key: cord-0717384-5yuz3m2v
authors: Zeng, Jie; Liu, Fuqiang; Wang, Yushu; Gao, Ming; Nasr, Basma; Lu, Cong; Zhang, Qing
title: The effect of previous oral anticoagulant use on clinical outcomes in COVID-19: A systematic review and meta-analysis
date: 2022-02-03
journal: Am J Emerg Med
DOI: 10.1016/j.ajem.2022.01.059
sha: e7398354c987b71d52ff620cb174c53ca0ce6adc
doc_id: 717384
cord_uid: 5yuz3m2v

Data on the prognosis of patients treated with oral anticoagulation (OAC) prior to hospital admission for COVID-19 remains controversial and insufficient. Therefore, we endeavored to perform a systematic review and meta-analysis to evaluate the effect of chronic use of OAC prior to the diagnosis of COVID-19 on intensive care unit (ICU) admission and mortality. An electronic search of the Pubmed, Embase, Cochrane library databases was conducted. Meta-analysis and statistical analyses were completed with using the RevMan 5.3 and Stata 12.0. A total of 13 articles representing data from 1,266,231 participants were included in this study. The meta-analysis of unadjusted results showed no decrease in mortality (OR = 1.31, 95%CI: 0.99 to 1.73, P = 0.059) or ICU admission rate (OR = 0.71, 95%CI: 0.29 to 1.77, P = 0.46) in COVID-19 patients with prior OAC therapy at hospital admission compared to patients without prior use of OAC. Moreover, the meta-analysis of adjusted results showed no lower risk of mortality (OR = 1.08, 95%CI: 0.90 to 1.30, P = 0.415) or ICU admission (OR = 1.50, 95%CI: 0.72 to 3.12, P = 0.284) in patients with prior OAC use compared to patients without previous OAC use. In conclusion, the results of this study revealed that the use of OAC prior to hospital admission appeared to be ineffective in reducing the risk of intensive care need and mortality in COVID-19 patients. Randomized controlled trials are needed to evaluate and optimize the use of OAC in COVID-19 infection.

The coronavirus disease 2019 pandemic is characterized by high morbidity and mortality, particularly in patients with concomitant cardiovascular diseases [1, 2] . Increasing evidence suggested that alterations in coagulation patterns were associated with more severe outcomes of COVID-19 [3] . Studies have revealed that thrombosis is one of the potential pathophysiologies and complications of COVID-19 infection [4, 5] . Some studies showed that anticoagulation with low-molecular-weight heparin (LMWH) could lead to a better prognosis in patients with 7] . Anticoagulants, antiplatelet, and antithrombotic strategies have been widely implemented in treating COVID-19 infection due to the frequent occurrence of arterial or venal thrombosis. Nevertheless, data on the prognosis of patients treated with oral anticoagulation (OAC) prior to hospital admission for COVID-19 remains controversial and insufficient. To the best of our knowledge, there have been no previous meta-analysis evaluating the effect of previous OAC use on clinical outcomes in COVID-19. Therefore, we endeavored to perform a systematic review and meta-analysis to evaluate the effect of chronic use of OAC prior to the diagnosis of COVID-19 on mortality and ICU admission rate.

An electronic search of the Pubmed, Embase, Cochrane library databases was conducted from inception to October 2021 with no language restrictions. The following keywords and/or medical subject heading terms searches were applied:

("novel coronavirus" or "2019-nCoV" or "coronavirus disease 2019" or "SARS-CoV-2" or "COVID-19") and (oral anticoagulation or NOAC or DOAC or J o u r n a l P r e -p r o o f directly acting oral anticoagulants or vitamin K antagonists or VKA or warfarin or apixaban or edoxaban or rivaroxaban. We also conducted a manual search for additional articles using references from comparable articles and published reviews to seek potentially relevant citations.

Two independent investigators (YW and JZ) performed the initial screening of titles and abstracts. Full-length articles of identified studies were retrieved. We included studies if they (1) enrolled patients diagnosed with COVID-19 infection; (2) provided a comparison of outcomes of interest between patients with and without OAC use; (3) included patients on oral anticoagulation before admission for COVID-19; (4) availability of a risk ratio (RR) with 95% confidence intervals (CI) for overall survival or relevant clinical events from which it could be calculated. We excluded studies if they were abstracts, conferences, editorials, or reviews. All decisions in terms of eligibility were made according to pre-specified selection criteria. Any differing decision was resolved by a third investigator.

Two main investigators (YW and JZ) independently extracted the data and reached a consensus on all items. The following items were extracted from each study if available: name of the first author, study design, country, number of participants, age of patients, number of male and female participants, type of oral anticoagulation therapy, and outcomes of interest. The endpoint was the effect of chronic oral anticoagulation treatment on rates of ICU admission and mortality of COVID-19. For non-random controlled studies, the risk of bias/quality of studies was assessed using a nine-item Newcastle-Ottawa Scale (NOS) independently by two investigators. If J o u r n a l P r e -p r o o f necessary, a third investigator was consulted for any discrepancies. We considered a study of high quality if its score was ≥7, whereas a low-quality study had a score of <7.

We completed meta-analysis and statistical analyses using RevMan 5.3 (Cochrane Collaboration) and Stata 12.0 (StataCorp). Unadjusted and adjusted risk ratios (RRs) with 95% CIs were used as the statistical summary for dichotomous outcomes. Cochrane chi-square test (Q test) and the I 2 statistic were calculated to detect heterogeneity. An I 2 is less than 25%, 25% to 50%, and greater than 50%, corresponding to low, moderate, and high heterogeneity, respectively. A fixed-effect model was used in case of a low level of heterogeneity (I 2 < 50%), otherwise a random-effect model was utilized. Sensitivity analysis was performed to evaluate the influence of a single trial on the overall effect estimate by sequentially excluding one study. If substantial heterogeneity was presented in the meta-analysis, subgroup analysis was conducted based on the countries. P < 0.05 was considered statistically significant.

We retrieved 893 potentially eligible literature by searching electronic databases.

Among them, we excluded 132 articles due to duplicated searches. Subsequently, 705 studies were regarded as absolute irrelevant studies by examining titles and abstracts.

A full text of 56 studies was reviewed, and 43 records were eliminated because they were abstract, letters, conferences, reviews or with no comparison groups between OAC and no-OAC treatment or with no outcomes reported. Therefore, a total of 13 full-text studies with 1266231 patients were incorporated in the final analysis [8-20].

The sample size of patients ranged from 467 to 738423. Two studies were from Turkey, while other studies were from European countries. All included studies were retrospective in design. Three studies reported data on hospitalized and outpatient SARS-CoV-2 infected patients [10, 13, 18] , while other studies enrolled hospitalized patients. Most studies reported that OAC treatment was continued in patients using OAC as long as no clinical condition developed that would limit its use. However, in one study by Gülcü et al. [16] , parenteral anticoagulation treatments were given at therapeutic doses to patients who had previously used DOAC. Of note, the in-hospital discontinuation of OAC was considered an exclusion criterion in the Russo et al. [19] study to avoid bias deriving from the out-of-range therapeutic periods caused by in-hospital anticoagulation treatment switching or discontinuation. The characteristics of the study are demonstrated in Table 1 . The overall quality of included studies was high, with NOS scores ≥7. The quality of the included articles is assessed and displayed in Table S1 . The meta-analysis of unadjusted results showed no decrease in mortality (OR=1.31, 95%CI: 0.99 to 1.73, P=0.059; I 2 =94.6%) (Fig.1A) Our results should be interpreted with caution. All of the studies included were retrospective in design, which could be subject to selection bias and potential confounders. Data on duration, type, the dose of OAC, and other clinical outcomes were insufficient in most incorporated studies; hence, they cannot be further analyzed.

In conclusion, the results of this study revealed that the use of OAC prior to hospital admission appeared to be ineffective in reducing the risk of intensive care need and Heparin as a therapy for COVID-19: current evidence and future possibilities. Am J Physiol Lung Cell Mol Physiol. 2020;319:L211-7. Table legend   Table 1 Characteristics of included studies Table 1 Study quality assessment using the Newcastle-Ottawa Scale J o u r n a l P r e -p r o o f

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