Clinical Events After Interruption of Anticoagulation in Patients with Atrial Fibrillation

APPENDIX

Clinical Events after Interruption of Anticoagulation in Patients with Atrial Fibrillation:

An Analysis from the ENGAGE AF-TIMI 48 Trial

Appendix TABLE 1.Baseline Characteristics of Excluded Patients

Excluded Patients
(N=4163) / Included Patients
(N=9148)
Age, yrs, median (IQR) / 74 (67-79) / 73 (65-78)
Female sex, n (%) / 1631 (39.2) / 3527 (38.6)
Body Mass Index, kg/m2, median (IQR) / 28.6 (25.3-32.4) / 28.5 (25.3-32.5)
White race, n (%) / 3526 (84.7) / 7210 (78.8)
Region, n (%)
North America
Latin America
Western Europe
Eastern Europe
Asia–Pacific region and South Africa / 1152 (27.7)
384 (9.2)
871 (20.9)
1189 (28.6)
567 (13.6) / 2458 (26.9)
1310 (14.3)
1296 (14.2)
2539 (27.8)
1545 (16.9)
Type of atrial fibrillation, n (%)
Paroxysmal
Persistent
Permanent / 1045 (25.1)
918 (22.1)
2199 (52.8) / 2539 (27.8)
2202 (24.1)
4405 (48.2)
Qualifying risk factor, n (%)
Age ≥ 75 yrs
Prior stroke or transient ischemic attack
Congestive heart failure
Diabetes mellitus
Hypertension / 1968 (47.3)
1236 (29.7)
2249 (54.0)
1585 (38.1)
3852 (92.5) / 3988 (43.6)
2488 (27.2)
5283 (57.8)
3315 (36.2)
8571 (93.7)
CHADS2 score >3, n (%) / 1032 (24.8) / 2121 (23.2)
HAS-BLED score >3, n (%) / 2136 (51.3) / 4532 (49.5)
History of non-intracranial bleeding, n (%) / 547 (13.1) / 956 (10.5)
Creatinine Clearance at randomization, ml/min, median (IQR) / 65.5 (49.9-87.2) / 68.1 (52.1-89.1)
Charlson Comorbidity Index‡, mean (SD) / 2.90 (1.13) / 2.86 (1.1)
Dose reduction at randomization, n (%) / 1288 (30.9) / 2527 (27.6)
Vitamin K Antagonist naive§, n (%) / 1292 (31.0) / 4215 (46.1)
Aspirin use at randomization, n (%) / 1100 (26.4) / 3024 (33.1)

‡ Charlson Comorbidity Index calculation: 1 point each for prior myocardial infarction, congestive heart failure, peripheral artery disease, dementia, transient ischemic attack, stroke, carotid disease, peptic ulcer disease or diabetes; 2 points each for hemiplegia and moderate or severe kidney disease; 6 points each for malignant tumor and metastasis.

§Vitamin K Antagonist naive was defined as ≤ 60 days of prior continuous Vitamin K Antagonist exposure.

Appendix TABLE 2.Baseline Characteristics of Patients Who Interrupted Study Oral Anticoagulation According to Treatment Allocation

Warfarin / HDER / LDER / P
Value
N=3222 / N=3011 / N=2915
Age, yrs, median (IQR) / 73 (65-78) / 73 (65-78) / 73 (65-78) / 0.85
Female sex, n (%) / 1254 (38.9) / 1132 (37.6) / 1141 (39.1) / 0.41
Body Mass Index, kg/m2, median (IQR) / 28.3 (25.1-32.3) / 28.6 (25.4-32.8) / 28.6 (25.3-32.6) / 0.11
White race, n (%) / 2524 (78.3) / 2400 (79.7) / 2286 (78.4) / 0.74
Region, n (%)
North America
Latin America
Western Europe
Eastern Europe
Asia–Pacific region and South Africa / 866 (26.9)
487 (15.1)
440 (13.7)
886 (27.5)
543 (16.9) / 812 (27.0)
412 (13.7)
439 (14.6)
841 (27.9)
507 (16.8) / 780 (26.8)
411 (14.1)
417 (14.3)
812 (27.9)
495 (17.0) / 0.90
Type of atrial fibrillation, n (%)
Paroxysmal
Persistent
Permanent / 905 (28.1)
774 (24.0)
1542 (47.9) / 805 (26.7)
753 (25.0)
1453 (48.3) / 829 (28.4)
675 (23.2)
1410 (48.4) / 0.41
Qualifying risk factor, n (%)
Age ≥ 75 yrs
Prior stroke or transient ischemic attack
Congestive heart failure
Diabetes mellitus
Hypertension / 1397 (43.4)
867 (26.9)
1874 (58.2)
1169 (36.3)
3027 (93.9) / 1315 (43.7)
809 (26.9)
1751 (58.2)
1103 (36.6)
2823 (93.8) / 1276 (43.8)
812 (27.9)
1658 (56.9)
1043 (35.8)
2721 (93.3) / 0.94
0.62
0.51
0.79
0.61
Dyslipidemia, n (%) / 1689 (52.4) / 1558 (51.7) / 1590 (54.5) / 0.08
Current/former smoker, n (%) / 1287 (39.9) / 1280 (42.5) / 1253 (43.0) / 0.07
Coronary artery disease, n (%) / 1137 (35.3) / 1105 (36.7) / 1052 (36.1) / 0.50
CHADS2 score >3, n (%) / 747 (23.2) / 704 (23.4) / 670 (23.0) / 0.94
HAS-BLED score >3, n (%) / 1622 (50.3) / 1509 (50.1) / 1401 (48.1) / 0.15
History of non-intracranial bleeding, n (%) / 332 (10.3) / 329 (10.9) / 295 (10.1) / 0.56
Creatinine Clearance at randomization, ml/min, median (IQR) / 68.2 (51.8-88.5) / 68.1 (52.2-88.9) / 68.2 (52.4-89.8) / 0.89
History of hepatic disease, n (%) / 119 (3.7) / 118 (3.9) / 114 (3.9) / 0.87
Alcohol intake (≥ 1 drink per day), n (%) / 308 (9.6) / 286 (9.5) / 261 (8.9) / 0.32
Increased risk of falling†, n (%) / 163 (5.1) / 159 (5.3) / 143 (4.9) / 0.80
History of neuropsychiatric disease¶, n (%) / 283 (8.8) / 273 (9.1) / 284 (9.7) / 0.41
Charlson Comorbidity Index‡, mean (SD) / 2.86 (1.10) / 2.85 (1.10) / 2.88 (1.09) / 0.39
Dose reduction at randomization, n (%) / 902 (28.0) / 830 (27.6) / 795 (27.3) / 0.82
Vitamin K Antagonist naive§, n (%) / 1726 (53.6) / 1633 (54.2) / 1573 (54.0) / 0.87
Aspirin use at randomization, n (%) / 1089 (33.8) / 997 (33.1) / 938 (32.2) / 0.40

†Increased risk of falling was defined as prior history of falls, lower extremity weakness, poor balance, cognitive impairment, orthostatic hypotension, use of psychotropic drugs, severe arthritis or dizziness.

¶ History of neuropsychiatric disease was defined as history of dementia, depression, Parkinson’s disease, schizophrenia or seizures.

§Vitamin K Antagonist naive was defined as ≤ 60 days of prior continuous Vitamin K Antagonist exposure.

Appendix Figure 1.Flow Diagram of the Interruption Cohort (> 3 Days) Included in the Study.

During 2.8 years median follow-up 13,311 patients interrupted oral anticoagulation at least once (reasons for the first interruptionare reported in the figure). After excluding 4163 patients for different pre-specified reasons, the population for the present analysis included 9148 patients.

HDER=Higher-Dose Edoxaban Regimen (60/30 mg); LDER=Lower-Dose Edoxaban Regimen (30/15 mg); D4=Day 4 after last oral anticoagulation dose.

AppendixFigure 2.Panel A. 30-day Event Rate According to Reason For Interruption. Panel B. Hazard Ratios for Adverse Outcomes in Patients Who Interrupted Oral Anticoagulation for an Adverse Event vs. Those Who Interrupted for Other Reasons.

In Panel A,the x-axis represents reasons for oral anticoagulation interruption and the y-axis represents 30-day event rates (MACCE in red and the primary net clinical outcome in green). After adjustment for differences in baseline characteristics, patients who interrupted study drug for an adverse event, had significantly increased risk of MACCE and primary net clinical outcome but similar rates of ischemic stroke/SEE, compared to those who interrupted for other reasons(Panel B).

TIA=Transient Ischemic Attack; SEE=Systemic Embolic Event; MACCE=Major Cardiac and Cerebrovascular Event.

Appendix Figure 3.Kaplan-Meier Curves For Adverse Events in Patients Who Interrupted Higher-Dose Edoxaban vs. Warfarin.

Kaplan-Meier curves for ischemic stroke/SEE, MACCE and the primary net clinical outcome did not show significant differences after interruption of HDER (green)vs. W (red).

HDER=Higher-Dose Edoxaban Regimen (60/30 mg); W=Warfarin; SEE=Systemic Embolic Event; MACCE=Major Cardiac and Cerebrovascular Event; CV=Cardiovascular

Appendix Figure 4.Sensitivity Analysis: Kaplan-Meier Curves For Adverse Events With the At-Risk Time Window Starting the Day of the Last Anticoagulation Dose.

Kaplan-Meier rates for ischemic stroke or SEE showed an early hazard in the first 3 days after the last dose of anticoagulation with no differences between treatments.

HDER=Higher-Dose Edoxaban Regimen (60/30 mg); W=Warfarin; SEE=Systemic Embolic Event; MACCE=Major Cardiac and Cerebrovascular Event; CV=Cardiovascular.

Appendix Figure 5.Sensitivity Analysis: Kaplan-Meier Curves For Adverse Events With the At-Risk Time Window Starting 7 Days After the Last Anticoagulation Dose.

HDER=Higher-Dose Edoxaban Regimen (60/30 mg); W=Warfarin; SEE=Systemic Embolic Event; MACCE=Major Cardiac and Cerebrovascular Event; CV=Cardiovascular.

Appendix Figure 6.Kaplan-Meier Curves For Adverse Events in Patients Who Interrupted Lower-Dose Edoxaban vs. Warfarin.

Kaplan-Meier curves for ischemic stroke/SEE, MACCE and the primary net clinical outcome after interruption of LDER (light blue)showed numerically, although not statistically higher event rates, compared to W (red).

LDER=Lower-Dose Edoxaban Regimen (30/15 mg); W=Warfarin; SEE=Systemic Embolic Event; MACCE=Major Cardiac and Cerebrovascular Event; CV=Cardiovascular.