Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in patients with atrial fibrillation: a nationwide cohort study

Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in... Abstract Aims We examined the risks of all-cause mortality, stroke, major bleeding, and recurrent traumatic injury associated with resumption of vitamin K antagonists (VKAs) and non-VKAs oral anticoagulants (NOACs) following traumatic injury in atrial fibrillation (AF) patients. Methods and results This was a Danish nationwide registry-based study (2005–16), including 4541 oral anticoagulant (OAC)-treated AF patients experiencing traumatic injury (defined as traumatic brain injury, hip fracture, or traumatic torso or abdominal injury). Within 90 days following discharge from traumatic injury, 60.6% resumed VKA (median age = 80, CHA2DS2-VASc = 4, HAS-BLED = 2), 16.7% resumed NOAC (median age = 81, CHA2DS2-VASc = 4, HAS-BLED = 2), and 22.7% did not resume OAC treatment (median age = 81, CHA2DS2-VASc = 4, HAS-BLED = 3). Switch from VKA to NOAC occurred among 9.5%. Since 2009, the trend in OAC resumption increased (P-value <0.0001), in particular with NOACs (P-value <0.0001). Follow-up started 90 days after discharge, and time-varying multiple Cox regression analyses were used for comparisons. Compared with non-resumption, VKA and NOAC resumption were associated with lower hazard [95% confidence interval (CI)] of all-cause mortality [hazard ratio (HR) 0.48 (0.42–0.53) and HR 0.55 (0.47–0.66), respectively] and ischaemic stroke [HR 0.56 (0.43–0.72) and HR 0.54 (0.35–0.82), respectively], increased major bleeding hazard [HR 1.30 (1.03–1.64) and HR 1.15 (0.81–1.63), respectively], and similar hazard of recurrent traumatic injury [HR 0.93 (0.73–1.18) and HR 0.87 (0.60–1.27), respectively]. Conclusion AF patients resuming VKA and NOAC treatment following traumatic injury have lower hazard of all-cause mortality and ischaemic stroke, increased hazard of major bleeding but without additional hazards of recurrent traumatic injury. Withholding OAC following a traumatic injury in AF patients may not be warranted. View largeDownload slide View largeDownload slide Atrial fibrillation, Traumatic injury, Oral anticoagulation, Warfarin, NOAC, Bleeding Introduction Patients with atrial fibrillation (AF) requiring oral anticoagulants (OAC) are a fragile group of patients and a clinical challenge if they experience a traumatic injury.1–5 For instance, if a patient with AF is admitted due to a head injury caused by a ground-level fall, the occurrence of death during the injury hospitalization is estimated to be 24%, whereas this constitutes 32% if patients are treated with OACs before the ground-level fall admission.6 After traumatic injury, doctors and patients face the decision of whether to resume OAC therapy, a complex decision that needs careful consideration of the balance between benefit (stroke prevention) and risk (bleeding) of OAC treatment.7 Resumption of OAC treatment will reduce the stroke risk, but increase the bleeding risk, which in these fragile patients may be a major concern in the perspective of a risk for a recurrent traumatic injury. Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) are frequently used among elderly AF patients8; however, following a traumatic injury it is uncertain to what extent NOACs and VKAs are used and what the risks of outcomes are with respectively NOAC and VKA resumption compared with non-resumption. This study focused on OAC-treated AF patients who experienced a traumatic injury, and we examined the OAC resumption pattern and risk of all-cause mortality, ischaemic stroke, major bleeding, and recurrent traumatic injury associated with NOAC and VKA resumption compared with no OAC resumption. Methods Data sources All residents of Denmark are at birth or immigration, given a unique personal identification number that enabled us to cross-link individual information from the following Danish nationwide registries: (i) The Danish national patient registry holds information about all hospital contacts since 1978. A hospital contact is coded with one primary, and if appropriate, one or more secondary diagnosis codes based on the International Classification of Diseases 10th revision (ICD-10).9 (ii) The Danish national prescription registry keeps information about all filled prescriptions since 1995 including the Anatomical Therapeutic Chemical (ATC) codes, the day the prescription was filled, the package size, and dosages.10 (iii) The Danish civil registration system registers vital status.11 Study population and outcomes We conducted an observational study from 1 January 2005 to 31 December 2016. The study population constituted AF patients treatment with VKA or NOAC [dabigatran (since August 2011), rivaroxaban (since February 2012), or apixaban (since December 2012)] the day before a traumatic injury hospital admission. Traumatic injury involved hospitalization with traumatic cranial or brain injury (fracture of the skull, injury of optic nerve, intracranial injury, or crushing or multiple injuries of head), traumatic hip fracture (femoral neck, pertrochanteric, or subtrochanteric fracture), or traumatic torso or abdominal injury (serious open wound of thoracic wall, abdominal wall, or pelvis; injury of blood vessels, intrathoracic organs, intra-abdominal organs, and pelvic organs; and traumatic pneumothorax or haemothorax). Validation studies of administrative data report high positive predictive values for AF, hip fracture, and traumatic brain injury.12–14 Traumatic torso or abdominal injury was defined as done in a previous study from 2015.15 A quarantine period of 90 days subsequent to the discharge day was introduced to allow patients to fill a new prescription of an OAC drug following the traumatic injury. The package size of an OAC agent runs for a maximum of 3 months, and it is plausible that if patients resumed OAC treatment they finished the package from before the traumatic injury at first. All patients were followed up for 90 days, and with the 90 days of quarantine period, we were able to categorize patients into resumption and non-resumption of treatment and thereby limit misclassification and avoid conditioning on the future.16 The exclusion criteria are shown in Figure 1. Figure 1 View largeDownload slide Selection of the study population. NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; VKA, vitamin K antagonist. Figure 1 View largeDownload slide Selection of the study population. NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; VKA, vitamin K antagonist. The three treatment groups were resumption of VKA, resumption of NOAC, or no OAC resumption, and ATC codes are listed in the Supplementary material online, Table S1. Follow-up began after the 90 days of quarantine period and was limited to the first 3 years after the 90 days of quarantine period (90 days + 3 years). Outcomes of interest during follow-up were the earliest of all-cause mortality, ischaemic stroke, major bleeding, and recurrent traumatic injury. Outcome status was last assessed on 31 December 2016. All ICD-10 and ATC codes used to define the study population, treatment groups, and outcomes are listed in the Supplementary material online, Table S1. Concomitant pharmacotherapy and co-morbidity Concomitant pharmacotherapy was identified from filled prescriptions for a period of 90 days prior to baseline. Co-morbidities were identified from diagnosis codes registered within a period of 10 years prior to baseline. ATC codes and ICD-10 codes used to define concomitant pharmacotherapy and co-morbidities are listed in the Supplementary material online, Table S1. All patients were assessed for risk of stroke with the CHA2DS2-VASc score17 [Congestive heart failure, Hypertension, Age ≥ 75 years (2 points), Diabetes mellitus, Stroke/TE/transient ischaemic attack (2 points), Vascular disease, Age 65–74 years, and female Sex] and risk of bleeding with the HAS-BLED score [Hypertension, Abnormal renal or liver function, Stroke/TE, previous Bleeding, Labile international normalized ratio (INR; left out because data are unavailable), Elderly (age ≥ 65 years), and concomitant drugs (antiplatelet agents, non-steroidal anti-inflammatory drugs)/alcohol abuse]. Statistical analysis Time trends in OAC resumption according to calendar year were analysed with Cochrane Armitage trend tests in the period 2005–16. Baseline was set as 90 days after discharge from traumatic injury. We estimated the outcome-specific absolute risk (cumulative incidence) by the Aalen–Johansen method separately in the treatment groups to account for competing risks of death.18 Stroke, major bleeding, and recurrent traumatic injury were not accounted for as competing events. Outcome-specific hazards in the three treatment groups were modelled by multiple Cox regression. Each outcome-specific model was adjusted for potential confounders as determined by published literature and associated expert knowledge. All models were adjusted for calendar year, age (continuous), sex, and type of traumatic injury. All-cause mortality models were further adjusted for CHA2DS2-VASc and HAS-BLED factors, stroke models for CHA2DS2-VASc factors, major bleeding models for HAS-BLED factors, and recurrent traumatic injury models for CHA2DS2-VASc and HAS-BLED factors, osteoporosis, dementia, and benzodiazepine usage. For each outcome, the two Cox regression models were obtained, one using only baseline information and another using dynamic updates of all time-varying covariates (treatment group, co-morbidity, concomitant pharmacotherapy, calendar year, and age). Based on the outcome-specific Cox regression models using only baseline information, we computed differences in standardized absolute 1-year risks between the three treatment groups (g-formula).19,20 The standardized risks for treatment Group ‘A’ were obtained as the average of the predicted absolute 1-year risks in a copy of the real data where the treatment variable was set to ‘A’. The risks were predicted by combining the outcome-specific Cox regression models.20 The standardized differences were supplied with 95% bootstrap confidence limits based on 1000 bootstrap data sets. The level of significance was set at 5%. Data management and statistical analyses were performed using SAS (version 9.4 for Windows, SAS Institute, Cary, NC, USA) and R [R Core Team (2016). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria]. Ethics Retrospective registry-based studies do not require approval from the Research Ethical Committee System. The Danish Data Protection Agency approved the use of data for this study (ref.no: 2007-58-0015/GEH-2014-012 I-Suite no: 02720). Results Study population At baseline, which was on Day 90 following discharge from traumatic injury, we included a total of 4541 AF patients, treated with OAC before admission (Figure 1). During the quarantine period of 90 days, 1695 patients were excluded as they suffered from one of the outcomes of interest. Supplementary material online, Table S2 reports the characteristics of the population at the time of discharge from traumatic injury, and Supplementary material online, Figure S1 illustrates outcome-specific cumulative incidences during the quarantine period of 90 days. Among the 4541 included patients at baseline (Table 1), the resumption pattern was as follows: non-resumption 22.7%, VKA 60.6%, and NOAC 16.7% (dabigatran, n = 333, 7.3%; rivaroxaban, n = 211, 4.7%; and apixaban, n = 213, 4.7%). The median age was 81, 80, and 81 years in the non-resumption, VKA, and NOAC groups, respectively. All groups had a median CHA2DS2-VASc score of 4, but the median HAS-BLED score was highest in the non-resumption group being 3. In the non-resumption group, 40.8% had suffered from a traumatic brain injury, whereas among patients resuming VKA and NOAC this was 27.4% and 29.6%, respectively. In addition, concomitant usage of aspirin (27.1%), adenosine diphosphate receptor antagonists (4.8%), and benzodiazepines (25.3%) were more frequent among non-resumption than patients resuming OAC treatment. Table 1 Patient characteristics at baseline [AuthorQuery id="AQ20" rid="20"]?> Non-resumption VKA NOAC P-value n (%) 1031 (22.7) 2753 (60.6) 757 (16.7) Men, n (%) 513 (49.8) 1347 (48.9) 309 (40.8) <0.001 Age, median [IQR] 81 [75, 86] 80 [74, 85] 81 [74, 87] <0.001 CHA2DS2-VASc, median [IQR] 4 [3, 5] 4 [3, 5] 4 [3, 5] 0.289 HAS-BLED, median [IQR] 3 [2, 3] 2 [2, 3] 2 [2, 3] <0.001 Type of injury, n (%) <0.001  Traumatic brain injury 421 (40.8) 755 (27.4) 224 (29.6)  Hip fracture 475 (46.1) 1530 (55.6) 426 (56.3)  Traumatic torso or abdominal injury 135 (13.1) 468 (17.0) 107 (14.1) OAC before traumatic injury, n (%) <0.001  VKA 930 (90.2) 2750 (99.9) 72 (9.5)  NOAC 101 (9.8) 3 (0.1) 685 (90.5) Co-morbidities, n (%)  Stroke 263 (25.5) 588 (21.4) 217 (28.7) <0.001  Myocardial infarction 109 (10.6) 247 (9.0) 62 (8.2) 0.181  Ischaemic heart disease 364 (35.3) 950 (34.5) 203 (26.8) <0.001  Peripheral artery disease 83 (8.1) 183 (6.6) 35 (4.6) 0.016  Heart failure 327 (31.7) 849 (30.8) 194 (25.6) 0.010  Diabetes mellitus 141 (13.7) 409 (14.9) 112 (14.8) 0.646  Hypertension 535 (51.9) 1686 (61.2) 410 (54.2) <0.001  Chronic kidney disease 102 (9.9) 214 (7.8) 58 (7.7) 0.088  Liver disease 14 (1.4) 47 (1.7) 14 (1.8) 0.676  Prior bleeding 466 (45.2) 802 (29.1) 233 (30.8) <0.001  Alcohol misuse 45 (4.4) 119 (4.3) 50 (6.6) 0.027  Cancer 182 (17.7) 444 (16.1) 134 (17.7) 0.395  Dementia 92 (8.9) 157 (5.7) 89 (11.8) <0.001  Osteoporosis 187 (18.1) 502 (18.2) 198 (26.2) <0.001 Concomitant medication, n (%)  ADP receptor antagonists 50 (4.8) 41 (1.5) 13 (1.7) <0.001  Aspirin 279 (27.1) 488 (17.7) 36 (4.8) <0.001  Dipyridamole 15 (1.5) 9 (0.3) 0 (0.0) <0.001  Non-steroid anti-inflammatory drug 63 (6.1) 174 (6.3) 43 (5.7) 0.808  Loop diuretics 411 (39.9) 1168 (42.4) 275 (36.3) 0.008  Beta-blockers 487 (47.2) 1397 (50.7) 427 (56.4) 0.001  Calcium channel blockers 197 (19.1) 652 (23.7) 148 (19.6) 0.002  Renin–angiotensin system blocker 369 (35.8) 1107 (40.2) 267 (35.3) 0.007  Digoxin 344 (33.4) 976 (35.5) 189 (25.0) <0.001  Benzodiazepine 261 (25.3) 590 (21.4) 173 (22.9) 0.038 Non-resumption VKA NOAC P-value n (%) 1031 (22.7) 2753 (60.6) 757 (16.7) Men, n (%) 513 (49.8) 1347 (48.9) 309 (40.8) <0.001 Age, median [IQR] 81 [75, 86] 80 [74, 85] 81 [74, 87] <0.001 CHA2DS2-VASc, median [IQR] 4 [3, 5] 4 [3, 5] 4 [3, 5] 0.289 HAS-BLED, median [IQR] 3 [2, 3] 2 [2, 3] 2 [2, 3] <0.001 Type of injury, n (%) <0.001  Traumatic brain injury 421 (40.8) 755 (27.4) 224 (29.6)  Hip fracture 475 (46.1) 1530 (55.6) 426 (56.3)  Traumatic torso or abdominal injury 135 (13.1) 468 (17.0) 107 (14.1) OAC before traumatic injury, n (%) <0.001  VKA 930 (90.2) 2750 (99.9) 72 (9.5)  NOAC 101 (9.8) 3 (0.1) 685 (90.5) Co-morbidities, n (%)  Stroke 263 (25.5) 588 (21.4) 217 (28.7) <0.001  Myocardial infarction 109 (10.6) 247 (9.0) 62 (8.2) 0.181  Ischaemic heart disease 364 (35.3) 950 (34.5) 203 (26.8) <0.001  Peripheral artery disease 83 (8.1) 183 (6.6) 35 (4.6) 0.016  Heart failure 327 (31.7) 849 (30.8) 194 (25.6) 0.010  Diabetes mellitus 141 (13.7) 409 (14.9) 112 (14.8) 0.646  Hypertension 535 (51.9) 1686 (61.2) 410 (54.2) <0.001  Chronic kidney disease 102 (9.9) 214 (7.8) 58 (7.7) 0.088  Liver disease 14 (1.4) 47 (1.7) 14 (1.8) 0.676  Prior bleeding 466 (45.2) 802 (29.1) 233 (30.8) <0.001  Alcohol misuse 45 (4.4) 119 (4.3) 50 (6.6) 0.027  Cancer 182 (17.7) 444 (16.1) 134 (17.7) 0.395  Dementia 92 (8.9) 157 (5.7) 89 (11.8) <0.001  Osteoporosis 187 (18.1) 502 (18.2) 198 (26.2) <0.001 Concomitant medication, n (%)  ADP receptor antagonists 50 (4.8) 41 (1.5) 13 (1.7) <0.001  Aspirin 279 (27.1) 488 (17.7) 36 (4.8) <0.001  Dipyridamole 15 (1.5) 9 (0.3) 0 (0.0) <0.001  Non-steroid anti-inflammatory drug 63 (6.1) 174 (6.3) 43 (5.7) 0.808  Loop diuretics 411 (39.9) 1168 (42.4) 275 (36.3) 0.008  Beta-blockers 487 (47.2) 1397 (50.7) 427 (56.4) 0.001  Calcium channel blockers 197 (19.1) 652 (23.7) 148 (19.6) 0.002  Renin–angiotensin system blocker 369 (35.8) 1107 (40.2) 267 (35.3) 0.007  Digoxin 344 (33.4) 976 (35.5) 189 (25.0) <0.001  Benzodiazepine 261 (25.3) 590 (21.4) 173 (22.9) 0.038 Characteristics of the study population at the time of baseline. Table 1 Patient characteristics at baseline [AuthorQuery id="AQ20" rid="20"]?> Non-resumption VKA NOAC P-value n (%) 1031 (22.7) 2753 (60.6) 757 (16.7) Men, n (%) 513 (49.8) 1347 (48.9) 309 (40.8) <0.001 Age, median [IQR] 81 [75, 86] 80 [74, 85] 81 [74, 87] <0.001 CHA2DS2-VASc, median [IQR] 4 [3, 5] 4 [3, 5] 4 [3, 5] 0.289 HAS-BLED, median [IQR] 3 [2, 3] 2 [2, 3] 2 [2, 3] <0.001 Type of injury, n (%) <0.001  Traumatic brain injury 421 (40.8) 755 (27.4) 224 (29.6)  Hip fracture 475 (46.1) 1530 (55.6) 426 (56.3)  Traumatic torso or abdominal injury 135 (13.1) 468 (17.0) 107 (14.1) OAC before traumatic injury, n (%) <0.001  VKA 930 (90.2) 2750 (99.9) 72 (9.5)  NOAC 101 (9.8) 3 (0.1) 685 (90.5) Co-morbidities, n (%)  Stroke 263 (25.5) 588 (21.4) 217 (28.7) <0.001  Myocardial infarction 109 (10.6) 247 (9.0) 62 (8.2) 0.181  Ischaemic heart disease 364 (35.3) 950 (34.5) 203 (26.8) <0.001  Peripheral artery disease 83 (8.1) 183 (6.6) 35 (4.6) 0.016  Heart failure 327 (31.7) 849 (30.8) 194 (25.6) 0.010  Diabetes mellitus 141 (13.7) 409 (14.9) 112 (14.8) 0.646  Hypertension 535 (51.9) 1686 (61.2) 410 (54.2) <0.001  Chronic kidney disease 102 (9.9) 214 (7.8) 58 (7.7) 0.088  Liver disease 14 (1.4) 47 (1.7) 14 (1.8) 0.676  Prior bleeding 466 (45.2) 802 (29.1) 233 (30.8) <0.001  Alcohol misuse 45 (4.4) 119 (4.3) 50 (6.6) 0.027  Cancer 182 (17.7) 444 (16.1) 134 (17.7) 0.395  Dementia 92 (8.9) 157 (5.7) 89 (11.8) <0.001  Osteoporosis 187 (18.1) 502 (18.2) 198 (26.2) <0.001 Concomitant medication, n (%)  ADP receptor antagonists 50 (4.8) 41 (1.5) 13 (1.7) <0.001  Aspirin 279 (27.1) 488 (17.7) 36 (4.8) <0.001  Dipyridamole 15 (1.5) 9 (0.3) 0 (0.0) <0.001  Non-steroid anti-inflammatory drug 63 (6.1) 174 (6.3) 43 (5.7) 0.808  Loop diuretics 411 (39.9) 1168 (42.4) 275 (36.3) 0.008  Beta-blockers 487 (47.2) 1397 (50.7) 427 (56.4) 0.001  Calcium channel blockers 197 (19.1) 652 (23.7) 148 (19.6) 0.002  Renin–angiotensin system blocker 369 (35.8) 1107 (40.2) 267 (35.3) 0.007  Digoxin 344 (33.4) 976 (35.5) 189 (25.0) <0.001  Benzodiazepine 261 (25.3) 590 (21.4) 173 (22.9) 0.038 Non-resumption VKA NOAC P-value n (%) 1031 (22.7) 2753 (60.6) 757 (16.7) Men, n (%) 513 (49.8) 1347 (48.9) 309 (40.8) <0.001 Age, median [IQR] 81 [75, 86] 80 [74, 85] 81 [74, 87] <0.001 CHA2DS2-VASc, median [IQR] 4 [3, 5] 4 [3, 5] 4 [3, 5] 0.289 HAS-BLED, median [IQR] 3 [2, 3] 2 [2, 3] 2 [2, 3] <0.001 Type of injury, n (%) <0.001  Traumatic brain injury 421 (40.8) 755 (27.4) 224 (29.6)  Hip fracture 475 (46.1) 1530 (55.6) 426 (56.3)  Traumatic torso or abdominal injury 135 (13.1) 468 (17.0) 107 (14.1) OAC before traumatic injury, n (%) <0.001  VKA 930 (90.2) 2750 (99.9) 72 (9.5)  NOAC 101 (9.8) 3 (0.1) 685 (90.5) Co-morbidities, n (%)  Stroke 263 (25.5) 588 (21.4) 217 (28.7) <0.001  Myocardial infarction 109 (10.6) 247 (9.0) 62 (8.2) 0.181  Ischaemic heart disease 364 (35.3) 950 (34.5) 203 (26.8) <0.001  Peripheral artery disease 83 (8.1) 183 (6.6) 35 (4.6) 0.016  Heart failure 327 (31.7) 849 (30.8) 194 (25.6) 0.010  Diabetes mellitus 141 (13.7) 409 (14.9) 112 (14.8) 0.646  Hypertension 535 (51.9) 1686 (61.2) 410 (54.2) <0.001  Chronic kidney disease 102 (9.9) 214 (7.8) 58 (7.7) 0.088  Liver disease 14 (1.4) 47 (1.7) 14 (1.8) 0.676  Prior bleeding 466 (45.2) 802 (29.1) 233 (30.8) <0.001  Alcohol misuse 45 (4.4) 119 (4.3) 50 (6.6) 0.027  Cancer 182 (17.7) 444 (16.1) 134 (17.7) 0.395  Dementia 92 (8.9) 157 (5.7) 89 (11.8) <0.001  Osteoporosis 187 (18.1) 502 (18.2) 198 (26.2) <0.001 Concomitant medication, n (%)  ADP receptor antagonists 50 (4.8) 41 (1.5) 13 (1.7) <0.001  Aspirin 279 (27.1) 488 (17.7) 36 (4.8) <0.001  Dipyridamole 15 (1.5) 9 (0.3) 0 (0.0) <0.001  Non-steroid anti-inflammatory drug 63 (6.1) 174 (6.3) 43 (5.7) 0.808  Loop diuretics 411 (39.9) 1168 (42.4) 275 (36.3) 0.008  Beta-blockers 487 (47.2) 1397 (50.7) 427 (56.4) 0.001  Calcium channel blockers 197 (19.1) 652 (23.7) 148 (19.6) 0.002  Renin–angiotensin system blocker 369 (35.8) 1107 (40.2) 267 (35.3) 0.007  Digoxin 344 (33.4) 976 (35.5) 189 (25.0) <0.001  Benzodiazepine 261 (25.3) 590 (21.4) 173 (22.9) 0.038 Characteristics of the study population at the time of baseline. From 2009 to 2016, an increase in overall resumption of OAC treatment occurred from 68.7% to 85.6%, respectively (P-value <0.0001 for increasing trend), and a rapid yearly increase of NOAC usage occurred since 2011 (P-value <0.0001 for increasing trend). In 2016, an NOAC was prescribed for 39.6% of patients following a traumatic injury (Figure 2). Figure 2 View largeDownload slide Time trends showing resumption pattern of OAC following a traumatic injury from 2005 to 2016. NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; VKA, vitamin K antagonist. Figure 2 View largeDownload slide Time trends showing resumption pattern of OAC following a traumatic injury from 2005 to 2016. NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; VKA, vitamin K antagonist. Oral anticoagulants resumption vs. non-resumption and associated risk of outcomes During the follow-up period of 3 years, 1438 died, 285 suffered from an ischaemic stroke, 442 from major bleeding of which 130 were intracranial bleedings (non-resumption, VKA resumption, and NOAC resumption experienced 37, 83, and 10 intracranial bleedings, respectively), and 357 from recurrent traumatic injury. The cumulative risks obtained with the Aalen–Johansen method without covariate adjustment are shown in Supplementary material online, Figure S2. Take home figure shows the standardized absolute risks. The 1-year standardized absolute risks and absolute risk differences are reported in Table 2. Table 2 Standardized absolute risks At 1 year No. of events/ no. at risk Standardized absolute risk (95% CI) Absolute risk difference (95% CI)a Absolute risk difference (95% CI)a All-cause mortality  Non-resumption 224/723 19.5% (17.5 to 21.8%) Reference —  VKA 364/2101 15.3% (14.4 to 16.7%) −4.2% (−6.3 to −2.7%)a Reference  NOAC 92/388 15.1% (12.5 to 16.9%) −4.4% (−7.2 to −1.4%)a −0.02% (−2.7 to 1.4%) Stroke/thrombo-embolism  Non-resumption 45/696 4.0% (3.2 to 5.1%) Reference —  VKA 82/2056 3.4% (2.8 to 4.1%) −0.6% (−1.7 to 0.4%) Reference  NOAC 20/378 2.8% (1.8 to 4.1%) −1.2% (−2.7 to 0.3%) −0.6% (−1.9 to 0.8%) Major bleeding  Non-resumption 48/695 4.2% (3.3 to 5.3%) Reference —  VKA 120/2022 4.8% (4.1 to 5.6%) 0.5% (−0.5 to 1.5%) Reference  NOAC 20/379 3.6% (2.5 to 5.0%) −0.6% (−2.1 to 1.1%) −1.1% (−2.4 to 0.3%) Recurrent traumatic injury  Non-resumption 51/693 4.4% (3.5 to 5.6%) Reference —  VKA 103/2026 4.4% (3.7 to 5.1%) 0.0% (−1.2 to 1.0%) Reference  NOAC 27/373 4.0% (2.8 to 5.5%) −0.4% (−2.0 to 1.2%) −0.4% (−1.8 to 1.2%) At 1 year No. of events/ no. at risk Standardized absolute risk (95% CI) Absolute risk difference (95% CI)a Absolute risk difference (95% CI)a All-cause mortality  Non-resumption 224/723 19.5% (17.5 to 21.8%) Reference —  VKA 364/2101 15.3% (14.4 to 16.7%) −4.2% (−6.3 to −2.7%)a Reference  NOAC 92/388 15.1% (12.5 to 16.9%) −4.4% (−7.2 to −1.4%)a −0.02% (−2.7 to 1.4%) Stroke/thrombo-embolism  Non-resumption 45/696 4.0% (3.2 to 5.1%) Reference —  VKA 82/2056 3.4% (2.8 to 4.1%) −0.6% (−1.7 to 0.4%) Reference  NOAC 20/378 2.8% (1.8 to 4.1%) −1.2% (−2.7 to 0.3%) −0.6% (−1.9 to 0.8%) Major bleeding  Non-resumption 48/695 4.2% (3.3 to 5.3%) Reference —  VKA 120/2022 4.8% (4.1 to 5.6%) 0.5% (−0.5 to 1.5%) Reference  NOAC 20/379 3.6% (2.5 to 5.0%) −0.6% (−2.1 to 1.1%) −1.1% (−2.4 to 0.3%) Recurrent traumatic injury  Non-resumption 51/693 4.4% (3.5 to 5.6%) Reference —  VKA 103/2026 4.4% (3.7 to 5.1%) 0.0% (−1.2 to 1.0%) Reference  NOAC 27/373 4.0% (2.8 to 5.5%) −0.4% (−2.0 to 1.2%) −0.4% (−1.8 to 1.2%) a The corresponding absolute risk differences tested for significant differences between standardized absolute risks. Statistical significance was obtained when the 95% confidence limits for difference in absolute risks did not contain zero. Table 2 Standardized absolute risks At 1 year No. of events/ no. at risk Standardized absolute risk (95% CI) Absolute risk difference (95% CI)a Absolute risk difference (95% CI)a All-cause mortality  Non-resumption 224/723 19.5% (17.5 to 21.8%) Reference —  VKA 364/2101 15.3% (14.4 to 16.7%) −4.2% (−6.3 to −2.7%)a Reference  NOAC 92/388 15.1% (12.5 to 16.9%) −4.4% (−7.2 to −1.4%)a −0.02% (−2.7 to 1.4%) Stroke/thrombo-embolism  Non-resumption 45/696 4.0% (3.2 to 5.1%) Reference —  VKA 82/2056 3.4% (2.8 to 4.1%) −0.6% (−1.7 to 0.4%) Reference  NOAC 20/378 2.8% (1.8 to 4.1%) −1.2% (−2.7 to 0.3%) −0.6% (−1.9 to 0.8%) Major bleeding  Non-resumption 48/695 4.2% (3.3 to 5.3%) Reference —  VKA 120/2022 4.8% (4.1 to 5.6%) 0.5% (−0.5 to 1.5%) Reference  NOAC 20/379 3.6% (2.5 to 5.0%) −0.6% (−2.1 to 1.1%) −1.1% (−2.4 to 0.3%) Recurrent traumatic injury  Non-resumption 51/693 4.4% (3.5 to 5.6%) Reference —  VKA 103/2026 4.4% (3.7 to 5.1%) 0.0% (−1.2 to 1.0%) Reference  NOAC 27/373 4.0% (2.8 to 5.5%) −0.4% (−2.0 to 1.2%) −0.4% (−1.8 to 1.2%) At 1 year No. of events/ no. at risk Standardized absolute risk (95% CI) Absolute risk difference (95% CI)a Absolute risk difference (95% CI)a All-cause mortality  Non-resumption 224/723 19.5% (17.5 to 21.8%) Reference —  VKA 364/2101 15.3% (14.4 to 16.7%) −4.2% (−6.3 to −2.7%)a Reference  NOAC 92/388 15.1% (12.5 to 16.9%) −4.4% (−7.2 to −1.4%)a −0.02% (−2.7 to 1.4%) Stroke/thrombo-embolism  Non-resumption 45/696 4.0% (3.2 to 5.1%) Reference —  VKA 82/2056 3.4% (2.8 to 4.1%) −0.6% (−1.7 to 0.4%) Reference  NOAC 20/378 2.8% (1.8 to 4.1%) −1.2% (−2.7 to 0.3%) −0.6% (−1.9 to 0.8%) Major bleeding  Non-resumption 48/695 4.2% (3.3 to 5.3%) Reference —  VKA 120/2022 4.8% (4.1 to 5.6%) 0.5% (−0.5 to 1.5%) Reference  NOAC 20/379 3.6% (2.5 to 5.0%) −0.6% (−2.1 to 1.1%) −1.1% (−2.4 to 0.3%) Recurrent traumatic injury  Non-resumption 51/693 4.4% (3.5 to 5.6%) Reference —  VKA 103/2026 4.4% (3.7 to 5.1%) 0.0% (−1.2 to 1.0%) Reference  NOAC 27/373 4.0% (2.8 to 5.5%) −0.4% (−2.0 to 1.2%) −0.4% (−1.8 to 1.2%) a The corresponding absolute risk differences tested for significant differences between standardized absolute risks. Statistical significance was obtained when the 95% confidence limits for difference in absolute risks did not contain zero. Take home figure View largeDownload slide Standardized absolute risks of outcomes associated with non-resumption vs. resumption of VKA and NOAC following traumatic injury. For each treatment option separately, the standardized absolute risks are based on the outcome-specific multiple Cox regression models and obtained as averages of the predicted risks had all patients received this treatment. NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Take home figure View largeDownload slide Standardized absolute risks of outcomes associated with non-resumption vs. resumption of VKA and NOAC following traumatic injury. For each treatment option separately, the standardized absolute risks are based on the outcome-specific multiple Cox regression models and obtained as averages of the predicted risks had all patients received this treatment. NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Figure 3 shows the adjusted hazard ratios (HRs) obtained from time-varying Cox regression models. Compared with non-resumption, VKA and NOAC resumption were associated with significantly lower hazard of all-cause mortality and ischaemic stroke and an increased associated hazard of major bleeding. For traumatic injury, the HR was not decreased or increased with resumption of VKA and NOAC vs. non-resumption. Predictors for the hazard rate of major bleeding following a traumatic injury are presented in Supplementary material online, Table S3. Figure 3 View largeDownload slide Adjusted hazard ratios of outcomes associated with non-resumption vs. resumption of VKA and NOAC following traumatic injury. Time-dependent multiple Cox regression models were used to allow patients to change treatment group during follow-up. NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Figure 3 View largeDownload slide Adjusted hazard ratios of outcomes associated with non-resumption vs. resumption of VKA and NOAC following traumatic injury. Time-dependent multiple Cox regression models were used to allow patients to change treatment group during follow-up. NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Type of traumatic injury The adjusted HRs were estimated in a subgroup analysis based on the type of traumatic injury. The results in the subgroups (see Supplementary material online, Table S4) according to traumatic brain injury, hip fracture, and traumatic torso and abdominal injury were generally similar to the results in Figure 3. Switch of oral anticoagulants following traumatic injury Among those resuming OAC treatment, it was most common to resume the same OAC treatment as before the traumatic injury (Table 1); 99.9% of the patients who resumed a VKA were also on treatment with a VKA before the traumatic injury, and among those treated with NOAC after the traumatic injury, 90.5% were treated with NOAC and 9.5% with VKA before the traumatic injury. We evaluated those patients treated with VKA before the traumatic injury who either resumed VKA treatment or switched to a NOAC after the traumatic injury (see Supplementary material online, Table S4). Compared with non-resumption, staying on VKA treatment or switching to NOAC were both associated with a significantly lower hazard of all-cause mortality and ischaemic stroke but an increased hazard of bleeding; however, for NOAC switchers, the lower ischaemic stroke and increased major bleeding hazards were not significant. Sensitivity analyses A subgroup analysis was conducted including only patients with HAS-BLED score ≥4 (see Supplementary material online, Table S3). The results were broadly similar to the main results in Figure 3, albeit the analysis was influenced by lack of power. When testing the impact of changing the quarantine period to 30, 60, or 180 days, the results were comparable to the main results (see Supplementary material online, Table S5 and Figure 3). Discussion In our nationwide observational study, including 4288 OAC-treated patients with AF who suffered a traumatic injury, the main findings were as follows: (i) overall 60.6% resumed a VKA, 16.7% resumed a NOAC, and 22.7% did not resume OAC treatment during the study period 2005–16; (ii) since 2009 an increase in OAC resumption has occurred; and (iii) compared with non-resumption, resumption of VKA or NOAC treatment was associated with significantly lower hazard of all-cause mortality and ischaemic stroke, increased hazard of major bleedings, and no difference in the hazard of recurrent traumatic injury. Since more than 50% of the study population comprised octogenarians (median age was 80–81 years), it is plausible that falls were the most common cause of the traumatic injury hospitalization4,5; however, we were not able to identify the specific cause of the traumatic injury in the Danish national patient registry. The results from this study are particularly interesting assuming that the traumatic injury was caused by a fall, because fall risk among OAC-treated AF patients is feared with regard to major and fatal bleedings.21–23 Underuse of OAC treatment has been reported in several countries,24,25 and two main reasons for a doctor’s non-prescription of VKA are concerns regarding fall and bleeding risks.21 Hylek et al.7 found that previous falls were the most frequent physician-cited reason for not prescribing OAC among AF patients aged 80 years or older. In our study, 22.7% did not resume OAC treatment, and these patients had a higher occurrence of traumatic brain injury at baseline compared with those patients resuming VKA and NOAC treatment. In a study by Liu et al.15, the authors found that suffering a traumatic brain injury was associated with low odds of VKA resumption compared with non-resumption. The authors discussed that the low odds of VKA resumption after a traumatic brain injury may be related to doctors’ fear of fall risk in fragile elderly AF patients and perhaps that doctors overestimate a patient’s predicted bleeding risk. In our study, patients not resuming OAC had the highest predicted bleeding risk (median HAS-BLED = 3), however, we found that the 1-year standardized absolute risks of recurrent traumatic injury ranged from 4.0% to 4.4% without a difference between OAC resumption vs. non-resumption. These results suggest that perhaps doctors may consider being less reluctant with OAC due to recurrent fall risk (and the risk of fall-related bleedings), since the fall risk does not seem to vary between resumption of OAC and non-resumption patients. Moreover, in our study, a subgroup analysis including only patients with baseline HAS-BLED score ≥4 showed that the hazard of recurrent traumatic injury did not differ significantly between VKA and NOAC resumption compared with non-resumption. However, we found an increased hazard of major bleeding with VKA and NOAC resumption compared with non-resumption, which indicates that doctors’ concerns regarding bleeding risk with OAC treatment are relevant. Our study showed that VKA and NOAC resumption was associated with significantly lower hazard of ischaemic stroke and all-cause mortality. A retrospective study by Albrecht et al.26 examined the risk of stroke and major bleeding with warfarin usage after a traumatic brain injury and concluded that the benefits in stroke reduction with warfarin usage outweighed the risk of major bleeding. Similarly, a subgroup analysis in our study including only patients suffering from a traumatic brain injury pointed to a lower associated hazard of ischaemic stroke and all-cause mortality with VKA and NOAC resumption; however, lack of power in the NOAC group for the ischaemic stroke outcome could not confirm a significantly lower ischaemic stroke HR with NOACs. Similarly to Albrecht et al., the hazard of major bleeding was significantly higher in our study among patients resuming VKA and NOAC treatment compared with non-resumption following a traumatic brain injury. Since 2009, an increase in OAC resumption occurred following traumatic injury. This may suggest that even though doctors fear for a patient’s fall and bleeding risks, the awareness of appropriate stroke prophylaxis has improved with the consequence that more patients resume OAC treatment following a traumatic injury.27 It was more common that patients treated with VKA prior to the traumatic injury switched to an NOAC after discharge (9.5%) than switching from an NOAC to a VKA (0.1%). Case reports have described problems with the lack of reversal for NOAC therapy among trauma patients taking NOACs.22,23 However, the increased NOAC use observed in our study could indicate that the benefits of NOACs as stroke prophylaxis might counterbalance doctors’ fear of a patient’s fall and bleeding risks. Moreover, idarucizumab for dabigatran reversal was first introduced in Denmark in March 2016.28 In our study, a switch from VKA to NOAC or staying on VKA after the traumatic injury had similar effect and safety profile compared with non-resumption. In clinical practice, an AF patient’s individual risk factors for stroke, bleeding, and recurrent fall may be weighed in the decision-making of withholding or resuming OAC treatment following a traumatic injury. However, the first key finding in our study was that withholding of OAC was generally not beneficial to AF patients. Second, in 2016, ∼15% did not still resume OAC treatment within 90 days after the traumatic injury. This implies that there is a need for increased awareness of resumption of OAC treatment following a traumatic injury. Furthermore, good clinical practice requires clinicians to evaluate and minimize a patient’s risk of recurrent falls, e.g. considerations regarding a patient’s co-morbidities and concomitant pharmacotherapy.29–31 Limitations and strengths In our observational study, it was methodologically necessary to include a quarantine period of 90 days16; however, changing the quarantine period to 30, 60, or 180 days (see Supplementary material online, Table S5) did not alter our results. The data from the Danish administrative registries did not enable us to estimate when OAC resumption would be safe during the quarantine periods. A limitation was residual confounding with unmeasured confounders, such as INR, time in therapeutic range, haemoglobin levels, serum creatinine levels, and body mass index. Another limitation may be confounding by indication, since it was possible that patients not resuming OAC treatment were frailer with a higher risk of all-cause mortality, stroke, major bleeding, and recurrent traumatic injury than those resuming VKA and NOAC treatment. Importantly, our conclusions support associations. The main strength in our study, given by the Danish administrative registries, was the opportunity to examine a research question that would be challenging to perform as a randomized controlled trial. This study was able to include a large nationwide population and evaluated both VKA and NOAC resumption by filled prescriptions as directed by doctor, and the Danish registries have been validated intensely.9,12,13 Conclusions Among the OAC-treated patients with AF who experienced a traumatic injury, we conclude that within 90 days after the traumatic injury approximately 3 of 4 resumed OAC. Resumption of VKA or NOAC treatment was associated with significantly lower hazards of all-cause mortality and ischaemic stroke, at the cost of an increased hazard of major bleedings, but without any additional hazard of recurrent traumatic injury, compared with non-resumption. Our study suggests that resuming OAC following traumatic injury may result in better clinical outcomes, including lower risk of stroke. Supplementary material Supplementary material is available at European Heart Journal online. Funding This work was supported by the Velux Foundations and Boehringer-Ingelheim. The sponsors had no influence on the study design, interpretation of results, or the decision to submit the manuscript for publication. G.H.G. is supported by an unrestricted clinical research scholarship from the Novo Nordisk Foundation. Conflict of interest: L.S.: research funding from Boehringer-Ingelheim. E.L.F.: research funding from Lundbeck Foundation, Janssen Pharmaceuticals, and BMS. M.L.: speaker fees from BMS and Bayer. K.G.: research funding from BMS. G.Y.H.L.: consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer-Ingelheim, Microlife, and Daiichi-Sankyo and speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer-Ingelheim, Microlife, Roche, and Daiichi-Sankyo. C.T.P.: research contracts with Bayer and Biotronic and received speaker fees from Bayer and BMS. G.H.G.: research funding from Boehringer-Ingelheim, Pfizer, BMS, AstraZeneca, and Bayer and declares ownership of stocks in Lundbeck A/S, Novo Nordisk A/S, and ALK Abello Pharmaceuticals. J.B.O.: received speaker fees from Bayer, BMS, and Boehringer-Ingelheim and research funding from BMS and The Capital Region of Denmark. 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Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in patients with atrial fibrillation: a nationwide cohort study

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
ISSN
0195-668X
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1522-9645
D.O.I.
10.1093/eurheartj/ehx598
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Abstract

Abstract Aims We examined the risks of all-cause mortality, stroke, major bleeding, and recurrent traumatic injury associated with resumption of vitamin K antagonists (VKAs) and non-VKAs oral anticoagulants (NOACs) following traumatic injury in atrial fibrillation (AF) patients. Methods and results This was a Danish nationwide registry-based study (2005–16), including 4541 oral anticoagulant (OAC)-treated AF patients experiencing traumatic injury (defined as traumatic brain injury, hip fracture, or traumatic torso or abdominal injury). Within 90 days following discharge from traumatic injury, 60.6% resumed VKA (median age = 80, CHA2DS2-VASc = 4, HAS-BLED = 2), 16.7% resumed NOAC (median age = 81, CHA2DS2-VASc = 4, HAS-BLED = 2), and 22.7% did not resume OAC treatment (median age = 81, CHA2DS2-VASc = 4, HAS-BLED = 3). Switch from VKA to NOAC occurred among 9.5%. Since 2009, the trend in OAC resumption increased (P-value <0.0001), in particular with NOACs (P-value <0.0001). Follow-up started 90 days after discharge, and time-varying multiple Cox regression analyses were used for comparisons. Compared with non-resumption, VKA and NOAC resumption were associated with lower hazard [95% confidence interval (CI)] of all-cause mortality [hazard ratio (HR) 0.48 (0.42–0.53) and HR 0.55 (0.47–0.66), respectively] and ischaemic stroke [HR 0.56 (0.43–0.72) and HR 0.54 (0.35–0.82), respectively], increased major bleeding hazard [HR 1.30 (1.03–1.64) and HR 1.15 (0.81–1.63), respectively], and similar hazard of recurrent traumatic injury [HR 0.93 (0.73–1.18) and HR 0.87 (0.60–1.27), respectively]. Conclusion AF patients resuming VKA and NOAC treatment following traumatic injury have lower hazard of all-cause mortality and ischaemic stroke, increased hazard of major bleeding but without additional hazards of recurrent traumatic injury. Withholding OAC following a traumatic injury in AF patients may not be warranted. View largeDownload slide View largeDownload slide Atrial fibrillation, Traumatic injury, Oral anticoagulation, Warfarin, NOAC, Bleeding Introduction Patients with atrial fibrillation (AF) requiring oral anticoagulants (OAC) are a fragile group of patients and a clinical challenge if they experience a traumatic injury.1–5 For instance, if a patient with AF is admitted due to a head injury caused by a ground-level fall, the occurrence of death during the injury hospitalization is estimated to be 24%, whereas this constitutes 32% if patients are treated with OACs before the ground-level fall admission.6 After traumatic injury, doctors and patients face the decision of whether to resume OAC therapy, a complex decision that needs careful consideration of the balance between benefit (stroke prevention) and risk (bleeding) of OAC treatment.7 Resumption of OAC treatment will reduce the stroke risk, but increase the bleeding risk, which in these fragile patients may be a major concern in the perspective of a risk for a recurrent traumatic injury. Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) are frequently used among elderly AF patients8; however, following a traumatic injury it is uncertain to what extent NOACs and VKAs are used and what the risks of outcomes are with respectively NOAC and VKA resumption compared with non-resumption. This study focused on OAC-treated AF patients who experienced a traumatic injury, and we examined the OAC resumption pattern and risk of all-cause mortality, ischaemic stroke, major bleeding, and recurrent traumatic injury associated with NOAC and VKA resumption compared with no OAC resumption. Methods Data sources All residents of Denmark are at birth or immigration, given a unique personal identification number that enabled us to cross-link individual information from the following Danish nationwide registries: (i) The Danish national patient registry holds information about all hospital contacts since 1978. A hospital contact is coded with one primary, and if appropriate, one or more secondary diagnosis codes based on the International Classification of Diseases 10th revision (ICD-10).9 (ii) The Danish national prescription registry keeps information about all filled prescriptions since 1995 including the Anatomical Therapeutic Chemical (ATC) codes, the day the prescription was filled, the package size, and dosages.10 (iii) The Danish civil registration system registers vital status.11 Study population and outcomes We conducted an observational study from 1 January 2005 to 31 December 2016. The study population constituted AF patients treatment with VKA or NOAC [dabigatran (since August 2011), rivaroxaban (since February 2012), or apixaban (since December 2012)] the day before a traumatic injury hospital admission. Traumatic injury involved hospitalization with traumatic cranial or brain injury (fracture of the skull, injury of optic nerve, intracranial injury, or crushing or multiple injuries of head), traumatic hip fracture (femoral neck, pertrochanteric, or subtrochanteric fracture), or traumatic torso or abdominal injury (serious open wound of thoracic wall, abdominal wall, or pelvis; injury of blood vessels, intrathoracic organs, intra-abdominal organs, and pelvic organs; and traumatic pneumothorax or haemothorax). Validation studies of administrative data report high positive predictive values for AF, hip fracture, and traumatic brain injury.12–14 Traumatic torso or abdominal injury was defined as done in a previous study from 2015.15 A quarantine period of 90 days subsequent to the discharge day was introduced to allow patients to fill a new prescription of an OAC drug following the traumatic injury. The package size of an OAC agent runs for a maximum of 3 months, and it is plausible that if patients resumed OAC treatment they finished the package from before the traumatic injury at first. All patients were followed up for 90 days, and with the 90 days of quarantine period, we were able to categorize patients into resumption and non-resumption of treatment and thereby limit misclassification and avoid conditioning on the future.16 The exclusion criteria are shown in Figure 1. Figure 1 View largeDownload slide Selection of the study population. NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; VKA, vitamin K antagonist. Figure 1 View largeDownload slide Selection of the study population. NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; VKA, vitamin K antagonist. The three treatment groups were resumption of VKA, resumption of NOAC, or no OAC resumption, and ATC codes are listed in the Supplementary material online, Table S1. Follow-up began after the 90 days of quarantine period and was limited to the first 3 years after the 90 days of quarantine period (90 days + 3 years). Outcomes of interest during follow-up were the earliest of all-cause mortality, ischaemic stroke, major bleeding, and recurrent traumatic injury. Outcome status was last assessed on 31 December 2016. All ICD-10 and ATC codes used to define the study population, treatment groups, and outcomes are listed in the Supplementary material online, Table S1. Concomitant pharmacotherapy and co-morbidity Concomitant pharmacotherapy was identified from filled prescriptions for a period of 90 days prior to baseline. Co-morbidities were identified from diagnosis codes registered within a period of 10 years prior to baseline. ATC codes and ICD-10 codes used to define concomitant pharmacotherapy and co-morbidities are listed in the Supplementary material online, Table S1. All patients were assessed for risk of stroke with the CHA2DS2-VASc score17 [Congestive heart failure, Hypertension, Age ≥ 75 years (2 points), Diabetes mellitus, Stroke/TE/transient ischaemic attack (2 points), Vascular disease, Age 65–74 years, and female Sex] and risk of bleeding with the HAS-BLED score [Hypertension, Abnormal renal or liver function, Stroke/TE, previous Bleeding, Labile international normalized ratio (INR; left out because data are unavailable), Elderly (age ≥ 65 years), and concomitant drugs (antiplatelet agents, non-steroidal anti-inflammatory drugs)/alcohol abuse]. Statistical analysis Time trends in OAC resumption according to calendar year were analysed with Cochrane Armitage trend tests in the period 2005–16. Baseline was set as 90 days after discharge from traumatic injury. We estimated the outcome-specific absolute risk (cumulative incidence) by the Aalen–Johansen method separately in the treatment groups to account for competing risks of death.18 Stroke, major bleeding, and recurrent traumatic injury were not accounted for as competing events. Outcome-specific hazards in the three treatment groups were modelled by multiple Cox regression. Each outcome-specific model was adjusted for potential confounders as determined by published literature and associated expert knowledge. All models were adjusted for calendar year, age (continuous), sex, and type of traumatic injury. All-cause mortality models were further adjusted for CHA2DS2-VASc and HAS-BLED factors, stroke models for CHA2DS2-VASc factors, major bleeding models for HAS-BLED factors, and recurrent traumatic injury models for CHA2DS2-VASc and HAS-BLED factors, osteoporosis, dementia, and benzodiazepine usage. For each outcome, the two Cox regression models were obtained, one using only baseline information and another using dynamic updates of all time-varying covariates (treatment group, co-morbidity, concomitant pharmacotherapy, calendar year, and age). Based on the outcome-specific Cox regression models using only baseline information, we computed differences in standardized absolute 1-year risks between the three treatment groups (g-formula).19,20 The standardized risks for treatment Group ‘A’ were obtained as the average of the predicted absolute 1-year risks in a copy of the real data where the treatment variable was set to ‘A’. The risks were predicted by combining the outcome-specific Cox regression models.20 The standardized differences were supplied with 95% bootstrap confidence limits based on 1000 bootstrap data sets. The level of significance was set at 5%. Data management and statistical analyses were performed using SAS (version 9.4 for Windows, SAS Institute, Cary, NC, USA) and R [R Core Team (2016). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria]. Ethics Retrospective registry-based studies do not require approval from the Research Ethical Committee System. The Danish Data Protection Agency approved the use of data for this study (ref.no: 2007-58-0015/GEH-2014-012 I-Suite no: 02720). Results Study population At baseline, which was on Day 90 following discharge from traumatic injury, we included a total of 4541 AF patients, treated with OAC before admission (Figure 1). During the quarantine period of 90 days, 1695 patients were excluded as they suffered from one of the outcomes of interest. Supplementary material online, Table S2 reports the characteristics of the population at the time of discharge from traumatic injury, and Supplementary material online, Figure S1 illustrates outcome-specific cumulative incidences during the quarantine period of 90 days. Among the 4541 included patients at baseline (Table 1), the resumption pattern was as follows: non-resumption 22.7%, VKA 60.6%, and NOAC 16.7% (dabigatran, n = 333, 7.3%; rivaroxaban, n = 211, 4.7%; and apixaban, n = 213, 4.7%). The median age was 81, 80, and 81 years in the non-resumption, VKA, and NOAC groups, respectively. All groups had a median CHA2DS2-VASc score of 4, but the median HAS-BLED score was highest in the non-resumption group being 3. In the non-resumption group, 40.8% had suffered from a traumatic brain injury, whereas among patients resuming VKA and NOAC this was 27.4% and 29.6%, respectively. In addition, concomitant usage of aspirin (27.1%), adenosine diphosphate receptor antagonists (4.8%), and benzodiazepines (25.3%) were more frequent among non-resumption than patients resuming OAC treatment. Table 1 Patient characteristics at baseline [AuthorQuery id="AQ20" rid="20"]?> Non-resumption VKA NOAC P-value n (%) 1031 (22.7) 2753 (60.6) 757 (16.7) Men, n (%) 513 (49.8) 1347 (48.9) 309 (40.8) <0.001 Age, median [IQR] 81 [75, 86] 80 [74, 85] 81 [74, 87] <0.001 CHA2DS2-VASc, median [IQR] 4 [3, 5] 4 [3, 5] 4 [3, 5] 0.289 HAS-BLED, median [IQR] 3 [2, 3] 2 [2, 3] 2 [2, 3] <0.001 Type of injury, n (%) <0.001  Traumatic brain injury 421 (40.8) 755 (27.4) 224 (29.6)  Hip fracture 475 (46.1) 1530 (55.6) 426 (56.3)  Traumatic torso or abdominal injury 135 (13.1) 468 (17.0) 107 (14.1) OAC before traumatic injury, n (%) <0.001  VKA 930 (90.2) 2750 (99.9) 72 (9.5)  NOAC 101 (9.8) 3 (0.1) 685 (90.5) Co-morbidities, n (%)  Stroke 263 (25.5) 588 (21.4) 217 (28.7) <0.001  Myocardial infarction 109 (10.6) 247 (9.0) 62 (8.2) 0.181  Ischaemic heart disease 364 (35.3) 950 (34.5) 203 (26.8) <0.001  Peripheral artery disease 83 (8.1) 183 (6.6) 35 (4.6) 0.016  Heart failure 327 (31.7) 849 (30.8) 194 (25.6) 0.010  Diabetes mellitus 141 (13.7) 409 (14.9) 112 (14.8) 0.646  Hypertension 535 (51.9) 1686 (61.2) 410 (54.2) <0.001  Chronic kidney disease 102 (9.9) 214 (7.8) 58 (7.7) 0.088  Liver disease 14 (1.4) 47 (1.7) 14 (1.8) 0.676  Prior bleeding 466 (45.2) 802 (29.1) 233 (30.8) <0.001  Alcohol misuse 45 (4.4) 119 (4.3) 50 (6.6) 0.027  Cancer 182 (17.7) 444 (16.1) 134 (17.7) 0.395  Dementia 92 (8.9) 157 (5.7) 89 (11.8) <0.001  Osteoporosis 187 (18.1) 502 (18.2) 198 (26.2) <0.001 Concomitant medication, n (%)  ADP receptor antagonists 50 (4.8) 41 (1.5) 13 (1.7) <0.001  Aspirin 279 (27.1) 488 (17.7) 36 (4.8) <0.001  Dipyridamole 15 (1.5) 9 (0.3) 0 (0.0) <0.001  Non-steroid anti-inflammatory drug 63 (6.1) 174 (6.3) 43 (5.7) 0.808  Loop diuretics 411 (39.9) 1168 (42.4) 275 (36.3) 0.008  Beta-blockers 487 (47.2) 1397 (50.7) 427 (56.4) 0.001  Calcium channel blockers 197 (19.1) 652 (23.7) 148 (19.6) 0.002  Renin–angiotensin system blocker 369 (35.8) 1107 (40.2) 267 (35.3) 0.007  Digoxin 344 (33.4) 976 (35.5) 189 (25.0) <0.001  Benzodiazepine 261 (25.3) 590 (21.4) 173 (22.9) 0.038 Non-resumption VKA NOAC P-value n (%) 1031 (22.7) 2753 (60.6) 757 (16.7) Men, n (%) 513 (49.8) 1347 (48.9) 309 (40.8) <0.001 Age, median [IQR] 81 [75, 86] 80 [74, 85] 81 [74, 87] <0.001 CHA2DS2-VASc, median [IQR] 4 [3, 5] 4 [3, 5] 4 [3, 5] 0.289 HAS-BLED, median [IQR] 3 [2, 3] 2 [2, 3] 2 [2, 3] <0.001 Type of injury, n (%) <0.001  Traumatic brain injury 421 (40.8) 755 (27.4) 224 (29.6)  Hip fracture 475 (46.1) 1530 (55.6) 426 (56.3)  Traumatic torso or abdominal injury 135 (13.1) 468 (17.0) 107 (14.1) OAC before traumatic injury, n (%) <0.001  VKA 930 (90.2) 2750 (99.9) 72 (9.5)  NOAC 101 (9.8) 3 (0.1) 685 (90.5) Co-morbidities, n (%)  Stroke 263 (25.5) 588 (21.4) 217 (28.7) <0.001  Myocardial infarction 109 (10.6) 247 (9.0) 62 (8.2) 0.181  Ischaemic heart disease 364 (35.3) 950 (34.5) 203 (26.8) <0.001  Peripheral artery disease 83 (8.1) 183 (6.6) 35 (4.6) 0.016  Heart failure 327 (31.7) 849 (30.8) 194 (25.6) 0.010  Diabetes mellitus 141 (13.7) 409 (14.9) 112 (14.8) 0.646  Hypertension 535 (51.9) 1686 (61.2) 410 (54.2) <0.001  Chronic kidney disease 102 (9.9) 214 (7.8) 58 (7.7) 0.088  Liver disease 14 (1.4) 47 (1.7) 14 (1.8) 0.676  Prior bleeding 466 (45.2) 802 (29.1) 233 (30.8) <0.001  Alcohol misuse 45 (4.4) 119 (4.3) 50 (6.6) 0.027  Cancer 182 (17.7) 444 (16.1) 134 (17.7) 0.395  Dementia 92 (8.9) 157 (5.7) 89 (11.8) <0.001  Osteoporosis 187 (18.1) 502 (18.2) 198 (26.2) <0.001 Concomitant medication, n (%)  ADP receptor antagonists 50 (4.8) 41 (1.5) 13 (1.7) <0.001  Aspirin 279 (27.1) 488 (17.7) 36 (4.8) <0.001  Dipyridamole 15 (1.5) 9 (0.3) 0 (0.0) <0.001  Non-steroid anti-inflammatory drug 63 (6.1) 174 (6.3) 43 (5.7) 0.808  Loop diuretics 411 (39.9) 1168 (42.4) 275 (36.3) 0.008  Beta-blockers 487 (47.2) 1397 (50.7) 427 (56.4) 0.001  Calcium channel blockers 197 (19.1) 652 (23.7) 148 (19.6) 0.002  Renin–angiotensin system blocker 369 (35.8) 1107 (40.2) 267 (35.3) 0.007  Digoxin 344 (33.4) 976 (35.5) 189 (25.0) <0.001  Benzodiazepine 261 (25.3) 590 (21.4) 173 (22.9) 0.038 Characteristics of the study population at the time of baseline. Table 1 Patient characteristics at baseline [AuthorQuery id="AQ20" rid="20"]?> Non-resumption VKA NOAC P-value n (%) 1031 (22.7) 2753 (60.6) 757 (16.7) Men, n (%) 513 (49.8) 1347 (48.9) 309 (40.8) <0.001 Age, median [IQR] 81 [75, 86] 80 [74, 85] 81 [74, 87] <0.001 CHA2DS2-VASc, median [IQR] 4 [3, 5] 4 [3, 5] 4 [3, 5] 0.289 HAS-BLED, median [IQR] 3 [2, 3] 2 [2, 3] 2 [2, 3] <0.001 Type of injury, n (%) <0.001  Traumatic brain injury 421 (40.8) 755 (27.4) 224 (29.6)  Hip fracture 475 (46.1) 1530 (55.6) 426 (56.3)  Traumatic torso or abdominal injury 135 (13.1) 468 (17.0) 107 (14.1) OAC before traumatic injury, n (%) <0.001  VKA 930 (90.2) 2750 (99.9) 72 (9.5)  NOAC 101 (9.8) 3 (0.1) 685 (90.5) Co-morbidities, n (%)  Stroke 263 (25.5) 588 (21.4) 217 (28.7) <0.001  Myocardial infarction 109 (10.6) 247 (9.0) 62 (8.2) 0.181  Ischaemic heart disease 364 (35.3) 950 (34.5) 203 (26.8) <0.001  Peripheral artery disease 83 (8.1) 183 (6.6) 35 (4.6) 0.016  Heart failure 327 (31.7) 849 (30.8) 194 (25.6) 0.010  Diabetes mellitus 141 (13.7) 409 (14.9) 112 (14.8) 0.646  Hypertension 535 (51.9) 1686 (61.2) 410 (54.2) <0.001  Chronic kidney disease 102 (9.9) 214 (7.8) 58 (7.7) 0.088  Liver disease 14 (1.4) 47 (1.7) 14 (1.8) 0.676  Prior bleeding 466 (45.2) 802 (29.1) 233 (30.8) <0.001  Alcohol misuse 45 (4.4) 119 (4.3) 50 (6.6) 0.027  Cancer 182 (17.7) 444 (16.1) 134 (17.7) 0.395  Dementia 92 (8.9) 157 (5.7) 89 (11.8) <0.001  Osteoporosis 187 (18.1) 502 (18.2) 198 (26.2) <0.001 Concomitant medication, n (%)  ADP receptor antagonists 50 (4.8) 41 (1.5) 13 (1.7) <0.001  Aspirin 279 (27.1) 488 (17.7) 36 (4.8) <0.001  Dipyridamole 15 (1.5) 9 (0.3) 0 (0.0) <0.001  Non-steroid anti-inflammatory drug 63 (6.1) 174 (6.3) 43 (5.7) 0.808  Loop diuretics 411 (39.9) 1168 (42.4) 275 (36.3) 0.008  Beta-blockers 487 (47.2) 1397 (50.7) 427 (56.4) 0.001  Calcium channel blockers 197 (19.1) 652 (23.7) 148 (19.6) 0.002  Renin–angiotensin system blocker 369 (35.8) 1107 (40.2) 267 (35.3) 0.007  Digoxin 344 (33.4) 976 (35.5) 189 (25.0) <0.001  Benzodiazepine 261 (25.3) 590 (21.4) 173 (22.9) 0.038 Non-resumption VKA NOAC P-value n (%) 1031 (22.7) 2753 (60.6) 757 (16.7) Men, n (%) 513 (49.8) 1347 (48.9) 309 (40.8) <0.001 Age, median [IQR] 81 [75, 86] 80 [74, 85] 81 [74, 87] <0.001 CHA2DS2-VASc, median [IQR] 4 [3, 5] 4 [3, 5] 4 [3, 5] 0.289 HAS-BLED, median [IQR] 3 [2, 3] 2 [2, 3] 2 [2, 3] <0.001 Type of injury, n (%) <0.001  Traumatic brain injury 421 (40.8) 755 (27.4) 224 (29.6)  Hip fracture 475 (46.1) 1530 (55.6) 426 (56.3)  Traumatic torso or abdominal injury 135 (13.1) 468 (17.0) 107 (14.1) OAC before traumatic injury, n (%) <0.001  VKA 930 (90.2) 2750 (99.9) 72 (9.5)  NOAC 101 (9.8) 3 (0.1) 685 (90.5) Co-morbidities, n (%)  Stroke 263 (25.5) 588 (21.4) 217 (28.7) <0.001  Myocardial infarction 109 (10.6) 247 (9.0) 62 (8.2) 0.181  Ischaemic heart disease 364 (35.3) 950 (34.5) 203 (26.8) <0.001  Peripheral artery disease 83 (8.1) 183 (6.6) 35 (4.6) 0.016  Heart failure 327 (31.7) 849 (30.8) 194 (25.6) 0.010  Diabetes mellitus 141 (13.7) 409 (14.9) 112 (14.8) 0.646  Hypertension 535 (51.9) 1686 (61.2) 410 (54.2) <0.001  Chronic kidney disease 102 (9.9) 214 (7.8) 58 (7.7) 0.088  Liver disease 14 (1.4) 47 (1.7) 14 (1.8) 0.676  Prior bleeding 466 (45.2) 802 (29.1) 233 (30.8) <0.001  Alcohol misuse 45 (4.4) 119 (4.3) 50 (6.6) 0.027  Cancer 182 (17.7) 444 (16.1) 134 (17.7) 0.395  Dementia 92 (8.9) 157 (5.7) 89 (11.8) <0.001  Osteoporosis 187 (18.1) 502 (18.2) 198 (26.2) <0.001 Concomitant medication, n (%)  ADP receptor antagonists 50 (4.8) 41 (1.5) 13 (1.7) <0.001  Aspirin 279 (27.1) 488 (17.7) 36 (4.8) <0.001  Dipyridamole 15 (1.5) 9 (0.3) 0 (0.0) <0.001  Non-steroid anti-inflammatory drug 63 (6.1) 174 (6.3) 43 (5.7) 0.808  Loop diuretics 411 (39.9) 1168 (42.4) 275 (36.3) 0.008  Beta-blockers 487 (47.2) 1397 (50.7) 427 (56.4) 0.001  Calcium channel blockers 197 (19.1) 652 (23.7) 148 (19.6) 0.002  Renin–angiotensin system blocker 369 (35.8) 1107 (40.2) 267 (35.3) 0.007  Digoxin 344 (33.4) 976 (35.5) 189 (25.0) <0.001  Benzodiazepine 261 (25.3) 590 (21.4) 173 (22.9) 0.038 Characteristics of the study population at the time of baseline. From 2009 to 2016, an increase in overall resumption of OAC treatment occurred from 68.7% to 85.6%, respectively (P-value <0.0001 for increasing trend), and a rapid yearly increase of NOAC usage occurred since 2011 (P-value <0.0001 for increasing trend). In 2016, an NOAC was prescribed for 39.6% of patients following a traumatic injury (Figure 2). Figure 2 View largeDownload slide Time trends showing resumption pattern of OAC following a traumatic injury from 2005 to 2016. NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; VKA, vitamin K antagonist. Figure 2 View largeDownload slide Time trends showing resumption pattern of OAC following a traumatic injury from 2005 to 2016. NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; VKA, vitamin K antagonist. Oral anticoagulants resumption vs. non-resumption and associated risk of outcomes During the follow-up period of 3 years, 1438 died, 285 suffered from an ischaemic stroke, 442 from major bleeding of which 130 were intracranial bleedings (non-resumption, VKA resumption, and NOAC resumption experienced 37, 83, and 10 intracranial bleedings, respectively), and 357 from recurrent traumatic injury. The cumulative risks obtained with the Aalen–Johansen method without covariate adjustment are shown in Supplementary material online, Figure S2. Take home figure shows the standardized absolute risks. The 1-year standardized absolute risks and absolute risk differences are reported in Table 2. Table 2 Standardized absolute risks At 1 year No. of events/ no. at risk Standardized absolute risk (95% CI) Absolute risk difference (95% CI)a Absolute risk difference (95% CI)a All-cause mortality  Non-resumption 224/723 19.5% (17.5 to 21.8%) Reference —  VKA 364/2101 15.3% (14.4 to 16.7%) −4.2% (−6.3 to −2.7%)a Reference  NOAC 92/388 15.1% (12.5 to 16.9%) −4.4% (−7.2 to −1.4%)a −0.02% (−2.7 to 1.4%) Stroke/thrombo-embolism  Non-resumption 45/696 4.0% (3.2 to 5.1%) Reference —  VKA 82/2056 3.4% (2.8 to 4.1%) −0.6% (−1.7 to 0.4%) Reference  NOAC 20/378 2.8% (1.8 to 4.1%) −1.2% (−2.7 to 0.3%) −0.6% (−1.9 to 0.8%) Major bleeding  Non-resumption 48/695 4.2% (3.3 to 5.3%) Reference —  VKA 120/2022 4.8% (4.1 to 5.6%) 0.5% (−0.5 to 1.5%) Reference  NOAC 20/379 3.6% (2.5 to 5.0%) −0.6% (−2.1 to 1.1%) −1.1% (−2.4 to 0.3%) Recurrent traumatic injury  Non-resumption 51/693 4.4% (3.5 to 5.6%) Reference —  VKA 103/2026 4.4% (3.7 to 5.1%) 0.0% (−1.2 to 1.0%) Reference  NOAC 27/373 4.0% (2.8 to 5.5%) −0.4% (−2.0 to 1.2%) −0.4% (−1.8 to 1.2%) At 1 year No. of events/ no. at risk Standardized absolute risk (95% CI) Absolute risk difference (95% CI)a Absolute risk difference (95% CI)a All-cause mortality  Non-resumption 224/723 19.5% (17.5 to 21.8%) Reference —  VKA 364/2101 15.3% (14.4 to 16.7%) −4.2% (−6.3 to −2.7%)a Reference  NOAC 92/388 15.1% (12.5 to 16.9%) −4.4% (−7.2 to −1.4%)a −0.02% (−2.7 to 1.4%) Stroke/thrombo-embolism  Non-resumption 45/696 4.0% (3.2 to 5.1%) Reference —  VKA 82/2056 3.4% (2.8 to 4.1%) −0.6% (−1.7 to 0.4%) Reference  NOAC 20/378 2.8% (1.8 to 4.1%) −1.2% (−2.7 to 0.3%) −0.6% (−1.9 to 0.8%) Major bleeding  Non-resumption 48/695 4.2% (3.3 to 5.3%) Reference —  VKA 120/2022 4.8% (4.1 to 5.6%) 0.5% (−0.5 to 1.5%) Reference  NOAC 20/379 3.6% (2.5 to 5.0%) −0.6% (−2.1 to 1.1%) −1.1% (−2.4 to 0.3%) Recurrent traumatic injury  Non-resumption 51/693 4.4% (3.5 to 5.6%) Reference —  VKA 103/2026 4.4% (3.7 to 5.1%) 0.0% (−1.2 to 1.0%) Reference  NOAC 27/373 4.0% (2.8 to 5.5%) −0.4% (−2.0 to 1.2%) −0.4% (−1.8 to 1.2%) a The corresponding absolute risk differences tested for significant differences between standardized absolute risks. Statistical significance was obtained when the 95% confidence limits for difference in absolute risks did not contain zero. Table 2 Standardized absolute risks At 1 year No. of events/ no. at risk Standardized absolute risk (95% CI) Absolute risk difference (95% CI)a Absolute risk difference (95% CI)a All-cause mortality  Non-resumption 224/723 19.5% (17.5 to 21.8%) Reference —  VKA 364/2101 15.3% (14.4 to 16.7%) −4.2% (−6.3 to −2.7%)a Reference  NOAC 92/388 15.1% (12.5 to 16.9%) −4.4% (−7.2 to −1.4%)a −0.02% (−2.7 to 1.4%) Stroke/thrombo-embolism  Non-resumption 45/696 4.0% (3.2 to 5.1%) Reference —  VKA 82/2056 3.4% (2.8 to 4.1%) −0.6% (−1.7 to 0.4%) Reference  NOAC 20/378 2.8% (1.8 to 4.1%) −1.2% (−2.7 to 0.3%) −0.6% (−1.9 to 0.8%) Major bleeding  Non-resumption 48/695 4.2% (3.3 to 5.3%) Reference —  VKA 120/2022 4.8% (4.1 to 5.6%) 0.5% (−0.5 to 1.5%) Reference  NOAC 20/379 3.6% (2.5 to 5.0%) −0.6% (−2.1 to 1.1%) −1.1% (−2.4 to 0.3%) Recurrent traumatic injury  Non-resumption 51/693 4.4% (3.5 to 5.6%) Reference —  VKA 103/2026 4.4% (3.7 to 5.1%) 0.0% (−1.2 to 1.0%) Reference  NOAC 27/373 4.0% (2.8 to 5.5%) −0.4% (−2.0 to 1.2%) −0.4% (−1.8 to 1.2%) At 1 year No. of events/ no. at risk Standardized absolute risk (95% CI) Absolute risk difference (95% CI)a Absolute risk difference (95% CI)a All-cause mortality  Non-resumption 224/723 19.5% (17.5 to 21.8%) Reference —  VKA 364/2101 15.3% (14.4 to 16.7%) −4.2% (−6.3 to −2.7%)a Reference  NOAC 92/388 15.1% (12.5 to 16.9%) −4.4% (−7.2 to −1.4%)a −0.02% (−2.7 to 1.4%) Stroke/thrombo-embolism  Non-resumption 45/696 4.0% (3.2 to 5.1%) Reference —  VKA 82/2056 3.4% (2.8 to 4.1%) −0.6% (−1.7 to 0.4%) Reference  NOAC 20/378 2.8% (1.8 to 4.1%) −1.2% (−2.7 to 0.3%) −0.6% (−1.9 to 0.8%) Major bleeding  Non-resumption 48/695 4.2% (3.3 to 5.3%) Reference —  VKA 120/2022 4.8% (4.1 to 5.6%) 0.5% (−0.5 to 1.5%) Reference  NOAC 20/379 3.6% (2.5 to 5.0%) −0.6% (−2.1 to 1.1%) −1.1% (−2.4 to 0.3%) Recurrent traumatic injury  Non-resumption 51/693 4.4% (3.5 to 5.6%) Reference —  VKA 103/2026 4.4% (3.7 to 5.1%) 0.0% (−1.2 to 1.0%) Reference  NOAC 27/373 4.0% (2.8 to 5.5%) −0.4% (−2.0 to 1.2%) −0.4% (−1.8 to 1.2%) a The corresponding absolute risk differences tested for significant differences between standardized absolute risks. Statistical significance was obtained when the 95% confidence limits for difference in absolute risks did not contain zero. Take home figure View largeDownload slide Standardized absolute risks of outcomes associated with non-resumption vs. resumption of VKA and NOAC following traumatic injury. For each treatment option separately, the standardized absolute risks are based on the outcome-specific multiple Cox regression models and obtained as averages of the predicted risks had all patients received this treatment. NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Take home figure View largeDownload slide Standardized absolute risks of outcomes associated with non-resumption vs. resumption of VKA and NOAC following traumatic injury. For each treatment option separately, the standardized absolute risks are based on the outcome-specific multiple Cox regression models and obtained as averages of the predicted risks had all patients received this treatment. NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Figure 3 shows the adjusted hazard ratios (HRs) obtained from time-varying Cox regression models. Compared with non-resumption, VKA and NOAC resumption were associated with significantly lower hazard of all-cause mortality and ischaemic stroke and an increased associated hazard of major bleeding. For traumatic injury, the HR was not decreased or increased with resumption of VKA and NOAC vs. non-resumption. Predictors for the hazard rate of major bleeding following a traumatic injury are presented in Supplementary material online, Table S3. Figure 3 View largeDownload slide Adjusted hazard ratios of outcomes associated with non-resumption vs. resumption of VKA and NOAC following traumatic injury. Time-dependent multiple Cox regression models were used to allow patients to change treatment group during follow-up. NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Figure 3 View largeDownload slide Adjusted hazard ratios of outcomes associated with non-resumption vs. resumption of VKA and NOAC following traumatic injury. Time-dependent multiple Cox regression models were used to allow patients to change treatment group during follow-up. NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Type of traumatic injury The adjusted HRs were estimated in a subgroup analysis based on the type of traumatic injury. The results in the subgroups (see Supplementary material online, Table S4) according to traumatic brain injury, hip fracture, and traumatic torso and abdominal injury were generally similar to the results in Figure 3. Switch of oral anticoagulants following traumatic injury Among those resuming OAC treatment, it was most common to resume the same OAC treatment as before the traumatic injury (Table 1); 99.9% of the patients who resumed a VKA were also on treatment with a VKA before the traumatic injury, and among those treated with NOAC after the traumatic injury, 90.5% were treated with NOAC and 9.5% with VKA before the traumatic injury. We evaluated those patients treated with VKA before the traumatic injury who either resumed VKA treatment or switched to a NOAC after the traumatic injury (see Supplementary material online, Table S4). Compared with non-resumption, staying on VKA treatment or switching to NOAC were both associated with a significantly lower hazard of all-cause mortality and ischaemic stroke but an increased hazard of bleeding; however, for NOAC switchers, the lower ischaemic stroke and increased major bleeding hazards were not significant. Sensitivity analyses A subgroup analysis was conducted including only patients with HAS-BLED score ≥4 (see Supplementary material online, Table S3). The results were broadly similar to the main results in Figure 3, albeit the analysis was influenced by lack of power. When testing the impact of changing the quarantine period to 30, 60, or 180 days, the results were comparable to the main results (see Supplementary material online, Table S5 and Figure 3). Discussion In our nationwide observational study, including 4288 OAC-treated patients with AF who suffered a traumatic injury, the main findings were as follows: (i) overall 60.6% resumed a VKA, 16.7% resumed a NOAC, and 22.7% did not resume OAC treatment during the study period 2005–16; (ii) since 2009 an increase in OAC resumption has occurred; and (iii) compared with non-resumption, resumption of VKA or NOAC treatment was associated with significantly lower hazard of all-cause mortality and ischaemic stroke, increased hazard of major bleedings, and no difference in the hazard of recurrent traumatic injury. Since more than 50% of the study population comprised octogenarians (median age was 80–81 years), it is plausible that falls were the most common cause of the traumatic injury hospitalization4,5; however, we were not able to identify the specific cause of the traumatic injury in the Danish national patient registry. The results from this study are particularly interesting assuming that the traumatic injury was caused by a fall, because fall risk among OAC-treated AF patients is feared with regard to major and fatal bleedings.21–23 Underuse of OAC treatment has been reported in several countries,24,25 and two main reasons for a doctor’s non-prescription of VKA are concerns regarding fall and bleeding risks.21 Hylek et al.7 found that previous falls were the most frequent physician-cited reason for not prescribing OAC among AF patients aged 80 years or older. In our study, 22.7% did not resume OAC treatment, and these patients had a higher occurrence of traumatic brain injury at baseline compared with those patients resuming VKA and NOAC treatment. In a study by Liu et al.15, the authors found that suffering a traumatic brain injury was associated with low odds of VKA resumption compared with non-resumption. The authors discussed that the low odds of VKA resumption after a traumatic brain injury may be related to doctors’ fear of fall risk in fragile elderly AF patients and perhaps that doctors overestimate a patient’s predicted bleeding risk. In our study, patients not resuming OAC had the highest predicted bleeding risk (median HAS-BLED = 3), however, we found that the 1-year standardized absolute risks of recurrent traumatic injury ranged from 4.0% to 4.4% without a difference between OAC resumption vs. non-resumption. These results suggest that perhaps doctors may consider being less reluctant with OAC due to recurrent fall risk (and the risk of fall-related bleedings), since the fall risk does not seem to vary between resumption of OAC and non-resumption patients. Moreover, in our study, a subgroup analysis including only patients with baseline HAS-BLED score ≥4 showed that the hazard of recurrent traumatic injury did not differ significantly between VKA and NOAC resumption compared with non-resumption. However, we found an increased hazard of major bleeding with VKA and NOAC resumption compared with non-resumption, which indicates that doctors’ concerns regarding bleeding risk with OAC treatment are relevant. Our study showed that VKA and NOAC resumption was associated with significantly lower hazard of ischaemic stroke and all-cause mortality. A retrospective study by Albrecht et al.26 examined the risk of stroke and major bleeding with warfarin usage after a traumatic brain injury and concluded that the benefits in stroke reduction with warfarin usage outweighed the risk of major bleeding. Similarly, a subgroup analysis in our study including only patients suffering from a traumatic brain injury pointed to a lower associated hazard of ischaemic stroke and all-cause mortality with VKA and NOAC resumption; however, lack of power in the NOAC group for the ischaemic stroke outcome could not confirm a significantly lower ischaemic stroke HR with NOACs. Similarly to Albrecht et al., the hazard of major bleeding was significantly higher in our study among patients resuming VKA and NOAC treatment compared with non-resumption following a traumatic brain injury. Since 2009, an increase in OAC resumption occurred following traumatic injury. This may suggest that even though doctors fear for a patient’s fall and bleeding risks, the awareness of appropriate stroke prophylaxis has improved with the consequence that more patients resume OAC treatment following a traumatic injury.27 It was more common that patients treated with VKA prior to the traumatic injury switched to an NOAC after discharge (9.5%) than switching from an NOAC to a VKA (0.1%). Case reports have described problems with the lack of reversal for NOAC therapy among trauma patients taking NOACs.22,23 However, the increased NOAC use observed in our study could indicate that the benefits of NOACs as stroke prophylaxis might counterbalance doctors’ fear of a patient’s fall and bleeding risks. Moreover, idarucizumab for dabigatran reversal was first introduced in Denmark in March 2016.28 In our study, a switch from VKA to NOAC or staying on VKA after the traumatic injury had similar effect and safety profile compared with non-resumption. In clinical practice, an AF patient’s individual risk factors for stroke, bleeding, and recurrent fall may be weighed in the decision-making of withholding or resuming OAC treatment following a traumatic injury. However, the first key finding in our study was that withholding of OAC was generally not beneficial to AF patients. Second, in 2016, ∼15% did not still resume OAC treatment within 90 days after the traumatic injury. This implies that there is a need for increased awareness of resumption of OAC treatment following a traumatic injury. Furthermore, good clinical practice requires clinicians to evaluate and minimize a patient’s risk of recurrent falls, e.g. considerations regarding a patient’s co-morbidities and concomitant pharmacotherapy.29–31 Limitations and strengths In our observational study, it was methodologically necessary to include a quarantine period of 90 days16; however, changing the quarantine period to 30, 60, or 180 days (see Supplementary material online, Table S5) did not alter our results. The data from the Danish administrative registries did not enable us to estimate when OAC resumption would be safe during the quarantine periods. A limitation was residual confounding with unmeasured confounders, such as INR, time in therapeutic range, haemoglobin levels, serum creatinine levels, and body mass index. Another limitation may be confounding by indication, since it was possible that patients not resuming OAC treatment were frailer with a higher risk of all-cause mortality, stroke, major bleeding, and recurrent traumatic injury than those resuming VKA and NOAC treatment. Importantly, our conclusions support associations. The main strength in our study, given by the Danish administrative registries, was the opportunity to examine a research question that would be challenging to perform as a randomized controlled trial. This study was able to include a large nationwide population and evaluated both VKA and NOAC resumption by filled prescriptions as directed by doctor, and the Danish registries have been validated intensely.9,12,13 Conclusions Among the OAC-treated patients with AF who experienced a traumatic injury, we conclude that within 90 days after the traumatic injury approximately 3 of 4 resumed OAC. Resumption of VKA or NOAC treatment was associated with significantly lower hazards of all-cause mortality and ischaemic stroke, at the cost of an increased hazard of major bleedings, but without any additional hazard of recurrent traumatic injury, compared with non-resumption. Our study suggests that resuming OAC following traumatic injury may result in better clinical outcomes, including lower risk of stroke. Supplementary material Supplementary material is available at European Heart Journal online. Funding This work was supported by the Velux Foundations and Boehringer-Ingelheim. The sponsors had no influence on the study design, interpretation of results, or the decision to submit the manuscript for publication. G.H.G. is supported by an unrestricted clinical research scholarship from the Novo Nordisk Foundation. Conflict of interest: L.S.: research funding from Boehringer-Ingelheim. E.L.F.: research funding from Lundbeck Foundation, Janssen Pharmaceuticals, and BMS. M.L.: speaker fees from BMS and Bayer. K.G.: research funding from BMS. G.Y.H.L.: consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer-Ingelheim, Microlife, and Daiichi-Sankyo and speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer-Ingelheim, Microlife, Roche, and Daiichi-Sankyo. C.T.P.: research contracts with Bayer and Biotronic and received speaker fees from Bayer and BMS. G.H.G.: research funding from Boehringer-Ingelheim, Pfizer, BMS, AstraZeneca, and Bayer and declares ownership of stocks in Lundbeck A/S, Novo Nordisk A/S, and ALK Abello Pharmaceuticals. J.B.O.: received speaker fees from Bayer, BMS, and Boehringer-Ingelheim and research funding from BMS and The Capital Region of Denmark. 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European Heart JournalOxford University Press

Published: Nov 18, 2017

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