Cardiology

The effect of previous oral anticoagulant use on clinical outcomes in COVID-19: A systematic review and meta-analysis

a b s t r a c t

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 admission and mortality. An electronic search of the Pubmed, Embase, Cochrane Library databases was con- ducted. 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 un- adjusted 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 admis- sion 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 re- ducing 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.

(C) 2022 Published by Elsevier Inc.

Dear Editor,

The coronavirus disease 2019 (COVID-19) pandemic is characterized by high morbidity and mortality, particularly in patients with concomi- tant cardiovascular diseases [1,2]. Increasing evidence suggested that al- terations 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 COVID-19 [6,7]. Anticoagulants, antiplatelet, and anti- thrombotic 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

* Corresponding author at: No. 37 Guo Xue Xiang, Chengdu, Sichuan, China.

E-mail address: [email protected] (Q. Zhang).

1 Contributed equally to this work.

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 data- bases 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 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 diag- nosed with COVID-19 infection; (2) provided a comparison of outcomes of interest between patients with and without OAC use; (3) included

https://doi.org/10.1016/j.ajem.2022.01.059 0735-6757/(C) 2022 Published by Elsevier Inc.

Table 1

Characteristics of included studies.

Study

Country

Study design

Sample

Age

Sex

Oral anticoagulation therapy

Outcomes

size

OAC

No-OAC

Male

Female

used

Arachchillage

United Kingdom

Retrospective

5883

NR

NR

3247

2636

DOACs (rivaroxaban 20 mg, 15 mg or 10 mg daily, apixaban 5 mg or 2.5 mg daily

Mortality, thrombosis, major bleeding, multi-organ failure

Aslan

Turkey

Retrospective

1710

74 (67-81)

61 (51-70)

850

860

or edoxaban 30 mg or 60 mg daily, dabigatran 110 mg bd or 150 mg bd) or warfarin

DOAC

Mortality, need for ICU

Denas

Flam

Italy

Denmark

Retrospective

Retrospective

4697

496,277

NR

73.6 (7.6)

NR

69.3 (9.6)

2378

301,549

2319

194,728

VKAs, rivaroxaban, apixaban, edoxaban, dabigatran

DOAC (dabigatran, apixaban,

ICU admission, hospital admission, all-cause mortality

Hospital admission for COVID-19,

Frohlich

Germany

Retrospective

6637

80 (75-85)

65 (52-79)

3505

3132

rivaroxaban, edoxaban)

VKA, DOAC

ICU admission or death due to COVID-19

All-cause mortality, need for

Fumagalli

Italy

Retrospective

806

NR

NR

NR

NR

VKA, DOAC

non-invasive ventilation, need for invasive ventilation, ECMO, ARDS

Mortality

Iaccarino

Italy

Retrospective

2377

79.35 +- 0.86

67.59 +- 0.39

1489

888

Warfarin, DOACs

Mortality, ICU admission,

combined hard events

Gulcu

Turkey

Retrospective

5575

69 (59, 77)

64 (51, 73)

2801

2774

Warfarin, DOAC

Mortality

Rieder

Russo

Germany

Italy

Retrospective

Retrospective

1433

467

77.04 +- 10.31

73 +- 12

69.56 +- 13.61

65 +- 14

863

293

570

174

VKA or Non-VKA (rivaroxaban, apixaban, edoxaban, dabigatran etexilate)

NOACs or VKAs

All-cause mortality, thrombotic events, intracerebral bleeding, death or thrombotic event, death or intracerebral bleeding

Mortality, ARDS

Caravaca a

United

Kingdom

Retrospective

738,423

67.30 +- 15.43

45.50 +- 18.10

321,960

416,463

NOAC (dabigatran, apixaban,

rivaroxaban or edoxaban)

all-cause mortality,

hospitalization/re-hospitalization,

VTE and ICH, the composite of ischemic stroke/TIA/

SE, the composite of ICH/gastrointestinal bleeding, myocardial infarction, and the composite of any thrombotic or

thromboembolic event

Caravaca b

Schiavone

Spain

Italy

Retrospective

Retrospective

1002

844

NR

76.7 +- 11.6

NR

62.3 +- 15.9

593

521

409

323

NOACs or VKAs

NOACs or VKAs

All-cause mortality, all-cause mortality or any thromboembolic event, renal failure, Respiratory insufficiency, systemic inflammatory response syndrome, heart failure, sepsis

ICU admission, ARDS, all-cause

mortality, hospital length of stay,

non-invasive ventilation

DOAC:direct-acting oral anticoagulants;NOAC: novel oral anticoagulants; VKA:vitamin K antagonists; ARDS: acute respiratory distress syndrome; ECMO: extracorporeal membrane ox- ygenation; VTE: venous thromboembolism; ICH: intracranial hemorrhage; TIA: transient ischemic attack; SE: systemic embolism; ICU: intensive care unit.

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 ex- tracted from each study if available: name of the first author, study de- sign, country, number of participants, age of patients, number of male and female participants, type of oral anticoagulation therapy, and out- comes of interest. The endpoint was the effect of chronic oral anticoag- ulation 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) inde- pendently by two investigators. If 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 I2 statistic were calculated to detect heterogeneity. An I2 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 (I2 < 50%), oth- erwise a random-effect model was utilized. Sensitivity analysis was per- formed to evaluate the influence of a single trial on the overall effect estimate by sequentially excluding one study. If substantial heterogene- ity was presented in the meta-analysis, subgroup analysis was con- ducted based on the countries. P < 0.05 was considered statistically significant.

We retrieved 893 potentially eligible literature by searching elec- tronic databases. Among them, we excluded 132 articles due to dupli- cated searches. Subsequently, 705 studies were regarded as absolute irrelevant studies by examining titles and abstracts. A full text of 56 stud- ies 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 1,266,231 patients were in- corporated in the final analysis [8-20]. The sample size of patients ranged from 467 to 738,423. 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

Image of Fig. 1

Fig. 1. A. Meta-analysis of unadjusted results of association between oral anticoagulation and mortality. B. Meta-analysis of unadjusted results of association between oral anticoag- ulation and ICU admission. C. Meta-analysis of adjusted results of association between oral anticoagulation and mortality. D. Meta-analysis of adjusted results of association between oral anticoagulation and ICU admission.

hospitalized patients. Most studies reported that OAC treatment was continued in patients using OAC as long as no clinical condition devel- oped that would limit its use. However, in one study by Gulcu 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 treat- ment 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; I2 = 94.6%) (Fig. 1A) or ICU admission rate (OR = 0.71, 95% CI: 0.29 to 1.77, P = 0.46; I2 = 97%) (Fig. 1B) 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; I2

= 75.5%) (Fig. 1C) or ICU admission (OR = 1.50, 95% CI: 0.72 to 3.12, P =

0.284; I2 = 74.7%) (Fig. 1D) in patients with prior OAC use compared to patients without previous OAC use. The subgroup analysis based on countries significantly reduced the heterogeneity but did not signifi- cantly alter the overall results. Additionally, sensitivity analyses by omit- ting each study at a time did not significantly change the results either. The current systematic review and meta-analysis revealed that OAC use prior to admission was not associated with lower risks of mortality or ICU admission. This finding could be explained by the fact that pa- tients on OAC therapy are older, more susceptible to COVID-19 compli- cations, and have more comorbidities. In addition, comorbid diseases and advanced age are associated with morbidity and mortality in COVID-19 infection. Thus, those patients should be hospitalized and followed up more closely after the diagnosis of COVID-19 infection. Akiyama et al. indicated that microvascular thrombosis rather than classical pulmonary embolism could lead to hypoperfusion in COVID- 19 infection. Thus, directly acting oral anticoagulants (DOAC) therapy has no protective effect on leukocyte-related thrombosis and preven- tion of severe COVID-19 infection [21,22]. In addition, recent evidence associated the use of heparin and low-molecular-weight heparin (LMWH) with various non-Anticoagulant effects, including antiviral, anti-inflammatory/immunomodulatory properties [23,24]. Anti- inflammatory properties of heparin, inhibition of NF-?B transcription factor can potentially reduce the activation of inflammatory molecules and regulate the expression and production of proinflammatory cyto- kines, chemokines, and adhesion molecules [25]. The antiviral and anti-inflammatory/immunomodulatory effects indicated a potential role of heparin and LMWH in the treatment of COVID-19 infection [26]. Due to a certain proportion of patients who previously took OAC switching their in-hospital Antithrombotic treatment to heparin follow- ing the local attending physician criteria, parenteral anticoagulant ther- apy may be a serious confounding factor on outcomes. Our results should be interpreted with caution. All of the studies included were ret- rospective in design, which could be subject to selection bias and poten- tial 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 ap- peared 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 the course of the COVID-19. Supplementary data to this article can be found online at https://doi.

org/10.1016/j.ajem.2022.01.059.

Funding/Acknowledgments

None.

Declaration of Competing Interest

None.

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