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Preadmission Oral Anticoagulation for Atrial Fibrillation/Flutter and Death or Thrombotic Events During COVID-19 Admission

      Atrial fibrillation/flutter (AF) and COVID-19 are associated with an elevated risk of arterial and venous thrombosis. Whether preadmission oral anticoagulation (OAC) for AF reduces the incidence of in-hospital death or thrombotic events among patients with COVID-19 is unknown. We identified 630 patients with pre-existing AF and a hospitalization diagnosis of COVID-19 and stratified them according to preadmission OAC use. Multivariable logistic regression was employed to relate preadmission OAC to composite in-hospital mortality or thrombotic events. Unadjusted composite in-hospital mortality or thrombotic complications occurred less often in those on than not on preadmission OAC (27.1% vs 46.8%, p <0.001). After adjustment, the incidence of composite in-hospital all-cause mortality or thrombotic complications remained lower with preadmission OAC (odds ratio 0.37, confidence interval 0.25 to 0.53, p <0.0001). Secondary outcomes including all-cause mortality (16.3% vs 24.9%, p = 0.007), intensive care unit admission (14.7% vs 29.0%, p <0.001), intubation (6.4% vs 18.6%, p <0.001), and noninvasive ventilation (18.6% vs 27.5%, p = 0.007) occurred less frequently, and length of stay was shorter (6 vs 7 days, p <0.001) in patients on than those not on preadmission OAC. A higher CHA2DS2-VASc score was associated with an increased risk of thrombotic events. In conclusion, among patients with baseline AF who were hospitalized with COVID-19, those on preadmission OAC had lower rates of death, arterial and venous thrombotic events, and less severe COVID-19.
      Atrial fibrillation/flutter (AF) are the most commonly encountered cardiac dysrhythmias in the United States.
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      • Salciccioli JD
      • Philips B.
      Incidence and mortality trends of atrial fibrillation/atrial flutter in the United States 1990 to 2017.
      AF is associated with an increased risk of arterial and venous thromboembolism. Risk scores, such as CHA2DS2- -VASc, have been developed and validated to predict arterial thromboembolic events in patients with AF,
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      Torp-Pedersen C. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
      and oral anticoagulation (OAC) with either a direct oral anticoagulant (DOAC) or vitamin K antagonist (VKA) reduces the incidence of these events among those at elevated risk.
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      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
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      Apixaban versus warfarin in patients with atrial fibrillation.
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      COVID-19 is associated with micro- and macrovascular arterial and venous thrombosis, with meta-analytic data suggesting that thrombotic complications occur in 22% of hospitalized patients and 43% of those admitted to an intensive care unit (ICU) with COVID-19.
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      Prevalence and risk factors of thrombotic events on patients with COVID-19: a systematic review and meta-analysis.
      The risk of mortality
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      Atrial fibrillation and the risk of 30-day incident thromboembolic events, and mortality in adults >50 years with COVID-19.
      and thromboembolic complications
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      New-onset atrial fibrillation during COVID-19 infection predicts poor prognosis.
      is higher among patients with COVID-19 who also have AF. Whether preadmission OAC reduces in-hospital arterial and venous thrombosis in patients with COVID-19 and pre-existing AF remains to be established.
      • Harenberg J
      • Bauersachs R
      • Ageno W.
      Does chronic treatment with oral anticoagulants ameliorate the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in coronavirus disease 2019 (COVID-19)?.
      We related preadmission OAC used to incident death or thrombotic events among consecutive patients with AF admitted with COVID-19 to a large New England health system.

      Methods

      Data on demographics, co-morbidities, CHA2DS2−VASc score, vital signs, test results, treatments, and outcomes were extracted from the Epic electronic health record using automated queries. The Charlson co-morbidity index was calculated for each patient using International Classification of Diseases, Tenth Revision (ICD-10) codes.
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      Validation of an International Classification of Disease, 10th revision coding adaptation for the Charlson Co-morbidity Index in United States healthcare claims data.
      A study flow is shown in Figure 1. All patients ≥18 years of age with a history of AF admitted to Rhode Island, The Miriam, or Newport Hospital with a diagnosis of COVID-19 between March 1 and December 31, 2020, were included. The cohort was restricted to patients with AF to limit the impact of confounding by indication for anticoagulation given their persistently elevated thrombotic risk and a common indication for OAC.
      • January CT
      • Wann LS
      • Calkins H
      • Chen LY
      • Cigarroa JE
      • Cleveland Jr, JC
      • Ellinor PT
      • Ezekowitz MD
      • Field ME
      • Furie KL
      • Heidenreich PA
      • Murray KT
      • Shea JB
      • Tracy CM
      • Yancy CW
      2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients With atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines and the Heart Rhythm Society.
      ,
      • Lutsey PL
      • Norby FL
      • Alonso A
      • Cushman M
      • Chen LY
      • Michos ED
      • Folsom AR.
      Atrial fibrillation and venous thromboembolism: evidence of bidirectionality in the Atherosclerosis Risk in Communities Study.
      Patients on preadmission low molecular weight heparin, multiple anticoagulants, or who were missing information on preadmission OAC use were excluded. Co-morbidities, COVID-19 status, and in-hospital outcomes were ascertained using ICD-10 codes and discharge disposition (Supplementary Table 1). The study was approved by The Lifespan - Miriam Hospital Institutional Review Board and a waiver of informed consent was granted.
      Figure 1
      Figure 1Study Flowchart. 3,584 patients were admitted with COVID-19 between 3/1/20–12/31/20. After applying exclusion criteria, 630 of these had atrial fibrillation or flutter (AF), of which 361 (57%) were single-agent OAC users, and 269 (43%) were non-OAC users.
      Patients were classified according to whether they were prescribed a DOAC including apixaban, rivaroxaban, edoxaban, dabigatran, or the VKA, warfarin, before admission for the primary analysis. In secondary analysis, the CHA2DS2-VASc score was related to study outcomes. The calculation of this score is detailed in supplementary data. Supplementary Tables 2 to 4.
      The primary outcome of interest was a composite of in-hospital all-cause mortality or arterial or venous thrombotic events. Arterial events included acute coronary syndrome (unstable angina, non–ST-elevation myocardial infarction, and ST-elevation myocardial infarction), transient ischemic attack (TIA), acute ischemic stroke, acute limb ischemia, and acute mesenteric ischemia. Venous thromboembolism included acute deep vein thrombosis (DVT) and acute pulmonary embolism (PE). Secondary end points included the individual components of the primary outcome, admission to an ICU, invasive or noninvasive ventilation, the requirement for supplemental oxygen, cardiac arrest, red blood cell transfusion, major bleeding, length of stay, and discharge disposition.
      Continuous variables appear as mean ± SD or medians with interquartile ranges, depending on their distribution. Categorical variables were reported as counts with percentages and compared with Mantel-Haenszel chi-square or Fisher's exact test, as appropriate. Student's t test or Mann-Whitney U test were employed for unadjusted comparisons of these data, respectively. Plausible demographic and clinical characteristics that were related to the primary outcome (p ≤0.15) were entered into a multivariable logistic regression model, along with an indicator variable for preadmission OAC (Supplementary Table 5). A sensitivity analysis was applied to the AF subtype (permanent > persistent > paroxysmal) to examine the association of AF with the primary outcome. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina) and R statistical software version 4.0.3 (The R Project for Statistical Computing, Vienna, Austria). A p <0.05 was considered significant.

      Results

      During the study interval, 3,584 patients were admitted with COVID-19. Of these, 656 patients had a history of AF. After excluding patients who were on outpatient low molecular weight heparin (n = 11), multiple OAC agents (n = 10), or who were missing data regarding OAC therapy (n = 5), the final study cohort comprised 630 patients, of which 361 (57.3%) were prescribed outpatient OAC. Baseline demographic and clinical characteristics, stratified by preadmission OAC use, are shown in Table 1. Patients on preadmission OAC had a higher prevalence of demographic and co-morbid characteristics associated with adverse outcomes during hospitalization for COVID-19.
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      • Altunal LN
      • Barman HA
      • Aydin M
      • Kocas BB
      • Cam G
      • Guclu KG
      • Caliskan M
      Evaluation of modified ATRIA risk score in predicting mortality in hospitalized patients with COVID-19.
      ,
      • Raad M
      • Gorgis S
      • Abshire C
      • Yost M
      • Dabbagh MF
      • Chehab O
      • Aurora L
      • Patel S
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      • Yan J
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      • Syrjamaki J
      • Kaatz S
      • Parikh S
      COVID-19 risk index (CRI): a simple and validated emergency department risk score that predicts mortality and the need for mechanical ventilation.
      Patients on preadmission OAC were older, more frequent tobacco users, more often Hispanic, and more likely to have a history of heart failure, myocardial infarction, TIA, stroke, DVT, PE, chronic kidney disease, and cancer, and were less likely to have a history of alcohol use disorder. These patients were also less likely to be taking aspirin or a P2Y12 inhibitor, and more likely to be on a statin before admission when compared with those who were not taking OAC. The median CHA2DS2−VASc score was significantly higher among those on vs not on preadmission OAC (3 vs 2, p <0.001).
      Table 1Baseline demographic and clinical characteristics
      VariableTotal(N = 630)Anticoagulationp Value
      Yes (N = 361)No (N = 269)
      Age (years)77.4 ± 11.878.5 ± 10.675.9 ± 13.20.005
      Men354 (56.2%)206 (57.1%)148 (55.0%)0.61
      Body mass index (kg/m2)29.1 ± 7.829.2 ± 7.828.8 ± 7.90.59
      Race
       Black47 (7.5%)19 (5.3%)28 (10.4%)0.10
       White495 (78.6%)295 (81.7%)200 (74.3%)
       Asian6 (1.0%)4 (1.1%)2 (0.7%)
       Other77 (12.2%)41 (11.4%)36 (13.4%)
       Unknown5 (0.8%)2 (0.6%)3 (1.1%)
      Hispanic or Latino ethnicity75 (11.9%)35 (9.7%)40 (14.9%)0.029
      Smoking status
       Current33 (5.2%)18 (5.0%)15 (5.6%)< 0.001
       Former296 (47.0%)190 (52.6%)106 (39.4%)
       Never240 (38.1%)135 (37.4%)105 (39.0%)
       Unknown61 (9.7%)18 (5.0%)43 (16.0%)
      Hypertension542 (86.0%)311 (86.1%)231 (85.9%)0.92
      Hyperlipidemia398 (63.2%)229 (63.4%)169 (62.8%)0.88
      Diabetes mellitus280 (44.4%)158 (43.8%)122 (45.4%)0.69
      Ischemic heart disease346 (54.9%)203 (56.2%)143 (53.2%)0.44
      History of myocardial infarction95 (15.1%)64 (17.7%)31 (11.5%)0.031
      History of peripheral artery disease7 (1.1%)4 (1.1%)3 (1.1%)0.99
      Heart failure310 (49.2%)200 (55.4%)110 (40.9%)< 0.001
      Valvular heart disease91 (14.4%)59 (16.3%)32 (11.9%)0.12
      History of TIA or stroke92 (14.6%)62 (17.2%)30 (11.2%)0.034
      Chronic obstructive pulmonary disease83 (13.2%)55 (15.2%)28 (10.4%)0.08
      Chronic kidney disease178 (28.3%)113 (31.3%)65 (24.2%)0.049
      End stage kidney disease51 (8.1%)23 (6.4%)28 (10.4%)0.07
      Chronic anemia90 (14.3%)47 (13.0%)43 (16.0%)0.29
      Liver disease57 (9.0%)26 (7.2%)31 (11.5%)0.06
      Alcohol use disorder23 (3.7%)7 (1.9%)16 (5.9%)0.007
      Obstructive sleep apnea81 (12.9%)48 (13.3%)33 (12.3%)0.70
      Cancer84 (13.3%)57 (15.8%)27 (10.0%)0.035
      Inflammatory rheumatic disease118 (18.7%)77 (21.3%)41 (15.2%)0.05
      History of deep vein thrombosis31 (4.9%)23 (6.4%)8 (3.0%)0.05
      History of pulmonary embolism24 (3.8%)23 (6.4%)1 (0.4%)< 0.001
      Charlson comorbidity score2.8 ± 1.82.9 ± 1.72.7 ± 1.80.13
      CHA2DS2-VASc score3.0 (2.0, 4.0)3.0 (2.0, 4.0)2.0 (2.0, 3.0)< 0.001
      Ordinal CHA2DS2-VASc scores0.07
       019 (3.0%)8 (2.2%)11 (4.1%)
       193 (14.8%)46 (12.7%)47 (17.5%)
       2189 (30.0%)99 (27.4%)90 (33.5%)
       3171 (27.1%)103 (28.5%)68 (25.3%)
       481 (12.9%)53 (14.7%)28 (10.4%)
       543 (6.8%)27 (7.5%)16 (5.9%)
       631 (4.9%)23 (6.4%)8 (3.0%)
       73 (0.5%)2 (0.6%)1 (0.4%)
      Outpatient medications
      Vitamin K antagonist97 (15.4%)97 (26.9%)0 (0.0%)< 0.001
      DOAC
      There were no patients on pre-admission edoxaban.
      264 (41.9%)264 (73.1%)0 (0.0%)< 0.001
       Apixaban191 (30%)191 (72%)-
       Rivaroxaban66 (10%)66 (25%)-
       Dabigatran7 (1.1%)7 (3%)-
      Aspirin284 (45.1%)150 (41.6%)134 (49.8%)0.039
      Dual antiplatelet therapy35 (5.6%)10 (2.8%)25 (9.3%)< 0.001
      P2Y12 inhibitor
      There were no patients on pre-admission prasugrel.
      61 (9.7%)27 (7.5%)34 (12.6%)0.030
       Clopidogrel54 (8.6%)22 (6.1%)32 (11.9%)
       Ticagrelor3 (0.5%)1 (0.3%)2 (0.7%)
      Aspirin or oral P2Y12 inhibitor307 (48.7%)164 (45.4%)143 (53.2%)0.054
      Statin419 (66.5%)254 (70.4%)165 (61.3%)0.017
      Non-statin lipid lowering agent38 (6.0%)28 (7.8%)10 (3.7%)0.035
      Beta blocker351 (55.7%)210 (58.2%)141 (52.4%)0.15
      Calcium channel blocker208 (33.0%)122 (33.8%)86 (32.0%)0.63
      ACE inhibitor187 (29.7%)103 (28.5%)84 (31.2%)0.46
      ARB105 (16.7%)71 (19.7%)34 (12.6%)0.019
      Digoxin35 (5.6%)27 (7.5%)8 (3.0%)0.014
      Inpatient medications
      Remdesivir240 (38.2%)134 (37.2%)106 (39.4%)0.58
      Interleukin-6 antagonist
      IL-6 antagonists include the medications idarucizumab and rituximab
      2 (0.3%)2 (0.6%)0 (0.0%)0.22
      Systemic steroid
      Systemic steroids include the medications dexamethasone, prednisone, methylprednisolone, and hydrocortisone.
      350 (55.6%)190 (52.6%)160 (59.5%)0.09
      ACE = angiotensin converting enzyme; ARB = angiotensin receptor blockers; DOAC = direct oral anticoagulant; TIA = transient ischemic attack.
      Values n (%), mean ± SD, or median (IQR).
      low asterisk There were no patients on pre-admission edoxaban.
      There were no patients on pre-admission prasugrel.
      IL-6 antagonists include the medications idarucizumab and rituximab
      § Systemic steroids include the medications dexamethasone, prednisone, methylprednisolone, and hydrocortisone.
      Patients on preadmission OAC had lower initial body temperatures than those not on OAC therapy. Baseline estimated glomerular filtration rate, anion gap, d-dimer, C-reactive protein, and baseline and peak troponin were all lower in those on vs not on preadmission OAC (Table 2). Vital sign and laboratory value missingness, stratified by preadmission OAC use, is characterized in Supplementary Figure 1.
      Table 2Admission vital signs and laboratory data
      Reference rangeTotal(N = 630)Anticoagulationp Value
      Yes (N = 361)No (N = 269)
      Vital Signs
      Temperature (F)98.3 ± 1.498.2 ± 1.398.6 ± 1.5< 0.001
      Systolic blood pressure (mm Hg)130.8 ± 26.6128.8 ± 26.0133.4 ± 27.30.031
      Diastolic blood pressure (mm Hg)72.9 ± 16.672.2 ± 16.773.7 ± 16.40.26
      Heart rate (beats/min)93.4 ± 27.491.8 ± 26.795.6 ± 28.30.08
      Respiratory rate (breaths/min)21.2 ± 6.421.2 ± 6.421.2 ± 6.31.0
      Oxygen saturation95.1± 5.695.2 ± 6.494.9 ± 4.50.64
      Laboratory tests
      WBC (109/L)3.5 - 118.6 ± 5.48.2 ± 5.39.1 ± 5.50.06
      Hgb (g/dL)11.0 – 15.011.9 ± 2.411.8 ± 2.412.0 ± 2.40.41
      Platelets (x109/L)150-400213.7 ± 99.5218.2 ± 104.8207.6 ± 91.70.20
      eGFR (mL/min/1.73M)> 6068.0 ± 43.764.8 ± 38.072.3 ± 50.10.035
      Serum creatinine (mg/dL)0.44 – 1.031.7 ± 1.61.6 ± 1.31.8 ± 2.00.12
      Anion gap3 - 1311.3 ± 3.410.8 ± 2.911.8 ± 4.0< 0.001
      INR0.8 – 1.21.8 ± 1.32.2 ± 1.51.3 ± 0.5< 0.001
      D-dimer (mg/L)< 2321472.7 ± 5461.7829.3 ± 3774.32294.2 ± 6977.40.003
      C-reactive protein (mg/L)< 5.091.9 ± 83.981.8 ± 69.5105.9 ± 99.00.001
      Baseline troponin-I (ng/mL)0.006 – 0.060.6 ± 3.80.3 ± 1.21.1 ± 5.60.006
      Peak troponin-I (ng/mL)0.006 – 0.0601.2 ± 7.00.6 ± 3.32.0 ± 9.90.016
      Whole blood lactate (mEq/L)0.2 – 1.92.1 + 2.02.1 + 1.92.1 + 2.10.79
      eGFR = estimated glomerular filtration rate; Hgb = Hemoglobin; INR = international normalized ratio; WBC = white blood cell count.
      Of patients prescribed preadmission OAC, 264 (73%) were on a DOAC, and 97 (27%) had a VKA. Of those on a DOAC, 191 (72%) were on apixaban, 66 (25%) on rivaroxaban, and 7 (3%) on dabigatran. No patients were taking edoxaban.
      Among those who were not on preadmission OAC, therapeutic and non-therapeutic anticoagulation was initiated in 38.3% and 49.8%, respectively. The use of thrombolytic therapy and vasopressors was more common in those not on preadmission OAC. There was no difference in the rate of in-hospital systemic steroid, remdesivir, or interleukin-6 antagonist use between those who were and were not taking preadmission OAC (Table 2).
      Unadjusted outcomes are shown in Table 3. A primary composite outcome event occurred in 224 (35.6%) patients, 98 (27.1%) of those on and 126 (46.8%) of those not on preadmission OAC (p <0.001). After adjustment for multiple covariates, the use of preadmission OAC was associated with 63% lower odds of all-cause mortality or thrombotic complications (odds ratio 0.37, confidence interval 0.25 to 0.53, p <0.0001) (Figure 2). Primary outcomes were similar when comparing those on preadmission DOAC versus VKA (Supplementary Table 6).
      Table 3Unadjusted primary and secondary outcomes according to pre-admission anticoagulant use
      Total (N = 630)Anticoagulationp Value
      Yes (N = 361)No (N = 269)
      Composite of all-cause mortality and arterial or venous thrombosis224 (35.6%)98 (27.1%)126 (46.8%)< 0.001
      All-cause mortality126 (20.0%)59 (16.3%)67 (24.9%)0.007
      Composite arterial or venous thrombosis135 (21.4%)53 (14.7%)82 (30.5%)< 0.001
      Venous thromboembolism55 (8.7%)14 (3.9%)41 (15.2%)<0.001
      Acute DVT28 (4.4%)7 (1.9%)21 (7.8%)< 0.001
      Acute pulmonary embolism31 (4.9%)8 (2.2%)23 (8.6%)< 0.001
      Arterial thrombosis91 (14.4%)42 (11.6%)49 (18.2%)0.020
      Acute coronary syndrome52 (8.3%)25 (6.9%)27 (10.0%)0.16
      TIA5 (0.8%)4 (1.1%)1 (0.4%)0.30
      Stroke36 (5.7%)16 (4.4%)20 (7.4%)0.11
      Acute limb ischemia6 (1.0%)3 (0.8%)3 (1.1%)0.72
      Acute mesenteric ischemia3 (0.5%)0 (0.0%)3 (1.1%)0.044
      ICU admission131 (20.8%)53 (14.7%)78 (29.0%)< 0.001
      Intubation73 (11.6%)23 (6.4%)50 (18.6%)< 0.001
      Non-invasive ventilation141 (22.4%)67 (18.6%)74 (27.5%)0.007
      Supplemental oxygen requirement486 (77.1%)271 (75.1%)215 (79.9%)0.15
      Cardiac arrest23 (3.7%)9 (2.5%)14 (5.2%)0.07
      Red blood cell transfusion65 (10.3%)30 (8.3%)35 (13.0%)0.055
      Major bleed94 (14.9%)47 (13.0%)47 (17.5%)0.12
      Length of stay – days7.0 (4.0, 12.0)6.0 (3.0, 11.0)7.0 (4.0, 14.0)< 0.001
      ICU = Intensive care unit; DVT = deep vein thrombosis; TIA = transient ischemic attack.
      Values are n (%) or median (IQR).
      Figure 2
      Figure 2Multivariable Model of All-Cause Mortality and Thrombotic Outcomes in the Overall Cohort. Shown is a multivariable model relating pre-admission use of oral anticoagulation to composite in-hospital all-cause mortality and thrombotic complications.Abbreviations: RAAS = renin angiotensin aldosterone system. “Admission date +30” was defined as the index date of admission plus 30 days to evaluate the temporal effect of admission on outcomes.
      All-cause mortality was less frequent among those who were on preadmission OAC compared with those who were not. Composite thrombotic events were less frequent in patients on vs not on preadmission OAC. Patients on OAC were less likely to suffer acute venous or arterial thrombotic events, including acute DVT, acute PE, and acute mesenteric ischemia. There was no difference in the rate of acute coronary syndromes, TIA, acute ischemic stroke, or acute limb ischemia. There were also no between-group differences in the frequency of cardiac arrest, need for supplemental oxygen, noninvasive ventilation, intubation, red blood cell transfusion, or major bleeding. Length of stay was shorter in patients who were on vs not on preadmission OAC (Table 3). Among survivors, discharge disposition was no different according to preadmission OAC use (Supplementary Table 7). Secondary outcomes were similar to those on preadmission DOAC and VKA (Supplementary Table 8). Results were essentially unchanged when the CHA2DS2-VASc score was included in the multivariable model as an ordinal rather than a dichotomous categorical variable (Supplementary Figure 2). In a sensitivity analysis excluding patients with a CHA2DS2-VASc score of 0, where all remaining patients had a thrombotic risk high enough to warrant OAC, results remained unchanged (Supplementary Table 9). A higher CHA2DS2-VASc score (3.0 ± 1.4 vs 2.7 ± 1.4, p = 0.032) was associated with increased risk of thrombotic events (Supplementary Table 4) but did not predict in-hospital mortality or the composite, all-cause mortality or thrombotic events (Supplementary Tables 2 and 3). Lastly, when examining the effect of OAC according to AF subtype, the results did not change (interaction p = 0.5).

      Discussion

      In a study of patients with pre-existing AF who were hospitalized with COVID-19, we observed that those on preadmission OAC had lower composite rates of death or thrombotic events, and less severe COVID-19, as reflected by more favorable admission data, a lower incidence of ICU admission, intubation, noninvasive ventilation, and shorter length of stay. These observations were apparent despite the more adverse demographic and co-morbid profile of those on preadmission OAC. Furthermore, a higher CHA2DS2-VASc score was associated with a greater incidence of composite arterial and venous thrombotic complications.
      Although data suggest that thrombosis begins early during the disease course,
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      it is unclear whether “upstream” (i.e., preadmission) therapeutic-dose OAC confers a benefit. Multiple randomized trials have demonstrated that when compared with standard thromboprophylaxis, therapeutic anticoagulation reduces the risk of death and composite death or thrombotic events in non-critically ill patients admitted with COVID-19.
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      ATTACC InvestigatorsACTIV-4a InvestigatorsREMAP-CAP Investigators
      Therapeutic anticoagulation with heparin in noncritically ill patients with COVID-19.
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      In contrast, randomized trials in low-risk outpatients
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      Effect of antithrombotic therapy on clinical outcomes in outpatients With clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial.
      with COVID-19 have found no benefit with therapeutic anticoagulation. It is unknown whether outpatients who are at elevated baseline risk for thrombotic events, such as those with AF, might benefit from preadmission therapeutic anticoagulation.
      • Capell WH
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      Enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease-2019 (the Ovid study): a structured summary of a study protocol for a randomized controlled trial.
      Patients with AF are at persistently elevated risk for thromboembolism secondary to endothelial dysfunction, blood stasis, coagulation activation, and systemic inflammation, pathologic mechanisms similar to those observed in COVID-19.
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      Preadmission anticoagulation with either a DOAC or VKA may counteract the pro-thrombotic effects of the virus, ultimately preventing subclinical and clinical thrombosis. Notably, apixaban and rivaroxaban reduce d-dimer levels,
      • Kirchhof P
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      which have been associated with worse clinical outcomes in patients with COVID-19;
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      Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
      it is plausible that the impact such agents have on the coagulation cascade results in more favorable outcomes.
      Observational studies relating preadmission OAC to outcomes in patients hospitalized with COVID-19 have yielded mixed results. Multiple studies have reported increased disease severity and higher mortality rates in patients who were on OAC at the time of hospital admission.
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      Dashti HT, Bates D, Fiskio JM, Roche EC, Mora S, Demler O. Clinical characteristics and severity of COVID-19 disease in patients from Boston area hospitals [published online August 4, 2020]. Preprint. medRxiv. doi:10.1101/2020.07.27.20163071.

      Others have found no association,
      • Flam B
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      Direct oral anticoagulant use and risk of severe COVID-19.
      ,
      • Tremblay D
      • van Gerwen M
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      • Thibaud S
      • Kessler A
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      • Makki I
      • Qin Q
      • Dharmapuri S
      • Jun T
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      • Troy K
      • Cromwell C
      • Dunn A
      • Oh WK
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      Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study.
      whereas some have suggested that DOAC use is associated with a lower risk of adverse outcomes.
      • Ahlström B
      • Frithiof R
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      • Larsson IM
      • Strandberg G
      • Lipcsey M.
      The Swedish covid-19 intensive care cohort: risk factors of ICU admission and ICU mortality.
      • Fröhlich GM
      • Jeschke E
      • Eichler U
      • Thiele H
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      • Kastrati A
      • Leistner DM
      • Skurk C
      • Landmesser U
      • Günster C.
      Impact of oral anticoagulation on clinical outcomes of COVID-19: a nationwide cohort study of hospitalized patients in Germany.
      • Harrison RF
      • Forte K
      • Buscher MG
      • Jr Chess A
      • Patel A
      • Moylan T
      • Mize CH
      • Werdmann M
      • Ferrigno R
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      • Rossi R
      • Coppi F
      • Talarico M
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      Protective role of chronic treatment with direct oral anticoagulants in elderly patients affected by interstitial pneumonia in COVID-19 era.
      Most of these studies did not preferentially include patients at persistently elevated baseline risk for thrombosis, and few accounted for differential thrombotic risk between treatment and control groups. Our study overcame many of the limitations of previous studies by including a cohort exclusively comprised patients with AF who were consequently at elevated baseline thrombotic risk,
      • Lutsey PL
      • Norby FL
      • Alonso A
      • Cushman M
      • Chen LY
      • Michos ED
      • Folsom AR.
      Atrial fibrillation and venous thromboembolism: evidence of bidirectionality in the Atherosclerosis Risk in Communities Study.
      compared treatment and control groups with similar thrombotic risk and similar indications for OAC, and yielded a large number of both venous and arterial thrombotic events for comparison.
      The decision to initiate OAC in patients with AF is ideally made through shared decision-making that takes into consideration the risks of thromboembolic events and bleeding while incorporating patient preference. In our study cohort, after adjusting for baseline CHA2DS2-VASc score and restricting our analysis to those with a CHA2DS2-VASc score of 1 or higher, we observed that preadmission OAC use was associated with a more favorable in-hospital outcome. Although our study design does not allow us to infer causality, our results do call into question whether the risk-benefit balance should be reconsidered in ambulatory patients with AF who develop COVID-19. A higher short-term risk of death or thromboembolic events might favor the decision to initiate OAC in patients at high thrombotic risk who were otherwise not taking OAC.
      There are important limitations to our study. First, we cannot rule out the possibility of residual confounding or bias despite the use of multivariable adjustment. Second, the use of ICD-10 codes to define clinical outcomes may have resulted in under- or miscoding; however, had this occurred, it would have biased our results toward the null. Third, we cannot confirm patient adherence to outpatient OAC therapy before admission; had adherence been suboptimal, this also would have biased our results toward the null. Similarly, it is possible that those on OAC had better access to medical care which may have biased our results. Fourth, routine screening for thrombotic complications (e.g., vascular ultrasound testing and CT angiography) was not performed in our cohort, therefore, the true incidence of composite thrombotic events in our study cohort is unknown and our findings reflect only clinically manifest thrombotic complications as captured by ICD-10 coding. In addition, because this was a retrospective study of in-hospital outcomes, post-discharge thromboembolic complications and vital status were not known, and the reasons for OAC non-use preadmission were not available.
      In conclusion, among patients at elevated baseline thrombotic risk because of AF who were hospitalized with COVID-19, those on preadmission OAC had lower rates of death, arterial and venous thrombotic events, and less severe COVID-19. Further investigation is needed to establish the safety and efficacy of OAC in ambulatory patients with symptomatic COVID-19 who are at elevated thrombotic risk.

      Disclosures

      The authors have no conflicts of interest to declare.

      Appendix. Supplementary materials

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