, clinical pharmacologists or treating physicians collected data on medication prescribed prior to admission. The association between the medication and composite clinical endpoint, including mortality and ICU admission, was analysed by multivariable logistic regression models to adjust for potential confounders. A total of 4870 patients were enrolled. ACEi were used by 847 (17.4%) patients and ARB by 761 (15.6%) patients. No significant association was seen with ACEi and the composite endpoint (adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.79 to 1.12), mortality (OR 1.03; 95%CI 0.84 to 1.27) or ICU admission (OR 0.96; 95%CI 0.78 to 1.19) after adjustment for covariates. Similarly, no association was observed between ARB and the composite endpoint (OR 1.09; 95%CI 0.90 to 1.30), mortality (OR 1.12; OR 0.90 to 1.39) or ICU admission (OR 1.21; 95%CI 0.98 to 1.49). In conclusion, we found no evidence of a harmful or beneficial effect of ACEi or ARB use prior to hospital admission on ICU admission or hospital mortality. Since the outbreak of SARS-CoV-2, also known as COVID-19, conflicting theories have circulated on the influence of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) on incidence and clinical course of COVID-19, but data are scarce. The COvid MEdicaTion (COMET) study is an observational, multinational study that focused on the clinical course of COVID-19 (i.e. hospital mortality and intensive care unit [ICU] admission), and included COVID-19 patients who were registered at the emergency department or admitted to clinical wards of 63 participating hospitals. Pharmacists, clinical pharmacologists or treating physicians collected data on medication prescribed prior to admission. The association between the medication and composite clinical endpoint, including mortality and ICU admission, was analysed by multivariable logistic regression models to adjust for potential confounders. A total of 4870 patients were enrolled. ACEi were used by 847 (17.4%) 1.49 ). In conclusion, we found no evidence of a harmful or beneficial effect of ACEi or ARB use prior to hospital admission on ICU admission or hospital mortality. Principal investigator: For this study there was no principal investigator who carried direct clinical responsibility for patients. Local COMET study investigators collected pseudonymized data in their respective centres. The severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV-2) is responsible for coronavirus disease 2019 . SARS-CoV-2 invades human cells by binding a viral spike protein to angiotensin converting enzyme (ACE) 2, similar to SARS-CoV-1 which caused an earlier outbreak of SARS in 2002. [1] [2] [3] [4] Renin-angiotensin-aldosterone system (RAAS) activation ensures conversion of angiotensin I to angiotensin II by ACE1. Activating the type I angiotensin II (AT1) receptor causes vasoconstriction, inflammation and fibrosis, whereas conversion of angiotensin I and II by ACE2 leads to a pathway involving angiotensin-(1-9) and angiotensin-(1-7), which is thought to counter these detrimental effects ( Figure 1A ). The binding of SARS-CoV-2 and ACE2 leads to local downregulation of ACE2. 5 In turn, angiotensin II accumulates resulting in increased vascular permeability and an acute respiratory distress syndrome-like syndrome. In addition to its role in RAAS modulation, ACE2 is also involved in degrading several other substrates, such as apelin and bradykinin. Recently, its role in degrading bradykinin has been suggested to play a causal role in the development of severe acute respiratory distress syndrome. 6 Previous studies showed that during lung injury, ACE1, angiotensin II, and the AT1 receptor function as lung injury-promoting factors, whereas ACE2 protects against lung injury. 5, 7 Since RAAS inhibitors (RAASi), such as ACE(1) inhibitors (ACEi) or angiotensin II receptor blockers (ARB), have been described to have an effect on ACE2 expression (i.e. upregulation in various organs), these drugs may increase the risk of infectivity of SARS-CoV-2 resulting in a higher incidence of COVID-19 in patients using RAASi ( Figure 1B ). 8 The theoretical increased risk of infectivity has been strengthened by literature showing that conditions in which RAASi are used, such as hypertension, diabetes mellitus and cardiovascular diseases, correlate with COVID-19-related mortality. [8] [9] [10] [11] Paradoxically, beneficial effects have also been suggested, since an increase in ACE2, if truly present, might protect against inflammation and lung injury as described earlier ( Figure 1B ). [12] [13] [14] In the absence of evidence, randomized clinical trials have been initiated in which ACEi and ARB have been either discontinued or prescribed. [15] [16] [17] [18] The COMET study aims to evaluate the effect of ACEi and ARB use prior to hospital admission on COVID-19-related outcomes (e.g. mortality and ICU admission). The COvid MEdicaTion (COMET) study, is a European, multinational, multicentre, retrospective study. The rationale and design have previously been described in detail. 19 In summary, patients were included by pharmacists, clinical pharmacologists, or treating physicians from 63 hospitals in 10 countries. To prevent major selection bias, a minimum number of patients was set to participate in the study (i.e. 50 patients per centre or all patients if <50 patients were available). All participating investigators were requested to consecutively include either those patients who were SARS-CoV-2 positive registered at the Emergency Department (42% of participating hospitals) or on the clinical wards (58% of participating centres). The major criterion for a patient to be included in the study was The timeframe for data collection was limited as it took place during the first wave of COVID-19 infections. Data collection focused on prescribed medication prior to admission, patient and admission characteristics, and clinical outcomes (e.g. hospital mortality and ICU admission). The current analysis focused on the use of RAASi (ACEi or ARB) prior to admission and clinical outcomes. The following variables were collected: year of birth, sex, • Several studies have shown that the use of renin-angiotensin-aldosterone system inhibitors (RAASi) was not associated with a more serious course or higher mortality of COVID-19 patients compared to no use of RAASi. • A large multicentre, international cohort that further confirms the results shown in previously published studies. • In addition to mortality, there is no association between the use of preadmission RAASi and intensive care unit admission in COVID-19 patients. prescribed medication by ATC code, dosing regimen, hospital mortality and ICU admission. As the entry of comorbid disease is time consuming and often incomplete, data on type of drugs served as a proxy for disease; hypertension, atherosclerotic cardiovascular disease (i.e. coronary artery disease, cerebrovascular disease, or peripheral artery occlusive disease)and diabetes mellitus. These conditions were considered present in patients when any blood pressure-lowering drugs, antiplatelet drugs, or glucoselowering drugs or insulins were used, respectively. Medication in single pill combinations were coded into the individual drug classes (e.g. if a patient used a combination of both an ACEi and a beta blockers, they were included as using an ACEi and a β-blocker). In reference to the Bradford Hill criteria of causality, 20 an exploratory analysis was added to assess dose response relationship on the clinical course. Each daily dose of ACEi and ARB was proportionally converted to a standard dose. The standard dose is an equipotent daily dose within a drug class and was based on the usual maintenance dose of each drug recommended in reference pharmacopoeias. The standard dose has been suggested to describe equipotency better than the World Health Organization daily defined dose. 21 For example, lisinopril 20 mg was considered equivalent to 2 standard doses ACEi. Data were collected in an online database (Clinical Rules reporter, version 1.6.3, Digitalis Rx, Amsterdam, the Netherlands). A study number was assigned to each participant. The coding file was only available to the local investigator. Each local investigator collected pseudonymized data. The institutional review committee of the main site, Erasmus MC in the Netherlands, approved the study (MEC-2020-0277), as well each institutional review board of the participating hospitals approved the use of data, as described in our protocol study. 19 All data were treated according to the privacy regulations applicable for European countries and conducted in accordance with the Declaration of Helsinki. 22 The study endpoints were a composite of clinical course of the COVID-19 patients including mortality and ICU admission, and both mortality and ICU admission as individual endpoints. Both mortality and ICU admission were in-hospital endpoints and scored according to the patient records. Descriptive statistics were used to depict the characteristics of patients in the total study sample, and stratified for patients without RAASi, ACEi use and ARB use. All characteristics were described as counts (%) and medians [IQR] . Patients without RAASi were used as the reference category. For the study endpoints, a multivariable binary logistic regression model was used to analyse the data. Results were presented as odds ratios (OR) with corresponding 95%confidence interval (95%CI). First, crude, unadjusted estimates were obtained (Model I). These were then F I G U R E 1 Schematic illustration of the renin-angiotensin-aldosterone system including the role of ACE2 and link with SARS-CoV-2 infection. (A) ACE2 converts angiotensin II to Ang (1-7) and angiotensin I to Ang (1-9). Ang (1-7) and Ang (1-9) have an organic-protective effect and counterbalance the negative effects of binding AT 1 R by angiotensin II. (B) Binding of SARS-CoV-2 on ACE2 internalize the virus into the cell. ACE2 may be upregulated by renin-angiotensin-aldosterone system inhibitor, leading to the hypothesis that the infectivity of SARS-CoV-2 increases. However, due to the beneficial effects shown in (A), this increase in ACE2 might also be beneficial due to protection against inflammation and lung injury in conditions known for low ACE2 expression, such as diabetes and hypertension. Abbreviations: ACE, angiotensin converting enzyme; ACEi, ACE inhibitor; Ang, angiotensin; ARB, angiotensin receptor blocker; AT 1 R, type 1 angiotensin II receptor, AT 2 R; type 2 angiotensin II receptor; MasR, Mas receptor adjusted for age and sex (Model II), and finally for the concomitant blood pressure-lowering drugs other than RAASi, antiplatelet drugs and glucose-lowering drugs. (Model III). In addition, an exploratory model with adjustment for a propensity score (PS) of RAASi, ACEi or ARB use was developed (Model IV). The use of propensity scores was employed as a method for dealing with confounding factors. 23 The propensity score was defined as an individual's probability of being treated with the drug of interest given the variables of that individual. Thus, the use of a probability that a subject would have been treated allows adjustment of the estimated treatment effect, creating quasirandomized trial and reducing confounding by indication. 24 The PS was derived from a logistic A total of 4870 patients with COVID-19 were included. Table 1 describes the baseline characteristics. The association between RAASi and the study endpoints is displayed in ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; RAASi, renin-angiotensin-aldosterone system inhibitor. The association between the standard dose of medication and clinical outcome is displayed in Table 4 patients from 169 hospitals in 11 countries and examined the relationships between many variables and in-hospital mortality without a pre-specified hypothesis increasing the probability of chance associations. Remarkably, this study was withdrawn due to concerns about study design and data, because all the authors were not granted access to the raw data and the raw data could not be made available to a third-party auditor. 32 As a result, the primary data sources underlying this article were unable to be validated. 33 This emphasizes the importance of replication studies, preferably with different study designs since every study design has its own bias. Zhang et al. 27 and Li et al. 28 assessed the association between RAASi use and all-cause mortality and severe diseases outcomes respectively. They did not perform a differential analysis on the effect of ACEi or ARB on the COVID-19-related morbidity and mortality. In conclusion, the COMET study showed that RAASi use prior to hospital admission was not associated with an increase in COVID-19 related mortality or ICU admission. The results indicated that the preadmission use of RAASi has neither a harmful nor beneficial effect on hospital mortality or ICU admission. The data do not suggest that the relationship between hypertension and severity of COVID-19 can be explained by the use of ACEi or ARB prior to hospital admission and their regulation of ACE2. We thank Dr Nicola Goodfellow for textual corrections as a native speaker. No funding was received to support this work. The authors are solely and equally responsible for the design and conduct of this study, all study analyses, and the drafting and editing of the paper and its final contents. 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How to cite this article: Sablerolles RSG No association between use of angiotensinconverting enzyme inhibitors or angiotensin II receptor blockers prior to hospital admission and clinical course of COVID-19 in the COvid MEdicaTion (COMET) study other authors in the appendix are contributed to data collection and revision of the article. The data underlying this article will be shared on reasonable request to the corresponding author.